ENDOCRINE DISEASES 
F A L T A ENDOCRINE DISEASES 
INCLUDING THEIR 
DIAGNOSIS AND TREATMENT 
BY 
WILHELM FALTA 
i 11 
VIENNA ' 
TRANSLATED AND EDITED BY 
MILTON K. MEYERS, M. D. 
NEUROLOGIST TO THE NORTHERN LIBERTIES HOSPITAL; TO THE LUCIEN MOSS HOME, JEWISH HOSPITAL; 
TO THE DISPENSARY OF THE ST. AGNES HOSPITAL, PHILADELPHIA; ETC. 
WITH A FOREWORD BY 
SIR ARCHIBALD E. GARROD, K. C. M. G. 
M. D. (Oxon.), F. R. C. P. (London), F. R. S. 
REGIUS PROFESSOR OF MEDICINE, OXFORD UNIVERSITY 
THIRD EDITION 
With Supplementary Notes By The Editor 
[The previous editiorjs bore the title of The/Ductless Glandular Diseases] 
104 ILLUSTRATIONS IN THE TEXT 
PHILADELPHIA 
P. BLAKISTON’S SON & CO. 
1012 WALNUT STREET Copyright, 1923, by P. Blaktston’s Son & Co. 
PR I NTED IN U. S. A. 
BV THE MAPLE PRESS YORK PA DEDICATED 
TO MY 
CLINICAL MASTERS 
W. HIS, FR. v. MULLER 
AND 
C. v. NOORDEN PREFACE 
The considerable impetus that has been given to the study of the internal 
secretion in the last two decades quite justifies the experiment of publishing 
the diseases of the ductless glands connectedly. The experimental physiology 
and pathology has been dealt with in exhaustive fashion in the excellent work 
of A. Biedl. 
The present volume is concerned with the clinical aspects of the diseases 
of the ductless glands. Of the results of experimental pathology I have set 
forth only as much as seemed to me necessary for the explanation of the clinical 
manifestations. For the rest of these results the reader is referred to the work 
of Biedl. 
In most of the chapters I have tried to describe the clinical symptomatology 
on the basis of my own observations, such as I had occasion to make, for the 
most part, at the first medical clinic in Vienna. 
Prof. Dr. L. von Frankl-Hochwart and Privat-Docent Dr. R. Stern I thank 
cordially for the revision of the neurological part, Prof. Dr. Stoerck for the 
revision of the pathologico-anatomical part, and the latter also for numerous 
microscopical preparations. The X-ray examinations, when not especially 
credited, were by Dr. G. Schwarz, director of the Roentgen division of the first 
medical clinic. I thank Assistant Dr. S. Bernheim for aid in the working- 
through of numerous experimental questions. Finally I am indebted to my 
publishers, the firm of Julius Springer, for their assistance in the fitting-out of 
the book. 
W. Falta. 
Vienna. 
VII EDITOR’S PREFACE TO THIRD EDITION 
A wealth of endocrinological literature has appeared since the last edition 
of this work was published and from the consequent multiplicity of theories 
that have sprung up in this field, the selection of appropriate matter for this 
revision has been made. The careful sifting of both the American and the 
foreign literature so as to incorporate in the text, and the addenda, only what 
may be regarded as likely to be of permanent value has been a task more 
difficult than at first may appear. 
Falta’s work was so well founded—furnished such a substantial working 
basis—that many of the later ideas, theories, etc. advanced have been but a 
development of the general scheme of endocrinology as set forth by Falta, 
who was one of the pioneers in the field. 
Falta, so it seems to the editor, while not rigidly doctrinaire, has been 
sufficiently conservative to criticise and to reject views that were founded on 
but scanty scientific observation and experimentation. Likewise the editor 
has subjected to conservative criticism views that have been more or less 
popular, and this has been done in the spirit shown by Falta, and in the interest 
of ultimate truth. 
The term ‘‘endocrine” has now come into general use; hence it was decided 
to give the volume its present title. 
It is hoped that the work will continue to serve as a practical guide in the 
fertile field of endocrinology. 
Milton Kayton Meyers. 
Philadelphia. 
IX EDITOR’S PREFACE TO FIRST EDITION 
The aim and effort of the American editor has been to furnish, not merely 
a faithful rendering of the German text, but also a rounding out of the subject 
by the consideration of recent American and English views. To this end he 
has consulted a wealth of material, comprising some hundreds of references and 
numerous original articles, from which it is quite apparent that many of the 
investigators have been concerned with the purely scientific or abstruse, rather 
than with the clinical aspects of the subject. While consulting the literature, 
the editor could not help but feel that when it has been properly digested 
and classified, a considerable advance will have been made toward raising the 
status of the ductless glandular diseases to the level of an exact science. 
The American and English views mentioned will be found in the adden- 
dum that is at the end of nearly every chapter. If some of these addenda bear 
a too subjective tinge it is because the editor in his choice of the literature was 
guided more or less by his personal experience, in which case he may not have 
done full justice to certain chapters. Care has been taken, in adding the new 
matter, not to confuse the clear-cut scheme oiFalta, who so admirably separates 
the various groups of ductless glandular diseases by well-defined lines. This 
delimitation of the various groups of ductless glandular diseases at the present 
time is a most desirable generalization which will enable us to appreciate not 
only the various parts which the different ductless glands play in the make-up 
of an individual disease picture, but also to individualize in our diagnosis, even 
as we are now justified in individualizing, to a certain extent, in the types of 
Basedow’s disease. Granted that we are not as yet prepared for this along 
the whole line of the ductless glandular diseases, it then becomes our obvious 
duty to ascertain what symptoms the individual ductless glandular diseases, 
as expressed or evidenced in different patients, have in common, so that the 
patients may be classed in their respective groups. Only later will the 
emphasis of differences between individuals of the same group add pleasure 
and refinement to the diagnosis, and efficiency to the treatment. This is said 
with a knowledge of the prevailing tendency of certain foreign schools, chiefly 
the French, to regard each individual patient’s condition as a disease picture 
sui generis; which in truth in one sense it really is, but which, for purposes of 
analysis and ultimate progress, we are not as yet justified in regarding as 
such. 
As to the text proper, but very little difficulty has been found. Occa- 
sionally when the editor could think of no corresponding English expression, 
an approximate meaning is given, with the German word in brackets. “Die 
Erkrankungen der Blutdriisen” has been translated “The Ductless Glandular 
Diseases,” as forming a sufficiently comprehensive and universally intelligible 
title. It is especially, however, to the ductless glands with more or less well- 
XI XII 
editor’s preface to first edition 
defined internal secretions (endocrine organs) that our author directs his atten- 
tion, consequently such bodies as the spleen, the diseases of which are well 
described in relation with those of the hematopoietic system, and Luschka’s 
gland, and the carotid body are not here considered. 
“Ausfallerschienungen” has been variously translated “phenomena” or 
“manifestations” or “symptoms” due to “lack,” “deficiency,” “loss,” “with- 
drawal,” “absence” and in some cases “falling out.” “Uberlange” has 
been translated “upper length;” “Unterlange” “lower length.” The first 
mentioned of these anthropological measurements is taken from the vertex 
to the symphysis pubis, the second from the symphysis to the heels (according 
to A. Saenger, Ueber Eunuchoidismus, Deutsche Zeitschrift fur Nervenheil- 
kunde, Bd. 51, Heft. 5-6, 1914, p. 192). 
The author’s list of references has been corrected to some extent, and the 
abbreviations of journals have been changed to correspond to the standard 
abbreviations of the U. S. Surgeon General’s Catalogue. The index has been 
revised and enlarged. 
The editor’s thanks are hereby accorded to Messrs. P. Blakiston’s Son 
Co. for the uniform kindness and courtesy shown him in the preparation of 
this volume. 
Milton Kayton Meyers. 
Philadelphia. FOREWORD 
BY 
SIR ARCHIBALD E. GARROD, K. C. M. G. M. D. (Oxon.), F. R. C. P. 
(London), F. R. S. 
REGIUS PROFESSOR OF MEDICINE, OXFORD UNIVERSITY 
When Addison first described the syndrome which has ever since borne 
his name, and proved its dependence upon destructive lesions of the adrenal 
glands, he broke ground in a new field of medical enquiry of the extent of which 
neither he nor his contemporaries can have formed any conception. 
The ductless glands had long been known to anatomists as structures of 
wholly obscure functions, and only in quite recent times has any wide knowledge 
been gained of the important parts which they play in the animal economy. 
Indeed some thirty years elapsed after Addison's discovery before the next 
step in advance was achieved by the recognition of the dependence of cretin- 
ism and myxedema upon disease of the thyroid gland. Since then facts have 
accumulated rapidly, yet hardly so rapidly as to keep pace with the hypotheses 
built upon them. 
Nowadays the influences of the glands of internal secretion, in which cate- 
gory are included other organs besides the glands which are classed as ductless, 
hold a very prominent place in medical thought and investigation. As witness 
the many discussions which took place in various sections of the 17th Inter- 
national Medical Congress, which met in London in 1913, and in many informal 
gatherings of its members from all parts of the civilized world. 
Pathological investigations have come to the aid of physiological research 
in the elucidation of the functions of these glands in health, and of clinical 
medicine in the study of the diseases to which they are liable, and of the symp- 
toms by which these diseases are revealed. There is indeed no department of 
physiology in which more has been learned from the experiments which Nature 
herself has carried out. 
By the removal of individual glands, and by observation of cases in which 
they have been destroyed by disease, we have learned what results accrue 
from withdrawal of their influence, and have even been enabled to discrimi- 
nate between the individual functions of the parts of such of these organs as 
are compound structures. For it is a remarkable example of the economy of 
Nature that in some instances two or more structures yielding internal secre- 
tions have been welded together into a single compact organ. Thus the 
chromaffin medulla of the adrenals is clothed with the functionally distinct 
cortex; and the pituitary body, small as it is, appears to be even more complex. 
That certain morbid states result from loss of function of particular glands 
of internal secretion is a fact so clearly established as to admit of no two opin- 
XIII XIV 
FOREWORD 
ions. As regards the thyroid gland, if the effects of its removal left any room 
for doubt, the striking results of the administration of the gland substance in 
cases of myxedema and cretinism would remove that doubt. Nor is evi- 
dence lacking that such cases of athyroidism are but the extreme examples of 
series of cases of gradations of thyroid defect which bridge over the gap which 
separates myxedema from normality. To describe such conditions, of impaired 
but not abolished function, there have come into use such terms as hypothyroid- 
ism and hypopituitarism. 
Concerning diseases of another kind, of which exophthalmic goiter may 
be selected as the type, there is no such unanimity. It is widely held that 
such conditions present the reverse of the picture, and that they result from 
overactivity of the gland involved, and excessive production of its secretory 
products. 
Many facts may be adduced in support of this theory, such as the effects 
of partial removal of the thyroid gland in exophthalmic goiter, and of liga- 
ture of its arteries, and the results of administration of thyroid extract in excess. 
Moreover, there are certain less obvious symptoms which suggest a converse 
to myxedema. For example the exalted tolerance of carbohydrates, which is a 
feature of myxedema, as contrasted with the so frequent lowering of tolerance 
in exophthalmic goiter. Such evidence is fully set forth by Professor Falta in 
this work, for he is a staunch upholder of the view that all the morbid symptoms 
which result from diseases of the glands of internal secretion, so far as they can 
be ascribed to their secretory functions, are attributable either to depression or 
exaltation of the function of the gland concerned. 
However, there are some, who are entitled to speak with authority, who 
are unable to accept this interpretation, and who hold that the maladies so 
often ascribed to excessive functional activity are rather due to perversion of 
function, and the production by the gland concerned of an abnormal secretion. 
Such terms as dysthyroidism and dyspituitarism are used to express this 
conception. 
The arguments adduced in its favor are of several kinds. It must be 
acknowledged that the administration in excess of the active principle of the 
thyroid gland, although it brings about exaltation of the metabolic processes 
in strict contrast to the depression of those processes observed in myxedema, 
and produces some of the symptoms of exophthalmic goiter, does not reproduce 
the picture of that disease so exactly as to place its origin in excessive functional 
activity of the gland beyond all question. Again it is urged that it is difficult 
to conceive of overfunction as resulting from disease, which might rather be 
expected to impair the activities to a greater or less extent. 
As against this it may be urged that it is equally hard to imagine a perver- 
sion of the metabolic changes into new lines, other than those in which the 
several protein fractions, and even the several carbohydrates, are normally 
dealt with, stage by stage, by specialized enzymes. 
The more the internal secretions are studied the more clearly it is being 
realized how wide is the field of their activities. We are learning that, in 
addition to the control of metabolism, or rather in virtue of that control, the FOREWORD 
XV 
endocrine glands exert immense influence upon growth and development; and 
there their hormonic functions are exercised now in the direction of stimulation, 
and now in that of restraint. Indeed it is not possible to conceive of a control 
which is wholly one-sided; the controlling agent must be able to curb as well 
as to urge on. So we are led to think of inhibiting as well as exciting hormones, 
if that term may be so perverted from its literal meaning. 
In addition to our more exact knowledge, so encouraging in its progress, 
although as yet so incomplete, of the work of the individual glands, we begin 
to see evidences of an interaction of the organs of internal secretion, as mem- 
bers of a group of immense influence, a hormonopoietic system. Here we are 
stepping on to far less firm ground than we have hitherto trodden, and we need 
to move with caution lest our hypotheses carry us further than our facts 
warrant. Yet the evidence is at the least highly suggestive. We see how 
removal of a single gland, by operation or disease, is followed by changes in 
other glands of the group—changes which are best explained by removal of a 
wonted stimulus or withdrawal of a regulating control. 
Moreover there is evidence, as Claude and Gougerot were the first to point 
out, that the various glands of internal secretion may be attacked simultane- 
ously by a morbid process which is described as pluriglandular sclerosis. Where 
this is the case the clinical picture presents elements of the several syndromes 
which result from depression of function of the individual glands of the group. 
Thus there are suggestions of hyperthyroidism, of pituitary defect, of genital 
hypoplasia, and of Addison’s disease, side by side in the same patient. 
The interrelation of the endocrine glands and the nervous system is yet 
another subject full of interest, and which receives full consideration in Pro- 
fessor Falla’s pages. How close is the control exerted by the vegetative nervous 
system over the organs of internal secretion is brought home to us when we 
consider such phenomena as puncture glycosuria. It may now be taken as 
proven that the impulse conveyed to the adrenals by the splanchnic nerves 
excites a temporary excess of secretion of these glands, and to this the excretion 
of sugar is due. Thus it is suggested that not a few phenomena, attributable to 
nervous impulses, are produced through the instrumentality of the endocrine 
glands, and the symptoms referable to disturbances of their functions are not 
necessarily due to actual disease of these organs. It may be that such is the 
explanation of much which is still obscure as to the part played by the pancreas 
in diabetes. 
The literature of internal secretions is already a very large one, and in the 
monumental work of Biedl we have set before us all that is known of the subject 
from the standpoints of physiology and experimental pathology. 
The present work has a different scope and aim. In it the maladies of the 
hormonopoietic system are for the first time discussed in a single volume, and 
from the clinical standpoint. It will be welcomed by members of the medical 
profession in all lands, for in it will be found accurate and detailed descriptions 
of the symptom groups which have their origin in lesions of the glands of internal 
secretion, and also of some diseases for which such an origin has been suggested. XVI 
FOREWORD 
It is all the more valuable because it is the work of a physician who 
combines bedside observation with experimental research in the laboratory. 
Professor Falla’s important contributions to our knowledge of pathological 
chemistry are widely known, and he has been led on to the study of the 
regulators of metabolism by his interest in the chemical processes which it is 
their function to control. CONTENTS 
CHAPTER I 
Page 
General Part 1-61 
Historical Development and Definition i 
Reciprocal Action of the Ductless Glands io 
Question of Dysfunction 16 
Influence of the Ductless Glands on the Growth 19 
Influence of the Ductless Glands on the Regulation of Metabolism 21 
Embryology of the Ductless Glandular System 26 
Grouping of the Ductless Glands 27 
Relationship between the Ductless Glandular System and the Nervous System 29 
A. Influence of the Ductless Glandular System on the Nervous System 29 
B. Influence of the Nervous System on the Function of the Ductless Glandular System 37 
Influence of the Ductless Glands on the Hematopoietic Apparatus 39 
Pathogenesis and Etiology of the Ductless Glandular Diseases 41 
Relation between Diseases of the Central Nervous System and the Ductless Glandular 
System 43 
Pluriglandular Disturbances 48 
The Ductless Glands and Constitution 52 
Addendum * 55 
CHAPTER II 
The Diseases of the Thyroid Gland 62-163 
Anatomy and Embryology 62 
Tumors of the Thyroid Gland 63 
Inflammations of the Thyroid Gland 64 
(a) Morbus Basedowi—Hyperthyrosis 63 
Historical and Definition 66 
Occurrence and Symptomatology 66 
Pathogenesis 93 
Etiology 101 
Forms of Basedow’s Disease 102 
Diagnosis 106 
Prognosis and Treatment 106 
(b) Athyrosis or Hypothyrosis in 
Historical in 
1. Myxoedema Adultorum or Cachexia Thyreopriva Adultorum in 
Definition in 
Occurrence in 
Symptomatology 112 
Etiology and Course 124 
Differential Diagnosis 125 
2. Sporadic Cretinism 127 
Definition ..127 
Symptomatology 130 
Differential Diagnosis 144 
Treatment of Athyrosis or Hypothyrosis 144 
Addendum 150 
CHAPTER III 
The Cretinic Degeneration 164-183 
1. Goiter 166 
2. Goiter-heart 166 
XVII XVIII 
CONTENTS 
Page 
3. Endemic Cretinism 168 
Symptomatology 168 
Endemic Mutism 171 
Treatment 175 
Pathogenesis 179 
Differential Diagnosis 180 
Addendum 181 
CHAPTER IV 
Diseases of the Parathyroid Glands 184-232 
Anatomy 184 
Embryology 185 
Historical 186 
(a) Aparathyrosis or Hypoparathyrosis, Tetany 187 
Definition 187 
Symptomatology 187 
Pathogenesis of Tetany 209 
Forms of Tetany and Pathological Anatomy 215 
1. The Parathyroprivic or Traumatic Tetany 215 
2. Tetany in Diseases of the Thyroid Gland 217 
3. Tetany in Infectious Diseases and Intoxications 217 
4. Idiopathic Tetany (Occupation Tetany) 218 
5. The Tetany of Children 219 
6. The Tetany of Maternity 221 
7. Tetany in Gastrointestinal Diseases 222 
Differential Diagnosis. 224 
Prognosis 225 
Treatment 226 
(b) Condition of Hyperfunction of the Parathyroid Glands 228 
Addendum 228 
CHAPTER V 
Diseases of the Thymus Gland 233-244 
Anatomy and Embryology 233 
Physiology 234 
Pathology and Semiology 235 
Addendum 239 
CHAPTER VI 
Diseases of the Hypophysis 245-340 
Anatomy and Embryology 245 
(a) Acromegaly 250 
Definition 250 
Occurrence and Symptomatology 250 
Pathological Anatomy 280 
Pathogenesis 282 
Early Acromegaly 290 
Differential Diagnosis 293 
Treatment 294 
(b) Hypophysial Dystrophy 295 
Historical 295 
Definition 296 
Symptomatology 296 
The Metabolism 302 
Pathogenesis 326 
Differential Diagnosis 335 
Treatment 336 
Therapeutic Use of the Hypophysis Extracts 337 
Addendum 337 XIX 
CONTENTS 
CHAPTER VII 
Page 
Diseases of the Epiphysis 341-346 
Anatomy and Embryology 341 
Pathological Anatomy 341 
Symptomatology 342 
Diagnosis and Treatment 344 
Addendum 345 
CHAPTER VIII 
Diseases of the Suprarenal Apparatus 347A571 
Anatomy and Embryology 347 
(a) Condition of Hypofunction of the Suprarenal Apparatus 349 
1. Addison’s Disease 349 
Definition. 349 
Symptomatology 349 
Course 351 
Pathological Anatomy 352 
Pathological Physiology of the Suprarenals 354 
Pathogenesis of Addison’s Disease 358 
Differential Diagnosis 359 
Prognosis and Treatment 359 
2. Isolated Phenomena Due to Failure of Function of the Suprarenal Cortex 362 
(b) Conditions of Hyperfunction of the Suprarenal Apparatus 364 
1. Tumors that Proceed from Chromaffin Tissue 364 
2. Tumors that Proceed from the Cortex 367 
Treatment 374 
3. Tumors of the Suprarenal Gland that Apparently Consist in Cortex and Medulla .... 374 
Addendum 374 
CHAPTER IX 
Status Lymphaticus and Status Hypoplasticus 3 7 7-380 
A. Status Lymphaticus 377 
B. Status Hypoplasticus 379 
Addendum 379 
CHAPTER X 
Diseases of the Sexual Glands 381-450 
Embryology, Anatomical and Physiological Preliminary Remarks 381 
A. The Interstitial Glands 382 
B. The Generative Apparatus 386 
Pregnancy 388 
I. The Malformations 396 
1. Aplasia of the Sexual Glands 396 
2. Hermaphroditism 397 
II. Agenitalism, or Hypogenitalism 401 
1. Eunuchs 40 x 
Occurrence 40 x 
Symptomatology 402 
2. Late Castrates 404 
3. Eunuchoidism 407 
Definition 407 
Historical and Case Histories 407 
Symptomatology 416 
Occurrence and Pathogenesis 419 
Differential Diagnosis 420 
Prognosis and Treatment 421 XX 
CONTENTS 
Page 
4. Late Eunuchoidism 422 
Historical 422 
Definition 423 
Case Reports 423 
Symptomatology 426 
Differential Diagnosis 43° 
Treatment 43° 
5. Treatment of Genital Glandular Insufficiency 43° 
III. Hypergenitalism 432 
Definition 432 
Pathologico-anatomical Findings 432 
Symptomatology 433 
Treatment 434 
IV. Chlorosis 435 
Historical 435 
Symptomatology 43 6 
Pathogenesis 439 
Appendix, Osteomalacia 442 
Addendum 445 
CHAPTER XI 
Pluriglandular Diseases 457~472 
Multiple Ductless Glandular Sclerosis 452 
Historical 45 2 
Definition 45 2 
Case Reports 453 
Symptomatology 456 
Differential Diagnosis 463 
Treatment 463 
Gigantism 463 
Historical 463 
Symptomatology 464 
Pathogenesis 47° 
Addendum 472 
CHAPTER XII 
Vegetative Disturbances That Do not Depend Directly on Diseases of the Ductless Glands 473-510 
I. Infantilism 474 
Historical 474 
Definition 476 
Symptomatology 481 
Forms and Etiology 482 
Differential Diagnosis 483 
Pathogenesis 486 
Prognosis and Treatment 487 
II. True Dwarfism 487 
Historical 488 
Primordial Nanosomia 488 
Paltauf’s Dwarf 489 
III. The Rachitic Dwarf 49° 
IV. Chondrodystrophy 491 
Historical 491 
Definition 491 
Symptomatology 491 
Occurrence 497 
Etiology 5°° 
Differential Diagnosis. . 5°° XXI 
Page 
V. Mongolism 500 
Symptomatology 501 
Pathogenesis and Treatment 503 
Addendum 504 
CHAPTER XIII 
Diseases of the Insular Apparatus of the Pancreas and Their Relation to Diabetes Mellitus . 511-580 
Historical Development 511 
Anatomy and Embryology 513 
I. Experimental Part 515 
A. Diabetes after Extirpation of the Pancreas 515 
B. Experimental Nervous Diabetes 526 
II. Clinical Part 528 
A. Gross Anatomical Disturbances 529 
B. Genuine Diabetes Mellitus 536 
The Carbohydrate Metabolism 537 
The Protein Metabolism 1 539 
The Water Equilibrium 540 
The Basal Metabolism 541 
The Fasting Experiment 546 
Vegetative Nervous System 549 
Pathological Anatomy of Diabetes Mellitus 555 
Theoretical 568 
Differential Diagnosis 574 
Addendum 576 
CHAPTER XIV 
The Different Forms of Obesity and Adipositas Dolorosa 581-599 
A. The Different Forms of Obesity 581 
1. Pancreatogenic Obesity 583 
2. Thyrogenic Obesity 584 
3. Dystrophia Adiposo-genitalis 585 
4. Epiphysial Obesity 585 
B. Adipositas Dolorosa 586 
Historical 586 
Symptomatology 590 
Pathological Anatomy 593 
Pathogenesis 594 
Differential Diagnosis • 596 
Treatment 597 
Addendum 597 
Literature 600 
Index 655 
CONTENTS ENDOCRINE DISEASES 
CHAPTER I 
GENERAL PART 
Historical Development and Definition 
The clinical delimitation of a group of the disease pictures which to-day- 
are known as diseases of the ductless glands is to a certain extent very much 
older than the conception of the idea of internal secretion as elaborated by 
experimental pathology. The profound alterations in the development of the 
human organism after removal of the sexual glands in early life are too remark- 
able not to have awakened the interest of physicians and the laity as early as 
the days of antiquity. The breeders of animals had made use of empirical 
knowledge long before the question was discussed as to how the sexual 
glands influence the formation of the body and its distribution of fat. A 
material progress, however, in the development of the clinical aspects of the 
diseases of the ductless glands began only about the middle of the 19th century. 
It is associated indissolubly with the name of Thomas Addison. Addison in 
1855, on the ground of pathologico-anatomical findings, referred the sickness 
that bears his name to a destruction of both suprarenal glands. Then after 
Gull, Ord, and Charcot had described myxedema clinically, Theodore Kocher 
and Reverdin, in 1882 and 1883, demonstrated that it is due to the absence 
of the functional activities of the thyroid gland. We must regard the year 1886 
as a further landmark in the history of the diseases of the ductless glands. In 
this year Mohius first expressed the idea that a disease picture—Basedow’s dis- 
ease—depends on an abnormally increased activity of a ductless gland. First in 
the year 1889 Brown-Sequard reported to the Biological Society of Paris concern- 
ing experiments that made it seem as though the ductless glands furnished to 
the blood substances which, when carried by the blood to distant-lying organs, 
influenced these extensively. Brown-Sequard1 injected juice of the testicle 
subcutaneously into his own body and observed an increase in corporeal and 
mental powers that he attributed to the influence of these injections. It is true 
that Johannes Muller, Ruysch, and other authors preceded Brown-Sequard; it was, 
however, Brown-Sequard who first clearly formulated these thoughts, based 
them on experiments, and thus attracted the general interest of the medical 
world to them. With the extension of experimental pathology, disease pictures 
that had formerly been regarded as nervous diseases or constitutional diseases 
1 An interesting resume of Brown-Sequard's experiments and the physiological action of the 
injection on the experimenter is to be found in Stanley's article. Stanley (L. L.). Testicular sub- 
stance implantation. Endocrinology, Vol. v, No. 6, Nov., 1921, pp. 708-714.—Editor. 
1 2 
GENERAL PART 
were added to the new disease group in rapid succession. The discovery of 
pancreatic diabetes by von Mering and Minkowski placed the pancreas as the 
central figure in the pathogenesis of diabetes mellitus. Then later came the 
studies of Schulze and of Ssobolew as to the physiological and pathological inde- 
pendence of the insular apparatus, and of Opie, Saltykow, Weichselbaum and 
others as to the histological alterations in the insular apparatus in diabetes 
mellitus. The very much later discovery by Blum of the glycosuric action of 
the suprarenal extract and the knowledge that “sugar puncture” produces 
discharge [of the secretion] of the suprarenal through conduction to the chrom- 
affin tissue by way of the sympathetic paths have again brought about partial 
recognition of the neurogenic origin of diabetes as first advocated by Claude 
Bernard. For clinical purposes the chromaffin tissues won recognition through 
the teaching of Wiesel, that hypertonia in contracted kidney originates through 
hyperplasia of the chromaffin tissue, and through the recognition that in status 
lymphaticus the chromaffin tissue is ordinarily found to be hypoplastic {Wiesel, 
Hedinger). “Thyroid tetany” was discovered experimentally by Schif and 
clinically by N. Wein. The discovery of parathyroprivic tetany by Gley, 
Vassale, and Generali dissociated, however, the symptoms of tetany from those 
of absence of the thyroid gland and ascribed to the parathyroid gland the 
decisive role in pathogenesis of the individual forms of tetany {J eandelize, 
Pineles, Erdheim, Chvostek). After Pierre Marie had already brought the 
disease acromegaly, which had been described by him, into relation with the 
hypophysis, the fact became generally recognized that not, as was originally 
thought, a diminution but an increase in function of the hypophysis brought 
about this disease; while in 1901 A. Frohlich and after him especially v. Frankl- 
Ilochwart distinguished a disease type, in many respects the anti-type of acro- 
megaly, which through the newer investigations of experimental pathology can 
be regarded as the sequel of a diminution of function of this organ. The patho- 
logical anatomy of the hypophysis was especially advanced by Benda, who estab- 
lished the adenomatous character of the hyperplasia of the hypophysis in 
acromegaly, and by the studies of Erdheim on squamous epithelioma in hypo- 
physial dystrophy. The histology of the struma of Basedow’s disease was 
thoroughly studied earlier. The pathogenetic place of the thyroid then won 
further significance through the operative treatment of Basdeow’s disease 
(Rhen, Kocher, and others), and through the study of its relationship to sporadic 
cretinism (“ thyreoaplasie ” of Pineles), to endemic cretinism (F. Wagner, H. 
E. Bircher, Ewald, Scholz), and to goiter heart (Fr. Kraus). Also the signifi- 
cance of the sexual glands for many disease pictures was more exactly studied. 
Eunuchoidism was sharply delineated by Tandler and Grosz, and the clinical 
symptomatology of premature development of the sexual glands was more 
widely developed. Then were added new investigations as to the relation of 
the epiphysis [pineal gland] (Marburg, v. Frankl-IIochwart) and the suprarenal 
cortex to premature development. Only the thymus gland has not as yet 
found a secure position in the symptomatology of the diseases of the ductless 
glands. Finally, the symptomatology of multiple ductless glandular sclerosis 
has been more sharply delimited under the multiform syndrome of “insuffisance HISTORICAL DEVELOPMENT AND DEFINITION 
3 
pluriglandulaire ” described by Claude and Gougerot, and from it has been sepa- 
rated the disease picture of isolated late eunuchoidism. 
These few examples may suffice to furnish an idea of the impetus that the 
clinical aspects of the disease of the ductless glands have assumed in the last 
decade. The advance in experimental pathology and especially in physiological 
chemistry has really not kept pace with this development of clinical pathology 
and the extension of pathological anatomy. I do not mean to belittle the 
significance of what has been brought to recognition through experimental 
pathology; this alone has made possible the rapid advance of the clinical side; I 
only wish to say that the deficient knowledge of the chemical nature of the 
active substances given off by the ductless glands constitutes the weak point in 
our knowledge of the internal secretions and explains why even to-day we are 
very often compelled to work with hazy ideas. But even in this direction 
significant accretions [to our knowledge] are present; we can say, that through 
the isolation and chemical definition of adrenalin (Takamine)1 and through the 
knowledge that this body of relatively simple chemical structure and eminent 
physiological activity is the specific secretion of the chromaffin system, the 
foundation stone has been laid for the physiological chemistry of the internal 
secretions. Experimental pathology entered here most opportunely, and 
acted prominently in the discovery of the manifold actions of this substance 
and its points of attack on the organs supplied by the sympathetic nerves. 
The isolation of adrenalin, it is known, followed from that of iodthyroglobulin 
{Baumann, Oswald). In this case, however, slight doubts are still present as 
to whether we have in iodthyroglobulin the specific internal secretion of the 
thyroid in purest form. [It is not.—Editor.] Then, too, we are very much 
less exactly informed as to its way of action and point of attack. The knowledge 
of the specific secretion of the other ductless glands is as yet extremely faulty. 
Of the suprarenal cortex we only know that it contains cholin, a body of consid- 
erable physiologic activity that is distributed otherwise in the organism. That, 
however, we have in cholin a specific secretion of the suprarenal cortex is 
improbable. It has been possible recently to obtain from the lobes of the 
hypophysis extracts of great physiologic importance that have already secured 
for themselves a place in therapeutics; but there are wanting the chemical 
definition of them and the demonstration that they are given off to the blood. 
All postulates that we must ascribe to a substance in order that we may regard 
it as the specific secretion of the ductless gland in question have not as yet been 
fulfilled by any of the hormones. We must ascertain: 
i. That the substance in question be found in the efferent blood-path or 
lymph-path. 
1 Thyroxin has been isolated by Kendall. See a little farther on in the text.—Carlson 
does not accept as proved the fact that thyroxin is the true thyroid hormone. J. Am. M. Ass., Vol. 
LXXIX No. 2; July 8, 1922, p. 109. Perhaps not; but that it is one of the hormones or at least 
one of the active principles—indeed the chief active principle—there can be little or no doubt; even 
if certain chemical changes may take place in thyroxin before it is effective in the body.—Carlson 
doubts too whether an assured position as a hormone should be ascribed even to adrenalin (J. Am. 
M. Ass., Vol. LXXIX, No. 2, July 8, 1922, p. 102.—Editor. 4 
GENERAL PART 
2. That after experimental extirpation of the ductless gland in question 
the symptoms due to the removal are combated by peroral or subcuta- 
neous administration. 
3. That through the long-continued administration of this substance 
manifestations are elicited that are similar to those which clinical 
evidence leads us to regard as the symptoms following upon increased 
function, a conception that, as the results of the surgical therapy of 
these conditions, has in recent years been made certain. 
All these postulates are not fulfilled in the case of adrenalin. Adrenalin 
has been demonstrated in the blood of the suprarenal vein, but the relationship 
of this fact to clinical medicine is still lacking in clearness. In the case of iod- 
thyroglobulin, the demonstration in the blood or the lymph is as yet lacking. 
Hypophysis extract has as yet not been studied enough, so that we cannot say 
that it fulfills any of these postulates. As far as the other ductless glands are 
concerned (for example, the insular apparatus of the pancreas, or the parathy- 
roid glands), the significance of which in experimental or clinical pathology is 
extraordinarily imperfect, we have not as yet succeeded in obtaining active 
extracts, or we are not at all certain that the observed actions of the extracts 
are specific. The physiological chemistry of the internal secretions is still in its 
childhood. From it alone, however, is a sharp definition of the disease picture 
to be expected; the chemical demonstration of the specific substances in the 
blood even in combined form, the possibility of the demonstration that these 
substances in lessened, normal, or increased quantities circulate in the blood, 
would be of great importance for clinical medicine. The biological method in 
this direction has up to the present failed. The chemical definition and isola- 
tion in pure form of these specific substances will also constitute an important 
advance in the therapy of the diseases due to lack of these glandular substances 
in the organism. The domain of the internal secretions constitutes for physio- 
logical chemistry an inexhaustible field for labor that theoretically and practi- 
cally represents a rich reward. 
[Much of what is set forth in the two paragraphs just above must be discounted 
as the result of chemical studies since the first edition of this volume was published. 
In 1914, E. C. Kendall1 separated the iodine-containing compound of the thyroid 
1 Kendall (E. C.). The isolation in crystalline form of the compound containing iodine which 
occurs in the thyroid, its chemical nature and physiological activity. Tr. Ass. Am. Phys., Vol. 
XXX, 1915, pp; 420-429. 
Literature in part as follows: 
Kendall (E. C.). The isolation in crystalline form of the compound containing iodine which 
occurs in the thyroid, its chemical nature and physiological activity. Tr. Ass. Am. Phys., Vol. XXX, 
1915, pp. 420-449. 
Kendall (E. C.). Isolation of the iodine compound which occurs in the thyroid. First paper, 
J. Biol. Chem., Vol. XXXIX, 1919; pp. 125-147. 
Kendall (E. C.) and Osterbcrg {A. E.). The chemical identification of thyroxin. Second paper, 
J. Biol. Chem., 1919. Vol. XXXIX; pp. 125-147. 
Kendall (E. C.). Chemical influence of the active constituents of the ductless glands. Surg., 
Gynec., Obst., Vol. XXXII, No. 3; March, 1921; pp. 205-213. 
Plummer states that this substance functions as long as from 15 to 20 days after being adminis- HISTORICAL DEVELOPMENT AND DEFINITION 
5 
gland in pure crystalline form. It has been named thyroxin. It contains 
65 per cent of iodine, strongly attached to an organic nucleus. Its structural 
formula is 4, 5, 6 tri-hydro-4, 5, 6, tri-iodo-, 2 oxy-beta indoleproprionic 
acid.1* 2'—Editor] 
tered, and that it acts as a true catalyst, being used over and over, hour after hour, without destruction 
at a very low rate. 
Plummer (H. S.). Interrelationship of function of thyroid gland, and of its active agent, 
thyroxin, in tissues of body. J. Am. M. Ass., Vol. LXXVII, July 23, 1921; pp. 243, seq. 
My friend Dr. Hyman I. Goldstein, of Philadelphia, and of Camden, N. J., who used thyroxin in 
the cases he reported in his article on cretinism writes to me concerning thyroxin as follows: 
“The extraneous introduction of thyroid preparations give the most brilliant results in hypo- 
thyroidism—cretinism and myxedema. Geo. R. Murray (1891) gave an excellent description of the 
good effects of the internal administration of the thyroid gland. Since E. C. Kendall has isolated the 
thyroid hormone—thyroxin, the administration of thyroid has become much more accurate and effec- 
tive. Thyroxin may be given in small tablets by mouth or by intravenous injection. Thyroxin is 
the chemically pure active constituent of the thyroid gland. It contains 65 per cent iodine, organically 
combined. It is a definite proximate principle, bearing the same relation to the thyroid gland that 
atropine bears to befladona. One gram of thyroid gland contains approximately 1 mgm. (jqj4 gr.) 
of thyroxin. Normal individuals can take 2 mgm. of thyroxin a day without developing 
hyperthyroidism. 
“Thyroxin should be given in sufficient dosage to produce a normal metabolic rate. Basal 
metabolism estimation should be made in every case before instituting treatment. Thyroxin in pure 
crystalline form may be given intravenously in a carefully prepared solution to which a drop or two 
of ten per cent of sodium hydroxide solution to about 1 c.c. of water, is added. 
“The tablets may be given by mouth in doses 0.2 mgm., 0.4; 0.8 and 2 mgm. each. The tablet 
should be completely dissolved before administration in a glass of water containing teaspoonful 
of sodium bicarbonate. (Kalak water may be used.) The pulse rate should not be raised 
above 95 to 100 per minute. Nervous symptoms should not develop and loss of weight should not 
occur. During treatment, the patient should be carefully observed, the heart examined, the weight 
taken, the temperature and pulse rate noted. In young cretins it is advisable to begin with a dose 
0.2 to 0.4 mgm. once or twice daily. For high grade myxedema about to 2 or even 3 mgm. per 
day may be administered. Where physiological effects are not observed with the use of thyroxin 
by mouth, the intravenous injection should be employed. The intravenous injection is given once 
every twelve to fifteen days. It is advisable to stop the use of thyroxin occasionally, and to ad- 
minister the extract of the whole thyroid gland in doses of 1, 2, 3, 4, or 5 grs. two or three times daily 
depending on size, age of the patient, and other clinical data. Sometimes the use of the extract of the 
whole thyroid gland gives better results than any of the special preparations. At times it appears 
that better results are obtained from small doses gr. to 1 gr.) of the extract of the whole 
pituitary gland is added to the thyroid in the treatment of cretinism and myxedema. Dr. H. 7. 
Goldstein has noted that in several of his cases of cretinism the sella turcica appeared unusually 
small and nearly closed and in these cases the combined use of pituitary and thyroid gave better 
results.” 
It is probable that thyroxin will soon be in general use in the treatment of myxedema and cretin- 
ism.—Editor. 
1 In 1916 reports on a substance which has been named tethelin were published. The substance 
was isolated by Robertson from the anterior lobe of the pituitary gland. The editor has not been able 
to elicit that it is claimed that it is the purest principle of the anterior lobe in the sense that adrenalin 
and thyroxin are of their respective glands. A short account of the substance follows: 
Tethelin, which has been isolated by Robertson is the growth-controlling principle of the 
anterior lobe of the pituitary body, is soluble in water, ethyl alcohol, ethyl ether, chloroform, and 
carbon tetrachloride. It is insoluble in a mixture of one part by volume of absolute alcohol and one 
and one half parte of dry ether. It contains 1.4 per cent of phosphorus, and nitrogen in the proportion 
of 4 atoms of N for every atom of P, two of the N atoms being present in amino groups and one in an 
amino group which is converted into an amino group by hydrolysis with barium hydroxide. Among 
the products yielded by hydrolysis with barium hydroxide followed by hydrolysis with dilute H2SO4 
is found. Probably it contains an iminazolyl group. Relatively large doses intravenously in rabbits 
produce only a very slight transient fall in blood pressure and no diuresis. 6 
GENERAL PART 
The backwardness of the physiologico-chemical knowledge in this territory 
explains why it has not been possible up to the present to obtain a clear defini- 
tion of the idea of internal secretion. According to the original assumption, we 
understand by internal secretion the giving off of physiologically active sub- 
stances into the circulation, of substances that through their action on distantly- 
lying organs act in a regulatory manner on the complex processes sustaining 
life. According to this general definition, however, every tissue in the animal 
body really yields an internal secretion, as v. Krehl has already pointed out. 
The point of emphasis in this definition lies in the assumption of a chemical 
correlation of the individual organs of the body in contradistinction to the 
assumption of a nervous correlation, which formerly was almost all-sufficient. 
This distinction is indeed not to be maintained so rigidly for, as we shall see 
later on, it must be assumed that to many specific ductless glandular secretions 
must be ascribed an important and, after its fashion, a quite definite influence 
on the condition of excitation of the nervous system. We cannot indeed exclude 
the question as to whether the action of the ductless glandular secretions does 
The active constituent of the posterior lobe of the pituitary gland has not been isolated. In some 
respects its action resembles that of histamine. 
Robertson. (T. B.). On the isolation and properties of tethelin, the growth-controlling principal 
of the anterior lobe of the pituitary body. J. Biol. Chem., Vol., XXIV, 1916, pp. 409-421.—Editor. 
2 The latest addition to our list of active principles of the ductless glands is that of insulin (a 
definite chemical substance?) prepared from the islands of Langerhans by Canadian investigators. 
I quote from the article in the Canadian Medical Journal:— 
“An extract has been prepared from the whole gland [the pancreas, but containing mainly the 
principle of the islands of Langerhans that combats diabetes] which can be administered subcutan- 
eously to the human subject, the preparation of such an extract made possible at once the study of its 
effects upon the human diabetic, the preliminary results of which study are herein reported. The 
extract containing the active principle is being further purified and concentrated.” 
“ (i)Blood sugar can be markedly reduced even to the normal values.” 
“ (2) Glycosuria can be abolished. 
“ (3) The acetone bodies can be made to disappear from the urine. 
“ (4) The respiratory quotient shows evidence of increased utilization of carbohydrates. 
“ (5) A definite improvement is observed in the general condition of these patients and in addition 
the patients themselves report a subjective sense oFwell being and increased vigor for a period follow- 
ing the administration of these preparations.” Banting (F. G.), Best (C. H.), Collip (J. B.), Campbell 
(If7. R.) and Fletcher (A. A.). Pancreatic extracts in the treatment of diabetes mellitus. Canad. M. 
Ass. J. Vol. xii, No. 3, March, 1922, pp. 141-146. 
Other literature as follows:— 
Banting (F. G.), Best (C. II.), and Macleod (J. J. R.) The internal secretion of the pancreas. 
Am. J. Physiol., Vol. lix, Feb. 1922, pp. 479-480. 
Banting (F. G.), Best (C. II.), Collip (J. B.), Macleod (J. J. R.), and Noble (R. C.) The effect of 
pancreatic extract (insulin) on normal rabbits. Am. J. Physiol., Vol. lxii, No. 1. Sept. 1, 1920, pp. 
162-176. 
Banting (F. G.) and Best (C. II.) Internal secretion of pancreas. J. Lab. and Clin. Med., Vol. 
vii, Feb. 1922, pp. 251-266. 
Banting (F. G.) and Best (C. H.) Pancreatic extracts, J. Lab. and Clin. Med., Vol. iii, May, 1922, 
pp. 464-172. 
Hepburn (J.) and Latchford (J. K.) Effect of insulin (pancreatic extract) on the sugar con- 
sumption of the isolated surviving rabbit heart. Am. J. Physiol., Vol. lxii, No. 1, Sept. 1, 1922. 
pp. 162-176. [Bibliography on this phase of the subject.] 
Macleod (/. J. R.). Insulin and diabetes. A general statement of the physiological and 
therapeutic effects of insulin Brit. M. J., Nov. 4, 1922, pp. 833-835. 
See also special article in J. Am. M. Ass. Vol. lxxx, No. 17, April 28, 1923, pp. 1238- 
1242.—Editor. HISTORICAL DEVELOPMENT AND DEFINITION 
7 
not come about through alterations in the metabolic processes in the various 
parts of the somatic and vegetative neurones (ganglion-cells, myoneural junc- 
tions, etc.)- A. Biedl happily expresses these changes in our views by the 
dictum: “Formerly every correlation of organs was regarded as nervous; 
to-day, however, even nervous actions are regarded as brought about chemically.” 
Bayliss and Starling have found that under the influence of the acid gastric 
juice upon the epithelial cells of the intestinal mucosa a substance is secreted by 
the latter that brings about through the circulation the secretion of pan- 
creatic juice. They call such chemical messengers hormones (from op/xaa> = 
I call), a designation that now has found almost general use as applied also to 
the specific secretions of the ductless glands. With such a general application 
of the meaning of the internal secretions, not much is to be gained for clinical 
purposes, as may readily be seen. Nor is a morphological definition of the 
ductless glands possible, as Biedl has pointed out. The histological structure of 
the individual ductless glands varies according to their genesis from the different 
germinal layers. Whether the specific secretions of the ductless glands are to be 
separated from the other hormones through their chemical characteristics 
cannot be answered at all at the present day. Anatomy, morphology, embry- 
ology, experimental physiology, and pathological chemistry do not furnish 
to-day a satisfactory characterization of the ductless glandular system. Up 
to the present, the demonstration that an individual ductless gland belongs to a 
system is furnished most distinctly by clinical observation, particularly by the 
intimate reciprocal relations of the ductless glands under physiological and 
pathological conditions. 
It appears to me, therefore, that first and foremost it is more important for 
the clinical point of view not to associate the meaning of internal secretion 
exclusively with the ductless glands. I might formulate this standpoint in 
the following way: probably very many cell-complexes of the animal organism 
possess an internal secretion. We may designate the totality of all cell-complexes 
provided with an internal secretion a hormonopoietic system. There are, however, 
a series of organs the proper function of which we must regard as the 
production of especially important hormones, which are provided with powerful 
physiological characteristics. It is a common property of these organs 
that they separate out their specific secretion directly into the blood-path. 
We therefore call them ductless glands, and their collective total the ductless 
glandular system. 
[It is true that not all the glands which provide internal secretion are “duct- 
less,” nor are the internal secretions of certain glands—the spleen, the thymus 
gland (?), found to be of great physiologic importance. Yet the term “duct- 
less” is time-honored, and at the time of the publication of the first edition of 
this book there was no well-known exact English equivalent of the German 
word “Blutdriise.” The term “endocrine” has been applied to these glands 
as expressing the character of their secretion (Greek evbov, within, and npivoo, 
separate). The German now express the term internal secretion by “Inkre- 
tion,” so that the term “incretion” may creep into the literature. Barker has 
already used it .—-Editor] 8 
GENERAL PART 
The recognition that the ductless glands form a system was of great signifi- 
cance for the clinical aspects of the diseases of the ductless glands. This recogni- 
tion, that was especially furnished by the serviceable work of Pineles, depends 
not only upon the observations of intimate physiological reciprocal relations, 
but also upon numerous clinical experiences and pathological anatomical find- 
ings which show that diseases very frequently affect several ductless glands 
simultaneously, and lead not only to simultaneous increase of function, but also 
to simultaneous diminution in function, or to a combination of increase of 
function in some of these organs and of diminution of function in others. 
[The present status of the position of the various ductless glands in produc- 
ing disease is ably stated by A. J. Carlson1 as follows. It will be seen that 
according to Carlson the detoxication or dysfunction theory of the action of the 
glands has not been entirely abandoned. However, I believe that Carlson 
would agree that in the present stage of our knowledge to speak of “hyperthy- 
roidism” and “hypothyroidism” is now more nearly correct than to label both 
conditions ‘ ‘dysthyroidism ’ ’:—■ 
“Extirpation experiments in healthy animals have thus established the 
following general facts: 
“Loss of the thyroid is followed by cretinism in the young and myxedema in 
the adult. But it should be noted that some of the myxedema symptoms 
following hypothyroidism in man are not readily produced even by complete 
thyroidectomy in the healthy adult animal. 
Loss of the parathyroids induces depression, tetany and death in a few days, 
unless the animal is subjected to special dietary and diuretic control. 
“Loss of the pancreas leads to absolute diabetes and death from diabetes (in 
the dog) in from four to seven weeks. 
“Loss of the testes is followed by persistent sexual infantilism in the young, 
and in the adult by loss of the sex urge and sex functions, and by gradual atrophy 
of most of the secondary sex characters. 
“Loss of the ovaries results in persistent sex infantilism in the young and in 
premature menopause and gradual atrophy of most of the secondary sex 
characters in the adult. 
“Loss of the suprarenal medulla induces no symptoms and no disease, 
according to the most reliable observations. 
“Loss of the suprarenal cortex causes profound prostration and death within 
a few days, in what appears to be acute Addison’s disease. 
“Loss of the posterior lobe of the pituitary gland appears to produce no 
definite symptoms. There are competent investigators claiming that this lesion 
induces diabetes insipidus and disturbance of metabolism, while equally good 
workers hold that diabetes insipidus is caused by injuries to the base of the 
brain outside the hypophysis. The question is not settled. 
“Loss of the anterior lobe of the pituitary gland appears to produce impair- 
ment of growth and infantilism in the young, and in the adult a tendency to 
adiposity and somnolence, with atrophy of the gonads and failure of sex func- 
1 Carlson (A. V.). Hypofunction and hyperfunction of the ductless glands. J. Am. M. Ass., 
Vol. XXXIX, No. 2, July 8, 1922, pp. 98-104. HISTORICAL DEVELOPMENT AND DEFINITION 
9 
tions. According to one group of investigators, complete extirpation of the 
anterior lobe leads to death, in profound depression, in a few days; while another 
group of equally competent men claim that such deaths are due, not to the loss 
of the gland, but to injury to the base of the brain. This question is open. 
But all workers are agreed that almost complete loss of the anterior lobe 
(including unavoidable injuries to the base of the brain) leads to hypopituitary 
infantilism, at least in a percentage of the animals so operated on. 
"Extirpation of the pineal gland causes no symptoms. The loss of the 
spleen or the duodenum is also without endocrine effects. Extirpation of the 
thymus produces no effect, except perhaps slight hastening of adolescence in 
the young. 
These extirpation experiments on healthy animals, from embryos to adults, 
permit the following generalizations: 
"i. Each system of ductless glands appears to be essentially identical in 
function in all classes of vertebrates. This fact renders it highly probable that 
corresponding glandular hypofunctions in man will induce similar syndromes. 
We know that this is the case in regard to the gonads, from the effects of 
gonadectomy in healthy men and women. 
‘ ‘ 2. None of the ductless glands appear to work to full capacity under normal 
conditions, since from three quarters to seven eighths of each gland system 
may be removed in the healthy animal without producing any deficiency 
symptoms. This is a very disturbing factor in the clinical field when we attempt 
to relate the histopathology of the ductless glands to the patient’s disease. 
“3. No matter what changes in the way of atrophy or hypertrophy may be 
induced in the remaining ductless glands on extirpation of any one gland system, 
the essential effects following distinct hypofunction of each gland system 
appears to be specific for that system. In other words, extirpation experiments 
on healthy animals afford little or no evidence of substitution or vicarious 
functioning by the ductless glands that remain in the animal. 
“4. The symptoms produced by the extirpation of the ductless glands in 
healthy animals can be interpreted either on the hormone theory or on the 
detoxication theory. 
“5. No chemical methods are at present available by which we can demon- 
strate the presence of hormones and their quantitative variations in the blood 
and tissues, or even in the glands themselves. The iodin in the thyroid appears 
to be somewhat of an index of the thyroid secretion. We can make iodin deter- 
minations of the blood, the lymph, and the other tissues of the body, but we 
cannot conclude that the iodin found represents thyroidin and this only. We 
have chemical tests for epinephrin, but epinephrin is probably not a hormone. 
"In regard to the possibility that some, if not all, of the ductless glands may 
work on the principle of detoxication, it is equally true that we have no chemical 
tests for the toxins in the blood and tissues that may be responsible for the 
hypofunction syndromes, except possibly in the case of the parathyroids. 
Recent work seems to demonstrate that the tetany and death following extirpa- 
tion of the parathyroids are due to toxic protein derivatives produced by the 10 
GENERAL PART 
action of the colon group of organisms on the animal proteins of the food. 
Some of these toxic protein derivatives can be chemically isolated. The 
foregoing facts may be stated positively by saying that, so far, the tests for 
hypofunction of the ductless glands are indirect or biologic. 
“6. The relative immunity of some individuals to complete or nearly 
complete extirpation of some of the ductless glands is usually explained by the 
age factor (the young being less immune) and by abberrant or accessory glan- 
dules. That accessory glandules of some of the systems frequently occur is well 
known, but we question the adequacy of these explanations for all the exceptions. 
“The question of endocrine hyperfunction is not of as great importance in 
medicine as that of hypofunction, in view of our present knowledge. Hyper- 
function must, of course, be considered in connection with the alternative 
theory of dysfunction or toxic secretion. The question of hyperfunction has 
no meaning or application in glands that work by detoxication. 
“i. Spontaneous endocrine hyperfunction is unknown in experimental 
animals. Much work has been done in the attempt to produce experimental 
hyperthyroidism in animals by thyroid feeding. Large doses of thyroid extract 
produce some of the symptoms of toxic goiter, such as increased metabolism, 
tachycardia, emaciation and gastro-intestinal disturbances. The nervous 
and ocular manifestations of toxic goiter are not produced. 
“2. In man, endocrine hyperfunction is assumed by many people as a 
causative factor in: 
(1) Toxic goiter (the thyroids); (2) acromegaly (the hypophysis, anterior 
lobe); (3) hypertension (the suprarenal medulla and the thyroids); (4) preco- 
cious puberty (the suprarenal cortex, the hypophysis and the pineal gland); 
(5) diabetes (the thyroid); (6) excessive sex urge (the gonads); (7) excessive 
menstruation (the ovaries or the corpus luteum).”—Editor.] 
Reciprocal Action of the Ductless Glands 
I would like here to enter a little more fully into the question of the recipro- 
cal action of the ductless glands; the phrase has become, as Novak says, a 
catchword. An immense amount of work in recent years has been devoted to 
the study of this reciprocal action, and hypotheses and speculations have grown 
luxuriantly upon this soil. It is true that up to the present we really know 
nothing exactly concerning the intimate process in these reciprocal actions, but 
in a clinical relation such correlations force themselves unmistakably upon the 
observer; the knowledge of them makes easier the analysis of the often compli- 
cated disease picture. Finally, the expressions “reciprocal reinforcement” or 
“reciprocal inhibition” are in the first place nothing other than circumlocutions 
for [clinical] observations. If we view the thing from this standpoint it seems 
to me that the study of these correlations is productive. 
For the understanding of these often very complicated processes it seems 
to me that a separation of physiological and pathological correlations becomes 
absolutely necessary. Among physiological correlations I mean to include the RECIPROCAL ACTION OF THE DUCTLESS GLANDS 
11 
action that the alteration of function of a ductless gland—diminution or increase 
of function—exercises upon the function of another otherwise normal ductless 
gland. These conditions are fulfilled in an ideal manner, when the ductless 
gland has been extirpated, for example. This can occur in human pathology. 
I have reference to the total extirpation of the thyroid gland which, formerly, 
before we knew about the incurable results of the operation, was also undertaken 
in human beings; or to parathyroprivic tetany after operations on the thyroid 
gland; or to castration. Further, an inflammatory process may become estab- 
lished in an isolated ductless gland and cause its destruction. In such cases we 
must by all means be very careful as to the assumption of a pure physiological 
correlation, as, according to experiencs, inflammatory processes affect very 
commonly other members of the ductless glandular system. Here we often 
find, therefore, as we shall see later, transitions to pathological correlations. 
Also the increase in function may be produced experimentally in the pure form 
as, for example, after feeding with thyroid-gland substance. Again, in many 
cases of Basedow's disease and of acromegaly there are no grounds for doubting 
an increase in function of the ductless gland affected, though even here the 
transition to pathological correlations is extraordinarily common. 
I shall now quote some examples of the physiological correlations, con- 
fining myself chiefly to the investigations I carried out in collaboration with 
Eppinger and Rudinger. 
The total extirpation of the thyroid gland with careful avoidance of the 
parathyroid glands—the electric excitability must show no increase in con- 
sequence of the procedure—calls forth a diminution of the total processes 
of metabolism. Let us examine a little more in detail the carbohydrate 
metabolism in a thyroidless animal. The power of assimilation for carbo- 
hydrates is increased. Now, as it has been known that the capacity of assimi- 
lation depends upon the functional breadth of the insular apparatus of the 
pancreas, we may draw the conclusion that there must be a relative or an 
absolute increase of the function of the insular apparatus of the pancreas. 
But the extirpation of the thyroid gland also diminishes the excitability of 
the vegetative nerves. For example, the glycosuric action of adrenalin— 
in addition to other actions, such as the production of a hyperglobulia—is 
diminished. As it is known that the excitability of the myoneural junction 
of the sympathetic nerves depends upon the activity of the chromaffin tissue, 
we may readily infer that the activity of this ductless gland (■i.e., the chro- 
maffin tissue) is diminished whether it be because the production of adrenalin 
is diminished, or because there is a failure of sensitivization to adrenalin in the 
organs normally affected by it {Asher and Flack). A sensitivization for adre- 
nalin has also been assumed as due to the extract from the posterior lobe of the 
hypophysis (Kepinow). 
After the total extirpation of the pancreas there occurs an increase of all 
metabolic processes with a high-grade diminution of the assimilation limits 
for carbohydrates. In addition there are indications of an increased excit- 
ability of the sympathetic nerves (Lowi’s reaction, increased glycosuric action 
of adrenalin). Therefore we conclude that there is an increased function 12 
GENERAL PART 
of the chromaffin tissue or at least there is an increased action of the circu- 
lating adrenalin. Again, in Addison’s disease, in which the function of the 
chromaffin tissue is primarily diminished, we find a heightening of the assim- 
ilation limits for carbohydrates. We explain this as due to withdrawal of 
the inhibition exercised by the chromaffin tissue on the insular apparatus 
and to a secondarily increased function of the latter. 
Newburgh, Nobel and I have contributed a further observation. Peroral 
administration of thyroidin occasions in human diabetes a long-continued 
hypertonia. We interpret this as the functional increase of the chromaffin 
tissue in consequence of a heightened sensibility of this tissue or of its central 
projection fields. 
Through this and similar experimental findings and clinical observations 
we concluded that there was a reciprocal action between thyroid, insular 
apparatus of the pancreas, and chromaffin tissue. This is well shown in the 
accompanying diagram (see Fig. i). 
Fig. i.—P, Insular apparatus of the pancreas; T, thyroid; C. T., chromaffin tissue; —, inhibition; + 
reinforcement. 
As before stated, we are not as yet clear as to the intimate process of such 
physiological correlations. This applies not only to the reinforcement [Ford- 
erung] but also to inhibition. We have indeed assumed that increased activity 
of the insular apparatus inhibits the function of the chromaffin tissue or of 
the thyroid, and the converse. Another possibility consists in the fact that 
adrenalin and the pancreas hormone act antagonistically toward each other 
in the liver; the one in an acceleratory manner, the other in a retarding manner, 
upon the diastatic processes; or the one acts for the splitting up of glycogen, 
the other for its building up. Increased activity of one of these hormones 
would therefore disturb the balance between the two ductless glands.1 
As I have stated in a recent communication, the relations between thy- 
roid and pancreas seem to me better based and explained in the following 
way: Increased activity of the thyroid makes greater demand on the func- 
tion of the insular apparatus. If the insular apparatus does not come up to 
these demands, the balance between both becomes disturbed. This point 
of view is supported by a series of clinical observations. 
1 Experiments of Ziiltzer and of Von Bdlint and Molnar point in this direction. RECIPROCAL ACTION OF THE DUCTLESS GLANDS 
13 
It is futile to raise ideas as to physiological correlation which deal with 
the question whether one ductless gland can act compensatorily for another. 
Such an assumption depends upon entirely superficial observation. Every 
ductless gland has its specific function, although similar features may enter 
into the sum total of activity. As this point is of important significance, I 
will quote some examples. The extirpation of the hypophysis, just as that 
of the thyroid gland, brings about a condition in which the vegetative func- 
tions are diminished {Aschner). Nevertheless, a dog deprived of its hypo- 
physis looks otherwise than one deprived of its thyroid, as R. Paltauf lays 
stress on. Naturally this is also true in a clinical sense. Practically nobody 
confuses a typical myxedema with typical hypophysial dystrophy. The 
extirpation of the parathyroid glands increases the excitability of the vegeta- 
tive nerves, extirpation of the thyroid diminishes it; the mechanism, however, 
as I shall show later, is different. It is true that the tetany of the parathyro- 
privic animal runs a milder course (after associated or subsequent thyroidec- 
tomy), because on account of the absence of the secretion of the thyroid 
gland the excitability of the vegetative nervous system is diminished, but 
nevertheless the tetany is not thereby prevented. 
Now as to the pathological correlations! These are furnished by the 
ductless glands’ membership in the same system. Diseases which affect one 
gland often attack very commonly other ductless glands, or a disease process 
may affect simultaneously several ductless glands, or the entire ductless 
glandular system. By pathological correlations I understand the conceal- 
ment, intensification, or modification of symptoms due to the alteration of 
function of one kind of ductless gland through the presence of disease in another. 
This may also be shown experimentally. I have already mentioned that 
extirpation of the thyroid gland diminishes the excitability of the vegeta- 
tive nerves, while that of the parathyroids increases it. We observe that 
the glycosuric action of adrenalin, which is diminished after extirpation of 
the thyroid gland, is not diminished on simultaneous extirpation of the para- 
thyroid gland and may even be somewhat intensified. Another example: 
Extirpation of the thyroid gland raises the assimilation limits for carbohy- 
drates and reduces the protein metabolism during fasting. Extirpation of the 
pancreas reduces the assimilation limits very strongly and increases the pro- 
tein metabolism during fasting. Simultaneous extirpation of the thyroid gland 
and pancreas produces indeed a diabetes; this, however, pursues a milder 
course to the extent that the increase of the protein destruction is not so high 
and the diminution in weight does not progress so rapidly. Therefore, there 
has occurred a diminution of an otherwise increased metabolism. 
Now some examples from human pathology. 
Thyroid gland and the anterior lobe of the hypophysis show in many 
respects much similarity; as, for example, in a phylogenetic respect both were 
formerly glands with external secretion. They show similarity in morpho- 
logical structure, and in many respects also in their physiological activity. 
For example, young animals deprived of their thyroid gland or of their hypoph- 
ysis remain backward in growth, show diminution of the vegetative proc- 14 
GENERAL PART 
esses, etc. Often both glands become diseased simultnaeously. Indeed, 
in acromegaly the development of a Basedow’s struma is not unusual, and 
in the later stages of acromegaly the thyroid may degenerate, with atten- 
dant myxedema symptoms, as Pineles has described. In the cretinic degen- 
eration there is found not uncommonly both a goitrous degeneration of the 
thyroid gland and degeneration of the glandular hypophysis. A simultaneous 
affection of thyroid gland and glandular hypophysis is found also in multiple 
ductless glandular sclerosis. 
Another example concerns the insular apparatus of the pancreas and the 
thyroid. In typical myxedema the assimilation limit for carbohydrates is 
raised. Now there are individual cases of myxedema described in the litera- 
ture in which alimentary glycosuria may be obtained, and even indeed a 
spontaneous glycosuria may be present on ingestion of diet somewhat richer 
in carbohydrates than ordinarily. Such cases have been held up to me as 
irreconcilable with our theory as to the reciprocal actions of the thyroid gland 
and pancreas, but incorrectly. In such cases it may be assumed that there 
is a simultaneous affection of the insular apparatus. I have already 
mentioned that after simultaneous extirpation of the thyroid gland and the 
pancreas the oppositely directed effect of the absence of the thyroid on 
the carbohydrate metabolism compensates for the effect of the absence of the 
pancreas. It is therefore fully comprehensible that in an affection of the insular 
apparatus disturbances in the carbohydrate metabolism may occur in spite of 
the myxedema that is present. 
Finally, further example is afforded by the pancreas and the suprarenal 
glands. In the cases of cirrhose bronzee dependent upon severe alcoholism 
there are found extensive sclerotic processes in the liver, the spleen, and eventu- 
ally in different other organs, with simultaneous deposition of a pigment 
that is at first rich in iron and later free of iron (hemosiderosis). With involve- 
ment of the pancreas in the sclerotic process, diabetes mellitus not unusually 
occurs (diabete bronzee). Now, observations have shown that in such cases 
the diabetes later disappears, as not rarely the cirrhose bronzee involves also 
the suprarenal glands in the sclerotic processes and may finally even bring 
about the condition of symptoms resembling Addison’s disease; so that we 
may readily draw the conclusion that the retrogression of the diabetic dis- 
turbances of metabolism stands in connection with a more intense sclerosing 
of the suprarenal glands that occurs later [in the course of the disease]. 
[The Viennese school has been criticised by certain authors as empha- 
sizing to too great extent the reciprocal relationships between the glands of 
the endocrine system, and the antagonism of the action of their products. 
F. M. Allen in his article “Diabetes” in the Nelson Loose-leaf Living Medicine 
protests against our viewing the endocrine system as groups of glands arrayed 
against each other antagonistically. Probably the diagram of Fig. i, which 
has been used extensively has helped to fasten the idea that certain groups 
of endocrine glands are arrayed against other groups. Falta expressly points 
out that the secretion of each ductless gland is specific. He also points out 
that the term “reciprocal relations” is to be used as a convenient term to RECIPROCAL ACTION OF THE DUCTLESS GLANDS 
15 
explain certain observations. He also points out the fact that many diseases 
affect the various members of the ductless glandular system simultaneously. 
The intimate relationship of the ductless glandular system cannot be denied, 
and Falla’s opinions seem to the editor to be extremely conservative as com- 
pared with theories which do not appear to be of Viennese origin, according 
to which glands, either as result of organotherapy or of spontaneous action, 
compensate in irregular and haphazard ways for the disordered action of glands 
which are allied with them in combating the action of still other glands. 
According to this it becomes a matter of guesswork to decide whether a given 
patient’s health is improving or deteriorating. Apart from the correlations 
of glands due to their being affected by a common pathological process, it is 
quite unlikely that the hormones of one gland affect quantitively the hormones 
of another specifically, but that the hormones of both are increased or 
diminished respectively by the condition of the nervous system (either cere- 
brospinal or vegetative) or by the influence of the hormones of the gland 
affected primarily acting through the nervous system, or through the general 
metabolism. 
Carlson1 has again summarized well, this time concerning our knowledge 
of reciprocal relationship. Says he:— 
“In this held appears the maximum of fiction and the minimum of estab- 
lished facts. The principal facts are these: 
'T. It appears that the ovaries and testes (at least in mammals) cannot 
develop or maintain their normal function in marked hypothyroidism or marked 
hypopituitarism. 
"2. Thyroidectomy and, in some species at least, gonadectomy induces 
some hyperplasia of the hypophysis. 
“3. Thyroid feeding in experimental animals over long periods appears 
to induce some hyperplasia of the suprarenals (and the hypophysis), but this 
has probably no direct endocrine significance, because the thyroid feeding 
causes at the same time hyperplasia of the heart, the liver, the spleen and 
the kidneys. 
“4. Hypertrophy of the parathyroids has been described in thyroidectom- 
ized tadpoles. 
“5. In some cases, tumors of the suprarenal cortex seem to hasten matura- 
tion of the gonads, and gonadectomy may be followed by hyperplasia of the 
suprarenal cortex. 
“6. Castration retards the involution of the thymus. This may mean 
that hormones from a mature gonad are directly or indirectly responsible for 
the post-adolescence involution of the thymus. It has no further endocrine 
significance, since evidence is lacking for any endocrine activity of the thymus 
itself. 
“7. It is reported that crushing the suprarenal cortex induces a temporary 
fever, and that the latter is aborted by thyroidectomy. Assuming this to be 
a fact, it might indicate a stimulating action of the suprarenal cortex on the 
1 Carlson (A. /). Hypofunction and hyperfunction of the ductless glands. J. Am. M. Ass., 
Vol. LXXIX, No. 2, July 8 ,1922, pp. 98-104. 16 
GENERAL PART 
thyroid, inasmuch as complete suprarenalectomy does not induce hyperpyrexia. 
But crushing the suprarenals is not a simple experiment, and we must await 
further work before the results can be clearly interpreted in the sense of mutual 
endocrine control. It may be noted in this connection that the feeding of 
suprarenal, that is, cortical residue or extract, is reported as a cure of toxic 
goiter. If toxic goiter means thyroid hyperactivity, this may indicate inhibi- 
tory action of the suprarenal cortex on the thyroid. But all of us known that 
the ‘cures’ for mild cases of toxic goiter are legion, and severe cases may resist 
all available therapy, including rest and diet. —Editor.] 
Question of Dysfunction 
The study of the pathological correlations seems to me to throw light on 
the question as to whether we are justified in postulating, in addition to an 
increase in function and a diminution in function of the ductless glands, also 
a dysfunction. I shall in this book try to explain the individual ductless 
glandular diseases exclusively as due to quantitative alterations in the duct- 
less glands. I know well full that to-day this opinion is not throughout the 
generally prevailing one, [?—Editor\ and I expect to meet with opposition. 
I believe, however, that I can at least adduce so much evidence for my 
standpoint that a certain justification for it will not be denied. 
As has been previously stated, the physiologico-chemical basis of the 
hormone teaching is still insufficient. Up to the present only a single hor- 
mone, adrenalin, has been defined chemically. [This statement probably no 
longer holds. See P. 4.—Editor.] A dysfunction of the chromaffin tissue 
would then signify that a qualitatively altered, faulty, adrenalin is obtained 
from the chromaffin tissue and given off into the blood-path. But every 
ground for this opinion has, up to the present, been lacking. As a principal 
argument for dysfunction is adduced the variability of the clinical pictures 
that may be expressed by the disease of a definite ductless gland. The study 
of the pathologic correlations teaches us, however, that often the pure picture 
of a functional increase or deficiency may be set aside and concealed if other 
ductless glands become affected at the same time. Thus it not rarely happens 
that trophoneuroses accompany the diseases of the ductless glands, the com- 
bination seeming to me only a loose one. For instance, special stress has 
been laid on the observation that in the later stages of Basedow’s disease 
sometimes signs of myxedema occur, while the signs of hyperthyrosis are 
still present. In the description of Basedow’s disease I shall dwell at length 
on these cases, and I believe that in no case is the evidence for the existence of 
a myxedema absolutely convincing. In common with Newburgh and Nobel, 
I have further shown, in connection with this question, that the great multi- 
plicity of syndromes in conditions of functional increase of a definite ductless 
gland are for the most part to be explained through diversities of constitution. 
We have attempted to justify this experimentally. The individual hormones 
or ductless glandular extracts have very different kinds of action throughout. 
As I shall come to speak of adrenalin in this connection later, I shall choose as QUESTION OF DYSFUNCTION 
17 
example at this place the thyroid-gland substance. By peroral administration 
of large amounts of thyroid-gland substance, we can see the following symptoms 
make their appearance: 
1. Tachycardia. 
2. Great depression in the blood pressure from center to the periphery. 
3. Increase of the basal metabolism. 
4. Increase of the protein metabolism. 
5. Increase of the elimination of salts. 
6. Lowering of the assimilation for carbohydrates, and finally spon- 
taneous glycosuria. 
7. Sweats. 
8. Mononucleosis. 
9. Tremor. 
10. Diarrheas. 
11. Psychic agitation, etc., etc. 
Thus there are produced almost all the symptoms of a Basedow’s disease. 
We almost never, however, succeed in obtaining all these symptoms in a 
single individual, but do note the regular appearance of tachycardia as the 
cardinal symptom. To this other symptoms group themselves to form definite 
syndromes; for example, tachycardia, sweats, mononucleosis, or tachycardia, 
mononucleosis, tremor, etc. We can therefore obtain in miniature almost 
all the syndromes that we find in cases of Basedow’s disease. As thyroidin 
is always the same, the cause of this dissociation must be ascribed only to the 
various constitutions of the persons tested. The question as to why this is 
so in the individual case is naturally hard to answer, as the sum of the partial 
constitutions (to use an expression of Martins’s) that go to make the total 
constitution is enormous. In many respects it seems most reasonable in 
experimental hyperthyroidism to seek the explanation in the different reac- 
tion activities of the ductless glandular system. When, for example, we see 
that administration of thyroid substance produces glycosuria in one individ- 
ual and in another does not alter the carbohydrate metabolism, we may 
readily infer that, on account of the known physiological correlation between 
thyroid and pancreas, in the first case the insular apparatus has not kept 
pace with the demands that the hyperthyroidism has made upon it, while 
in the other case the functional capacity of the pancreas is sufficient. In 
other cases entirely different constitutional factors appear more strongly in 
the foreground. For example, in neuropathic predisposition, the symptoms 
on the part of the nervous system and the mind occur more markedly and 
have other features. This, ceteris paribus, holds just as good for the [diseases 
due to] functional increases as [for those due to] deficiencies. [The adminis- 
tration of thyroxin produces all the symptoms that are manifest after the 
administration of thyroid gland extract, except that it does not produce exoph- 
thalmus. According to a group of authors exophthalmus is the destinctive 
symptom as between true exophthalmic goiter and hyperthyroidism (such as 18 
GENERAL PART 
is seen in adenoma of the thyroid gland). [(According to Carlson1 also 
nervous symptoms are not produced after thyroxin is administered).— Editor] 
Our standpoint as to dysfunction is important not only theoretically but 
practically. If we discard dysfunction, the therapeutic indications are much 
clearer. The results of substitution therapy are thuse readily made intelli- 
gible, and the operative treatment of conditions due to hyperfunction prop- 
erly receives its justification only in this way. It appears to me that the 
study of the pathologic correlations is important for the explanation of many 
a therapeutic failure. In symptoms due to lack of a gland, a complete result 
as the consequence of substitution therapy is not to be expected when other 
parts of the ductless glandular system are involved at the same time. Perhaps 
in such cases more can be achieved through combined organotherapy. Per- 
tinent contributions in the French literature appear to me to be in part very 
optimistic. A similar consideration of the pathological correlations is perhaps 
due in the position of the indications for the operative treatment of the hyper- 
functional disease. One would perhaps take exception to a resection of the 
thyroid when at the same time other manifestations are present that point 
to exhaustion of another ductless gland, for instance, the chromaffin tissue. 
In this connection still another factor is important, namely, the relations 
between the ductless glandular system and the central nervous system. I 
shall speak about this subject later. 
Only a few words as to the intoxication theory that plays so great a 
role in the study of the internal secretions. The expression “poisoning” is, 
according to my opinion, well adapted in many diseases due to hyperfunction; 
for example, in Basedow’s disease. On this account we do not need to assume 
a dysfunction, as a normal secretion, too, given in excess to the body, may 
poison it. A fitting example is furnished by adrenalin poisoning. On the 
contrary, I must assume that no sufficient experimental evidence is at hand for 
the detoxication theory of the disease due to lack of secretions; that is, for 
the assumption that poisons normally formed is the organism are rendered 
non-poisonous in the ductless glands, and that they poison the body when the 
ductless glands are insufficient. Even the pathogenesis of tetany may be 
explained without the aid of detoxication theory, as we shall see in the chapter 
on the subject. 
[According to Carlson,1 there is still evidence for the dysfunction theory, 
especially for the detoxication theory. Admitting this evidence, the wffiolesale 
labelling of diseased conditions of an individual ductless gland as “dysfunction” 
of a gland (e.g. dysthyroidism, dyspituitarism) indiscrimately, irrespectful 
of the fact that in the more advanced stage of our present knowledge there is at 
least seeming hyperfunction or hypofunction, or an anatomical lesion, e.g. hyper- 
thyroidism, Graves’ disease, toxic adenoma of the thyroid, hemorrhage into 
the parathyroids, acromegaly, cyst of the anterior lobe of the pituitary, 
eunuchoidism, etc.), is to be deprecated. The attention of the profession 
1 Carlson (A. /.). Hypofunction and hyperfunction of the ductless glands. J. Am. M. Ass., 
Vol. LXXIX, No. 3, July 8, 1922, pp. 98-104. INFLUENCE OF THE DUCTLESS GLANDS ON THE GROWTH 
19 
has also been called to this subject by Krumbaar1 who has proposed a 
nomenclature for functional states accompanying pituitary disease which is at 
least more pregnant of results, even although it may not be founded on more 
actual knowledge, than the prevailing term “dyspituitarism.”—Editor] 
The great number of works as to the physiology and pathology of the 
ductless glandular system that have appeared lately show the growing 
interest that physiologists and clinicians take in this subject. What makes 
the subject so fascinating is the fact that it allows us to have what up to 
the present was a scarcely anticipated look into the complicated regulatory 
mechanism of the animal organism. In many respects this influence is espe- 
cially true for the influencing of the growth and of the metabolic processes. But 
also the development and the activity of the hematopoietic apparatus stand 
under the control of this ductless glandular system. Finally, the most intimate 
relations exist between the ductless glandular system and the nervous system, 
whereby practically all the somatic and vegetative functions, yes even the 
mind itself, are brought within the zone of influence. To describe in detail this 
invasive activity of the ductless glandular system into all the vital processes 
does not lie within the limits of the task I have set for myself. I shall only 
sketch a few points in gross. 
Influence of the Ductless Glands on the Growth 
I begin with the influence of the ductless glands upon the growth and the 
configuration of the body. This influence is apparent and has long been 
known in eunuchs and through the experience of breeders of animals, although 
exact experimental work in this direction dates only from recent years. It 
seems to me most suitable for our purposes to select certain better studied types 
and to sketch them. 
1. Loss or high-grade hypoplasia of the sexual glands at an early age leads 
to tall growth; the skeleton is built slenderly and shows characteristic propor- 
tions (large lower length, large span width, small head). There is found here- 
with a characteristic distribution of fat and faulty development of the secondary 
sexual characters. The closure of the epiphysial junctures, and especially of 
those which under physiological conditions close the latest, are markedly 
delayed. This is the foundation of the characteristic proportions and the cause 
of the tall growth. (The assumption of secondary increase in function of the 
hypophysis, as I shall treat in Chapter X, I do not regard as warranted.) We 
may therefore assume that there is exercised by the sexual glands, especially at 
the time of puberty, an influence upon the zone of ossification in the sense of a 
definite bone formation. This influence is exercised on the part of the 
interstitial glands. 
2. Absence or high-grade diminution of the function of the thyroid gland at 
an early age leads to dwarf growth; that is, to inhibition of growth. The 
skeleton retains in general the childish dimensions. The epiphysial closure is 
1 Krumbaar (E.B.). Pituitary disorders in their relations to acromegaly (hyper-pre-pi tuitar- 
ism) with suggestion for the use of a more precise terminology. M. Clinic of N. America. Nov. 
1921, pp. 927-956. 20 
GENERAL PART 
to a marked degree delayed. The fontanelles remain open for a long time, the 
root of the nose is drawn in, the development of the bone-nuclei is very much 
retarded. The bones already formed show a slight degree of sclerosis. The 
bones are thick. In youthful individuals with Graves’ disease there is found on 
the contrary a slightly accelerated growth in the length, and a somewhat pre- 
mature closure of the epiphyses. The eunuchoid distribution of fat is absent. 
The genitals remain backward in development, but not so markedly as in 
eunuchoidism. Under the influence of the insufficiency of the thyroid gland 
the endochondral and periosteal ossifications are to a slight degree retarded. 
3. Absence of the hypophysis in early years also leads, as clinical and 
recently, also, experimental observations show, to an inhibition of growth. 
Closure of epiphysial junctures and development of the bone-nuclei are likewise 
delayed, perhaps not so markedly as in the thyrogenic inhibition of growth; 
this, however, is hard to decide, at least in the clinical observations, as the 
observations on the disturbances do not seem to deal with cases at such an early 
age. The hypoplasia of the genitalia and especially of the interstitial glands is 
very much marked, also when the disturbance sets in later. Correspondingly 
there is found a eunuchoidal distribution of fat and even a (secondary) influenc- 
ing of the body proportions which approximate more or less closely the 
eunuchoid type. 
In cases of youthful acromegaly the relations are very much more complex. 
The typical cases appear to me, as I shall treat of in greater length in Chapter 
VI, to be those with a marked accentuation of the functions of the interstitial 
glands. We find then premature closure of the epiphysial junctures, more 
emphatic pronunciation of the secondary sexual characters, and premature 
thickening of the bones with exostosis formation and thickening of the soft 
parts. In other cases we find, however, inhibition of development in the genital 
sphere, together with a marked eunuchoidal tendency in the proportioning, 
with tall growth. 
4. In disorders of hyperfunction of the sexual glands, of the suprarenal 
cortex, or of the epiphysis in youthful life, we find premature development of the 
whole body, accelerated growth with potentized childish dimensions, premature 
development of the genitalia, and then later premature epiphysial closure; 
in short, a transitory gigantism. Whether these vegetative disturbances can 
be the direct outcome of those of the organs mentioned, or whether they are 
always dependent on a primary or secondary increase in function of the supra- 
renal cortex, is as yet uncertain. 
As to the influence of the other ductless glands on the growth and conforma- 
tion of the body as yet little that is reliable is known. I shall only mention 
that extirpation of the thymus glands leads to an inhibition of growth that is 
later compensated. I shall treat of this further in the appropriate chapter. 
The manner and means in which the ductless glands affect the growth is 
only partly known. It may be said with certainty that the closure of the epi- 
physes and hence a definite cessation in the normal growth occurs under the 
influence of the sexual glands and indeed the interstitial glands; further, that 
the development of the bone-nuclei and the growth in length of the bones is INFLUENCE OF THE DUCTLESS GLANDS ON THE REGULATION OF METABOLISM 
21 
strongly influenced by the thyroid gland and the hypophysis. I would ascribe 
to the thyroid in this connection an influence at least as great as that of the 
hypophysis. The influence of the latter seems to be very much overestimated, 
to the extent that it has been regarded as the dominating growth center. The 
disturbances in growth produced by the thyroid differ importantly from those 
produced by the hypophysis; I would especially attach importance to the fact 
that in the thyroidal growth disturbances the bones are thick [German word 
“plump” = coarse, thick, awkward]; in the hypophysoprivic they are slender; 
the contrary may be seen in the increase of function of these glands in early 
youth. In youthful Basedow’s patients the bones are slender; in youthful 
acromegalics they are thick and provided with exostoses, and, so far as the 
disease is not complicated with associatede unuchoidism, the only processes are 
thickened. For the overestimation of the significance of the hypophysis for the 
growth in length the Brissaud-Meige’s formula for gigantism should be held 
responsible. According to this formula, gigantism is nothing other than an 
acromegaly of youth. It seems to me, however, that in gigantism, at least in 
the earlier stages, there is found mostly a hyperplasia also of other ductless 
glands, perhaps of the whole ductless glandular system; and especially the 
suprarenal cortex is often hyperplastic and, according to recent investigations, 
may influence in many ways the clinical picture of gigantism as well as of 
acromegaly. I have previously mentioned that also premature development 
can be associated with an increase of function in this organ, perhaps is regularly 
associated with it. 
Although here, too, very little is as yet known and explained in a satis- 
factory manner as to the influence on the growth and bodily conformation 
through the ductless glands, yet this influence is so striking that we may con- 
clude that a harmonious development of the body is not possible without orderly 
functioning of the ductless glandular system. We as yet know nothing as to the 
intimate processes in this kind of hormone action. Trophic influencing of the 
nervous system may come into play in many of these actions, as the symmetry 
in such formative influences seems to signify. Further, a specific influencing 
of the metabolic processes, for example in an athyrosis, is to be thought of; 
further, a modeling influence on the skeleton through alteration of the muscle 
tonus, etc., etc. It would, however, be a mistake to bring into relationship 
with the ductless glandular system all variations and diminutions or increases 
in the growth energy of the protoplasm. 
Influence of the Ductless Glands on the Regulation of Metabolism 
The ductless glands assume a still more considerable influence in the regu- 
lation of metabolism. I shall here choose only a few of the most marked 
examples. First let us consider the carbohydrate metabolism. The pancreatic 
insular apparatus governs the carbohydrate assimilation, for after extirpation 
of the pancreas the glycogen formation in the liver and also otherwise in the 
tissues, especially the muscles, is markedly disturbed. That this consists 
chiefly in a disturbance of glycogenesis seems to arise from the fact that on low- 
grade insufficiency of the pancreas the disturbances first become manifest only 
on alimentary overloading, while otherwise the regulation of the carbohydrate 22 
GENERAL PART 
metabolism is proceeding normally. Then an increased sugar production occurs 
first in the high grades of the disturbance, for now there occurs also on fasting— 
hence, with full exclusion of the alimentary influence—hyperglycemia and 
glycosuria. 
On the other hand, the mobilization of glycogen seems to stand chiefly 
under the influence of the chromaffin tissue, for artificially induced hyper- 
adrenalinemia (through subcutaneous injection of adrenalin or through sugar 
puncture) brings about a rapid melting down of the glycogen present in the 
liver and muscles, and perhaps also an increased combustion of sugar 
(for after injection of adrenalin we saw a rise of the respiratory quotient). 
Thereby occurs hyperglycemia and eventually glycosuria; after extirpation of 
the suprarenals or in Addison’s disease there exists, on the contrary, a 
hypoglycemia. 
Both the pancreatic insular apparatus and the chromaffin tissue are to be 
regarded as most important regulators of the carbohydrate metabolism, 
and we must add to them as a regulator the thyroid gland; for, as previously 
mentioned, in typical myxedema the assimilation limits are raised, and in 
Basedow’s disease or in artificial thyroidism they are not rarely reduced, in 
some cases to such an extent that spontaneous glycosuria occurs. I again 
emphasize, that the thyroid gland seems to influence especially the pancreatic 
insular apparatus or the hormone produced by it, as here the alimentary factor 
is so prominent. A similar regulatory influence, although probably not such a 
strong one, seems to proceed from the hypophysis; I shall speak of this in the 
appropriate chapter. 
So far as the protein metabolism is concerned, we have known for some 
time that the thyroid gland influences it enormously. In Basedow’s disease 
the protein requirements are increased; the patient must ingest more protein 
if he does not wish to use up the protein constituents of his body. In myxedema 
the protein requirements are abnormally low. In hypophysial and suprarenal 
diseases these disturbances in the protein economy are not so distinctly promi- 
nent. Also the severe diabetic ordinarily has no heightened protein 
requirements.1 
From these examples it will be seen that the regulatory influence of indivi- 
dual ductless glands on the different metabolic processes is to a great extent 
specific. While pancreas and chromaffin tissue govern the carbohydrate 
metabolism, the thyroid gland is especially important for the protein metabolism. 
For the calcium metabolism the function of the parathyroid would seem to be 
of especial importance, as in tetany the assimilation of calcium in the nervous 
system seems to be disturbed, although also other ductless glands would seem 
to take a part in the regulation of calcium metabolism. Thus the thymus gland 
seems to be of importance for the assimilation of calcium in young bones. 
Administration of thyroid-gland substance or of extracts of the posterior lobe 
of the hypophysis increases chiefly the elimination of calcium; adrenalin 
increases that of potassium and sodium, while the elimination of calcium is 
1 Also qualitative alterations of the protein metabolism are observed in ductless glandular 
diseases; in tetany, for example, there is a heightening of the ammonia, amino-acid, and polypeptid 
fractions. INFLUENCE OF THE DUCTLESS GLANDS ON THE REGULATION OF METABOLISM 
23 
restricted. The significance of these experiments for clinical medicine is not as 
yet clear. 
The influence of ductless glands on the purin metabolism has as yet been 
investigated but little. The observations that in acromegaly the endogenous 
factor of the uric-acid elimination is raised, that in hypophysial dystrophy it 
may lie strikingly low, and that also the exogenous factor may show oppositely 
directed alterations, and that, further, alterations of purin metabolism also 
occur in the thyroid-gland diseases, as I shall show in Chapter II, make probable 
the regulatory influences of the ductless glands on the purin metabolism. I 
must not off-hand make any statement as to whether the problem of gout will 
be elucidated by such investigation. 
The study of the respiratory gaseous exchange has furnished a deep insight 
into the regulation of metabolism in the ductless glandular diseases. Here, 
too, I will limit myself to certain important facts. In Basedow’s disease the 
basal metabolism is increased. In thyroprivic or spontaneous myxedema the 
basal metabolism and the caloric requirements are reduced. In acromegaly a 
distinct rise of the basal metabolism is present only when symptoms of Base- 
dow’s disease are present at the same time. In hypophysial dystrophy the 
basal metabolism is reduced only in especially severe cases. In failure of the 
sexual glands the reduction of the basal metabolism is still a moot question and 
if present is but slight. Investigations of the metabolism in premature develop- 
ment as the result of suprarenal cortical, sexual glandular, and epiphysial 
tumors have not as yet been made.1 In severe diabetes mellitus, as will be told 
about in detail in Chapter XIII, the caloric production in the rest-fasting experi- 
ments is not essentially increased; the caloric and oxygen requirements are 
increased, correspondingly to the loss of sugar and of ketone bodies. According 
to the investigations up to the present, a considerable influence on the basal 
metabolism is to be attributed only to the thyroid gland. It seems to me, how- 
ever, that for a correct appreciation of the influence that the ductless glands 
exercise on the metabolic processes and nutritional conditions, it is just as 
important that we consider the endogenous factors as well as the exogenous 
factors. By basal metabolism we mean, as is known, the amount of the car- 
bonic-acid production and of the oxygen requirements, or of the heat produc- 
tion, on ruling out of digestion and muscular work.2 If we calculate the basal 
metabolism per kilogram of body weight, we find in (grown) small and thin 
individuals higher values than in (grown) large and fat individuals. In youth- 
ful individuals the basal metabolism is relatively larger than in adults. In the 
1 As the result of numerous basal metabolism experiments done on all classes of patients since 
the publication of the second edition of this work, the statement made in this sentence of the 
text probably does not hold. The organs that affect the basal metabolic rate are mentioned by 
Aub, for reference to whom see page 26 of this work.—Edityr. 
2 “In each mammal there is a basal metabolism. By the term ‘basal metabolism’ or ‘basal 
metabolic rate’ of an organism, is meant the animal heat production of that organism, measured from 
twelve to eighteen hours after the ingestion of food and with the organism at complete muscular rest. 
This minimal heat production may be determined directly by actual measurement by means of a 
calorimeter, or indirectly by calculating the heat production from an analysis of the end-products 
which result from oxidation within the organism, or specifically from the amount of oxygen used and 
the corresponding amount of carbon dioxide produced, together with the total nitrogen eliminated 
in the urine.” Boothby (W. M.) and Sandiford (I.). Laboratory manual of the technique of basal 
metabolic determinations. Saunders, Phila. and London, 1920.—Editor. 24 
GENERAL PART 
small individuals the variations to which it is subject are ordinarily only very 
slight. The basal metabolism change is a measure for the work that in a resting 
fasting organism is performed by the heart, the glands, the nervous system, etc., 
including that which is furnished by a certain muscular tonus that cannot be 
excluded. That the thyroid enormously influences the basal metabolism may 
be readily understood when we consider that in Basedow’s disease the organs 
are in a condition of marked excitement, while in myxedema the vegetative 
functions are markedly reduced. A certain influencing of the basal metabolism 
is to be expected also on the part of the other ductless glands as they too influ- 
ence the vegetative nervous system in manifold ways, so far as its condition of 
irritability is concerned, even if their influence does not cause such distinct 
effects. But also the exogenous factor of the metabolism is influenced by the 
ductless glands more or less pronouncedly. I have reference to the unrest and 
mental irritability of Basedow’s disease and to the apathy and lack of interest 
of the myxedemic. In tetany we find in addition to the increase in the 
vegetative functions also an extraordinary influencing of the exogenous 
factors through the fibrillary twitchings and through the spasms. Also as 
far as the sexual glands are concerned does an exogenous factor come into 
play; for instance, in eunuchs there are absent the stimulus to motion and 
the animation of the normal man. All these are factors that are of great 
importance for the regulation of the total metabolism and for the condition 
of nutrition. 
Even more significant appears to me the following circumstance: That a 
normal grown man retains the same bodily weight for years depends on a 
correct relation between assimilation and dissimilation assured by such different 
factors as appetite, impulse for movements, etc. On these processes the duct- 
less glands have a considerable influence. We can with great probability, as we 
shall see later, divide the hormones into anabolic and catabolic (retarding and 
acceleratory, or assimilatory and dissimilatory). An important anabolic 
hormone is, for example, the pancreas hormone, as it is very important for the 
carbohydrate assimilation and, as I am inclined to assume, also for the fat 
assimilation. This fact also makes comprehensible an influence of the ductless 
glandular system upon the regulation of the total exchange (not the caloric 
production alone). A fattening,1 that is, a significant increase in the assimila- 
tory processes, would only then be possible when the ability for it, that is, a 
certain breadth of function of the ductless glands in question, is present, other- 
wise the organism would protect itself against the increased supply of food. 
This seems to throw some light on the obesity associated so commonly with 
certain ductless glandular diseases. The consideration of the basal metabolism 
alone would not carry us to the goal, for it is very well conceivable that the fine 
mechanism of regulation between assimilation and dissimilation is disturbed with- 
out an alteration of the activity of the vegetative organs to such an extent as to 
influence the basal metabolism. Only in diseases in which the diminution of 
the basal metabolism is quite clear, for instance in myxedema, must there be 
added, if obesity is to develop, a disturbance in the relation between assimila- 
1 Increase in weight due to feeding (Mastung).—Editor. INFLUENCE OF THE DUCTLESS GLANDS ON THE REGULATION OF METABOLISM 
25 
tion and dissimilation, as otherwise the ingestion of nutrition would simply 
diminish with the lessened need. 
Also in those ductless glandular diseases that according to experience are 
associated with emaciation must there be present a similar disturbance of 
the mechanism of regulation although in the opposite direction. The increase 
in the basal metabolism in Basedow’s disease can otherwise be vitiated by 
corresponding increased ingestion of food. Here indeed the relations are 
very much more complicated, as the ingestion of much food may be made 
difficult through vomiting or through diarrhea. It seems to me, however, 
that this explanation is not sufficient for all cases. We sometimes see indeed 
in this very Basedow’s disease a paradoxical relation; in spite of the per- 
sistence of Basedow’s disease, an obesity can develop after initial wasting, 
and some have seen in this obesity evidence for a dysfunction of the thyroid 
gland. 
It seems to me very likely that in such cases, in spite of persistence of an 
increased dissimilation, the assimilatory processes on account of a gradual 
developing hyperfunction of the pancreas, win the upper hand. On the 
other hand, emaciation may enter in on account of primary disturbance of 
assimilation as is the case in severe diabetes mellitus; here the gross metabolism 
is increased, although the production of calories does not become greater. 
Finally there must be ascribed to the ductless glandular system an influ- 
ence on the heat-regulation of the animal organism. These disturbances of 
the heat regulation occur most commonly and most pronouncedly in diseases 
of the thyroid gland. In myxedema the bodily warmth often sinks far below 
the normal; in Basedow’s disease hyperthermia is not rare. In the one the 
vegetative functions are diminished, in the other increased; the diminished or 
increased heat production cannot, however, alone be the cause. There must 
occur in addition other sorts of disturbances, especially in the mode of action 
of the vessels of the skin or in the vegetative nervous system, changes that 
I shall not go into here on account of their complexity. On the ground last 
mentioned, it is well also to ascribe to the chromaffin tissue an important 
role in the regulation of heat, because adrenalin, as may readily be demonstrated 
experimentally, through contraction of the vessels of the skin and prevention 
of the perspiration may lead transitorily to a significant hyperthermia, even 
with shivering. Also the hypophysis seems to enter into the regulation of 
temperature on account of its influencing the vegetative nervous system; to 
this statement points the fact that in hypophysial dystrophy the temperature 
always is instituted at an abnormally low level. I content myself with these 
few examples; the intimate relation of the ductless glands to the vegetative 
nervous system, which I shall speak about later, furnishes obvious explana- 
tion. The same holds true for the influencing of the water economy; retention 
of water in myxedema, with throwing off of water in this condition by the use 
of thyroidin, polyuria in the “hypertonic diathesis,” diabetes insipidus in 
individuals with disease of the hypophysis, diabetes decipiens or high-grade 
polyuria in diabetes mellitus, are all questions which have as yet been very 
little investigated and the study of which represents many results. 26 
GENERAL PART 
[A ub1 has compiled the literature on the subject of the relation of the internal 
secretions to metabolism. As far as our knowledge goes (says Aub), this 
influence is largely exercised on the heat production as a whole rather than on 
individual components of metabolism such as carbohydrates or salt. (This is not 
true, says he, of the pancreas or of the parathyroids.) Of course here the 
thyroid gland stands preeminent. The gonads are also a factor, probably 
in part at least by action through the thyroid. The influence exerted by the 
anterior pituitary is similar to that of the gonads, in that after their extirpa- 
tion, there is a gradual reduction of the basal metabolic rate. The fourth 
organ which regulates the metabolism is the suprarenal;—Aub and Uridil (see 
Aub’s article) have noticed a rapid reduction of the metabolic rate in cats after 
the removal of the suprarenal glands. The glands that most influence the 
total metabolism are the thyroid and the suprarenal (probably by epine- 
phrin). The mechanism of their actions is independent. It may be that 
the suprarenal exert acute effects, while the thyroid is the more sluggish in 
its regulatory activity.—Editor.] 
Embryology of the Ductless Glandular System 
Before I attempt to group the ductless glands according to their functions, 
I should like to say a few words as to the embryology of the ductless glandular 
system. It is a shame that this subject has to the present been somewhat 
neglected by the embryologists. All three germinal layers contribute to the 
structure of the ductless glandular system. According to the contributions 
that I have found in the literature, it seems to me that the following grouping 
is possible: 
The chromaffin tissue is of neuroectodermal origin. 
The posterior lobe of the hypophysis is also of neuroectodermal origin. 
The pars intermedia is also of ectodermal origin. It is questionable, 
however, whether the pars intermedia develops from the anterior or 
the posterior lobe. In the latter case it would be of neuroectodermal 
origin. 
The anterior lobe of the hypophysis develops from an extrusion of the 
dorsal wall of the ectodermal primary mouth cavity where it passes 
over into the entodermal head-gut. 
The middle lobe of the thyroid gland develops from the ventral wall of the 
entodermal head-gut, the lateral lobes apparently in part from the 
ventral wall of the fourth pharyngeal pouch. The anterior lobe of 
the hypophysis and the thyroid gland are phylogenetically older struc- 
tures and were formerly glands with external secretion that poured 
their secretions into the intestines. 
The parathyroid glands are of entodermal origin and develop from the 
dorsal wall of the third and fourth pharyngeal pouches. 
1 Aub (/. C.). The relation of the internal secretions to metabolism. J. Am. M. Ass., Vol. 
LXXIX, No. 2; July 8; 1922, pp. 95-98. EMBRYOLOGY OF THE DUCTLESS GLANDULAR SYSTEM 
27 
The thymus gland is also of entodermal origin and develops from the 
ventral wall of the third pharyngeal pouch. 
The pancreatic insular apparatus develops from an extrusion from the 
pancreatic excretory ducts and according to Weichselbaum is of ento- 
dermal origin. 
The suprarenal cortex comes from the epithelium of the body cavity 
and is of mesodermic origin. 
The sexual glands develop from a neighboring site oh the celomic epithe- 
lium and are therefore also of mesodermal origin; this is generally 
assumed to be true of the interstitial cells, while the glands of genera- 
tion, according to the views of many authors, develop directly from 
the primordial cells. The cells of the suprarenal cortex and the cells 
of the interstitial glands show a certain morphological similarity. 
The epiphysis develops from an extrusion of the roof of the third ventricle; 
it is therefore in part of neuroectodermal origin; in a clinical respect 
it shows a certain relationship with the interstitial glands and the 
suprarenal cortex, so that we can believe that it is in part of meso- 
dermic origin. 
Hence we may group the ductless glands, according to their origin from 
the germinal layers, into those of neuroectodermal origin (chromaffin tissue, 
posterior lobe of the hypophysis), those of ectodermal origin (anterior lobe 
of the hypophysis), endodermal origin (a) from the head-gut (thyroid), (b) 
from the branchial derivatives (parathyroid glands, thymus gland), and 
finally those of mesodermal origin (suprarenal cortex, interstitial glands, 
pancreatic insular apparatus). The glands of generation seem, on account of 
their development from the original primordial cells, to take a special place. 
Although this grouping is incomplete, still it seems to me that important 
analogies may be derived from it. It is striking that the posterior lobe of the 
hypophysis (and pars intermedia?) and chromaffin tissue, the active prin- 
ciples of which, adrenalin and pituitrinum infundibulare, show a certain 
similarity in their action, are both of neuroectodermal origin, and that the 
anterior lobe of the hypophysis and the thyroid gland, whose relationship 
in a physiological and pathological sense has been many times referred to, 
show phylogenetically a certain relationship in that formerly they were both 
glands with an external secretion. Finally, it is striking that the interstitial 
glands and the suprarenal cortex, which are both of such importance for the 
development of the secondary sexual characters and stand in immediate 
relation to premature development, both develop from the celomic epithelium. 
From this standpoint it would be interesting to see whether in eunuchs the 
suprarenal cortex is not hypoplastic. I am well aware that this grouping of 
the ductless glands is associated with much that is speculative, but never- 
theless it seems to me that their study in this direction is of practical value. 
Grouping of the Ductless Glands 
Let us now attempt a classification of the ductless glands according to 
their physiological actions. I first attempted such a classification four years 28 
GENERAL PART 
ago, in which I differentiated acceleratory and retarding hormones. This 
differentiation was founded on observations as to the in many respects 
antagonistic influencing of the metabolic processes through the hormones or 
ductless glandular extracts. Biedl later used the terms dissimilatory and assim- 
ilatory for them. We can also say catabolic and anabolic. This division 
cannot be carried out for the totality of the ductless glands, yet it seems to 
me one well adapted for its purpose. I quote the following examples: 
The hormone of the thyroid gland we may regard with full right as accel- 
eratory or dissimilatory or catabolic. As far as we know its actions, it quickens 
metabolism and increases excitability. That in absence of the thyroid in 
early youth growth and assimilation remain behind does not seem to me to 
speak against this assumption, for the arrest in growth is to be regarded only 
as the effect of serious inhibition of all metabolic processes. 
Also the hormone of the chromaffin tissue is of pronounced acceleratory 
or catabolic action. It increases the excitability of the sympathetic nerves— 
decomposes glycogen, increases the respiratory metabolism, etc. (the more 
intense formation of glycogen in the course of a chronic adrenalinizing I regard 
as only a secondary one, through compensatorily increased activity of the 
pancreatic insular apparatus). 
Again, the posterior lobe of the hypophysis belongs to this group of duct- 
less glands, at least we must regard the actions of the pituitrinum infundibu- 
lare as pronouncedly catabolic or dissimilatory. 
To this group we may oppose the glands with retardative or anabolic 
or assimilatory hormones. To the latter belong the pancreatic insular appara- 
tus, that controls the building up of glycogen and also the assimilation of 
fat, and diminishes the excitability of the sympathetic nerves (.Lowi); further 
the parathyroid glands, that probably assist the assimilation of calcium in 
the ganglion-cells and at the same time reduce their excitability. Both work 
assimilatory and excitability-diminishing, each however in a specific way; 
cataract formation may accompany deficiency of either. [Alien and A. E. 
Taylor have recently stressed the fact that the pancreatic hormone is both 
catabolic and anabolic—see the chapter on diabetes.—Editor.] 
Probably to this group belongs also the anterior lobe of the hypophysis, 
the extract from which reduces the basal metabolism and the functional 
increase of which brings about, as is known, an abnormal growth energy in 
the bones and soft parts. Further I might here include the interstitial glands, 
as they influence the ossification of the epiphysial junctures, the growth of the 
larynx,1 etc. 
I might express the opinion that the generative glands on the contrary 
belong to the catabolic group, as in the inhibitions of growth that occur after 
removal of the interstitial glands as, for example, by X-ray, only the genera- 
1 Novak has quoted just the sexual glands as an example to show that we are not yet prepared 
for a division into an acceleratory and retardative group. He says: If after the removal of a sexual 
gland we cause an increase in growth and at the same time find a decrease in beard formation and 
inhibition in the growth of the larynx, is then the gland growth-inhibiting or growth-increasing? 
If, however, we regard the increased growth only as a result of the delayed epiphysial closure, 
we find that all effects of the removal of the interstitial glands in youth are growth-inhibiting. DUCTLESS GLANDULAR AND NERVOUS SYSTEM 
29 
tive glands are damaged; furthermore, we shall see in the chapter on the 
sexual glands that in the premenstrual period in women all life processes are 
increased when the follicle ripens; it is probable that in man, too, tonic excit- 
ability-increasing influences proceed from the generative apparatus. 
Thymus gland and epiphysis probably belong to the anabolic group. 
If this classification, which I regard as speculative, is confirmed by further 
investigation, it would lead to a result that appears to me to b e very sig- 
nificant. As is known, the ductless glands are for the most part arranged in 
the organs in pairs. It would then be seen that the pairs regularly belong to 
different groups. This is well shown in the accompanying diagram. 
Acceleratory group 
(catabolic-dissimilatory) 
Retardative group 
(anabolic-assimilatory) 
Germinal layer 
Ductless gland 
Ductless gland 
Germinal layer 
Fore-gut 
Thyroid gland 
Parathyroid 
Pharyngeal pouch 
Neuroectodermal 
Posterior lobe of 
Anterior lobe of 
Ectodermal 
hypophysis 
hypophysis 
Neuroectodermal 
Chromaffin tissue 
Suprarenal cortex 
Mesodermal 
Primordial cell 
Glands of generation 
Interstitial glands 
Mesodermal 
[It is especially to this grouping of glands as antagonistic in their action 
that recent criticism has been directed—see page 14.—Editor] 
Relation between the Ductless Glandular System and the Nervous System 
I finally consider the relations between the ductless glandular system and the 
central nervous system. The most recent years have furnished an abundance 
of observations and ideas just in this direction, but these observations and 
ideas are still very unclear and contradictory; so that a concise consideration 
of this subject is hardly possible without strong subjective coloring. 
I shall not consider more intimately here the manifold reciprocal influ- 
ences that are already furnished by the spatial relationship between many of 
the ductless glands and the nervous system (for example pressure action on 
the mid-brain by hypophysial and epiphysial tumors, and of brain tumors on the 
hypophysis and epiphysis). 
A. Influence of the Ductless Glandular System on the Nervous System 
Very significant is the-influence of the ductless glandular system on the 
psychical and mental functions. This subject has been dealt with very often 
in recent years, for instance, by Laignel-Lavastine, Bauer, Marburg, Munzer, 
and others; and recently a considerable study has been published on the subject 
by v. Frankl-Hochwart. 
I refer to the alteration in character that is almost always associated with 
the development of Basedow’s disease; to the psychical irritability, the inclina- 
tion to irascibility, the manic-euphoristic attitude of patients with Base- 
dow’s disease; to the apathy and the lack of interest of the myxedematous; 30 
GENERAL PART 
to the characteristic quiet mental attitude in hypophysial dystrophy, and the 
feeling of mental want of strength in those suffering with Addison’s disease; 
to the depressive attitude of the tetany patient, and finally to the profound 
influence that the ripening of the sexual glands at the time of puberty or 
the loss of function of the sexual glands in castrates exercises on the psyche. 
The relations of the ductless glandular system to the vegetative nervous 
system, as we shall see later, are not only important for the pathogenesis of 
the ductless glandular diseases, but they possess also a great practical interest 
through the fact that in many ductless glandular diseases they simplify the 
solution of the individual symptom-complexes in many respects. These 
relations are of two kinds: 
1. The ductless glands themselves are vegetative organs. They are sup- 
plied by vegetative nerves and possess, therefore, central projection 
fields.1 Thus the function of the ductless glands is in great measure 
regulated by the nervous system. 
2. The ductless glandular system influences the excitability of the vege- 
tative nervous system by the hormones that it gives off to the circula- 
tion. At least this has been ascertained with certainty with regard 
to adrenalin, and is in probability true of the other ductless glandular 
hormones. I shall take up this point first. But before this I wish to 
say something as to the anatomy and physiology of the vegetative 
nervous system. 
As is known, the vegetative nervous system supplies chiefly the organs 
with smooth muscle fibers. In its function it is partially independent, in 
great degree, of the central nervous system. While the somatic or animal 
nerves pass uninterruptedly from the central nervous system to their organs 
of supply, the vegetative nerves are always interrupted in the vegetative 
ganglia. We hence distinguish preganglionic and postganglionic vegetative 
neurons. Langley divides the vegetative nervous system into two groups, 
according to anatomical relations, into the cranio-sacral and the sympa- 
thetic groups. He terms the whole vegetative nervous system autonomous, 
the group of the cranio-sacral autonomous nerves parasympathetic, the other 
group sympathetic. The Viennese authors, who have busied themselves 
much with this question, call the cranio-sacral autonomus nerves without 
further ado autonomous, hence distinguishing between autonomous and 
sympathetic nerves. This terminology has secured a large foothold in the 
German literature. The disturbance in these two groups depends upon 
an extensive difference not only in their anatomical relations, but also in 
1 Cannon and Rapport have described a reflex center for adrenal secretion which is located near 
the upper or front edge of the floor of the fourth ventricle, and which is subject to both excretory and 
inhibitory nervous influences. (Studies on the conditions of activity in endocrine glands. The 
reflex center for adrenal secretion and its response to excitory and inhibitory influences. Am. J. 
Physiol., Vol. LVIII, Dec. i, 1921; pp. 338-352). Ceni has described central thyroid centers in verte- 
brates. Pie ascribes to these trophodynamic inhibitory actions; while he regards the central gen- 
erative centers as excitory in their action on the internal organs of generation. Ceni (C.). 
II cervello e la funzione tiroidea. Riv. sper. di freniat., Vol. XLIV, Fasc. I—III, July, 30 1920; pp. 
243-286.—Editor. DUCTLESS GLANDULAR AND NERVOUS SYSTEM 
31 
their physiological behavior. The action of both groups on the organs they 
affect is in great part an antagonistic action. While, for example, the sym- 
pathetic accelerator nerve accelerates heart action, heart action is slowed 
by the autonomous vagus nerve. While the sympathetic splanchnic nerves 
inhibit the peristalsis of the intestine, this is reinforced through irritation 
of the autonomous vagus. The following scheme, which is taken from the 
experimental pharmacology of H. H. Meyer and R. Gottlieb, shows these rela- 
tions in a manner that may be readily understood (p. 32). 
The two groups also are different in a most noteworthy manner in their 
behavior toward certain pharmacological agents. Indeed there has been based 
on this difference a pharmacologic test of function that should furnish evidence 
as to the condition of excitability of the vegetative nerves. As it is also used in 
affections of the ductless glands I shall here briefly detail the most important 
facts. [But see Cannon's comment, page 37.—Editor.] 
Nicotine shows a specific affinity for all vegetative nerves, but only for the 
preganglionic fibers, interrupting conduction in these fibers. 
Adrenalin acts as a simulant to the myoneural junction of the sympathetic 
nerves in all their organs of supply, and indeed is furthering or inhibitory accord- 
ing as the activity of the organ of supply, is furthered [fordern] or inhibited by 
electrical stimulations. Only the sweat-glands are not, when the doses are not 
too large, influenced by adrenalin. On the contrary, ergotin shows a specific 
affinity for the stimulator sympathetic fibers, while the inhibitory fibers remain 
unaffected. 
On the contrary, pilocarpine, muscarine, physostigmine, and cholin act as 
stimulants on all the autonomous nerves, but only the sweat-glands innervated 
by the sympathetic are energetically stimulated by these agents. Picrotoxin 
acts similarly, but with a central point of attack. On the contrary, atropine 
acts as a paralyzant on the autonomous nerves and also inhibits the activity 
of the sympathetically innervated sweat-gland. 
The fact that among the substances mentioned there is a true hormone, 
adrenalin, leads us to expect that this direction of investigation is very import- 
ant for the internal secretions. In addition, specific affinities for the vegetative 
nervous system are shown by certain ductless glandular extracts not well 
defined chemically. 
Let us examine more closely the action of these hormones or ductless 
glandular extracts in this direction. 
Concerning adrenalin, the internal secretion of the chromaffin tissue, we 
have already mentioned that it is of great significance for the excitability of the 
myoneural junctions. As in a genetic relationship the chromaffin tissue belongs 
to the sympathetic system, this system possesses within itself a regulator of its 
excitability (Bayliss and Starling). As for the physiological significance of the 
chromaffin tissue, it must furthermore be considered that by the lasting function 
of this tissue there is maintained a certain distribution of blood. The sympa- 
thetic innervation of the different vascular districts is of different richness; for 
example, the vessels of the muscles and skin are very abundantly supplied, while 
the vessels of the lungs, of the coronary arteries, and of the brain possess a weak 32 
<GENE1RA.IL P1H 
fto; Diagram of the vegetative iiervous system (according to U; U. Meyer and Hi OattUeb): The autonomous innervation is colored 
green* the sympathetic red. 
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33 
sympathetic supply. Priestley and / have pointed out that the venous blood 
emanating from the organs with a rich sympathetic innervation are adrenalin- 
free or are essentially poorer in adrenalin than the arterial blood flowing to them. 
The liver is supplied with blood rich in adrenalin only by the hepatic arteries, 
while the very much larger amount of blood that flows to it through the portal 
vein is adrenalin-free or at least poor in adrenalin, as this blood has already 
passed through the capillary system of the intestine. Hence in a quiet fasting 
organism there occurs a definite blood distribution, a distribution that may be 
regarded as purposeful. Thus the resting organs (muscle, skin, intestine, etc.) 
contain very little blood, while those organs whose activity is necessary for the 
maintenance of life (heart, central nervous system, lungs, liver, etc.) are rela- 
tively rich in blood. The former become supplied with more abundant blood, 
through the regulatory activity of the sympathetic simultaneously with 
increased cardiac activity, only when they are functionally more in demand. 
The chromaffin system plays an important role in the regulation of the 
blood's plasma contents. After the injection of large amounts of adrenalin, 
Bertelli, Schweeger and I saw an appreciable increase in the count of the red 
cells of the circulating blood. As this hyperglobulia survives the vaso-contrac- 
tion for a long time, the cause of this is to be sought not only in the pressing-out 
of the plasma, but also in an alteration of the permeability of the vessel wall on 
account of which the return flow of plasma is delayed for a long time. Now it is 
known that in individuals who are brought relatively rapidly into an atmos- 
phere poor in oxygen (mountains, balloon trips, etc.) the number of red blood 
cells increases very rapidly. The hyperglobulia brings about greater respira- 
tory surface, this counterbalancing the slighter partial pressure of the oxygen. 
To-day it is generally assumed that at least in rapid transitions it is not the 
result of the increased production of erythrocytes. We believe rather that it is 
due chiefly to a regulatory exudation of plasma into the tissues, and that in this 
regulation is involved the chromaffin tissue. 
Finally, our investigations have shown that injection of adrenalin produces 
neutrophilic hyperleucocytosis and induces a disappearance of the eosinophiles 
from the circulating blood. Whether this is due directly to excitation of the 
sympathetic nerves or indirectly to alteration in the distribution of blood is hard 
to decide. I would only point out that the curves of the white and red cells 
are not parallel throughout, and that we can show that drugs such as pilocarpine 
and cholin lead always in the first stage of their action to an appreciable relative 
and absolute increase of the mononuclear cells, eventually, too, to a changed 
distribution of the neutrophilic cells in the vascular tree. These accumulate in 
the organs less well innervated by the sympathetic, such as the lungs and the 
liver, while there are fewer of them in the vessels of the skin and muscles. 
Hence the chromaffin tissue seems to exercise a regulatory influence on the 
activity of the blood-forming apparatus, chiefly through excitation of the 
medullary system [of the bones]. 
The actions of thyroidin on the nervous system are far more manifold than 
those of adrenalin. We must, however, refer most of the various symptoms of 
hyperthyroidism to alterations of tonus in the organs supplied by the vegetative 34 
GENERAL PART 
nerves, for example, the tachycardia to excitations of the sympathetic accelera- 
tor nerve, the marked fall in blood-pressure to diminution of the vascular tonus 
in the muscles, skin, and intestinal vessels, the irregularity of the breathing to a 
heightening of the vagal tonus, the sweats to an excitation of the nerves of the 
sweat-glands, etc., etc. Probably the excitability throughout the entire vegeta- 
tive nervous system is increased, although an elective affinity for definite 
sympathetic or autonomous nerves is unmistakable. 
The same holds true for extracts of the hypophysis. The pituitrinum 
infundibulare, obtained from the posterior lobe, works as an increaser of blood 
pressure and as a strong diuretic; it also acts as a slower of the pulse through 
excitation of the vagus, and as an increaser of excitability of the autonomous 
nervus pelvicus, moreover as an increaser of the excitability of the uterus, etc.; 
here also there are elective affinities for certain vegetative organs supplied by 
the sympathetic or autonomous nerves. 
Pituitrinum glandulare, according to our investigations, changes the dis- 
tribution of the blood in the opposed sense. It reduces blood-pressure and 
lessens the volume of the liver. 
Let us now consider the alterations of the excitability on the tonus of the 
vegetative organs in the ductless glandular diseases. 
In Basedow’s disease there is an abundance of symptoms that depend on 
an increased tonus of both the autonomous and the sympathetic vegetative 
organs, for example, the tachycardia, the eye symptoms, the sweats, the in- 
creased falls of blood-pressure, etc., etc. As these symptoms are found in more 
or less pronounced manner in artificial thyroidism, the conclusion is justified 
that they are produced also in Basedow’s disease by an increased production of 
the secretion of the thyroid gland. Reversely, in typical myxedema the vegeta- 
tive functions are found to be delayed, slow; the excitability of the organs sup- 
plied by the sympathetic and autonomous nerves is reduced (slower pulse, 
sluggishness of the intestine, etc., or reduction of the glycosuric action of 
adrenalin, absent or deficient hyperglobulia after the injection of adrenalin, 
reduced action of pilocarpine, etc.). 
Then again the parathyroid bodies influence the excitement or the excita- 
bility of the vegetative nerves. In the acute stage of tetany are found hyper- 
globulia, spasmodic conditions of the stomach and intestines, the bladder, ciliary 
muscles, the heart, etc. The different actions of sympathicotropic or autono- 
motropic agents, such as adrenalin and pilocarpine, are essentially strengthened. 
The circumstance that in tetany the manifestations on the part of the vegetative 
organs are essentially different from those of Basedow’s disease shows that the 
affinities for the vegetative organs displayed by the hormone of the parathyroids 
and the hormone of the thyroid are electively different; and also the point of 
attack in the neurone is different, as in the one case the hyperirritability [or 
hyperexcitability, Uberregbarkeit], the other the hyperexcitement [Uberregung], 
is more prominent. 
In Addison’s disease, as is to be expected, there is a reduction of the excita- 
bility and a slighter tonus of the organs innervated by the sympathetic, and 
especiallv prominent are the reduction of the blood-pressure and the lessened DUCTLESS GLANDULAR AND NERVOUS SYSTEM 
35 
action of adrenalin. Here the picture is complicated by a number of symptoms 
depending on a strong excitement of the vegetative organs, symptoms the 
genesis of which is as yet doubtful. 
In the rest of the ductless glandular affections these relations are still less 
apparent. I shall report the appropriate investigations and observations in 
the respective chapters, and here shall only indicate the following: In hypo- 
physial dystrophy and in eunuchoidism the excitability of some of the vegetative 
nerves seems to be somewhat decreased. Probably there exists a certain slug- 
gishness of the vegetative functions, which however does not attain the degree 
of sluggishness of those in myxedema. Diabetes insipidus, which not rarely is 
associated continuously or temporarily with diseases of the hypophysis, seems 
to depend on an irritation of the posterior lobe of the hypophysis [or of some of 
the near-by structures.—Editor] or on a specific increase of the function of the 
kidneys. In acromegaly are found, not rarely, profuse sweats, even when no 
other manifestations of complicating hyperthyroidism are present. In some 
cases of diabetes mellitus, Lowi has shown an increased excitability of the 
dilator pupillae, which is innervated by the sympathetic; we found in a definite 
category of cases which perhaps are similar to Lowi's cases a strikingly strong 
glycosuric action of adrenalin; in such cases, in which also the neurogenous 
factor of the glycosuria markedly predominates, there is sometimes found an 
increase of blood-pressure (hypertonic diabetes). 
Also the glands of generation seem to exercise an important influence on 
the tonus of the vegetative organs. This is expressed in the female sex especially, 
in the form of the known wave-movement. With maturation of the follicles 
(especially of the fertilized ovum in pregnancy) there occurs an increased 
vitality of the whole organism, an increase of the vegetative functions which is 
in part indirectly due to the higher activity of the whole ductless glandular 
system. At the climacteric, when the generative glands discontinue their 
function, there occurs in woman lability of the vegetative nervous system, 
especially of the vasomotors, a sort of vasomotor ataxia which first disappears 
again with the complete loss of ovulation. In men too, these climacteric 
disorders occur, although they are rare. 
At the time of puberty there very decidedly sets in an increase of vegetative 
functions; it is attended with the enormous development of the glands of 
generation, again rather stronger in woman than in man; it often takes place in 
an incoordinated manner, giving occasion to various disturbances. In specially 
predisposed female individuals the revolutions in the organism at this time lead 
to an exhaustion which seems to stand in relation with the development of 
chlorosis. 
In the other ductless glandular diseases the behavior of the vegetative 
nervous system is still less clear. In premature development due to pineal, 
suprarenal cortical, or sexual glandular tumors this pubertal increase of the 
vegetative functions is probably anticipated. As to the influence of the thymus 
gland on the vegetative nervous system, we can state nothing certain. 
This condensed survey suffices well to show to what extent the activity of 
the vegetative organs and the excitability of the vegetative nervous system is 36 
GENERAL PART 
influenced by the ductless glands. This direction of investigation has just 
been determined on. As to its further development, especially when physio- 
logical chemistry has established still more hormones, there is to be expected a 
deepening of our knowledge as to the symptomatology of the ductless glandular 
diseases. From the observations up to the present, however, it may be stated, 
although with insufficient surety, that the affinity of the hormones for the vegeta- 
tive nerves is an elective affinity; not even adrenalin itself influences the entire 
sympathetic group, for it leaves the sweat-glands unaffected. The other duct- 
less glandular extracts, as we know, always show especial elective affinities for 
certain organs, whether these are supplied by sympathetic or autonomous 
nerves; clinical observations furnish still more evidence to this effect. Hence 
it seems to me improper to draw too extensive conclusions from the pharma- 
cological tests of function. Certainly they have furnished us with very valuable 
inferences, and have provided a deep view into the functions of the organ in- 
nervated by the vegetative nervous system. For example, Lowi’s reaction is 
practically constant in the dog without a pancreas. Another example is the 
reduction of the excitability of the sympathetic nerves after extirpation of the 
thyroid; this is evidenced not only by the diminished glycosuric action of adre- 
nalin, but also by the remaining absent of a marked hyperglobulia. This also 
occurs in typical myxedema so far as it remains uncomplicated by pathological 
correlations, for example by a tetany. I believe, however, that we would not 
be just to the complex relationships if we were to draw from the result of such 
functional tests a conclusion as to the condition of excitability of the whole 
sympathetic or the whole autonomous group. In this respect I would not 
subscribe to the views of Eppinger and Hess so far as these views are concerned 
with diseases of the ductless glands. These are based chiefly on the observa- 
tions that in individuals in whom adrenalin works diuretically, the action of pilo- 
carpine remains absent, and reversely that in individuals who show a strong 
pilocarpine reaction, adrenalin does not produce glycosuria. The absence of a 
glycosuric action of adrenalin does not show that the entire sympathetic group 
is hyposensitive. Adrenalin acts as a raiser of blood-pressure, accelerates 
cardiac action, acts as a diuretic, produces aneosinophilic hyperleucocytosis, 
etc., etc. The glycosuric action is only a partial manifestation of a very mani- 
fold action-complex. Besides this, hyperglycemia and considerable increase of 
the respiratory quotient can occur without glycosuria, if diuresis does not come 
in the way; and besides, perhaps glycosuria may remain absent in cases where 
the consumption of sugar is high. We saw, for instance, in the acute stage of 
tetany, absence of glycosuria in spite of enormous vascular action. In other 
cases we may observe marked glycosuria, while the vascular and cardiac action 
remain almost entirely absent. In bronchial asthma I never saw glycosuria 
after the injection of adrenalin; the hypereosinophilia which was often present 
was, however, diminished markedly. Also the other active ductless glandular 
extracts, as for example thyroidin, show such a dissociation of their action. 
The relations are rendered still more complex by the fact that individual 
organs are innervated by furthering [stimulating—reinforcing,—fordern] as 
well as inhibitory fibers of the same group. As Elliot has shown, adrenalin in THE DUCTLESS GLANDULAR SYSTEM 
37 
minimal doses produces vascular dilatation, and only in large doses vascular 
contraction. Pituitrinum infundibulare increases the peristaltic wave-move- 
ment of the gravid rabbit uterus. The same extract acts for the most part 
inhibitory on the virginal rabbit uterus. I can therefore agree at most with 
Eppinger and Hess when in an insufficiency of the chromaffin tissue they assume 
a relative preponderance of the autonomous innervation. But even in Addison’s 
disease (perhaps through failure of the cortex, perhaps through other as yet 
obscure factors) there may occur acute, highly complex, conditions of excitement 
in the vegetative nervous system. 
In many later works there is found the tendency to distinguish between 
vagotonic and sympathicotonic conditions in ductless glandular diseases. 
For instance, Adler supposes after the failure of the sexual glands a sympathe- 
ticotonic condition, on account of the fact that he found glycosuria in certain 
castrated individuals after the injection of relatively small doses of adrena- 
lin, while pilocarpine for the most part did not cause sweating; and he regards 
the complicated process in the vegetative nervous system in dysmenorrhea 
as vagotonic. I do not believe that these things allow of such a grouping. 
[“The ill-based theory of vagotonia has almost no respectable evidence 
to support it. Not only the criticism of laboratory workers but also the 
testimony of clinical observers has done much to discredit it. Cases are 
cited in which patients are equally hyper-sensitive to epinephrin and pilo- 
carpin, in which pilocarpin, atropin and epinephrin produce practically identical 
effects on the blood, in which both atropin and epinephrin will stop auricular 
fibrillation, and in which careful studies on various bodily functions showed 
no consistent sensitization to either the ‘sympathicotonic’ or the ‘vagotonic’ 
drugs. In the presence of the foregoing evidence, “vagotonia” becomes 
merely a name—a name which, as applied to the entire cranial autonomic 
division and presupposing a general reinforcing and vagotonic hormone is 
wholly without meaning” {Cannon1).—Editor.] 
15. Influence of the Nervous System on the Function of the Ductless 
Glandular System 
I now come to the consideration of those relations between the ductless 
glandular system and the nervous system which are characterized by the fact 
that the ductless glandular system is itself vegetative, that it is made up of 
organs supplied by vegetative nerves that possess central projection-fields. 
We shall have investigated in what measure activity of the ductless glandular 
system is regulated by the nervous system. Our knowledge as to this kind 
of relationship is as yet very deficient. We may scarcely put aside the sup- 
position that in this respect the ductless glands behave very differently. The 
impulses emanating from the central nervous system are very important 
for the activity of the chromaffin tissue; for example, perhaps a regulated 
activity is not possible even for a short time if the central innervation is want- 
1 Cannon (1W. B.). Some conditions controlling internal secretion. J. Am. M. Ass., Vol. 
LXXIX, No. 2; July 8, 1922, pp. 92-95. 38 
GENERAL PART 
ing. Centers for these ductless glands lie on the floor of the fourth ventricle 
and according to the later investigations of Aschner also in the subthalamic 
region. Stimulation of these centers leads, just as the stimulation of the 
nervous paths proceeding from them to the chromaffln tissue, to the dis- 
semination of adrenalin. [See foot-note, page, 30.—Editor.] Priestley and I 
have shown that after interruption of these paths by transection of the lowest 
part of the cervical cord the amount of sugar in the blood rapidly decreases; 
apparently, therefore, the activity of the chromaffin tissue is discontinued if its 
connection with central projection fields is interrupted. The number of experi- 
ments is not at all great, as the operative attack is difficult. It seems to me, 
however, noteworthy that indications are wanting that after this attack, which 
also deprives the insular apparatus of its central innervation, disturbances in the 
insular apparatus occur during the short time that the animals survive the 
attack. I would not at all state that the activity of the insular apparatus 
is not regulated by the central nervous system; it seems, however, as though 
this influence were very much slighter than is true in the case of the chromaffin 
system; the insular apparatus seems better able to continue its activity for 
some time even after interruption of its connecting paths. That the production 
of the assimilatory hormone is accessible to few nerve influences seems 
purposeful; such ductless glands always seem to work with a certain surplus; 
while the giving off of the dissimilatory hormone must be very finely graduated 
in order to do justice to the rapidly changing demands; this is only possible, 
however, if the central nervous system governs the function of the ductless 
gland furnishing them. 
That the activity of the thyroid gland is dependent on the central nervous 
system may be concluded from the older literature. How otherwise can 
we explain that existence of an acute Basedow’s disease with the rapidly 
developing thyroid swelling that comes over night? Newer investigations 
of Asher and Flack make it very probable that the nerves regulating the thy- 
roid glandular activity run in the nervi recurrentes. These investigations 
also make it seem possible that rapid variations in the function of the thyroid 
gland are governed by nervous influence. 
Practically nothing as yet is known in this connection with respect to 
other ductless glands.1 I must discuss a little more thoroughly only the sex- 
ual glands. The sexual glands seem to assume an individual position by 
virtue of their independence of the central nervous system. At least the 
results of transplantation experiments up to the present would seem to indi- 
cate this. With the thyroid gland only autotransplantation is successful, 
1 This remains approximately true. The subject is well dealt with by Cannon, in his article in 
J. Am. M. Ass., July 8, 1922, pp. 92-95. The experiments in which nervous impulses have been 
ascribed to the posterior lobe of the pituitary body are referred to, and there is a list of references. 
Cannon concludes however that a nervous control of secretion from the posterior lobe of the 
pituitary is questionable, although Cannon and Rapport have demonstrated to their satisfaction a 
central center governing adrenalin production. Cannon acknowledges that in natural quiet existence, 
the suprarenal medulla probably gives off no secretion whatsoever, at least there is no evidence that 
it does. The influence of the central nervous system in the production of Basedow’s disease can 
scarcely be doubted from the clinical side, although whether purely through the production of thyroxin 
may be questioned.—Editor. DUCTLESS GLANDS ON THE HEMATOPOIETIC APPARATUS 
39 
that is, the transplantation of the thyroid gland to another place in the same 
individual. Homiotransplantation (transplantation to another individual 
of the same kind) fails. But up to the present it has not been possible to 
maintain autotransplants capable of retaining their function, even when 
their vessels are united directly with the vessels of the part by means of suture. 
This shows, provided of course that the efforts of the surgeons are not crowned 
with success at some time in the future, that the function of the thyroid gland 
is not possible for a length of time without connection with a central projection- 
field. It is different with the sexual glands. Here in many cases not only 
autotransplantation but also homiotransplantation succeeds. Indeed here 
even the results of heterotransplantation far surpass all that has been seen on 
the transplantation of the other ductless glands. This separate position of 
the sexual glands was really to have been expected. According to the note- 
worthy views of many authors the generative glands originate from the primor- 
dial cells, which through division of the same kind of the preceding cells, the ovum 
and the spermatozoon, are organisms in themselves and lead an independent life. 
That the sexual glands are also accessible to influences on the part of the central 
nervous system and have central projection-fields in no way contradicts this 
idea. According to Aschner such a projection-field lies in the subthalmic 
region. On its long-continued excitation degeneration of the sexual glands 
occurs. Indeed it may be supposed that the hypophysis furnishes trophic 
influences to the sexual glands by way of the blood. [This is approximately 
correct if we ascribe internal secretory activity to the germinal cells them- 
selves. In the male at least it seems that transplanted sex cells would soon die. 
Internal secretory cells might reside in the Sertoli cells. But I know of no work 
which regards them as germ-plasm in Weismann’s sense. See addendum 
to chapter on the sex glands.—Editor.] 
If we summarize the little we know concerning this important subject 
we find that the ductless glandular system shows a certain degree of autonomy 
which, however, is developed in very different ways on the part of the individual 
ductless glands. The sexual glands are provided with the greatest degree of auto- 
nomy, the chromaffin tissue with the least. 
Influence of the Ductless Glands on the Hematopoietic Apparatus 
Before I speak of the significance of the influences just described on the 
pathogenesis and etiology of the ductless glandular affections, I would like 
to make a few remarks on the influence that the ductless glandular system 
exercises on the activity and development of the hematopoietic apparatus. 
I should like to emphasize the fact that the thyroid secretion is necessary 
for a normal development and activity of the hematopoietic apparatus. In 
myxedema, and still more in thyroid glandular insufficiency in youthful years 
do disturbances in the formation of blood occur. Especially in infantile 
myxedema does there come about a degree of anemia which is often not 
inconsiderable, and a reduction of the erythrocyte count and the amount of 
hemoglobin; the involution of the lymphatic apparatus is insufficient; in the 40 
GENERAL PART 
blood picture the neutrophilic leucocytes retrogress, and the mononuclear 
and eosinophilic predominate. On the administration of thyroid extract 
these disturbances disappear, wholly or at least in great part. Similar, but 
less pronounced, manifestations occur in other ductless glandular diseases 
due to absence of secretion, as, for example, hypophysial dystrophy and 
eunuchoidisin. The production of neutrophilic granulocytes hence seems to 
require a furthering influence on the part of the thyroid gland and chromaffin 
tissue. From this fact are elicited relations of the ductless glands to the so- 
called status lymphaticus. The significance of a hypoplasia of the chromaffin 
system for this condition has been mentioned, especially by Wiesel, Hedinger, 
and Eppinger and Hess. 
A noteworthy influence on the hematopoietic apparatus is exercised by 
the increase of function of the thyroid gland. The finding of Kocher, that 
the count of mononuclear cells in the blood considerably predominates, is 
one of the most constant features of Basedow’s disease. In addition to this 
relative and (to a great extent) absolute increase of the mononuclears (and 
sometimes of the eosinophiles), there is found, just as frequently, an absolute 
diminution of the neutrophilic cells in the circulating blood. Often the 
relative increase of the former is only the sequel of the absolute diminution of 
the latter. It seems to me that in this connection should be mentioned the 
fact that Bertelli and / after the administration of thyroidin to dogs found an 
accumulation of neutrophilic cells in the blood of the liver. It seems there- 
fore that thyroidin influences the distribution of blood in the vascular tree. 
The alterations in the blood picture in Basedow’s disease are therefore not 
analogous throughout to those of myxedema; which is best explained by 
the fact that on administration of thyroidin in myxedema the blood picture 
approaches the normal, while in Basedow’s disease it diverges from the 
normal (Falta, Newburgh, and Nobel). We are dealing in the first case with 
symptoms of absence, in the latter case with irritative manifestations. 
Since, as has already been described, sympathicotropic and autonomo- 
tropic substances influence the blood picture and the distribution of the 
leucocytes in the vascular tree in a definite way, we can comprehend the 
fact that symptoms of irritation in ductless glandular affections and in part 
also the symptoms of absence are the result of an altered condition of excit- 
ability in the vegetative nervous system. 
With this agrees the fact that in many nervous diseases that have involved 
especially or partially the vegetative nervous system, as especially in the 
vagal neurosis, there have been found mononucleosis and eventually hypereo- 
sinophilia, while in the initial 'stage of the hypertonic diathesis, for example, 
the count of neutrophilic cells lies at the upper boundary of the normal or 
even exceeds this. 
On long continuance, however, there are found in many ductless glandular 
diseases morphological alterations in the hematopoietic apparatus. The 
alterations in the blood pictures that are observed are at first hand very hard 
to interpret. It may be stated that in acromegaly there is very frequently 
found mononucleosis and eventually slight eosinophilia. We have seen PATHOGENESIS AND ETIOLOGY OE DUCTLESS GLANDULAR DISEASES 
41 
mononucleosis in chronic tetany (in this disease under the influence of acute 
exacerbation there may occur rapid reversals of the blood picture). Mono- 
nucleosis (without status lymphaticus) may be observed even in severe dia- 
betes. I agree with Borchardt, who has likewise studied these relations, 
that in general in most of the ductless glandular diseases there is observed 
a tendency to mononucleosis and neutropenia, and in many a slighter or 
severer grade of status lymphaticus. 
Pathogenesis and Etiology of the Ductless Glandular Diseases 
On turning our attention to the consideration of the pathogenesis and etiol- 
ogy of the ductless glandular diseases, we find that the idea we have developed 
as to the influencing of the function of these glands by the nervous system 
is not without significance. However, the etiology of a great number of 
ductless glandular diseases is to be .sought in an entirely different direction. 
Let us first consider the diseases due to absence or deficiency. Here we meet 
with congenital aplasia or marked hypoplasia, as, for instance, in thyro- 
aplasia. A defective development [of a “rudiment” or “Anlage”] often 
seems to be a favorable soil for a later infection. Wiesel, for instance, assumes 
that a tuberculosis infection very frequently becomes established in the 
suprarenals on hypoplasias of the chromaffin tissue. But on such a defective 
mapping out, an insufficiency may become manifest, temporary, or perma- 
nent, even without the addition of an infectious process, if larger demands 
are made on the ductless gland in question; for example, glycosuria may occur 
on marked alimentary overloading with carbohydrates if a (often heredi- 
tary) weak mapping-out of the insular apparatus is present. In addition, 
we should mention trauma. This, for example, may affect the testicles and 
lead to eunuchoidism or late eunuchoidism; in operation on goiter too much 
of the functionating thyroid glandular tissue may be extirpated, or the para- 
thyroid glands may be injured. A very great role in the pathogenesis of the 
disease due to absence is played by infection. Tuberculous, luetic, or other 
bacteriological processes, for the most part not as yet investigated, may tempo- 
rarily damage the ductless glands or lead to permanent destruction or sclerosis. 
These infectious processes may spread to the ductless gland from the neigh- 
borhood, they may affect the acini of the pancreas through the ducts and 
involve the insular apparatus by contiguity; in most cases, however, the 
infection follows by the hematogenous route. In many cases in which the 
infectious process involves many ductless glands at a time and causes destruc- 
tion (multiple ductless glandular sclerosis), a congenital or acquired predis- 
position of the ductless glandular system is perhaps present. Also chronic 
intoxications, as alcoholism, poisoning by the toxin of goiter, etc., may damage 
single or several ductless glands. Furthermore, tumors that proceed from 
parts in the neighborhood or from the ductless gland itself may destroy the 
functionating tissue. Again, in many ductless glands, purely functional 
disturbances on a nervous basis are possible, analogous to those hyposecret.ions 
that occur in glands with external secretion. The possibility of a functional 42 
GENERAL PART 
Addison’s disease was long ago discussed by v. Neusser. [Once and for all, 
it should be stated that so-called SergenVs white line—a white line on the 
skin of the abdomen or thorax after one of these parts has been streaked by 
the observer’s fingers—cannot in view of the work of Kay and Brock/ if for 
no other reason, be regarded as significant of hypoadrenalism, or functional insu- 
ficiency of the suprarenal gland. These investigators found that the white line 
is by no means pathognomonic of so-called suprarenal insufficiency.—Editor.] 
A like supposition, [i.e. a disorder of glandular function] seems to me as likely 
a subject of discussion as applied to the insular apparatus of the pancreas as 
applied to the chromaffin tissue. Nor would trophic degenerations of the 
ductless glands be impossible. 
A greater importance should be ascribed to nervous influences in the 
pathogenesis of the diseases of hyperfunction. The pathologico-anatomical 
correlate of hyperfunction is hyperplasia, or in ductless glands of definite 
morphological structure, adenoma formation. The latter is found in 
the disease of hyperfunction of the glandular hypophysis, of the thyroid 
gland, and the suprarenal cortex; while in the sexual glands sarcomatoid 
tumors are more often found. Hyperplasia of the chromaffin tissue is found 
in the hypertonic diathesis. Even where, however, the adenoma formation is 
most common, indeed constant, can a nervous cause of the hyperfunction not 
always be precluded. In peracute Basedow’s disease, the entire symptom- 
complex and the swelling of the thyroid gland can develop in a few hours; here 
we cannot well blame the adenoma formation, as it is very much more likely 
that in such cases the adenoma formation sets in at some later stage of the 
disease. Such cases and the fact that many symptoms of Basedow’s dis- 
ease, for instance the marked exophthalmos, can hardly be produced by 
hyperthyroidization have led certain authors back to the conception of the 
older French authors, according to which Basedow’s disease was regarded 
as a vegetative neurosis and in which many of the symptoms of the Basedow’s 
were considered as coordinated with the hyperthyroidism. According to 
this we might distinguish Basedow’s disease as a hyperthyrosis from the 
symptom-complex of hyperthyroidism. Whether such views are to be applied 
to the adenomata of the hypophysis and suprarenal cortex can hardly be 
decided at the present time. As far as severe diabetes is concerned, we can 
hardly get away from the assumption of a hyperfunction, whether it be sec- 
ondary or primary. In Chapter XIII the opinion will be advocated that 
the entire apparatus regulating sugar metabolism (central projection-fields, 
pancreas, and chromaffin tissue as organs affected by these fields) is diseased, 
in the course of which disease process diminution of function in one part and 
excess of function in another come to exist in juxtaposition. 
Nor can we explain the cause of the hyperfunction better if we regard as 
its seat the central projection-fields. The problem is only shifted, although we 
cannot deny that in this manner the solution of the symptom-complex is made 
easier, or indeed first made possible. 
1 Kay (W. E.) and Brock (S.). White adrenal line (Sergent): its clinical significance. Am. J. 
M. Sc., Vol. CLXI, April, 1921, pp. 555-561. CENTRAL NERVOUS SYSTEM AND DUCTLESS GLANDULAR SYSTEM 
43 
Relation between Diseases of the Central Nervous System and Ductless 
Glandular System 
The knowledge that the ductless glands as vegetative organs indeed show a 
certain autonomy, but in part, as far as their function is concerned, stand under 
control of the central nervous system, together with the supposition that we 
have to reckon with the possibility of a purely functional increase or decrease of 
their secretion, requires of us that we now investigate whether in the diseases 
of the central nervous system alterations of the ductless glands are demonstra- 
ble. The investigations should first of all be important for neuroses of the 
vegetative nervous system, but must also reach to the psychoses and the other 
diseases of the central nervous system. So far as the psychoses are concerned 
there have been pointed out very recently appreciable variations in the condi- 
tion of excitement and the tonus of the vegetative organs. I refer, among other 
investigations, to the investigations of Potzl, Eppinger, and Hess, who have 
found in melancholia a reduction in the excitability of the vegetative nervous 
system, and in mania, especially during the first attack, appreciable heighten- 
ing of the excitability of the vegetative nervous system. Also in other 
diseases of the central nervous system, for example in tabes, symptoms on 
the part of the vegetative nervous system become conspicuous in the 
disease picture. 
This investigation seems to have so much the more force because later ob- 
servations always confirm the view that in diseases of the nervous system and 
in the psychoses1 the metabolism is often altered in a profound way. I would 
here quote some examples. Rosenfeld first established that a considerable 
nitrogen retention occurs in catatonics. Siege found enormous variation in the 
nitrogen elimination in the circular psychoses. Especially intensive studies on 
metabolism have been made by Kaufmann from Anton’s clinic. Especially 
mentionable are, for example, the enormous variations in body weight in 
psychoses: for instance, Kaufmann found rapid fall of the body weight in spite 
of copious forced feeding. According to Kaufmann, such rapid variations are 
to be referred chiefly to disturbances in the amount of water in the organism in 
the wake of nervous influences. In hysteria, Kaufmann found considerable 
variations in the amount of urine and in body weight, together with the fact 
that the pyschical disturbances may recede while the vegetative disturbances 
are still present. Also in progressive paralysis, in tabes, and in a series of other 
brain diseases are alterations of the metabolism observed—Paghini found in 
many brain diseases increase of the elimination of endogenous uric acid and of 
the xanthin bases. Lowe found increase in the elimination of phosphorus after 
epileptic attacks and in definite phases of paralysis and in delirium tremens. 
The thought has also been expressed that the appreciable indicanuria accom- 
panying brain diseases is sometimes of nervous origin. There are also observed 
in cerebral and mental diseases considerable variations in the salt metabolism. 
As is known, there is frequently found in neurasthenia considerable increase in 
1 For remarks as to the results of the Abderhalden reaction in mental diseases see foot-notes, 
p. 56.—Editor. 44 
GENERAL PART 
the elimination of calcium. The brittleness of the bones that is so often seen in 
tabes indicates a considerable loss of calcium and phosphorus. Disturbances 
in the carbohydrate metabolism (especially appreciable lowering of the assimila- 
tion boundary) are frequent phenomena in cerebral and mental disturbances. 
Disturbances of the regulation of the heart are not at all a rare symptom. In 
progressive paralysis Kaufmann often found hyperthermia, and in the akinetic 
diseases as well as after epileptic attacks reduction of temperature. These few 
examples might suffice. It can well be conceived that these alterations in 
metabolism come about through a functional influencing of the ductless 
glandular system. 
[In connection with the ductless glands in the insanities, an important 
work is that of Mott} In a recent article his previous work is referred to, and 
there is a bibliography—this in connection with work done with Prados y Such? 
See addendum—Editor.] 
Special attention has been devoted in this respect to the behavior of the 
ductless glands in the neuroses of the vegetative nervous system. Egger saw 
in the vasomotor psychoneuroses increases of temperature that lasted' for 
months and years. In visceral neuroses, Pollitzer saw positive alimentary galac- 
tosuria, while alimentary glycosuria was negative. This reminds one of the 
alimentary levulosuria described by the author in some cases of Basedow’s 
disease, or in the disturbances in the qualitative decomposition of protein in 
tetany. Curschmann saw a case of bronchial asthma with intermittent exoph- 
thalmus, tremor, and tachycardia. In the vagal neurosis I regularly found 
appreciable mononucleosis of the blood, and Eppinger and Hess observed also 
hypereosinophilia. In the vasomotor neurosis Roth found in addition to 
marked lymphocytosis and lability of the pulse, also lability of the temperature. 
Why rare cases of pentosuria and isolated levulosuria are almost always associ- 
ated with vasomotor neurosis is as yet unexplained. A short time ago I saw a 
case of pentosuria with pronounced Herz’s vasomotor ataxia. 
In Raynaud’s disease is often seen slight rise in temperature, distinct trophic 
and secretory disturbances, and in the attack often marked rise in blood- 
pressure; sometimes there is polyuria and in rare cases glycosuria. 
Partially related to the vasomotor neurosis is perhaps that condition 
which affects the group of diabetics in which the neurogenous factor espe- 
cially predominates in the glycosuria. Here we usually find marked 
vasomotor excitability, and under circumstances increase of the blood-pressure 
without nephritis (hypertonic diabetes, see Chapter XIII). 
Among the many symptoms of the vasomotor neuroses are found, accord- 
ing to this, those which point to an alteration in the metabolism and in general 
to a functional influencing of the ductless glandular system. It seems to me 
that there is wanting in this case any secure foundation for bringing a primary 
alteration of the ductless glandular system into an etiological relationship. 
1Mott (F. IF.). Further pathological studies in dementia precox, especially in relation to the 
interstitial cells of Leydig. Proc. Roy. Soc. of Med., Vol. XV, No. 5, March, 1922, pp.1-14. Section 
on Psychiatry. 
2 Mott (.F. IF.). The reproductive organs in relation to mental disease. Brit. M. J., March 25, 
1922; pp. 463-466. CENTRAL NERVOUS SYSTEM AND DUCTLESS GLANDULAR SYSTEM 
45 
Of the vasomotor neuroses, scleroderma seems to merit a more exact con- 
sideration. In this affection there are a series of findings that point to a marked 
involvement of the ductless glandular system, v. Striimpell has pointed out a 
certain opposition in the symptom picture of scleroderma and acromegaly. In 
the latter the bones and skin are hyperplastic, while in the former there are 
processes of shrinkage in both organs. The opinion that the basis of sclero- 
derma is a functional disturbance of the hypophysis finds, according to Roux, 
corroboration through the fact that in this case apparent sclerotic processes are 
found in the hypophysis. Until the present, however, this case has remained 
isolated; the opinion is often expressed that scleroderma depends on an altera- 
tion of function of the thyroid gland. After v. Leube first pointed out the coex- 
istence of scleroderma with Basedow’s disease, numerous pertinent cases were 
found in the literature, which have been compiled by Saltier. Cassirer mentions, 
however, that in these cases the diagnosis Basedow’s disease is to be accepted 
with caution, as important symptoms of Basedow’s disease, such as pigment 
displacements, changes in the thyroid gland, irritability of the heart, also 
belong to scleroderma in itself. Even the exophthalmus may be stimulated 
by the sclerodermic mask. Cassirer himself calls attention to the fact that these 
symptoms similar to Basedow’s do not always follow in their intensity the course 
of sclerodermic process. The occasional appearance of myxedemic symptoms 
of (Grasset, Osier, Dehu, et al.) and the not rare finding of sclerotic changes in the 
thyroid glands of those sick with scleroderma have permitted Jeanselme, 
Singer, Hectoen, v. Notthaft, Leredde and Thomas, and others to regard the cause 
of the scleroderma as an insufficiency of the thyroid gland, the more probably 
for the reason that in many cases good results are obtained by thyroid medica- 
tion. The common occurrence of pigmentations in scleroderma seems to indi- 
cate the associated involvement of the chromaffin tissue. The pigmentations 
may stimulate those of Addison’s disease. In not rare cases there are also 
observed typical smoke-gray discolorations of the mucous membrane of the 
mouth. In a large number of cases the combination of scleroderma with Addi- 
son’s disease has also been assumed, although there are numerous observations 
(.Lichtwitz, Kren, and others) of scleroderma with typical Addisonoid pigmenta- 
tions of the skin and mucous membranes that showed no alterations in the 
suprarenal glands at autopsy. Finally the combination of scleroderma with 
tetany has been described in a case of Dupre and Guillain’s. In this case it 
seems as though a pronounced Addison’s disease were also present. As the 
supposition of change in one ductless gland is not satisfactory, there has been 
upheld by several recent authors a pluriglandular pathogenesis of scleroderma 
{Dupre and Kahn, Rasch, and others). With regard to this, it is conceivable 
that sclerotic processes in certain ductless glands in scleroderma do not mean 
very much. The scleroderma often spreads to the deeper-lying tissue and may 
also extend to the bones and muscles; it is therefore not wonderful if now and 
then the process should involve individual ductless glands. Moreover, there 
are found in the majority of cases of scleroderma a great number of manifold 
symptoms on the part of the vegetative nervous system, conditions of excite- 
ment of manifold nature, such as vasomotor disturbances, tachycardia, shiver- 46 
GENERAL PART 
ing, faintings, rush of blood to the head, feeling of anxiety; as Klinger observed, 
such conditions may occur in attacks. Hess and Konigstein saw in one case 
of diffuse scleroderma, during such attacks, an especial sensitiveness against 
adrenalin and marked excitement of the heart-action, associated with mani- 
festations of acroparesthesia and with subsequent outbreaks of sweat. In 
addition to this are found in the majority of cases a series of trophic distur- 
bances, such as transitory edema, erythema, urticaria, etc. These make the 
diagnosis of a coexistent Basedow’s disease very much more difficult. On the 
other hand, I do not doubt that in many of the cases there was actually an 
increase of function of the thyroid gland, and that it was not at all impossible 
that the pigmentations had their basis in a disturbance of function of the 
chromaffin tissue. Nor do* I doubt that in certain cases slight symptoms of 
thyroid insufficiency may occur. When I acknowledge, therefore, the possi- 
bility of pluriglandular symptoms in scleroderma, I would regard them as 
only secondary, in part due to the sclerodermic process extending over the 
ductless glands, and still more due to functional influencing of the ductless 
glandular system. There are in addition cases of scleroderma in which the 
manifestations on the part of the vegetative nervous system are much less 
prominent. 
I agree fully with Cassirer in the supposition that in scleroderma the disease 
process is not primary in the ductless glandular system. 
There has also been an attempt to bring another group of diseases, the 
trophoneuroses, into relation with the ductless glandular system, diseases such 
as acute circumscribed edema and symmetrical lipomata. In both are regu- 
larly found neurosis symptoms on the part of the vegetative nervous system. 
Here also is found the possibility of functional disturbances on the part of the 
individual glands, although the symptoms are here less distinctly prominent. 
This same thing seems to me to hold good for adipositas dolorosa. This condi- 
tion will be considered in detail in Chapter XIV; here I wish to dispense with 
the supposition of ductless glandular etiology in that syndrome. The same is 
true for xanthelasma, the pathology of which Chvostek has made the subject of a 
penetrating study. Chvostek in consideration of the occurrence [of xanthelasma] 
in gradations [schubweise], the kind of distribution, and especially the often 
rigid symmetry, comes to the conclusion that nervous influences are the basis. 
The individual with xanthelasma shows a series of symptoms on the part of the 
nervous system and especially on the part of the vegetative nerves. Here also 
the changes in the ductless glands seem to me to be only of a secondary nature. 
Not only in trophoneuroses, but also in other diseases of the central nervous 
system, do we find the most manifold symptoms that point to disturbances in 
the function of the vegetative nervous system. It seems to me that the study 
of these conditions has been handled rather half-heartedly by neurologists. 
Myasthenia, paralysis agitans, and myotonia have been brought into etiologi- 
cal connection with the parathyroid glands. As we shall see, however, in 
Chapter IV, I regard the hypothesis of a primary affection of the parathyroid 
glands in these diseases as insufficiently supported. Myasthenia, because like 
scleroderma it is sometimes associated with slight symptoms of Basedow’s CENTRAL NERVOUS SYSTEM AND DUCTLESS GLANDULAR SYSTEM 
47 
disease or tetany (Tobias), has been regarded as a polyglandular disease (Mark- 
eloff), certainly not with more correctness than has been scleroderma. Finally, 
I wish to make some remarks in this connection with regard to multiple sclero- 
sis, tabes, and progressive paralysis. In multiple sclerosis, often symptoms on 
the part of the vegetative nervous system become distinctly prominent. There 
often exist tachycardia and great lability of the pulse, most pronounced dermo- 
graphism, furthermore, sweats, inclination to hyperthermia, manifestations on 
the part of the gastrointestinal canal, polyuria, bladder disturbances, etc. In 
a series of cases that we investigated we found a great sensitiveness against 
adrenalin and pilocarpine, often appreciable alimentary glycosuria, strong 
diuretic action of pituitrinum infundibulare, low degree of tolerance against 
thyroidin, etc. In some cases even Chvostek’s phenomenon was observed. It 
is further known that in multiple sclerosis the activiy of the generative glands 
mostly disappears early. I think that most will agree with me that if we speak 
of pluriglandular disturbances in this disease, we shall have to assume a func- 
tional and trophic influencing of the ductless glands. The relations in tabes 
and progressive paralysis seem to me to be very similar. Kraepelin grouped 
paralysis with the diseases of metabolism, to which group Raymond ascribed 
tabes. This seems to me to be overdrawn. In the same manner we could 
regard the infectious diseases as metabolic diseases. Indeed it is true that in 
tabes and paralysis the alterations of metabolism are so prominent that at 
times they almost dominate the clinical picture. I refer to the losses of weight, 
to the marked cachexia of tabetics, to the decalcification of the bones, which 
gives rise to the spontaneous fractures, to the positive alimentary glycosuria 
that is so marked in this condition; also to the irritative symptoms on the part 
of the nervous system that are so fulminant, the tabetic gastric crises, the vesico- 
intestinal crises, the enormous hypersecretion of gastric juice, moreover the 
vasomotor disturbances, tachycardia, sweats, dermographism, and the trophic 
disturbances, abnormal pigmentations, mal perforant du pied, etc. If here I 
look around for symptoms on the part of the ductless glands, I find almost only 
the degenerative changes in the sexual glands that have been demonstrated by 
Marchand and others; these may be conditioned by the syphilis, but it might also 
be conceived that they exist on a trophic degenerative basis. I could regard any 
of the other symptoms as ductless glandular, only in the sense that they might 
be secondary. R. Stern regards as the basis of the fact that only a percentage 
of persons infected with lues become affected with metasyphilis the vulnera- 
bility of the ductless glandular system in the mapping out [Anlage] of such per- 
sons. According to this view, the affection of these glands furnishes the impulse 
for the development of the tabes or the paralysis. Even though in my disserta- 
tions I arrive at a standpoint that is almost the opposite of Stern’s, I would 
nevertheless recognize the ingenious character of Stern’s work. 
I would here summarize briefly the facts arrived at from the above exposi- 
tion. Even though we may be inclined to refer to functional alterations of the 
ductless glandular system changes in metabolism in the course of neuroses of 
the vegetative nervous system or in the course of nervous diseases in which 
manifestations on the part of the vegetative nervous system become prominent, 48 
GENERAL PART 
we are not on this account justified in regarding these diseases as true ductless 
glandular affections. At all events it must be acknowledged that it is not yet 
possible to draw a clear line of demarcation between certain ductless glandular 
affections and the vegetative neuroses; the neurosis theory of Basedow’s 
disease has not as yet been fully rejected, nor is the supposition that in the patho- 
genesis of diabetes mellitus there is the admixture of a marked component of 
neurosis. But a sufficiently firm foundation has been built by experimental 
pathology, in the majority of ductless glandular affections, to justify a sharp 
demarcation from the vegetative neuroses, at least nosologically. 
Pluriglandular Disturbances 
Proceeding from this standpoint, we now go on with a consideration of the 
question of the pluriglandular disturbances. Of late this question has been 
especially discussed in France. Claude and Gougerot, on the basis of clinical 
observations and certain pathologico-anatomical findings, first conceived the 
idea of an insufhsance pluriglandulaire Proceeding from the observation that 
under circumstances certain ductless glands may become diseased simultane- 
ously, they attempted to furnish the demonstration that in the most diverse 
ductless glandular diseases symptoms are found almost regularly that point 
to the affection of another ductless gland. The authors have found many 
disciples. The direction of this is characterized by the classification of 
Laignel-Lavastine. Laignel-Lavastine distinguishes “syndromes pluriglandu- 
laires a predominance thyreoidienne, a predominance hypophysaire, a predomi- 
nance genitale et sans predominance marquee.” Claude and Gougerot have 
further developed their teaching in that they point out that also conditions of 
hyperfunction of several ductless glands may exist simultaneously, and that not 
rarely conditions of hyperfunction of one ductless gland are combined in the 
clinical picture with manifestations of absence or deficiency of the function of 
another. They distinguish, of ductless glandular diseases, seven categories: 
1. Syndromes uniglandulaires avec lesion pluriglandulaire; example, 
classical myxedema. 
2. Syndromes pauciglandulaires; that is, predominance of the disease in 
one ductless gland, but distinct alteration in the others. 
3. Syndromes d’insuffisance pluriglandulaire sans predominances. 
4. Syndromes d’hyperfonction pluriglandulaire; example, acromegaly, 
hyperfunction or dysfunction of the hypophysis with hyperfunction 
of the thyroid gland, suprarenal glands, etc. 
5. Syndromes pluriglandulaires de balancement; that is, a hyperfunc- 
tion that developed compensatorily as the result of a primary falling 
away of the function; for example, Basedow’s disease that follows a 
“hypoovarie.” 
6. Syndromes pluriglandulaires disharmoniques; example, Basedow’s 
disease combined with myxedema and “ hypoovarie. ” 
7. Cas d’attente a syndromes frustes. PLURIGLANDULAR DISTURBANCES 
49 
Gougerot goes still further, including the glands with external secretion 
in the pluriglandular syndrome; for instance, he describes: syndrome Miku- 
licz, lacrymo-parotidien avec symptomes d’hypoovarie evidente, hypothy- 
reo'idie et hypoepinephrie probable. The disciples of Claude and Gougerot 
have also included the trophoneuroses. Thus Siccard and Rous ay, later 
together with Berkowitsch, explain a case of Dercum’s disease as insuffisance 
ovarothyreoidienne. From these views Renon and Delille have drawn far- 
reaching therapeutic consequences, in that they propose an “opotherapie 
associee” in those conditions in which a trial with simple opotherapy fails. 
Thus the authors found that in one case of Dercum’s disease ovarian sub- 
stances, and later thyroidin, remained inactive, while on the contrary the 
combination of these two remedies was effective. A case of myasthenic bul- 
bospinale was improved by the combined administration of ovarian and 
hypophysial substances, a scleroderma by thyroidin and ovarian substances, 
a Basedow’s disease disappeared on the administration of hypophysial and 
ovarian substances, a case of acromegaly was essentially improved through 
ovarian substances and thyroidin, etc. R. Dupuy used polyopotherapy 
for the development of individuals who had remained behind or were at a 
standstill, and saw a striking improvement after one-half to one year’s treat- 
ment. The admixture of all nosological unities goes so far that Grasset says: 
The insufficiency of a ductless gland always becomes more and more a rarity 
or a “creation artificielle,” the group of insuffisance pluriglandulaires crowds 
the others more and more and perhaps in time will quite replace them. With 
all this, who does not feel foundations wavering under him? 
I must not leave unmentioned the fact that voices, even in France, have 
been raised against these extreme overdrawings. Roussy maintains a very 
reserved attitude. He believes that they are an ingenious hypothesis, but 
[regards] methodical sections as lacking. 
[Barker in the Nelson’s Loose Leaf Living Medicine under the caption 
polyglandular syndrome distinguishes the following types: 
1. Thyro-testicular-hypophyseo (suprarenal) syndrome. This corresponds 
to the multiple ductless glandular sclerosis oiFalta. 
2. Thyro-genito-chromaffin-syndrome in which there are marked altera- 
tions in the pigmentation of the skin, combined with symptoms of 
Graves’s disease and certain eunuchoid tracts. 
3. Suggestion of myxedema with hypophysial insufficiency. 
4. Acromegalic changes, combined with genital and gastro-intestinal 
disturbances, hypertrophies of the breasts, pigmentation, asthenia, 
and, sometimes, distinct signs of hypophysial tumor. 
5. The Timme syndrome. See addenda to chapters on status lymphaticus, 
thyroid gland, and infantilism. 
Of these 3 and 4 and possibly 2 may be excluded from the author’s concep- 
tion of ductless glandular sclerosis. Perhaps also the syndrome described by 
Timme had already been foreshadowed by such authors, for example, Wiesel 
and Bartels. 50 
GENERAL PART 
Status lymphaticus, status hypoplasticus, status thymicus, and infantil- 
ism are in the present stage of our knowledge not well separated and certain 
forms of infantilism may be associated with thymic or lymphatic hyperplasia. 
Other members of the ductless glandular system are frequently involved in 
these conditions, but these facts were well recognized before Timme1 described 
his syndrome. What Timme has pointed out is the frequent involvement 
of the pituitary gland in the later stages of the syndrome (at least to the X-ray) 
and the relief of the symptoms on continued feeding with pituitary gland. 
Timme has regarded his picture as a thymus-adrenal-pituitary combination. 
Editor] 
The question seems to me to gain clearness if we distinguish between 
pluriglandular insufficiency or pluriglandular syndromes on the one hand 
and multiple ductless glandular sclerosis on the other, for the existence of a 
pluriglandular syndrome does not signify the existence of a multiple ductless 
glandular disease. On the basis of what I have already written, I must assume 
that the pluriglandular syndrome comes about: 
1. Through physiological correlation. 
2. Purely functionally through influencing on the part of the vegetative 
centers. 
I have gone more intimately into the question of the latter factor in the 
consideration of the vegetative neuroses. As far as the physiological corre- 
lation is concerned, it seems to me that it affords no ground for a confusing 
of the sharply delimited disease pictures of the individual ductless glandular 
diseases. Let me first consider the diseases due to deficiency. That in 
myxedema the activity of the glands of generation is diminished or that in 
hypophysial dystrophy there occurs even marked degeneration of the sexual 
glands belongs to the disease pictures themselves. On account of this, no 
doubt is cast on the view that in the first case the thyroid gland is the central 
figure of the pathogenesis, in the second the hypophysis. The disease pictures 
which, however, we assume as the result of a pathological correlation already 
belong to multiple ductless glandular diseases: I refer once more to the simul- 
taneous degenerative lesions of the thyroid gland and the glandular hypophy- 
sis, of the thyroid gland and the insular apparatus of the pancreas, etc. The 
pathological correlation finds its most complete expression in that clinical 
picture, well characterized in a symptomatological respect, which I have 
termed multiple ductless glandular sclerosis. 
Undoubtedly more complicated are the relations in the hyperfunctional 
diseases—not so very much in Basedow’s disease. Although in this condi- 
tion we may acknowledge a functional increase of the chromaffin tissue, this 
is secondary and well enough explained by physiological correlation. That 
long-continued oversaturation of the body with thyroid gland secretion may 
1 Timme {W. A.). New pluriglandular compensatory syndrome. Endocrinology. Vol. II, 
July-Sept., 1918; pp 209-240. 
Timme (IF .A.). New pluriglandular compensatory syndrome. M. Clinics of North America. 
Vol. II, No. 4, Jan., 1919, pp. 959-985. PLURIGLANDULAR DISTURBANCES 
51 
give rise to disturbances of the functions of the sexual glands is not at all 
remarkable, only the significance of the thymus hyperplasia is as yet unclear. 
But on this account, not to wish to consider Basedow’s disease as a clinical 
entity seems to me incomprehensible. Sooner could acromegaly be regarded 
as a pluriglandular disease; this is not new, however, but was already men- 
tioned by Pineles in his classical work. In addition to hyperplasia of the 
hypophysis, we not rarely find, in acromegaly, symptoms of Basedow’s dis- 
ease, in the later stages eventually symptoms similar to myxedema, also 
to diabetes,_ and in the most cases, as is known, premature disturbances on 
the part of the glands of generation, which may, however, be sometimes pre- 
ceded by temporary increase of their function. Of late years, too, have been 
issued reports as to hyperplasia of the suprarenal cortex; briefly, in acromegaly 
there comes about a pluriglandular hyperplasia of the ductless glandular 
system, which mostly is rapidly followed by a degeneration and exhaustion. 
This, however, likewise belongs to the disease picture of acromegaly, and on 
this account we would hardly be likely to confuse a Basedow’s disease with 
an acromegaly. 
These pluriglandular disturbances are found much more pronouncedly 
in many cases of gigantism. Here the hyperplasia would seem to be a par- 
tial manifestation of an abnormal predisposition to growth of the entire body. 
[Edelmann and Saxl1 have described what they consider a characteristic 
disease in which cachexia (in two of the cases ascribed to hunger) is associated 
with a glandular insufficiency that involves the glands of external secretion 
as well as those of internal secretion, and in which the external secretory 
changes are supposed to depend on the internal secretory changes. Three 
cases are reported. The factor of diet in the etiology of ductless glandular 
conditions has been mentioned by Carlson.2—Editor.] 
Concerning the therapeutic results of opotherapie mixte, that have been 
hailed with such enthusiasm, they must be regarded with much scepsis, espe- 
cially in so far as they are concerned with the trophoneuroses of the vege- 
tative nervous system. However, I do not wish to deny the justification 
for this therapy in combined diseases due to absence [Ausfall]. 
Desirable seems to me a sharper delimitation of the ductless glandular 
diseases, not only from the vegetative neuroses, but also from certain vege- 
tative disturbances. The regarding of chondrodystrophy as a ductless gland- 
ular disease has been practically done away with. Mongolism is regarded 
to-day as a product of degeneration, in which a thyogenic component is asso- 
ciated, at most. Lately, true dwarfism has been regarded as a disease due 
to deficiency of the hypophysis, a view that will hardly meet with general 
acceptance. Most obstinate are the attempts to obtain a place among the 
ductless glandular diseases for true infantilism. In true infantilism the 
1 Edelmann (A.) and Saxl (JP.). Ueber ein eigenartiges Krankheitsbild-f-Kachexie und poly- 
glandulare Insuffizienz der Driisen mit ausserer und innerer Sekretion. Wiener Archiv f. innere 
Med. Vol. Ill, Nov. 15, 1921, pp. 227-234. 
2 Carlson (A. /.). Hypofunction and hyperfunction of the ductless glands. J. Am. M. Ass., Vol. 
LXXIX, No. 2, July 8, 1922, pp. 98-104. 52 
GENERAL PART 
organism, on account of a damage in fetal or postfetal life, does not progress 
beyond the child stage of development. In this remaining behind, the duct- 
less glandular system participates, as well as the central nervous system 
and every other organ of the body. There are, however, no indications that 
the ductless glands functionate deficiently, which dictum holds also for the 
sexual glands—these functionate, but only as in the child organism; if they 
were not to functionate, the genitalia and dimensions of the body would be 
eunuchoid, but not infantile. 
The Ductless Glands and Constitution 
After the above attempts to delimit the ductless glandular diseases from 
the disease groups that are related to them, I would add a few remarks as to 
the significance of the ductless glandular system for the total constitution of the 
body. Martins says “die Gesamtkonstitution ist die Summe der Teilkon- 
stitutionen” [the total constitution is the sum of the partial constitutions]. 
I might suppose that from the study of the physiology and pathology of the 
ductless glandular system we have obtained a deeper insight into one of these 
partial constitutions. At all events we must not accept the ductless glandu- 
lar system for itself alone, but must regard as a constitutional component 
the ductless glands as vegetative organs together with the nervous system 
regulating their functions. Wunderlich distinguishes a strong, an irritable, 
and a lax constitution. This classification seems also to apply to those com- 
ponents of the general constitution whose differentiation we are at present 
concerned with. We can group individuals into those with stabile, those 
with debile and those with labile, vegetative nervous systems, and individuals 
with stabile, debile, and labile ductless glandular systems. 
The certain degree of autonomy that is an attribute in general of the duct- 
less glandular system has as a sequel the fact that the corresponding partial 
constitutions may occur separately; the intimate relations that exist between 
both systems would lead us to expect, however, that they are to be very often 
found united in the same individual or that where one is present the other is 
at least suggested. As the hereditary factor is very prominent in both, we 
find them in the most diverse variations and combinations in members of the 
same family. In individuals with a predisposition to a debile vegetative 
nervous system there develop, under the demands that life makes on the 
organism, an asthenia of the vegetative organs with general enteroptosis, 
sluggishness of evacuations, anomalies of the secretion of gastric juice, depres- 
sive mental attitude, in short the features that are an expression of Stiller’s 
asthenia. In the individuals predisposed to a debile vegetative nervous 
system, readily accessible to irritations, there exists a tendency to neuras- 
thenia, hysteria, and the vasomotor-trophic neuroses. It seems to me that 
this classification may be applied in the smallest detail to the ductless gland- 
ular system. The ductless glandular debile individuals are those in whom 
there is not only a small functional breadth, but perhaps also a certain tend- 
ency for certain diseases, especially for infections, or a slighter resistance THE DUCTLESS GLANDS AND CONSTITUTION 
53 
against alcohol or against certain toxins that may proceed from a focus of 
infection somewhere in the body. To me the most interesting are the duct- 
less glandular labile individuals. These are individuals who several times in 
the month show extraordinary variations in the body weight, or those in 
whom the thyroid swelling that occurs normally during pregnancy leads to 
slight manifestations of Basedow’s disease, or those in whom a strong emo- 
tional excitement calls forth temporary glycosuria, or perhaps those in whom 
slight symptoms of acromegaly occur during pregnancy, or women in whom 
exist marked dysmenorrheic distresses. In this group are always to be found, 
too, some symptoms that point to an especial lability of the vegetative nerv- 
ous system. I need not attempt the description of the stabile individuals. 
They are those with an enviable equilibrium of their vegetative functions, 
their metabolism, and their psyche. 
The relationship of both the disease groups is also shown, as has already 
been mentioned, in the fact that they sometimes occur combined or alter- 
nating in the members of one family. I here submit an example: 
Grandfather 
(Obesity and Gout) 
Son 
(Slight thyroid 
swelling, later 
light diabetes 
with light Base- 
dow’s symp- 
toms.) 
Daughter 
(Slight thyroid 
glandular swell- 
ing, climacteric 
psychosis, light 
diabetes.) 
Daughter 
(Slight thyroid glan- 
dular swelling, mani- 
festations of hyper- 
thyrosis.) 
Son 
(Obesity.) 
Granddaughter 
(Severe exuda- 
tive diathesis, 
later bronchial 
asthma.) 
Granddaughter 
(Obesity.) 
Granddaughter 
(Pronounced lability 
of the ductless glandu- 
system, great varia- 
tions in the body 
weight during preg- 
nancy, light Base- 
dow’s symptoms, 
great sensitiveness 
against cocaine.) 
Granddaughter 
(Likewise lability of 
the ductless glandular 
system, migraine, par- 
oxysmal tachycardia.) 54 
GENERAL PART 
I would consider it probable that such family trees are not at all hard to 
find, at least they do not occur isolated, but readily could be traced in the 
family trees of families with diatheses. 
This affords me the opportunity of saying a few words with regard to 
the significance of the ductless glandular system for the diatheses. Accord- 
ing to W. His we understand by diathesis an individual, congenital, and 
often inherited condition, which consists in the fact that physiological stim- 
uli call forth an abnormal reaction, and that conditions of living which are 
borne without harm by the majority of the race call forth conditions of dis- 
ease. The circumstance, that in the great group of arthritic diatheses, as 
also under the diatheses of pediatrics and dermatology, there are found con- 
ditions that we regard as vegetative neuroses, shows that the vegetative 
nervous system has a prominent place here. Rapin sees also in a familial and 
inherited lability of the nervous system the connecting link between the indi- 
vidual diatheses. In this connection we must turn our attention to the duct- 
less glandular system. Actually we find that diabetes and obesity play a 
prominent part in the reat group of garthritism. The connection 
between gout and the ductless glandular system is, of course, at first hand as 
yet quite unclear. In the pathogenesis of the spasmophilic diathesis we 
must, even with the use of the utmost reserve, ascribe some significance to 
the parathyroid glands. Also for the genesis of lymphatism the observations 
that status lymphaticus is regularly associated with hypoplasia of the chrom- 
affin tissue cannot be quite without significance. For the predisposition to 
the dermatoses the processes in the sexual sphere are of importance, as Bloch 
emphasizes, for just at the trasitional periods, at puberty and at the climacteric, 
certain dermatoses are very common, and others, like favus or trichophytina, 
disappear with the beginning of puberty. Here the ductless glandular system 
exerts a certain influence on the natural immunity. 
A very much older observation concerns the known inclination of dia- 
betics for furunculosis, and the great vulnerability of their tissue. This 
may be shown experimentally: It is known that after extirpation of the pan- 
creas it is not easy to obtain a reactionless healing of the laparotomy wound. 
Bloch infected the skin of dogs with yeast before and after the extirpation 
of the pancreas and found that the affection was much worse in the dogs 
without a pancreas. The fact in itself cannot be gainsaid, but as yet we 
are without any deep insight into the nature of this disease susceptibility. 
[The susceptibility of the tissues in diabetes has been held by Allen to be due 
to the fact that the normal action of the pancreatic hormone is absent—See 
chapter on diabetes, p. 550.—Editor.] 
As may be gathered from the elucidation of the idea of diathesis through 
the summarizing “Referate” [references] of His, Pfaundler, and Bloch, we 
are dealing in the diathesis not with sharply circumscribed disease pictures, 
but with an exceedingly manifold disease susceptibility resting on as yet 
hard to define factors; alterations in the function of the ductless glands con- 
stitute only one of these factors; in a theoretical sense I would not, however, 
estimate this factor as of slight importance, for if we see in the interest that ADDENDUM 
55 
physicians have taken in the question of diathesis a sort of resurrection of 
the old humoral pathology, and if we seek in an altered blood admixture and 
the consequent changing of the tissues the cause of the tendency to disease, 
we find that the little that the study of the ductless glandular diseases has 
afforded for the knowledge of diathesis has up to the present first furnished an 
idea as to the genesis of this alteration of the blood admixture and the tissue 
changes that follow it. 
Finally a few words as to senility. Horsley first pointed out that the 
alterations of the skin and other tissues that occur in old age, especially the 
increase of the connective tissue, have a certain similarity with those that 
occur after extirpation of the thyroid gland, and that on the other hand 
localization of the fat deposits in old age is similar to that in eunuchoidism. 
In a detailed study Lorand has upheld the idea that the degeneration of 
the ductless glandular system is chiefly the cause of senility. I would not 
concur with this, so far as physiological old age is concerned, but believe much 
more, as does also Ewald, that the ductless glandular system like every other 
organ participates in the involution of old age. There is, on the other hand, a 
pathological old age, setting in prematurely or associated with distinct accentu- 
ation of the cachexia. The premature senility which develops in most of the 
diseases due to giving out of function, and especially in multiple ductless glandu- 
lar sclerosis, makes intelligible to me the fact that degeneration in the ductless 
glandular system may be one of the causes of pathological age. [This state- 
ment is not vitiated by Steinach’s1 rejuvenation works on rats. See addendum 
to chapter on the sexual glands.—Editor.] 
Addendum 
With regard to what has been written in toto, it may be said that the 
author’s views respecting the grouping, the reciprocal action, etc., of the duct- 
less glands, and their effects on the various organs and systems of the body, are 
sound. On the whole they seem to be somewhat in advance of the general 
conception in America of the purport and scope of the ductless glandular 
apparatus, at least in regard to their definiteness. There seems to be a tendency 
among some recent investigators to claim too much for the ductless glandular 
system and to jump to conclusions, attributing effects to the system of endocrine 
organs that might just as well be explained by metabolic processes that are 
general, or that are part of constitutional factors at least one step removed from 
purely internal secretory activities. 
The author’s chapter on ductless glands and constitution has the tendency 
to counterbalance this drift. Here the various ductless glandular constitutional 
states are considered as part of a “total constitution,” which is made of factors 
that mutually influence each other, including the ductless glandular system. 
If to the modern mind such an attempt to revive the idea of “constitution” 
1 Steinach (E.). Verjungung durch experimentelle Neubelebung der alterden Pubertatsdriise. 
Berlin, Springer, 1920. 56 
GENERAL part 
and its sister conception “ diathesis” savors too much of the old humoral path- 
ology (which by the way in its serological form has led or will lead to a later 
chemical aspect of the subject which will perhaps be all-embracing so far as 
relation between cell and tissue juices is concerned), it must not be forgotten 
that “constitution” itself represents but one factor of a far more extensive 
subject—heredity, a subject that in its last analysis resolves itself again into 
factors that are mechano-chemical, and perhaps is part dependent on the 
activities of just these ductless glands. 
The Abderhalden reaction has already furnished results with regard to the 
reciprocal activities of the various ductless glands. To the editor’s mind it 
would seem that the importance of the significance of the Abderhalden reaction 
(in general, not simply the pregnancy test) has not as yet been sufficiently 
realized, at least in this country.1 That its basic principle, the formation of 
ferments—chemical substances—for the splitting up of alien or other proteids, 
as a matter of “Abwehr,” defense, is a biological phenomenon at the basis of 
life itself, and it will be indeed strange if this principle, capable as it is of exact 
chemical demonstration, does not yield practical results far in advance of 
present indications.2 
The matter of “Abwehr” leads us to two other so-called discoveries of 
recent years—the Freudian theory of the genesis and treatment of hysteria 
and allied neuroses and the so-called “kinetic theory” of Crile. Of these the 
latter merits discussion here because of its direct relation with the ductless 
glandular diseases, and the former because of the relation of the various neuroses 
(and even psychoses) to the ductless glandular system. It is a pity that Crile 
has not as yet so far as the editor knows, published the results of his experiments 
in toto and in detail, as much of what he claims for his theory (based as it is on 
painstaking examination of, among other objects, 40,000 nerve cells) seems to be 
substantiated by older and more recent theories of the central nervous origin of 
such ductless glandular conditions as Basedow’s disease and diabetes mellitus. 
{Crile will be mentioned again in the addendum to the chapter on Basedow’s 
disease.) 
With regard to Freud, I have been anticipated in what I wished to say by 
Cushing; as I consider the matter very well expressed by that author, I shall 
quote in extenso passages from one of his works: 
1 Much work has recently been done with the Abderhalden reaction, especially in the field 
of nervous and.mental disease. Remarkably striking have been the labors of Fauser and his followers,, 
in the Abderhalden diagnosis of dementia precox. I shall not enter into this matter here but refer 
the reader to the bibliography appended to A bderhalden’s Abwehrfermente des tierischen Organismus, 
etc., or to that at the end of Orton’s article (Am. J. Insanity, vol. LXXI, 1915, p. 573). Allusions to- 
the Abderhalden reactions will be found in certain of the addenda to the chapters of the present 
work. 
2 This remains as written in the previous editions of this work. The Abderhalden school still 
publishes suggestive results, results which, although somewhat contradictory in detail deserve 
consideration as tending to show that in the psychoses the blood-serum reacts to the extracts of various 
ductless glands, and that in dementia precox the sex glands play an important part. Mott and 
Prados y Such’s work, while not serological, points in the same direction (see p. 60). The subject 
of the Abderhalden reaction so far as results are concerned has recently been dealt with in a com- 
prehensive manner by Vitry.—Vitry (M.). La reaction d’Abderhalden technique, resultats cliniques. 
Annales de medicine, Vol. Ill, 1920, pp. 301-324. ADDENDUM 
57 
“The pituitary body and the germinal glands appear to be protagonists. 
Hypophysial insufficiency and a lowering of the activity of the reproductive 
functions go hand in hand, and in some of our examples of hypoplasia, glandular 
feeding has unquestionably led to a restoration of potentia. The reverse is 
probably also true, for, as stated, a libidinous tendency often accompanies 
states of secretory hyperplasia, and certain experiments undertaken with Dr. 
Emil Goetsch have indicated that feeding pituitary extracts to preadolescent 
animals leads to a precocious ovulation and spermatogenesis. These observa- 
tions, coupled with the knowledge that secretory discharges from the hypophy- 
sis may be elicited through the sympathetic nervous system, suggest that the 
liberation of a chemical messenger may account for the recognized effect of the 
emotions upon the sexual sphere.” 
“It is plain that the two intracranial glands, hypophysis and epiphysis, 
normally exercise a remarkable influence not only upon the nutrition and 
skeletal growth, but also upon the sexual sphere, and it is not a matter for 
surprise that in the presence of a definite pathological derangement of either 
of these structures which dates from childhood, mentality should be so modi- 
fied as to produce peculiar if not defective individuals when measured by the 
standard of the average. 
“With this conception we may find some physiological or pathological 
basis for what is regarded by many as a psychotherapeutic phantasy; for the 
various neuroses and asthenias may arise primarily as the result of some dis- 
turbance of internal secretion which paves the way for the dreams, symbolisms, 
neurograms and other acrostical manifestations dissected by the psychoan- 
alyst. If therefore we are to swallow the Freudian doctrines whole—a difficult 
morsel for many—and are to interpret hysteria and the psychoneuroses solely 
as the resultant of early mental conflicts and compromises between the libido 
and its repressions, it will be easily seen that any secretory duration which on 
the one hand excites, or on the other diminishes, sexual activities must be an 
important element in modifying the terms affecting the ultimate compromise. 
“We have of course been considering extreme examples, but is quite prob- 
able that the psychopathology of everyday life hinges largely upon the effect 
of ductless gland discharges upon the nervous system. This is particularly 
worthy of consideration in the study of child psychology in its relation to puberty 
and adolescence, especially in those individuals in whom there is some under- 
lying, possibly inherited, functional deviation in the chemistry of the internal 
secretion. At any age, however, in the presence of some ductless gland irregu- 
larity, which in chemically speaking more stable individuals would be transient, 
may produce secretory disturbances, characterized by more or less chronicity.” 
“it is hoped that some serological test, possibly in the direction of Abder- 
halden’s investigations on the serodiagnosis of pregnancy, will serve to give as 
a chemical reaction of diagnostic value, at least, for states of over-activity of 
individual glands . . . and we possibly may come to attach an importance to the 58 
GENERAL PART 
findings of pathological serology far greater than that which in the past we 
have given to the cytological changes shown in the microscope.” 
It was part of the philosophy of the ancients to explain change in matter 
as due to the “love” of the elements. We still speak of chemical affinities. 
Nowadays we resolve love into its chemical constituents. All of which makes 
not one whit less, but rather much more wonderful, the phenomena manifested 
by the various bindings together of atoms. 
Thus is the Freudian theory placed on a materialistic basis with regard to 
the genesis of certain of the epiphenomena of some of the neuroses. That the 
underlying factor of heredity governs here the constitution, predisposing either 
the ductless glandular or the nervous factor or both to abnormal action, there 
can be no doubt. One thing at least we may be assured of: without internal 
secretion, no thoughts. The fact, however, that the nervous tissue seems to be 
especially susceptible to the influence of the internal secretions of what is 
ordinarily known as the ductless glandular system does not preclude its influ- 
encing by products of cellular activity elaborated in the course of diseases that 
have nothing to do with the ductless glandular system (I am indebted for this 
idea to remarks by McCarthy, in an extempore address) or in which, as in the 
infectious diseases, the ductless glandular system is influenced only indirectly. 
This subject last mentioned, that of ductless glandular affection in the course of 
infectious disease has been taken up especially by Sajous, to whom we are 
indebted so much for attracting our attention to the importance and scope of 
ductless glandular affections. 
What is especially noticeable in the ductless glandular diseases is the 
employment of chemical substances or glandular extracts in their diagnosis— 
a use for these substances or extracts that independently of the ameliorative 
effect is perhaps new in the art of diagnosis, and that may perhaps mark the 
beginning of a new science, that of pharmacodiagnosis. 
Sajous has published a resume of his conclusions with regard to the 
function of the various constituents of the ductless glandular system. This 
resume approaches first principles to a greater extent than any of Falla’s 
conclusions, and is interesting as furnishing a basis of comparison with the 
results of Falta’s work. Sajous maintains that the thymus gland supplies to 
all tissues the excess of phosphorus in organic combination (possibly as nucleins) 
required to build up cell-nucleins while the animal organism is developing. The 
thyroparathyroid secretion (thyroidase) sensitizes these nucleins to the action 
of oxygen. The adrenal secretion (through its catalytic ferment, adrenoidase) 
endows the blood with its oxygenizing properties. The pancreas supplies the 
ferments which in the intestinal canal and nutritional leucocytes change food 
materials into products harmonious to, and for the building up of, tissue cells, 
that is, for the anabolic phases of metabolism. The same pancreatic ferments 
also carry on the catabolic phase of metabolism. All endogenous and exo- 
genous substances that are not appropriate for tissue-building—bacteria, 
toxins, toxic wastes, toxic venoms, etc., are subjected in the phagocytic leuco- 
cytes, the tissue cells, the lymphatic system and the blood plasma to the cata- ADDENDUM 
59 
bolic phase of metabolism, which serves to convert them into eliminable 
end-products. 
This addendum up to the present point has been retained practically as in 
the second edition. We may note that the Germans have been paying especial 
attention to the so-called “constitution. ” They regard it as the sum of the total 
characteristics of the body (/. Bauer) who calls it “ Korperverfassung, ” in- 
herited or acquired, which can be correlated with the so-called phaenotype of 
Johannsen, as made up of two factors, a constitution (genotype of Johannsen), 
which means the inherited attributes of the constituents of the body (these 
react to environmental influences) and the condition, which is the resultant of 
accidental and acquired attributes, wrought by exposure to the environment. 
A list of general references to the general subject of constitution will be found 
at the end of the list of references below. 
The editor would like to add a word of caution against the senseless adminis- 
tration of ductless glands in conditions in which such use would be irrational. 
Weisenberg and Patton have also called attention to this maladministration. 
Polypharmacy in the use of glandular products is especially to be deprecated. 
(See the comment on the article of Hoskins in a recent number of the J. Am. M. 
Ass. and what Carlson has to say about glandular therapy in that number. 
The summary of Blumgarten1 in that number is so appropriate that I append it 
in a foot-note.) 
With regards to the truth or falsehood of the Freudian hypothesis, the 
editor wishes only to state that neuropsychiatrists occupy opposing camps— 
uselessly in his judgment. The benefits that Freud has brought to neuro- 
psychiatry has been well stated by Bleuler. It is probably a fact that Freud has 
not taken cognizance of the whole truth; even Bleuler does not accept the entire 
Freudian hypothesis, but he does give Freud credit where credit is due.2 It is no 
1 Blumgarten (A. S.). “I think we can summarize the present status of organotherapy in reference 
to dried extracts by stating that thyroid extract is curative in cases of thyroid deficiency, such as 
myxedema and cretinism. Pituitary extracts are valuable in relieving many of the symptoms of 
pituitary deficiency, largely of a subjective nature; and more valuable in females than in males. Ob- 
jective results with pituitary extracts are rather rare. The other dried extracts are still in the 
experimental stage. Epinephrin and pituitary extract are useful for the production of their specific 
pharmacologic effects. The problem of the future consists in recognizing specific states of glandular 
deficiency and obtaining preparations that will produce definite results.” It is probable that the 
extract of the islands of Langerhans recently isolated by Canadian investigators—insulin—see 
foot-note, page 6, will prove of distinct service in the treatment of diabetes meilitus.—Editor. 
2 The reader is referred to Bleuler’s work. It seems that the fad of Simon-pure Freudism has 
reached its acme in this country and is on the wane. It may not be well known to the reader of 
purely medical works that Freudism has been criticised from the anthropological point of view, at 
first by Boas and lately by Goldenweiser, in his volume on “Early Civilization” (New York, 1922). 
Still, in the Freudian doctrine there was much that was presented from a novel point of view and 
which corrected a tendency to emphasise the form of mental disorder rather than its subject matter. 
The fact that the medical world felt the effects of the wave of the new doctrine—although the 
medium of transmission was not absolutely pure after its own kind—in other words although the 
doctrine was not based on absolutely pure scientific, verifiable truth—was perhaps a shock vital 
enough to spur on psychologic and psychiatric investigation to achievement, so that in the future 
the subject-matter of the psychoses will be based on a hypothesis which be universally acceptable 
and perhaps verifiable. MacCurdy has recently attempted to put order and system in the more or 
less poorly systematized views of Freud and his disciples and followers. MacCurdy (J. T.). 60 
GENERAL PART 
answer to Freud to state that Janet’s methods were used with success before 
Freud’s advent. There is an aspect of the controversy that is likely to be 
overlooked:—Some psychiatrists are adopting theories in their application of 
endocrinology, which are as hypothetical, to say the least, as anything that can 
proceed from the pen of Freud. Spaidding, who has used both psychotherapeutic 
measures and endocrine therapy in the treatment of apparent endocrine dis- 
turbances well recognizes this fact.—She states “Even as unsubstantiated as 
some of the psychogenetic theories may still be considered by certain physicians, 
the psychiatrist may criticize to even greater extent, the supposed rationalizations 
of the endocrinologists” and concludes that “there are a large number of 
psychoneurotics and social deviates of various kinds who have been socially 
inefficient for years. They have gone from medical man to surgeon, from 
neurologist to psychiatrist, but have failed to regain their nervous equilibrium 
because their need has been so definitely two-fold in nature. For when their 
glandular balance has been recognized, the fact has not been appreciated that 
they have formed compensatory mechanisms and conditioned reflexes that 
must be treated from the mental side alone. ” 
Dercum, who was one of the first in America to call the attention of the 
profession to the earlier work of Fauser in the application of the Abderhalden 
reaction to the sera of dementia precox patients has recently written an essay on 
the physiology of the mind and dwells much therein on the theory of the 
synapse, as elaborated by Sherrington, whereby the synapse is held as the 
material basis for the explanation of the facts of consciousness and its disorders. 
As a matter of fact, Child has pointed out that the nerve tissues of the body 
develop at the places of greatest metabolic activity, i.e., where chemical activity 
is proceeding at its fastest rate. If one should regard memory and the material 
basis of the nerve system as manifestations of metabolic activity in which atoms 
and ions,—perhaps also electrons—play their part, much of the controversy 
between the orthodox neurologists and the exponents of the Freudian school 
might perhaps be avoided;—and in the chemical-physical explanation of mental 
activity and of the material substratum of the nerve system endocrine chemical 
products undoubtedly play their part. Mott and Prados y Such have empha- 
sized a period of intra-embryonic life in which the interstitial glands of the 
sexual organs reach a high degree of development. In the male at least, the 
interstitial glands disappear soon after birth, to reappear in rather intense 
development about the age of puberty. May not these facts be correlated 
with the forgotten sexual memories dwelt upon by the Freudians? At least 
Mott seems to have taken Jung (one of the Freudian school) into account in his 
article in the “British Medical Journal.” Mott’s work is suggestive along this 
line if the interstitial glands be proved to be really the part of the testicle (or 
ovary) that furnishes the internal secretion of the sexual gland. But this is 
decidedly doubtful. Mott has shown however that dementia precox in the 
male is also associated with aberrations of the spermatogenetic function. 
Problems in Dynamic Psychology, a Critique of Psychoanalysis and Suggested Formulations. 
New York, MacMillan, 1922. See also Turner (/.) The Psychology of Self-consciousness. 
London, Kegan Paul, French Trubner and Co., 1923.—Editor. 61 
ADDENDUM 
Crile (G. IF.). The kinetic system, Cleveland M. J., Vol. XII, No. 4, October, 1913, p. 665, 
associated with which is: 
Hitchings (F. IF.), Sloan (II. G.), and Austin (J.B .). Laboratory studies of the brain and the 
adrenals in response to specific stimuli, Ibidem, pp. 684-691. 
Crile (G. IF.) and Lower (IF. E.). Anoci-association. W. B. Saunders Co., Phila., 1914. 
Cushing (HI). Psychic disturbances associated with disorders of the ductless glands. Am. J. 
Insanity No. 5, 1912, special number, pp. 965-990. 
Sajous (C. E. de MI). Among other articles: Hypoadrenia as a cause of death in infections 
and its treatment. Monthly Cyclopaedia and Medical Bulletin, Vol. IV, 1911, pp. 725-729. Also 
his Internal secretions and the principles of medicine, 5th edition, Phila., F. A. Davis and Co., 1912. 
Sajous (C. E. de MI). The theory of the internal secretions. The Practitioner, Feb., 1915, 
pp. 180-197. 
Weisenberg (T. HI) and Patton (C. A.). Methods of investigation of pituitary disorders, with 
observations on some of the causes and manifestations of dyspitiutariam. Med. Clinics of N. 
America, Nov., 1921, pp. 759-782. 
Hoskins (R. GI). Some principles of endocrinology applicable to organotherapy. J. Am. M. 
Ass., Vol. LXXIX, No. 2, July 8, 1922, pp. 104-109. 
Carlson (A. J.). Hypofunction and hyperfunction of the ductless glands. J. Am. M. Ass., 
Vol. LXXIX, No. 2, July 8, 1922, pp. 98-104. 
Bleuler (E.). Lehrbuch der Psychiatrie. Berlin, Springer, 1920. 
Bleuler (E.). Naturgeschichte der Seele und ihres Bewusstwerdens. Berlin, Springer, 1921. 
Spaulding (E. R.). The importance of endocrine therapy in combination with mental analysis 
in the treatment of personality disorders. Medical Record, Vol. Cl, No. 2, Jan. 14, 1922, pp. 50-54. 
Dercum (F. X.). The physiology of mind. Philadelphia, Saunders, 1922. 
Sherrington (C. SI). The integrative action of the nervous system. London, Constable, 1906. 
Child (C. MI). The origin and development of the nervous system from a physiological view- 
point, Chicago, 1921. 
Mott (F. IF.). Further pathological studies in dementia precox, especially in relation to the 
interstitial cells of Leydig. Proc. Roy. Soc. of Med., Vol. XV, No. 5, March, 1922, pp. 1-14, Sect, 
on Psychiatry. 
Prados y Such (MI). The morbid histology of the testes in dementia precox. Ibid., pp. 14-30. 
Mott (F. IF.). The reproductive organs in relation to mental disease. Brit. M. J., March 
25, 1922, pp. 463-466. 
Martins (E.). Konstitution and Vererbung in ihren Beziehungen zur Pathologic. Berlin, 
Springer, 1914. 
Johannsen (IF.). Elemente der exacte Ehrblichkeitslehre. Jena, Fischer, 1909. 
Brugsch (TI). Allgemeine Prognostik., etc. Berlin, Urban, 1918. 
Kraus (F.). Die allgemeine und spezielle Pathologie der Person. Klinische Syzygiology, 
Vol. I, Leipzig, Thieme, 19x9. 
Bauer (J.). Die Konstitutionel'e Disposition zu innern Krankheiten (2nd Edition) Berlin, 
Springer, 1921. 
Bauer (J.). Vorlesungen fiber allegemeine Konstitutionslehre and Vererbungslehre. Berlin, 
Springer, 1921. 
Bauer (K. HI). Ueber den Konstitutionsbegriff. Zeitschrift fur Konstitutionslehre. Zweite Abh. 
Band VIII, Heft 2, pp. 155-183. CHAPTER II 
THE DISEASES OF THE THYROID GLAND 
Anatomy and Embryology.—The thyroid gland of man is butterfly-shaped. 
Its two lobes, which lie on the lateral surfaces of the trachea and larynx, are 
joined together by the isthmus, which is sometimes prolonged for a certain 
distance superiorly as the so-called processus pyramidalis. The weight of the 
thyroid gland in the adult approximates 36-50 gm. 
The isthmus is developed from an unpaired evagination from the ventral 
wall of the head-gut cavity. In many of the lower animal classes the connection 
with the head-gut—the ductus thyroglossus—is retained. Here the thyroid is 
a gland with external secretion. In the higher animal classes the ductus thyro- 
glossus obliterates early. Concerning the devel- 
opment of the lateral lobes opinions to-day are 
still divided. It is safe to say that a portion of 
the lateral thyroid gland rests are developed 
through evagination from the median rest. It 
is further certain, according to the investigations 
of Erdheim and Schilder, that the so-called post- 
branchial bodies, which originate from the 
ventral wall of the fourth branchial pouch, can 
give rise to thyroid gland tissue; for in the cases 
of thyroaplasia in which the medium rests of 
the thyroid remain rudimentary, the indifferent 
rests of the post-branchial bodies regularly con- 
tain some thyroid gland follicles. We are uncer- 
tain, however, as to what extent under normal conditions the lateral rests of 
the thyroid gland take part in the formation of the lateral lobes. To aid the 
better comprehension of the subject, I subjoin the accompanying sketch taken 
from the work of Maurer in which is shown the development of the parathyroid 
and the thymus glands. 
The rudiments of the thyroid wander downward with the heart. Along the entire 
tract from the root of the tongue to the aorta may be found cut-off portions of thyroid 
glandular tissue—accessory thyroids—which may give occasion to the formation of abnor- 
mally situated goiters (tongue goiters, retrosternal goiters, etc.). 
The thyroid is remarkably well vascularized. It consists histologically 
of follicles lined with cubical or cylindrical epithelium, which for the most 
part are filled with colloid. This contains the specific secretion, which, accord- 
ing to the need, gets into the circulation, probably through the lymph paths. 
Fr. Kraus therefore designates the thyroid a reserve or storage gland. The 
thyroid is signalized by an especially high content of iodine; in the formation 
Fig. 3.—7Y = Thyroid;/, II, III, 
IV = pharyngeal pouches; e3e4 = 
rudiments of the parathyroid glands; 
p = postbranchial bodies; Tm — rudi- 
ment of thymus. 
62 TUMORS OF THE THYROID GLAND 
63 
of the specific secretion, the iodine is bound to a protein body thyroglobulin. 
[The active principle of this secretion is thyroxin.-—Editor.] 
W e may divide the diseases of the thyroid gland into those which for the 
most part do not especially restrict its functions, but chiefly produce local 
symptoms, and those the principal symptoms of which depend on the alteration 
of the internal secretory function. To the first belong certain forms of the 
goiters, the tumors, and the inflammations. The goiters are discussed in the 
chapter on the cretinic degeneration. 
Fig. 4.—Normal thyroid gland with colloid formation. 
Tumors of the Thyroid Gland.—Among the tumors are found most com- 
monly adenoma, carcinoma, and sarcoma. The simultaneous occurrence of 
sarcoma and adenoma in the thyroid gland has been reported (Saltykow gives 
the literature). The tumors just mentioned all show a great tendency toward 
the formation of metastases. In carcinoma, bone-metastases are especially 
frequent, especially in the bones of the skull and in the sternum; in sarcoma, 
metastases are frequently found in the lung. The metastases of adenocarci- 
noma of the thyroid gland contain not inappreciable amounts of iodine. Gierke 
reports two cases of carcinoma of the thyroid with metastases in the vertebral 
column. In the case of Ewald, the highly decomposed primary adenocarcinoma 
of the thyroid was iodine-free; the metastases in the lungs and lymph-glands 
contained iodine. The decision as to whether an adenoma of the thyroid is 
malignant or benign is often very difficult (v. Eiselberg). Microscopically 64 
THE DISEASES OF THE THYROID GLAND 
metastases may appear as gelatinous goiters, and yet the very presence of 
metastases may in itself be regarded as the sign of malignancy. Sometimes 
the metastases when examined microscopically show a formation similar to 
carcinoma. 
On account of their proximity to many important organs (trachea, esopha- 
gus, sympathetic, vagus, etc.), tumors of the thyroid not infrequently cause 
very manifold local manifestations, which will not be discussed further at this 
place. They may also give rise to alterations in the thyroid function. Symp- 
toms of deficiency [of secretion] are relatively rare, and it may then happen that 
the symptoms of myxedema retrogress when metastases develop (v. Eiselsberg) 
or when accessory thyroids begin to grow. This may even occur when the 
metastases have become degenerated carcinomatously. Indeed v. Eiselsberg 
found in the metastases in such a case follicles still filled with colloid. Not so 
very rarely malignant tumors of the thyroid gland give rise to the characteristics 
of Basedow’s disease. Sattler has collected sixteen such cases, of which eleven 
were carcinomata, and three sarcomata, while in two the character was not 
determinable. The Basedow’s symptoms may not appear until just at 
the time that the metastases develop (/. Lowy has collected the literature). 
We find therefore that malignantly altered thyroid gland tissue may not only 
affect the normal function, but, when proliferation is rapid, may even lead to 
hyperfunction. The interpretation of the symptoms of Basedow’s as hypo- 
thyrosis (Minnich) is not to be regarded as correct. 
Inflammations of the Thyroid Gland.—We distinguish between thyroiditis 
and strumitis. The first is very much rarer, as apparently the normal thyroid 
shows little tendency for inflammatory processes: This has also been determined 
experimentally on animals. In thyroiditis, too, as Jeanselme mentions, the 
termination in suppuration is much rarer. A light inflammation of the thyroid 
is very often an accessory phenomenon of acute infections {Roger and Gamier, 
Kashiwamura, de Quervain, Sarbach, and others). The histological alterations, 
which consist in epithelial desquamation and disappearance of the follicles, 
hyperemia, etc., may be not inappreciable after scarlet fever and variola, and 
also after other infectious diseases. Thyroiditis is not uncommon in the early 
stages of syphilis (according to Engel-Remiers in 56 per cent, of cases). Slight 
sclerotic processes are often present in tuberculosis and in severe alcoholism. 
Severe inflammatory processes in the thyroid have been observed after typhoid 
fever, variola, influenza, malaria, puerperal processes, etc.; especially, however, 
after angina and acute articular rheumatism. A detailed summary of the 
literature is that by de Quervain. The primary form of acute thyroiditis which 
does not go on to suppuration, was first described by Mygind and more recently 
by de Quervain in a very thorough report. The onset for the most part is 
sudden; with evident general symptoms and fever the thyroid gland becomes 
swollen, and there may be local symptoms of pressure. This is followed by 
severe pains radiating to the ear and throat; the climax of the clinical manifesta- 
tions is for the most part soon reached, and quickly, or more or less slowly 
(lytically), all phenomena subside. The histologic picture of the thyroid gland 
is in many respects similar to that of the Basedow thyroid. Nothing is known basedow’s disease 
65 
as yet as to the causative agent. De Quervain recommends as treatment quinine 
and salicylic acid; we must operate only when distinct fluctuation is present. 
Not infrequently the inflammations of the thyroid gland lead to pro- 
nounced disturbances of its function. In a case of Reinhold’s symptoms of 
Basedow’s appeared after influenza, and in a case of Gilbert and Gastaigne’s in 
the convalescence of typhoid fever. Worth mentioning is a case of de Quervain’s 
with recurring articular rheumatism and associated symptoms of a slight 
thyroiditis and a Basedow’s. Apelt reports a case of suppurative inflammation 
of a goiter of the tongue; after three days a thyroiditis made its appearance: 
This gave rise to a Basedow’s which later disappeared almost entirely. Also the 
clinical primary forms maybe associated with similar manifestations. In a case 
of Breuers a typical Basedow’s developed immediately after an acute thyroidi- 
tis. As Mobius has already pointed out, we cannot deny for these observations 
a certain significance in the pathogenesis of Basedow’s disease. 
Chronic inflammatory sclerosing processes commonly lead to myxedema1 
(see later). 
I may not leave unmentioned that administration of iodine serves to 
increase the acute thyroiditis (Dunger). In the case of Himmelheber the 
thyroiditis appeared immediately after a gynecologic operation; Himmelheber 
ascribed to the iodine absorbed from the iodine catgut; after high fever, tachy- 
cardia, acute cardiac dilatation, and delirium, the thyroid swelling rapidly 
disappeared. 
The second group of diseases, those in which the internal secretory activity 
of the thyroid gland stands in the foreground, may be divided into diseases 
associated with increase of function and those with diminution or lack of func- 
tion. I begin with the first, as they are better adapted to give an idea of the 
normal function of the thyroid gland. 
a. Morbus Basedowi [Basedow’s Disease]—Hyperthyrosis 
Synonyms.—Graves’ disease, Morbo di Flajani (Flajani’s disease), goitre exophthal- 
mique [exophthalmic goiter], [Parry’s disease]. 
Historical.—In the year 1840, v. Basedow first thoroughly described three 
cases of the disease named after him. Of his precursors, we especially mention, 
Graves, who in 1835 described cases of the disease and brought it into close 
relationship with hysteria. Since v. Basedow’s time, the views as to this disease 
have undergone great changes. The French school regarded it as a neurosis; 
then Mobius first in 1886 assumed as the cause, an abnormally increased activity 
of the thyroid gland and pointed out the opposition that exists between this 
disease and myxedema. 
Definition.—By Basedow’s disease we understand to-day a disease which is 
brought about principally by the abnormally increased activity of the thyroid gland. 
1 “That infection of the thyroid can stimulate the gland to hyperfunction is indicated by a 
moderate degree of hyperthyroidism early in the history of patients having diffuse thyroiditis ulti- 
mately resulting in myxedema.”—Plummer (H.S.) Interrelationship of function of thyroid 
gland, and of its active agent, thyroxin, in the tissues of the body. J. Am. M. Ass., Vol. LXXVII, 
July 23, 1921, pp. 243-247.—Editor. 66 
THE DISEASES OF THE THYROID GLAND 
This is almost always accompanied by an enlargement and increased vascular 
engorgement of the thyroid gland and leads eventually, through the local symp- 
toms conditioned by the enlargement, to a great number of very manifold mani- 
festations, of which especially the tachycardia, the well-known eye symptoms, the 
tremor, and the increase in metabolic processes are the most important. Most of 
the manifestations are to be explained by a heightened condition of excitement of 
the vegetative nerves. Regular and very manifold is the involvement of other 
glands of internal secretions, which for the most part is secondary. The syn- 
drome that results depends therefore not upon the degree of hyp erfunction, but 
on the constitution of the individual affected, that is, on the reaction capability of 
the ductless glandular apparatus. The cause of hyperthyrosis is not at present 
known. The possibility exists that it is conditioned centrally, and that many 
symptoms of Basedow’s are coordinate with the hyperthyroidism. 
Occurrence.—Basedow’s disease is rather irregularly distributed. A 
careful collection as to its occurrence has been made by Sattler. Most of the 
investigations concerned with this subject, founded in part on a very great 
observation material, agree that the classic form of Basedow’s disease is rela- 
tively of rare occurrence in regions where goiter is endemic. I mention only 
the contributions of H. Bircher, Fr. Kraus, and W. Scholz. In Germany, for 
example, typical cases of Basedow’s disease are very much commoner in the 
northern parts; they seem to be especially numerous in the Russian Baltic 
provinces (Kroug). It is very much more common in the female sex than in the 
male. In Sattler’s compilation 3120 of the 3800 cases were females. It is not 
very common in childhood (according to Sattler, out of 3477 cases only 184 were 
in children under fifteen years of age). Basedow’s disease in sucklings appears 
to be very rare. Clifford White has reported a case. The mother of the child 
had also previously given birth to a child affected with symptoms of Basedow’s. 
In the case described there were present exophthalmus and a struma, which 
microscopically gave a picture very similar to that of a typical Basedow’s 
struma. Familial occurrence of Basedow’s disease is not at all uncommon. 
E. Frey reports a family of five persons, of whom four suffered with Basedow’s 
disease. Osterreich reports likewise a family in which ten members were affected 
with Basedow’s disease. In the familial type we find not rarely many mitigated 
hyperthyroses or hypothyroses. In addition occur neuroses of the vegetative 
nervous system, diabetes mellitus, and even psychoses. Grober publishes the 
family tree of such a family. 
Finally it should be stated that the disease is met with in animals (dogs, 
cows, horses), in isolated cases. 
Symptomatology.—The pathologic alteration may develop in a previously 
normal thyroid gland or in a thyroid gland degenerated into a goiter. The 
thyroid gland increases in volume, becomes soft and elastic, through dilatation 
of the blood-vessels, and becomes very vascular through new formation of 
blood-vessels; under circumstances it shows expansive pulsations and frequently 
also variations in volume, paralleling the phenomena of Basedow’s disease; in 
many cases the apparently not enlarged thyroid may become palpable through 
voluntarily induced increase of the intrathoracic pressure (Fr. Kraus). In acute basedow’s disease 
67 
cases the swelling of the thyroid may appear over night and even lead to diffi- 
culty in breathing. It can subside just as suddenly (Trousseau, Mobius, et al.). 
On the application of a stethoscope to the gland, we can for the most part 
hear vascular murmurs synchronous with the heart action (Guttmann). 
The hand laid on the gland feels a distinct thrill; we can diminish the size of the 
gland by pressure. The enlargement of the gland is a very common symptom, 
yet there certainly do occur cases with distinct manifestation of hyperthyrosis, 
in which the enlargement of the thyroid gland is barely demonstrable. With 
longer duration of the disease, the consistence of the gland becomes firmer. 
The microscopical examination shows, in addition to increased vasculariza- 
tion, rich new formation of epithelial plugs and of glandular acini which later 
are often well filled with desquamated cells; in addition there are accumula- 
tions of lymphoid cells (Gibson, Greenfeldt, F. Muller, Lubarsch, et al.). Other 
authors (.Farner, and others) find less typical alterations, although Askanazy 
points out correctly that the aberrant findings come from goiter districts; it 
may therefore be assumed that in these cases the alterations of Basedow’s 
have developed in thyroids that are already degenerated. Kocher designates 
the typical Basedow struma as a struma hyperplastica parenchymatosa telangi- 
ectodes; it ordinarily contains no colloid, and for the most part is poor in iodine. 
Among the cardiovascular symptoms, tachycardia stands in the foreground 
For the most part there exists in addition an especial lability of the pulse. It 
may happen that on complete rest the pulse rate is only slightly above the 
normal, while slight psychic emotions or physical movements send it up unusu- 
ally high. Moreover, there exist increased strength of the heart action and 
cadiac palpitation. The patients feel the heart beat “ up to the throat.” The 
cardiac impulse is then increased and broadened, and the thoracic wall is 
strongly agitated. Very often broadening of the cardiac dullness occurs, 
depending more commonly on cardiac dilatation than on hypertrophy. Fre- 
quently there are accidental systolic murmurs. All manifestations on the 
part of the heart show great variations that parallel the remainder of the mani- 
festations of the course of the disease. In the fully developed form of the disease 
the arteries of the gland often pulsate very strongly, a phenomenon that gives 
these cases their own characteristic feature. Especial cases may even go as far 
as a penetrating venous pulse in the thyroid gland or to a pulsatory shaking of 
the head (Musset’s sign) or to choroid pulse (Becker). Also there have been 
observed marked beating of the abdominal aorta, hepatic pulsation, and splenic 
pulsation (C. Gerhardt). In opposition to increased heart action and the stormy 
pulsation in the neck, the radial pulse is often small and weak and the blood- 
pressure not raised or even slightly diminished (SpiethojJ, Donath). Height- 
ening of the blood-pressure is relatively rare. There occurs then an abnormal 
fall from center to periphery (Fr. Kraus) which is explainable by the abnormal 
laxity of the tonus in the peripheral vessels. Even the earlier observers 
{Graves, Stokes, Hirsch, Trousseau, et al) noticed this opposition between the 
increased cardiac activity as evidenced on the part of the heart and the vessels 
of the neck, and the relatively slight filling of the peripheral vessels. To the 
slight tonus of the peripheral vessels testify also the often observable reddening 68 
THE DISEASES OF THE THYROID GLAND 
of the face, the ears, the tips of the fingers and the nail matrices (A. Kocher). 
[.Hamilton1 has found that the great majority of hearts in cases of hyperthyroid- 
ism show no evidence of damage. Heart failure is not found here even when 
death occurs. Cases of auricular fibrillation without true signs of heart failure 
have stood operation well. All auricular fibrillation with hypertrophy can be 
improved by digitalization. Hashimoto, however, in experimental work has 
found myocardial changes. See addendum—Editor.] 
So much for clinical observation. Experimental investigations on the 
action of the thyroid gland secretion upon the cardiovascular apparatus are 
very numerous, but an agreement among them has not as yet been obtained. 
Oliver and Schafer, Fenyvessy, Haskovec, and others found after intravenous 
administration of juice of thyroid gland sinking of the blood-pressure and 
slowing of the pulse. Other observers found no action, or acceleration of the 
pulse-rate. The different species of animals behave differently, v. Cyon 
found that on the cat iodothyrin acted tonus-increasing on the vagus and the 
depressor, v. Cyon and Oswald found the same true of iodthyroglobulin, while 
iodine-free thyroglobulin is inactive. The increase of excitability of the depres- 
sor nerve was also found by Asher and Flack, v. Ficrth and Schwarz consider 
the depressor action of the extract not specific for the thyroid gland, but attri- 
bute it to the cholin contained in the extract. The differences in the results are 
to be explained by the fact that on the intravenous administration of thyroid 
gland, substances that influence the cardiovascular apparatus are also intro- 
duced that have nothing to do with the thyroid. According to the investiga- 
tions of Falta, Newburgh, and Nobel, the feeding of thyroid gland produced in 
most cases an increase in the fall of blood-pressure from center to periphery, 
such as one observes in Basedow’s disease. Tachycardia is present, the brachial 
blood-pressure remains the same (blood-pressure measurement according to 
Rocci) and fall of the blood-pressure in the periphery (blood-pressure measure- 
ment according to Gartner).2 On the administration of large doses of thyroidin 
there results a significant fall in the blood-pressure (Pilez). By the heightening 
of the fall the velocity of the circulation is increased, which best corresponds to 
the increased oxygen requirement. 
The tachycardia is a result of the irritation of the accelerator, and the 
slight tonus of the peripheral vessels is a result of irritation of the vasodilator; 
the dilation of the thyroid-gland vessels is the result of the irritation of the 
depressor nerve, for irritation of the root of the depressor nerve calls forth an 
increase on the blood-pressure in the thyroid (v. Cyon). Also Asher and Flack 
found that the excitability of the depressor nerve is increased by the internal 
secretion of the thyroid gland. The increase of the blood stream favors the 
increased output of secretion and thus a circulus vitosus is established. Per- 
haps also a secondary increase of the activity of the chromaffin tissue or a 
greater sensitivity to adrenalin or the part of the organs supplied by the sympa- 
1 Hamilton (B. E.). Clinical notes on hearts in hyperthyroidism. Boston M. and S. J., Vol. 
CLXXXV, Feb. 16, 1922, pp. 216-218. 
2 An exception to this is shown only by diabetics, who show an increase in blood-pressure (see 
chapter on pancreas). basedow’s disease 
69 
thetic nerves is associated with the cardiovascular symptoms (tachycardia). 
The facts are that on the simultaneous administration of thyroid-gland secretion 
and adrenalin action pulses may also be produced in animals (Kraus and 
Friedenthal); this v. Cyon attributes to a simultaneous irritation of the vagus 
and sympathetic, and to the fact that, according to Asher and Flack, the thyroid- 
gland secretion may increase the activity of adrenalin. 
The eye symptoms may be expressed in different degrees of intensity. 
Often there is only a slightly heightened glitter of the eye, the alterations 
Fig. 5.—Basedow struma. 
showing only on very exact examination; in other cases occur those striking 
alterations that Mobius compares with those of the facial expression of intensest 
terror. 
As an example I shall quote the following case: 
Observation I.—Anna K., twenty-six years old. For about two months cardiac pal- 
pitations, conditions of excitement, pains in the cardiac region, sweats, tremor, and en- 
largement of the neck. 
The increased width of the palpebral fissures is evident. Protrusion slight, rare blink- 
ing, thyroid diffusely enlarged, weakly elastic vascular murmurs, tachycardia up to 361 
[sic.],1 blood pressure (Riva-Rocca) 100. Increase of temperature up to 37.7° C., alimentary 
glycosuria negative. 
In many cases the development of the eye symptoms comes about very 
gradually. In other cases, the terrifying alterations may develop in a few 
days, indeed over night. We should distinguish between protrusion and 
1 361 in the German edition—-probably an error for 136.—Editor. 70 
THE DISEASES OF THE THYROID GLAND 
widening of the palpebral fissures. In fully developed cases both symptoms 
are for the most part really present together. The protrusion of the eye-balls is 
well seen in the accompanying illustration. 
Observation II.—K. I., fifty years old, the morbus Basedowi has lasted about ten years, 
tachycardia, sweats, formerly profuse diarrhea, tremor, formerly marked emaciation, and 
high-grade nervousness; lately condition better, for years [before this] a stationary condition. 
The protrusion of the eye-balls is explained by most authors by an increased 
fullness of the orbital vessels. The rapid variations in the intensity that the 
protrusion of the eye-ball shows in many patients have led to this assumption. 
The essential cause is, however, an abnormal tonus of the Landstrom musculus 
palpebralis, innervated by the sympathetic. The protrusion may be produced 
Fig. 6.—Gaping of the palpebral fissures in Basedow’s disease. 
experimentally by electric stimulation of the cervical sympathetic (Claude 
Bernard). The protrusion may be of such a high grade that the globe becomes 
displaced. In old Basedow’s cases the protrusion remains stationary, which 
may be explained by increased deposition of retrobulbar fatty tissue. The 
gaping of the palpebral fissure (Dalrymple-Stellwag’s sign) on increased opening 
tension of the eye (L. Bruns) is dependent on an abnormal tonus of the oculo- 
motor nerve and is, therefore, according to Eppinger and Hess, to be regarded 
as a sign of autonomous irritation. 
The exophthalmus may also be unilateral. A confusion with unilateral 
affection of the sympathetic may be avoided by attention to the width of the 
pupils; the latter should show no differences in Basedow’s disease; Roasenda 
has described three Basedow’s cases with unilateral eye symptoms, and in one 
of these cases this symptom always remained limited to the one side. The 
unilateral exophthalmus sometimes accompanies unilateral enlargement of the 
thyroid gland, either homolateral or contralateral. Worms and Hamant have basedow’s disease 
71 
issued a compilation of such cases. [Falta1 himself has recently reported a 
case—Editor.] 
v. Grdfes symptoms, i.e., the failure of the upper lid to follow, or only 
retarded following the upper lid when the vision is turned slowly downward, the 
white sclera thus becoming visible at the upper border of the cornea, depends 
on an increased tonus of the levator palpebrae muscle, v. Stellwag’s symptom 
Fig. 7.—Protrusion of the eye-balls in Basedow’s disease. 
consists in a rarity and an incompleteness of the involuntary blinking. Whereas 
in the normal individual the blinking movement occurs three to five times 
in the minute, in Basedow’s disease it may not occur for minutes. 
The eye symptoms are very hard to reproduce experimentally, a fact that 
for a long time stood in the way of the hypothesis that Basedow’s disease was a 
1 Falla (W.). Morbus Basedowi mit einseitigem Exophthalmus. Klin.-therap. Wehnschr., 
Vol. XXVI, 1919, p. 295 or Ein Fall von Morbus Basedowi mit einseitigem Exophthalmus. Wien, 
klin. Rundschau. Vol. XXXIII, 1919, p. 90. 72 
THE DISEASES OF THE THYROID GLAND 
hyperthyrosis; however, Kraus and Friedenthal and Honicke were finally 
successful, through the administration of very large amounts of thyroidin in 
inducing a widening of the palpebral fissures and an exophthalmus, although not 
to a very marked degree. Recently through the use of material obtained by the 
removal of struma at operation on human beings it was possible to induce 
typical exophthalmus in a dog (Larnpe, Liesegang, and Klose, and Baruch). 
Worthy of mention here is also the case of Nothafft, in which an evident protru- 
sion developed after an excessive use of thyroid-gland tablets. 
Finally, Mobius’s symptom consists in a weakness of convergence; by 
fixation of the finger held near-by, the eye deviates without diplopia; perhaps 
this not common symptom is to be explained by a fatty degeneration of the 
Fig. 8.—Absence of the eye symptoms in Basedow’s disease. 
eye-muscles which is observed in severe cases of Basedow’s disease. Also 
pareses and paralyses of the eye-muscles have been observed. Kappis de- 
scribes a case in which the beginning of the illness occurred eleven years previ- 
ously; with gradual increase in all symptoms there developed an extensive 
paralysis of the eye-muscles and other cranial nerves. Kappis has collected 
forty cases of eye-muscle paralysis in morbus Basedowi. 
Sometimes there occurs in Basedow’s disease an excess of tears {Berger); 
sometimes, however, an abnormal dryness of the eye. In high-grade protrusion 
the cornea may ulcerate and erode, the lens may fall out, and the panophthalmia 
that develops may lead to death. Patients with Basedow’s disease bear cata- 
ract operation badly (Mobius). In rare cases there is observed atrophy of the 
optic nerves (also obtained experimentally through administration of thyroid 
gland, Birch-Hirschfeld and Nonmbuo Ynvuye); finally, mydriasis sometimes basedow’s disease 
73 
occurs on instillation of adrenalin (O. Lowi). The adrenalin mydriasis is also 
found in experimental hyperthyroidism (Eppinger, Falta, and Rudinger). 
[The subject of the eye changes in hyperthyroidism is touched on by 
Fridenberg1 and by Zentmyer,2 and in the discussion on their papers in a 
recent publication; by Zentmyer is mentioned Riesman’s eye-sign which is 
a bruit heard over the eye in exophthalmic goiter. As pointed out by Zentmyer 
this may not really be a vascular bruit., but may be a sound due to the activity 
of the orbicularis muscle. Suker’s “deficient complementary fixation in 
lateral eye-rotation” is also pointed out as an eye-sign of hyperthyroidism. 
We may add that in connection with the endocrines in eye and nose and throat 
conditions, when these conditions are studied alone, and apart from the general 
constitution of the patient, there may be too much rather than too little of 
“projective imagination,” a term used in the discussion ot these articles. 
Cooperation on the part of the specialist and of the internist is what is needed 
for the proper study and interpretation of these pictures. Now should the 
experimentalist and the clinical laboratory man be unconsidered as agents in 
the cooperative policy. One who speculates in medical theories has here a 
role, of course, in the interpretation of conditions affecting individual body 
organs, but to my mind, rather a minor role. Zentmyer himself states the case 
very well thus: “A note of warning has been sounded against the tendency on 
the part of enthusiasts to link up the endocrine organs with the etiology of 
obscure diseases. No doubt this adverse criticism is justified. Nevertheless 
only good can result at this time from calling attention to suggestive symptoms 
which have been noted in some eye conditions, the etiology of which up to the 
present has been in doubt.”—Editor.] 
The eye symptoms belong to the classic form of the disease. In the formes 
frustes they may be absent or only suggested. In the following briefly sketched 
case they were wanting altogether; 
Observation III.—S. Schm., fifty-six years, shoemaker. For about thirty years diffuse 
enlargement of the thyroid, circumference of the neck 42 cm. Until six months ago, perfectly 
healthy. Then occurred gradual increase in the size of the neck to 43 cm. and then to 44 
cm. Lassitude, sweatings, difficulty in breathing. His physician ordered for him an iodine 
cure, which rapidly made matters worse. Severe dyspnea, cardiac palpitations, marked 
tremor, profuse sweats, and profuse watery diarrheas, the bowels moving ten to twelve times 
daily, loss of weight about 18 kg. 
Markedly emaciated, skin moist, eye symptoms not present. Both lobes of the thyroid 
very much enlarged, the left somewhat larger, pulsation, vascular murmurs weak. Perithy- 
roidal lymph-glands palpable. Cardiac shadows widened to 13 cm. as seen on X-ray exami- 
nation, shadows of the aorta increased to 6 cm., tachycardia (110-130), leucocytes 8500. of 
which only 33.3 per cent, are neutrophiles. Slight tremor, sweats (Fig. 8). 
Of the alterations in the respiratory organs should be mentioned first 
soundlessness of the voice {Trousseau), sensation of scratching in the throat, 
and tormenting, irritating cough (Nothafft). The irritating cough was first 
described by Pierre Marie; he found it in twelve of fifteen cases. This symptom 
1 Fridenberg (P.) The endocrine system: Some relation to ophthalmology and otolaryngology 
The Pennsylvania M. J. Vol. XXV. No 8. May 1922; pp. 523-527. 
2 Zentmyer (IF.). The etiological relations of the eye to endocrine disease. Ibid., pp. 527-529. 74 
THE DISEASES OF THE THYROID GLAND 
may be very tormenting and may start in as an early symptom. It is accom- 
panied by little or no expectoration. Murray, however, observed some cases 
in which there existed a profuse expectoration, a veritable bronchorrhea, which 
he brings into analogy with the profuse watery diarrheas of the patients (parox- 
ysmal condition of excitement of the autonomous nerves). Further we should 
mention the increase in the frequency of respiration, the superficial breathing, 
and the air hunger, symptoms which occur paroxysmally even as early symp- 
toms, but which often last for a long time. These symptoms are closely allied 
with the increased need for oxygen, that is, with the need for rapid loss of heat 
on account of the increased heat production. Bryson’s sign—the patients are 
not able to expand the chest in the normal manner on deep inspiration of the 
thorax—has nothing to do with this, but depends apparently on a weakened 
condition of the respiratory muscles as a result of the fatty degeneration that 
was found by Askanazy in all the bodily musculature. The acceleration and 
becoming shallower of the respiration was also produced experimentally by 
Fenyvessy by the feeding of the thyroid gland substance to dogs. It was absent 
after cutting of the vagus nerves. The graphic registration of this breathing 
in Basedow’s disease shows very clearly the shallowing of the respiratory 
efforts and the periodic cessation of respiration (increased tonus of the vagus, 
Hofbauer). Eppinger and Hess have observed these respiratory curves, espe- 
cially in those Basedow patients who showed signs of increased tonus in other 
autonomous nerves. 
[The subject of the role of the endocrines in otolaryngology has been 
dealt with by Fridenberg} by Schatz} and by Wieder.3 Schatz’s article seems 
to be a careful compilation. Wieder evidently has adapted a view, lately in 
fashion, held I believe by Keith, that “people and even races, come under 
some predominating eudocrine influence which helps to mould their features, 
characteristics and temperaments.” (The same theory has been carried over 
recently to apply to mental phenomena in Berman’s “The Glands Under- 
lying Personality.”) That races come under the influence of some endocrine 
gland or another is at present highly speculative. Wieder quotes Browning 
that stammering is due to enlargement of the thymus gland. This too seems 
to me to be extremely difficult to prove. Perhaps from the standpoint of 
the laryngologist there are such things as hyperpituitary types and we know 
that in myxedema the nose and throat show changes, but it should be remem- 
bered that in the various specialties it is not safe to theorize about constitu- 
tions, without a thorough study of the various systems of the individual.—- 
See remarks under eye conditions in hyperthyroidism, p. 73.—Editor.] 
To the nervous symptoms belong almost all the symptoms of Basedow’s, 
as they are for the most part the expression of the condition of irritation 
of the vegetative nervous system. Of the nervous symptoms in the narrower 
sense is especially to be mentioned the tremor of the separated fingers, which 
1 Fridenberg (P.). The endocrine system—some relations to ophthalmology and otolaryngology, 
Pennsylvania M. J., Vol. XXV, No. 8, June, 1922, pp. 523-529. 
2 Schatz (Id.). The role of the thyroid gland in otolarnygology. Ibid., pp. 529-538. 
3 Wieder (H. S.). The endocrines and the nose and throat. The Laryngoscope; April, 1922, 
<8 pages). basedow’s disease 
75 
was first observed in 1862 by Charcot and was later described by Marie in a 
monograph as the principal and initial symptom of Basedow’s disease. Nolh- 
nagel has especially pointed out that the tremor is very fine. The observa- 
tions of A. Kocher give an idea as to the frequency [of occurrence] of the tremor. 
Kocher found it clearly manifested in sixty cases out of sixty-three. Slight 
psychic emotions can make the tremor more evident. Intended movements 
do not ordinarily increase it. Fine coordinated movements may, however, 
be disturbed or made impossible on account of strong tremor. Very strong 
tremor may also assume a choreic character. In iully developed cases the 
patients are often in an “etat de vibration perpetuelle.” The tremor may also 
affect the tongue, eyelids, lips, the lower extremities, diaphragm, and respira- 
tory muscles; the number of vibrations reaching about 8 to 9.5 in the second, 
as many as in progressive paralysis and alcoholism; whereas in senile tremor and 
paralysis agitans the number is less. The tremor may be readily reproduced 
experimentally by the feeding of thyroid gland. 
An exactly similar tremor is seen sometimes transitorily in hysteria and 
neurasthenia, as the graphic registration has shown. 
A further symptom is muscular weakness, even paraparesis of the legs 
has been observed (giving away of the legs). Stern regards this as hysterical. 
Also transitory monoplegias and hemiplegias have been observed. Not 
rarely occur drawing pains in the entire body, or only in the arms or legs, 
or in the shoulders, and especially in the neck. Kocher found them in a great 
number of his cases. Mobius does not believe that they are in direct con- 
nection with hyperthyrosis. That there is, however, such a connection 
is made certain by the investigations of Falta, Newburgh, and Nobel, who 
obtained the pains in numerous cases after the administration of thyroid 
gland substance. The same is also true of the headache which is very common 
in Basedow’s disease; indeed it may be the initial symptom and is very common 
in artificial thyroidism. Also the insomnia of the Basedow patient may 
occur as the initial symptom; in many cases it occurs for weeks, varying 
[in intensity], and may reduce the patient very much. 
Almost always occur alterations in the mental life, abnormal irritability, 
unmotivated gaiety, hasty speech, rapid flow of thoughts, an indication of 
flight of ideas, rapid change of mood, terrifying dreams; the character alters, 
the patient becomes mistrustful, choleric, capricious, strikingly euphoric, or 
often very much depressed. Mobius happily compares this condition with a 
very slight “Rausch” in which a maniacal mood may readily occur, and in 
which a conversion into depression may readily follow. Attacks of laughing 
and crying may occur, and combination with hysteria is not rare. Some- 
times the condition terminates in delirium, confusion with hallucination, and 
coma. 
The transition of these mental alterations into a true psychosis is not 
rare. Often it is the maniacal conditions, often the depressions, that pre- 
vail. Also the picture of melancholia may develop. According to Saltier, 
out of one hundred and fifty cases in literature, more than seventy belong 
to manic-depressive insanity. For the comprehension of these alterations in 76 
THE DISEASES OF THE THYROID GLAND 
the psychic life the observation is important that in individual cases similar 
conditions may occur after the administration of thyroid-gland tablets. Con- 
ditions of excitement are not uncommon in thyroidism. Cases of thyroidin 
intoxication insanity have also been observed (Boinet, Parhan and Marbe), 
The authors last mentioned observed two cases, in whom after the inges- 
tion of great amounts of tablets there set in complete confusion and hal- 
lucination. The manifestations disappeared with the withdrawal of the 
administration of thyroid. The following case (Falta, Newburgh, and 
Nobel) is instructive: 
Observation IV.—Woman, aged fifty, who for a half a year had suffered loss of weight 
headaches, insomnia, associated with psychic depression and thoughts of suicide. There 
was also present glycosuria. The condition gradually ameliorated and after some weeks’ 
stay at the clinic the patient felt very well. Then the patient took thyroid tablets for 
three days, upon which the psychic depression and thoughts of suicide recurred. On 
the withdrawal of the drug these disappeared. 
Already Brunet mentioned that Basedow’s disease is not associated with 
any special psychosis; when a true psychosis occurs in it, we may well assume 
that a psychopathic predisposition already existed and that the hyperthy- 
rosis constituted the determining factor. [Weinberg1 has recently called atten- 
tion to the fact that hyperthyroid patients sometimes show mental symptoms 
as an early sign of their hyperthyroidism. A sense of unreality, a dazed 
condition, heightened nervous irritability and vague persecutory delusions 
may, according to Weinberg, be experienced by these patients, and these psychic 
conditions become more marked as the disease progresses. According to 
Weinberg, these conditions may become marked enough to simulate the various 
types of psychoses. Weinberg’s statements are suggestive in that early 
mental changes of any sort may suggest that basal metabolism studies be made. 
Unless the metabolic rate be high, however, the editor cannot see that the diag- 
nosis of hyperthyroidism is justified in the absence of the other signs of the 
disease. Brunet’s views as stated by Falta seem sound.—Editor.] 
Of the symptoms affecting the digestive tract we shall mention first 
increased flow of saliva. This symptom often occurs paroxysmally, and even 
initially; more rarely there is a dryness of the mouth. When the flow of 
saliva is increased, there is an increased tonus of the nerves of the salivary 
glands; when the flow is diminished there is an increased tonus of the sympa- 
thetic nerves of the salivary glands (formation of a thickly flowing secretion) 
or irritation of the sympathetic nerves of the salivary glands (Eckhardt); 
also the noticeably increased diuresis may exercise an influence here. The 
slight degree of acidity of the gastric juice, that is usually observed in rare 
cases of Basedow’s disease (Eppinger and Hess), points also toward an increased 
gastric tonus. Sometimes crises of hyperacidity are observed (Mar- 
anon). Ordinarily, however, subacidity is present (Wolpe). Especially 
important symptoms are vomiting and diarrhea (Pierre Marie), because they 
greatly reduce the patient. Vomiting is found, according to Sattler, in 15 
1 Weinberg (M. H.). The mental side of hyperthyroidism [with discussion]. Pennsylvania 
M. J., Vol. XXV, No. 9, June, 1922, pp. 618-624. basedow’s disease 
77 
per cent, of all cases. Ordinarily it occurs paroxysmally, for the most part 
without any relation to ingestion of food, often without any nausea. When 
there has been no ingestion of food it is usually thin; the paroxysm may last 
for a whole day, in which case the vomiting may occur thirty times during 
the day and be uncontrollable. For the most part it is unaffected by medi- 
cation; it may disappear as rapidly as it came, and may be followed by a 
period of increased ingestion of food. More common are the profuse watery 
diarrheas (according to Sattler in 30 per cent, of all cases). For the most 
part they are painless. Twenty to thirty stools a day may occur. They 
may lead to scaphoidal retraction of the abdomen as in cholera (Fr. v. Muller). 
The diarrheas are hardly influenced by medication. In rarer cases, 
admixture with blood may be observed. Vomiting and diarrhea may 
also be produced in animal experimentation by feeding with or injection 
of thyroid gland substance. In human beings, administration of thyroid 
gland tablets continued over only a short period may suffice to produce action 
on the bowels. In two cases, Falta, Newburgh, and Nobel observed that 
on the third day of the thyroid medication the previously solid stools, that 
occurred only once a day, had now become soft and failed to show the impres- 
sions of the haustra, and that on the third day two soft stools occurred. 
On withdrawal of the medication, the stools again showed their former 
consistency. Kocher observed one case with obstinate constipation, in which 
simultaneously with the appearances of the rather acute development of 
Basedow’s, diarrheas developed. The statement of Kocher, that in none 
of the sixty-three cases of Basedow’s described by him did constipation 
exist, must not be generalized. I have seen several cases of formes frustes 
with constipation (see Observation V). Mobius regards the profuse diar- 
rhea of morbus Basedowi as the expression of the effort to cast out the thy- 
roid gland substance that is circulating in excess. From this standpoint 
it would not be uninteresting to test the stools as to their iodine contents. It 
is safe indeed to assume a marked increase in the secretion in the intestines. 
This and the paroxysmal occurrence confirms the assumption of Mobius. 
In the higher degrees, there is, in addition, apparently slight inflammatory 
swelling of the intestinal mucous membrane; at least we may observe this 
in experiments on animals in which, in the highest degrees of thyroidism, 
hemorrhages into the mucous membrane may occur. We may assume also 
an increased secretion of the pancreatic juice, in accordance with the experi- 
ments of Balint and Molndr; these authors found in the watery evacuations 
an abnormal quantity of tryptic and diastatic ferment. Whether we may 
regard the profuse diarrheas as an expression of vagotony, as Eppinger and 
Hess believe, appears to me questionable, for vagotony is inclined to be asso- 
ciated with spastic obstipation. 
We should sharply distinguish from these profuse diarrheas the dis- 
turbances of fat absorption that are sometimes found in morbus Basedowi. 
Adolph Schmidt and H. Salomon have described one case apiece. I have 
added seven cases, in which, as in Salomon’s case, the fat-splitting was rela- 
tively good, so that the disturbances lay especially in the absorption. In 78 
THE DISEASES OF THE THYROID GLAND 
the case very carefully investigated by me the dry substance contained 53 
per cent, fat, of which 24.7 per cent, was neutral fat, 44.2 per cent, soaps, 
and 31.1 per cent, fatty acids. Sometimes the fat stools are found only on 
the overloading of the intestines with fat (v. Noorden). Of late Bittorj has 
contributed a pertinent case. I here report two others: 
Observation V.—Ad. K, thirty-three years, locomotive stoker, entered the first medical 
clinic December, 1911. No hereditary taint, was always well until November, 1905. Then 
struck by a locomotive, fell on the left side, for three weeks hematuria and fever. At 
the beginning also unconsciousness, then severe headache, vertigo, nausea. Immediately 
after the accident began tremors, palpitation, anxiety, insomnia, and twitchings in the 
lower extremities. Eight days after the accident, the patient noticed an enlargement of the 
right lobe of the thyroid gland. Soon afterward marked pulsating in the vessels of the neck 
and oppressive feeling of heat, and burning of the skin of the throat and neck. This con- 
dition continued from this time on without essential alteration. The patient states that he 
has become peevish and irritable and afraid of people. His muscular strength has diminished, 
he tires easily, and often has drawing pains, also headaches, vertigo, and sometimes vomiting, 
also very heavy sweats. Ordinarily slight constipation, from time to time a period in which 
three or four broth-like evacuations of a gray color occur daily. 
Rather thin; the face especially, but also the skin of the throat and upper part of the 
breast a burning red. On disrobing and on excitement the redness increases. Pronounced 
dermographism. On stroking the skin with the handle of the percussion hammer there 
are elicited streaks the breadth of which is that of a finger. 
The right lobe of the thyroid is enlarged, about the size of an apple. Surface smooth, 
elastic, but not hard in consistence, evident pulsation, vascular murmurs. In the neigh- 
borhood, enlarged lymph-glands. Points of exit of the trigeminal nerves tender to pressure. 
Slight paralysis of the sympathetic on the right. All eye symptoms negative. To Rontgen 
examination slight widening of the shadow of the aorta to 6 cm., and of the heart to cm. 
Pulse 120-140. 
Blood pressure, according to Riva-Rocci, taken on the arm 140. On the left middle 
finger (Gartner) 85. 
Later measurements: 
Riva-Rocci, 130-120; 
Gartner, 70. 
After two weeks: 
Riva-Rocci, 120-110; 
Gartner, 55. 
Blood: Erythrocytes, 5,000,000. 
Leucocytes 9200, of which: 
Polynuclear neutrophiles, 55 per cent. 
Lymphocytes, 32 per cent. 
Large mononuclears, 14 per cent. 
Eosinophiles, 1 per cent. 
Several later blood examinations gave similar results. 
Alimentary glycosuria (100 gm. dextrose) 4.24 gm. of sugar. 
The stools frequently show the luster of fat and a gray color. After 250 gm. of oat- 
meal and 300 gm. butter, typical fat stools. The microscopical examination shows little 
neutral fat, but many soap balls and fat needles. 
Profuse sweats, in which the bedclothes are soaked through. On the soles of the 
feet exist pea- to bean-sized vesicles filled with serous fluid, which burst, and leave the 
cutis exposed. 
Marked tremor of the hands, intensified on movements. 
Examination of the basal metabolism {Dr. Bernstein). basedow’s disease 
79 
C02 
O2 
RQ 
Per kilogram body weight 
237.6 
289.O 
0.804 ] 
C02 
o2 
2 20.2 
293.O 
0.741 1 
3- 25 
4.17 
23O.I 
296.5 
o.776 j 
The basal metabolism is therefore somewhat increased. 
Result: Forme fruste of Basedow’s after trauma with all important symptoms (tachy- 
cardia, sweats, tremor, increase of the basal metabolism, mononucleosis) with exception 
of the eye symptoms. In addition, fat stools and alimentary glycosuria. 
Observation VI.—A. Schr., woman aged thirty-three years. First entered clinic Jan. 9, 
1913. Father was very nervous and easily excited. Menstruation, which began at the 
age of fourteen years, occurs regularly every four weeks, lasts four to eight days, not painful. 
Seven years ago, luetic infection, after which unilateral headache, for one year diplopia. 
Two children, that are very nervous, two miscarriages, the one before the infection, the 
other after it. For three months menstruation very sparse. 
The present illness began three months ago. At first insomnia and severe headaches, 
then marked palpitations. Dyspnea, profuse sweats, severe tremors in the hands and 
feet. Conditions of excitement, sometimes vomiting. During the last three months has 
lost about 10 kg., the throat is enlarged, for six weeks the eyes protrude. During the first 
week five to six stools daily, of normal consistence, but of a white-grayish color. 
Exophthalmus distinct, but not marked. Thyroid enlarged, diffusely, distinct tremor, 
marked tachycardia. 
Blood-pressure. Gartner, 95. Riva-Rocci, 135. 
Leucocytes 5500 (of which 5.5 per cent, polymorphonuclear neutrophiles and 1 per cent, 
eosinophiles). 
Alimentary glycosuria positive (with 100 gm. dextrose 0.57 gm., with 50 gm. dextrose 
2.4 per cent, with 30 gm. dextrose, negative). 
Overloading with fat at present does not lead to fat stools. No diarrhea now. 
The cases with fat stools all seem to show certain characteristics. Al- 
most always they are formes frustes with absent or slightly developed eye 
symptoms. In addition all cases up to the present have shown latent dis- 
turbances in the carbohydrate metabolism. In three cases, the disease 
developed after a trauma. For a close relationship between thyrogenic 
glycosuria and fat stools speaks also the observation that both disturbances 
retrogress simultaneously, either spontaneously or after therapeutic pro- 
cedures (exposure to Rontgen rays). It is not unlikely that both come about 
through an inhibition of the internal secretory activity of the pancreas. At 
least there must also be assumed a direct action of the excessively produced 
thyroid-gland secretion on the intestinal mucous membrane, for in diabetes 
mellitus the absorption capacity of fat is perfectly normal. I do not speak 
here of the fat stools in cases of diabetes mellitus with closure of the pan- 
creatic ducts, as in these it is known that the disturbance in the splitting 
of neutral fat is prominent. The observations of Balint and Molndr, that 
I have already mentioned, do not speak, as these authors believe, against 
my assumption, for they are dealing with watery diarrheas that have nothing 
to do with fat stools and that mostly occur in the other forms of Basedow’s 
disease. Up to the present I have seen only one case with fat stools in which 
formerly profuse diarrheas had existed. 80 
THE DISEASES OF THE THYROID GLAND 
The examination of the blood in Basedow’s disease usually gives normal 
figures for the red blood cells and the hemoglobin. In cases where a diminu- 
tion is present, the iron-content is, according to the investigations of Rossin 
and Jellinek, very much reduced. The coagulation capacity of the blood 
is in the most cases delayed. Kottmann and A. Lidsky found in thirty-seven 
cases this delay in 78.3 per cent., a normal coagulation time in 5.4 per cent., 
and an acceleration in 16.2 per cent. In the cases in which it was delayed, 
it approximated normal figures after operation [on the thyroid gland]. The 
delay also exists in experimental hyperthyroidism (Kostlivy). These facts 
explain why in operations on Basedow’s patient the control of hemorrhage 
is often difficult. According to Kottmann the serum of Basedow’s patients 
works in a retarding way on autolysis; also the freezing-point lies lower than 
under normal conditions. Fr. Kraus and Friedenthal found that the blood- 
serum of Basedow’s patients acts in a mydriatic manner. A. Frdnkel found 
an increased action on the wave-motions of the rabbit-uterus after the death 
of the animal. These findings do not point absolutely to an existing adrenalin- 
emia (O’Connor, Falta, Fleming). Therefore the far-reaching conclusions that 
Kostlivy has drawn from these findings, as to the sympathicotonizing components 
of the secretion of the thyroid gland, are purely hypothetical. Of greater 
importance is the alteration in the leucocyte formula first described by Th. 
Kocher. There exists at first a light leucopenia and almost regularly, even 
in the early stages, mononucleosis. The statements of Kocher have been 
confirmed by numerous investigations (Caro, Ciuffini, Gordon and v. Jagic, 
R.oth, Buhler, Kappis, VanLier, Kostlivy, Turin and others). The mononucleo- 
sis is also found in the formes frustes; but it is also common in struma without 
Basedow’s symptoms (Muller, Ch. Kappis, van Lier, and others). Cases 
of Basedow’s with absent mononucleosis seems to belong to the great exceptions 
(Kostlivy, Roth, Bor char dt, the author). 
Observation VII.—C. A., twenty-one years old, student. For about six weeks rapid 
enlargement of the thyroid gland. Former circumference of the throat 39 cm., now 42 
cm. Tachycardia, labile pulse, sweats, tremor, stools formerly sluggish, sluggish also at 
present. Diffuse enlargement of the thyroid gland, consistence weak, pulsation of the 
carotid. No eye symptoms. Apex-beat broadened and increased. In the urine traces 
of sugar, after overloading (2 rolls, four pieces of sugar), 2 per cent. 
Blood examination: 
Leucocytes, 7000 of which: 
Neutrophiles, 68.6 per cent. 
Lymphocytes, 25.3 per cent. 
Mononuclears, 4.6 per cent. 
Eosinophiles, 1.5 per cent. 
After several months, essential improvement in all manifestations, high tolerance for 
carbohydrates. 
It seems to me, however, that great caution is necessary in regarding the 
blood picture in cases of Basedow’s as normal, as the alterations of the blood 
picture, like those of the other symptoms of Basedow’s undergo great changes. 
The following is a case in point: 
Observation VIII.—FI. R., woman, thirty-five years of age. First came under observa- 
tion Dec. 12, 1912. Apparently no hereditary nervous predisposition. Menses first ap- basedow’s disease 
81 
peared in the eleventh year of life, flow abundant, regular, lasts for three days every four 
weeks. Five normal births. Three years ago a miscarriage at the second month. Since 
that time, development of Basedow’s disease. Since that time, too, menses are accompanied 
with severe pain, especially backache. The flow is less in amount. When the exophthal- 
mus first developed, her face took on a terrified appearance, which her acquaintances observed; 
she felt very well otherwise, and the ophthalmologist made the diagnosis, Basedow’s disease. 
Only several months afterward began to develop watery diarrheas, cardiac palpitations, 
dyspnea, nose-bleeds, headaches, rheumatoid pains in the extremities, lassitude, sensation 
of dizziness, and extraordinary psychic irritability; the condition gradually became worse 
with a transitory period of amelioration during the summer before I saw her. There 
occurred moreover insomnia, sweats, pains in the calves, pain in the forehead and eyes on 
reading, also transitory marked flow of tears. The appetite very changeable, at times 
voracious appetite, then again anorexia. 
Distinct protrusion, v. Grafe’s symptoms, plainly positive Lowi’s symptom plainly 
positive. Tachycardia extremely yariable, the pulse varying from 80 to 150. Subjec- 
tively, rather marked oppressions; marked falling-out of hair, inclination to slight rises 
of temperature. Marked sweats, very variable. Thyroid gland diffusely enlarged (right 
lobe somewhat more than the left), soft, plainly pulsating, distinct palpable thrill, over it 
a diastolic vascular murmur. 
Alimentary glycosuria (200 gm. dextrose) negative. 
Blood-pressure—Riva Rocci 130, Gartner 85; these differences were regularly found on 
repeated examinations. 
At the beginning of the observation the above symptoms were present, except that the 
tachycardia was very slight and the tremor of the hands scarcely demonstrable. 
The blood examination now shows: 
Leucocytes, 8000 of which: 
Polymorphonuclear neutrophiles, 70 per cent. 
Eosinophiles, 2 per cent. 
Lymphocytes, 21 per cent. 
Large mononuclears, 7 per cent. 
Later the condition became worse, the pulse rate rose to about 130, the tremor became 
distinct, the blood examination now showed 9000 leucocytes, of which: 
Polymorphonuclear neutrophiles, 60 per cent. 
Eosinophiles, 2 per cent. 
Lymphocytes, 27 per cent. 
Large mononuclears, n per cent. 
Also the examination of the respiratory exchange of gases gave indeed always an essential 
increase, but appreciable variations (Dr. Bernstein). 
CO2 
o2 
CO-2 per kg. 
and m. 
02 per kg. 
and m. 
RQ 
On Jan. 12th 
220.5 
280.5 
3.82 
4.86 
0.786 
15 th 
213-1 
270.8 
3-67 
4.67 
00 
o' 
16th 
229.9 
316.9 
3 96 
5-46 
0.725 
19 th 
238.6 
285.4 
4.11 
4.90 
0.839 
Also the examination of the excretion of urine showed in the first period 0.45 and 0.37 
gm. U. (on the 7th and 8th day of the purin free diet). 
In the second period 0.52—3rd day the of purin free diet. 
0.78 20 gm. sodium nucleinate (the greater part vomited). 
o-S3 
0.75 200 gm. meat. 
0.61 82 
THE DISEASES OF THE THYROID GLAND 
In this case we find therefore, in spite of very evident Basedow’s symptoms, 
the blood picture at first normal, and then showing the typical changes. I 
observed a short time ago a still more striking case. Here in the beginning all 
the typical signs of a Basedow’s disease were present. The tremor was espe- 
cially strong. The blood examination showed 8800 leucocytes with 65.8 per cent, 
polymorphonuclear neutrophiles, 2.2 per cent, eosinophiles, 0.5 per cent, mast- 
cells, 5.5 per cent, transitionals, and 26 per cent, lymphocytes. After two weeks 
another blood examination was made. This showed 53 per cent, poly- 
morphonuclear neutrophiles, 7 per cent, eosinophiles, 0.5 per cent, mast cells, 
45.5 per cent, lymphocytes. The clinical picture was not essentially changed 
otherwise. It is worthy of mention that for some days before the second count 
much meat had been ingested. 
For the interpretation oi the blood alterations in Basedow’s disease it is 
important to note that the mononucleosis increases on the ingestion of thyroid- 
gland tablets, while, as we shall see later, it decreases in conditions of athyrosis, 
the blood picture approaching the normal. This relationship was first de- 
scribed by Falta, Newburgh, and Nobel; and lately Th. Kocher apparently without 
knowing our work, has written about the practical significance of this finding. 
Intercurrent febrile diseases bring about the transitory disappearance of 
the mononucleosis {Roth). I have seen a case of Basedow’s disease, in which a 
croupous pneumonia developed. Before the development of the pneumonia, 
there were 6200 leucocytes with 46 per cent, neutrophilic cells; at the height of 
the pneumonia there were 17,100 leucocytes with 87 per cent, neutrophiles. It 
is also known that a transitory neutrophilic hyperleucocytosis occurs in Base- 
dow’s patients a short time after the removal of the struma. 
The mononucleosis is readily produced experimentally by feeding with 
thyroid-gland tablets. Berlelli, Schweeger, and / have regarded it as the expres- 
sion of an excitation of the autonomous system. Eppinger and Hess have 
explained in like manner the hypereosinophilia sometimes observed in Base- 
dow’s disease. We must consider in this connection not only the absolute or 
often only relative increase in the mononuclear cells, but must regard as of 
value the relative and always absolute diminution in the neutrophilic cells in the 
peripheral vessels. In the cases with leucopenia the number of mononuclear 
cells is not increased absolutely, in spite of the marked relative increase; here 
the alteration of the leucocyte formula is brought about exclusively through the 
marked deficiency in neutrophilic cells. In the initial stage, especially on 
sudden overdissemination of thyroid glandular secretion, there may well be 
chiefly an abnormal distribution of the neutrophiles in the vascular tree, leading 
to the above-mentioned leucocytic formula; for after feeding with thyroid 
substance to dogs we found in the capillary blood of the livers of these dogs 
hyperleucocytosis with marked predominance of the neutrophilic cells. Later 
there occurs a permanent alteration of the hematopoietic apparatus, consisting 
in a hyperplasia of the lymphatic apparatus. With this alteration stand in 
harmony the swelling of the lymph-glands so often observed in Basedow’s 
disease (Gowers), especially the swelling of the peri thyroidal lymph-glands (Fr. 
Muller, Passler, Kocher, and others), and also the perivascular round-cell infiltra- basedow’s disease 
83 
tion of the typical Basedow struma, the hyperplasia of the rest of the lymphatic 
apparatus (Fr. Muller and others), the tonsils, lingual papillae, intestinal follicles, 
the hyperplasia of the spleen and the thymus gland {Bonnet, Gierke, Thorbecke,v. 
Hansemann, Rossle, Hart). In severe acute cases, a distinct splenic tumor can 
Fig. 9.—Diffuse enlargement of the thyroid gland in Basedow’s disease 
appear as an early symptom. Schlesinger, a short time ago, reported such a 
case. Of late great practical significance has been ascribed to the hyperplasia 
of the thymus. According to Capelle’s statistics, 44 per cent, of the cases of 
Basedow’s disease that died of intercurrent diseases showed a hyperplasia of 84 
THE DISEASES OE THE THYROID GLAND 
the thymus, 82 per cent, of the cases that died of Basedow’s disease itself, and 
almost 100 per cent, of the Basedow’s cases that died on operation. In these 
cases it is questionable whether the thymus hyperplasia is responsible for the 
death. Perhaps death was due more to the status lymphaticus, perhaps more 
to the failure of the chromaffin organs. I shall defer the consideration of the 
thymogenic Basedow’s disease until the discussion of the theory. 
[.Plummer1 has recently studied the blood picture in exophthalmic goiter. 
An average of the blood counts of 578 patients with this disease gives: Hb 83.1 
per cent.; R. b.c. 4790000; W. b.c. 6983.5; polymorphonuclears 58.3 per cent.; 
small lymphocytes 34.8 per cent, large lymphocytes 4.4 per cent.; transitionals 
1.1 per cent., eosinophiles 1.6 per cent.; basophiles 0.49 per cent. The figures 
in the differential count are well within the normal limits. The absolute small 
lymphocyte count in the leucopenias were within normal limits; the number of 
polynuclear neutrophiles was however reduced in these cases. In the high 
counts the polys were also reduced as compared with the small lymphos, but 
not to the same degree as in the lower counts. There is nothing to show that the 
duration of symptoms bears any relationship to the degree of lymphocytosis. 
Neither the leucocyte count nor the degree of mononucleosis is dependent on the 
severity of the symptoms. There was no change in the relative counts 
during digestion. Thyroidectomy does not influence the blood picture during 
the first three weeks following operation. A relative lymphocyte count below 
20 per cent, is of some negative value, one above 40 per cent, is of some positive 
value. Falta’s views with regard to the distribution of the neutrophiles in the 
vascular type are mentioned, although Plummer states that a hyperplasia of the 
lymphoid tissues may also be a factor in the predominance of the lymphocytes.— 
Editor.] 
Of the metabolic disturbances should be mentioned first of all the emacia- 
tion, which is so important practically. A. Kocher found this in 88 per cent, of 
the cases among his very large number. It is present in the fully developed 
form. It may set in very early and progress in a uniform manner; in other 
cases it may increase in acute exacerbations that may frequently be repeated 
(crises d’ amaigrissement, Iluchard). Almost regularly such periods of in- 
creased emaciation are associated with the increase of other Basedow’s symp- 
toms. In the fully developed forms 15-20 kilograms may be lost in a few 
months. Even in the incomplete forms, a slight grade of emaciation is 
absent relatively seldom. In the case of Basedow’s in which the emaciation is 
marked, there not infrequently develops a severe grade of cachexia (cachexie 
thyreoidienne, Gauthier). In other patients there may gradually set in a 
reversal of affairs, in which the loss may be more or less rapidly made up. In 
rare cases, even obesity may develop. In the great majority of cases the appe- 
tite is increased, especially at the beginning; and there is often polyphagia. Of 
course, the increase of appetite often remains behind the much greater require- 
ments. Later the appetite often becomes less. If vomiting or diarrheas are 
superadded, the body weight rapidly falls. 
1 Plummer (W. A.). The blood picture in exophthalmic goiter. Minnesota Medicine, Vol. II. 
Sept., iqiq, pp. 330-332. basedow’s disease 
85 
The cause of emaciation in spite of the increased appetite depends in part 
on an increase of the caloric production through the thyroid secretion produced 
in excess. Fr. v. Muller first pointed out that in spite of the abundant supply 
of calories, in Basedow’s disease the body weight often falls. The demonstra- 
tion, that the basal metabolism, that is the C02 production and the 02 consump- 
tion in a fasting condition with the exclusion of all muscular activity, is increased 
in Basedow’s disease, was first furnished by Magnus-Levy, and later by Thiele 
and Nehring, Stiive, H. Salomon and others, by means of the Zuntz apparatus. 
Steyrer investigated the increase of exchange by the Voit-Pettenkofer respiration 
apparatus. In the severer cases the increase of exchange may reach 70 per 
cent. I reproduce here Magnus-Levy's instructive table: 
Age, 
years 
Height, 
cm. 
Weight, 
kg. 
02 
CC. 
CO 2 
CC. 
02 
cc. per 
kg. 
Per cent. 
normal 
values 
i. Acute, very severe case 
20 
158 
5° 
7 
348.9 
295.0 
6.89 . 
170 
2. Very severe chronic case 
26 
150 
5° 
5 
344-o 
236.2 
6.80 
170 
3. Severe chronic case 
22 
161 
55 
I 
305-8 
256.0 
5-55 
142 
4. Somewhat lighter chronic case 
55 
156 
43 
9 
266.9 
299-3 
5-3i 
122 
5. Light case 
20 
148 
55 
O 
213.2 
181.1 
4-74 
105 
6. Cured by operation ten years ago.. 
about40 
171 
84 
0 
282.8 
241.0 
3-37 
IOO 
7. Simple goiter 
66 
142 
5° 
5 
176.7 
i43 -i 
3-43 
9° 
A very interesting example is furnished by the following case investigated 
by Dr. Bernstein. 
Observation IX.—H. J., twenty-two years old, pronounced true infantilism. Two years 
ago and one year ago tetany, simultaneously with aggravation of a stomach affection that 
had lasted a long time. With the decline of the second period of tetany pronounced mani- 
festations of hyperthyrosis. After a gastroenterostomy there was no recurrence of the 
tetany. The Basedow’s manifestations (tachycardia, sweats, tremors) remained, or improved 
only a little. Eye symptoms were entirely absent. The investigations of the basal meta- 
bolism 
Per 
Per kilogram of body weight 
C02 
O2 
RQ 
CO2 
O2 
l82.2 
229. I 
O.796] 
180.2 
227.4 
o-793 | 
4-45 
5.61 
185.6 
222.X 
0.836] 
In other cases Salomon could show that the caloric production is also 
present in the- formes frustes. The case just detailed (Observation IX) and 
Observation V agree in that they show that the increase of the exchange may 
also be distinct in the formes frustes that pursue their course without eye 
symptoms. 
Furthermore, I would refer to Observation VIII where the examination of 
the gaseous exchange showed that like the rest of the Basedow’s symptoms the 
caloric production is subject to great variation. 
The increase of the basal metabolism may also be demonstrated experi- 
mentally through the administration of thyroid gland; it is however, not very 
great, and in some individuals remains absent. 86 
THE DISEASES OF THE THYROID GLAND 
The question as to which way the influence of the thyroid-gland secretion 
acts in increasing the metabolism has been much discussed. The tremor alone 
is not responsible for it, for after exclusion of the tremor by hyoscine the 
exchange is not essentially reduced (Magnus-Levy). This author believes in a 
raising of the exchange in the resting cells. Andersson and Bergman have con- 
tradicted this, as after large doses of iodothyrin and thyroidin they found no 
increase after complete relaxation of the muscles and during sleep. These 
experiments however do not show very much, because, as previously mentioned, 
many normal individuals behave refractorily to the administration of thyroid 
gland. To my mind, we should not leave unconsidered in the explanation of 
the increase of the basal metabolism the violent increase of tonus of the whole 
vegetative nervous system and the heightened activity of the organs affected 
by it. The increase of the caloric production cannot alone constitute the cause 
of the emaciation, but there must be added to it a disturbance in the regulatory 
mechanism that governs the taking up of nutrition. Here come into considera- 
tion especially the disturbances of the stomach and intestines. I refer to what 
I have said on this subject in the first chapter. 
In Basedow’s disease also the protein metabolism is increased, that is, the 
individuals affected need more protein or more oxygen-free energy especially 
in the form of protein-sparing carbohydrates to maintain themselves in nitrogen 
equilibrium. In the accounting of the equilibrium we must consider also the 
N-loss on account of profuse sweats. HirschlajJ estimates it as 2-4 gm. in 
twenty-four hours. As is the case with all the other Basedow’s symptoms, the 
increase of the protein metabolism may show great variations. 
The increase of the protein metabolism is shown very prettily in the ex- 
periments of Rudinger. In a nearly N-free diet, rich in carbohydrates and fats 
(according to Landergreen), in normal human beings, the nitrogen in the urine 
falls rapidly to 4-5 gm. a day. In Basedow’s patients, Rudinger found 7-8 gm. 
N. on the fourth day. The increase of the protein metabolism may also be 
demonstrated experimentally by the feeding with thyroid-gland substance. 
Bleibtreu and Wendelstadt saw after administration of thyroid-gland tablets in 
human beings a negative N-equilibrium that could be raised by the addition of 
butter and sugar. Since the time of Bleibtreu and Wendelstadt’s experiments, 
many investigations have been carried out that show the raise in the protein 
metabolism through thyroid medication (Mayerle). In an experiment of 
Matthes there was shown after strumectomy, with the patient on the same diet, 
an improvement of a previously negative N-equilibrium. On the administra- 
tion of dried goiter, the excretion of nitrogen rose again. Also in animal experi- 
mentation could be demonstrated a rise of the protein metabolism (Fritz Voit). 
This was shown plainest in investigation of the metabolism during fasting 
(.Eppinger, Falta, and Rudinger). 
The question whether in hyperthyroidism the increase of the protein 
metabolism is primary or only the result of an increased carbohydrate and fat 
metabolism is mostly answered that the increase of the protein metabolism is 
primary. Fritz Voit found in dogs after feeding with thyroid-gland substance a 
negative nitrogen equilibrium even when the diet contained abundant fat, so basedow’s disease 
87 
that fat could even be deposited [in the body]. This experiment does not seem 
conclusive as the nitrogen-free energy in the diet was exclusively upheld by fat. 
The same objection may however be made against the statement of Magnus- 
Levy that on the administration of fat or on abundant fat deposition, the loss of 
nitrogen is indeed appreciably restricted, but not entirely done away with. 
In the experiment of Rudinger the elimination of nitrogen could be depressed 
to the Lander green's minimal quantity, if larger quantities of nitrogen-free 
energy (with abundant carbohydrates) were ingested for a long time. We can 
therefore conclude that in hyperthyroidism there exists only a heightening of 
the physiological relations. This is indeed true for the lighter grades, but in the 
higher grades the degenerative changes of the muscular substances such as are 
described by Askanzy, speak for a toxic disturbance. 
Jaquet and Svenson state that in the Basedow’s patients the metabolism 
after ingestion of food is raised higher than in normal individuals. In the 
investigations of Forges and Pribram the basal metabolism after transitory 
copious administration of protein was found to be abnormally high. It there- 
fore seems as though the metabolism of Basedow’s patients were especially 
labile, the administration of protein perhaps increasing the activity of the 
thyroid gland in an especial manner. For this perhaps speaks also the fact 
that we can make the thyroid of dogs extremely poor in iodine by abundant 
administration of meat, this pointing to a rapidly leading off of the specific 
secretion; also, as is known, the Basedow struma is characterized by its very 
slight iodine contents. 
The disturbances of carbohydrate metabolism in Basedow’s disease do not 
seem to be of a uniform nature. There exists a combination of hyperthyroid- 
ism with true diabetes (v. Noorden, Ewald, Grawitz, Hannemann, Bettmann, 
Falta, and others). This diabetes shows only a slight dependence on the course 
of the hyperthyroidism. In the cases I described, X-ray irradiation had only a 
slight influence on the elimination of the sugar. With this agrees the fact that 
in true diabetes mellitus we can influence the sugar elimination by administra- 
tion of thyroid gland only in the aglycosuric condition or on light glycosuria, 
while in the higher grades of glycosuria the influence is not so prominent. Also 
in the dog after complete extirpation of the pancreas, under the administration 
of thyroid-gland tablets there was no appreciable increase of the D: N quotient. 
In my cases of diabetes and Basedow’s there were profuse diarrheas, while cases 
of true thyrogenic glycosuria, of which I shall speak presently, show disturbances 
of fat absorption following overloading with fat. 
The combination of Basedow’s with true diabetes is not so very rare. 
Sattler has collected forty cases from the literature. In twenty-six cases the 
Basedow’s disease was present before the diabetes, in eight cases the diseases 
appeared about the same time, in the rest the Basedow’s occurred in the course 
of the diabetes. 
In many individuals the hyperthyroidism determines a predisposition for 
glycosuria. The disturbance may be occult, that is, glycosuria appears only 
on the administration of large amounts of pure grape-sugar. The alimentary 
glycosuria in Basedow’s disease was first described by Kraus and Ludwig, and 88 
THE DISEASES OF THE THYROID GLAND 
by Chvostek. It seems to have its complete experimental correlate in the ali- 
mentary glycosuria which may be elicited on the abundant administration of 
thyroid-gland tablets in many normal individuals and in animal experiment 
(Ewald, J. Dale, Denning, v. Noorden, Bettmann, Georgiewsky, Strauss, and 
others). The disturbance in the carbohydrate metabolism may, however, also 
be manifest, that is glycosuria is found on mixed diet. Such cases of spontane- 
ous glycosuria do not appear to be common (.Lewin, v. Nothafft, A. Kocher, 
Falta). Also Observation VII, reported previously, belongs to this group. 
The glycosuria is characterized as thyrogenic by the fact that it comes on with the 
development of Basedow's disease, and disappears again with its amelioration, and 
that after the cure of the Basedow's also the overloading tests show entirely normal 
relations. It is to be distinguished from the alimentary glycosuria of Basedow’s 
in degree only, as the alimentary glycosurias also disappear on the spontaneous 
or therapeutically induced improvement of the Basedow’s. This is observed 
especially after X-ray irradiation of the thyroid {Schwarz, Hirschl, Falta). 
The thyrogenic glycosuria seems chiefly to occur in traumatic Basedow’s, and 
as had been mentioned previously, is frequently combined with disturbances of 
fat absorption. 
In the combination of Basedow's with true diabetes there may well be as- 
sumed, in addition to the disease of the thyroid gland, an independent lesion of 
the insular apparatus of the pancreas. On the other hand I would regard that 
in the true thyrogenic glycosuria the hyperthyroidism brings with it a marked 
additional loading of the internal secretory activity of the pancreas, with the 
implication that the internal secretory activity of the pancreas is weakened, 
whether by the thyroid secretion or by other factors is not known. If, how- 
ever, the pancreas is not equal to the necessary breadth of function, especially if 
an alimentary overloading is added, glycosuria makes its appearance. This 
hypothesis seems to be explained in an unforced manner: i. by the fact that 
hyperthyroidism does not lead to glycosuria in all individuals; 2. that the glyco- 
suria disappears with the retrogression of the hyperthyroidism, and that after 
this retrogression alimentary overloading does not lead to glycosuria. Distinc- 
tion of the pancreatogenic from the thyrogenic glycosuria is not attended with 
any difficulty; but there are, however, transitions, that is to say those cases in 
which the glycosuria occurs under the use of thyroidin medication {Fried. 
Muller). In such cases, just as in the case of Ewald (myxedema in which dia- 
betes developed on the continued use of thyroidin medication and persisted 
after its withdrawal) there might very well be supposed also a disease of the 
insular apparatus, which up to the time had been latent, and which had been 
made manifest through the thyroidin medication. 
[The combination of hyperthyroidism with diabetes is rare {Fitz,1 Allen) 
Fitz used as material 39 cases of diabetes complicated with thyroid disease that 
were not reported before. He tabulated the results of thyroid operations on 
the diabetes, and concludes that it has not been established that the coincidence 
of hyperthyroidism and diabetes is more than a chance. The diabetes usually 
1Fitz (R.). The relation of hyperthyroidism to diabetes mellitus. Archives of int. Med., Vol. 
XXVII, No. 3, pp. 305-314. The substance of the above paragraph is taken from this article. basedow’s disease 
89 
follows the thyroid disturbance, but may precede it; it tends to parallel in 
severity the severity of the thyroid intoxication. There is no reason for assum- 
ing that partial thyroidectomy alone has any curative effect on diabetes:— 
Cases with non-toxic goiter who were operated on showed no improvement in 
the diabetes: on the other hand, certain patients with hyperthyroidism and 
diabetes improve to a considerable degree after the thyroid symptoms are 
checked—probably because of a change in the rate of metabolism and not 
because a portion of the thyroid gland has been made functionless. It does 
not seem over-radical to advise operation for properly selected and properly 
prepared toxic cases with diabetes, since the risk does not seem out of proportion 
to the possible benefit to be gained, and since the prognosis is otherwise grave. 
According to Sainton,x who has written a very good resume of the subject of 
exophthalmic goiter, Lueders is credited with the statement that in certain 
cases of exophthalmic goiter, acidosis may occur without glycosuria.—Editor.] 
For the understanding of many of the characteristics of the metabolism 
in Basedow’s patients we must note that the action of thyroidin depends on the 
constitution of the affected individual. As was mentioned previously, in 
normal individuals the action of thyroidin on the gas exchange, the protein and 
the carbohydrate metabolism is often intensive, while other individuals are 
entirely refractory to the same dose of thyroidin. The constitutional differences 
probably lie in the different degrees of excitability of the vegetative nervous 
system, and this has perhaps its deeper foundation in the different reaction 
capability of the ductless glandular system. Now it seems that in Basedow’s 
patients alterations of constitution occur in the course of the disease. So, for 
example, v. Wagner mentions a case of Basedow’s disease, in which the initial 
rapid emaciation was followed by the development of an obesity, that had the 
characteristics of an essential obesity. Not so very rarely, too, are observed 
cases of Basedow’s disease in which the initial rapid emaciation changes to a 
condition in which the patients not only recover what they have lost, but when 
placed on a little superfluous diet, they become fat in spite of the fact that they 
may still show symptoms of hyperthyroidism. Magnus-Levy reports a case of 
Basedow’s that after subjective and objective amelioration received daily for 
four and one-half weeks two or three thyroidin tablets, without there occurring 
an aggravation of the Basedow’s symptoms or an increase ot the exchange of 
gases. A similar case was observed by the author. It was that of a forme 
fruste with distinct Basedow’s symptoms (without eye symptoms) and glyco- 
suria. After X-ray irradiation of the thyroid gland all symptoms disappeared; 
and high tolerance for carbohydrates soon came on. When the patient again 
presented himself after several months, thyroidin medication for three days 
(nine tablets a day) could be administered without increase of the pulse rate 
or alimentary glycosuria. 
1 Sainton (P.). Les signes nouveaux et les petits signes du goitre exophthalmique. Le 
journal medical franfais, Vol. IV, 1920, pp. 273-283. (In reference to Lueder’s article it 
is found that this seems to be implied rather than to be stated explicitly. Lueders (C. W.). 
The use of laboratory methods in the diagnosis of early hyperthyroidism. Arch. Int. Med., Vol. 
XXIV, Oct., 1919, pp. 432-444. Lueders points out that some cases of exophthalmic goiter may 
be associated with hypothyroidism. This does not mean however that they were cases of 
hypothyroidism primarily.—Editor. 90 
THE DISEASES OF THE THYROID GLAND 
The thyroid-gland secretion has an enormous influence on the salt met- 
abolism. As W. Scholz first pointed out, it increases the elimination of phos- 
phorus, especially through the intestine. The increase [of the phosphorus] 
in the feces may reach as much as 25 per cent. Older observations of v. Noorden 
and the later ones of Oeri have shown that the distribution of phosphorus to the 
kidney and intestine is exclusively dependent on the elimination of calcium; 
of calcium only a very slight part is to be found in the urine, by far the greater 
part is to be found in the feces. When the calcium elimination increases, a 
part of the phosphorus goes to the intestine with the calcium. Investigations 
of Bolaffo, Tedesco and the author on fasting dogs show that under the influence 
of thyroidin the N : P205 quotient in the urine is markedly increased, and that 
further, in agreement with Scholz, the elimination of phosphorus in the feces is 
very much increased and that the abnormal distribution of phosphorus to the 
kidneys and intestine is called forth by an increase ot the calcium elimination 
by way of the intestine. 
It should be mentioned further that in Basedow’s disease Forschhach found 
strikingly slight amounts of creatinin in the urine. Also the exogenous factor 
(addition of meat extract) seems to be very small. In many a case of Basedow’s 
disease there exists in addition a pronounced polyuria, that cannot be explained 
alone by the greater gram molecular amount [Molenmenge] of the urine on 
account of the increased metabolism. Here there is well present an excitation 
of the nerves of the renal vessels. 
[According to recent investigations, thyroid illness or extirpation works 
no appreciable alteration of nitrogen excretion by way of the urine; also the 
creatinin in the urine remains unaltered.—Editord] 
Later investigations, not as yet published, by Zehner and me as to the uric 
acid metabolism in Basedow’s disease have led to a very remarkable result. 
We found in all the severe cases thus far investigated by us not only that the 
endogenous factor of the U-elimination was strikingly small, but that also the 
exogenous U-elimination was quite unusually small. I have reported such an 
investigation in Observation VIII, and would express the opinion that a 
portion of the uric acid is further decomposed under the influence of the 
hyperthyroidism. 
There are found not rarely in Basedow’s disease ephemeral increases in 
temperature. These were first described by Bertoye. Already Charcot had 
mentioned in opposition to Bertoye that they were very much less frequent than 
Bertoye stated. Among his numerous cases, they were never seen by Kocher. 
They have been seen however by Sattler. At all events, it is certain that in 
many cases of Basedow’s disease the equilibrium of heat is very labile, and that 
on slight provocations the regulation is broken through in the sense of a hyper- 
themia. Frederich Muller saw regularly in one case marked rises of temperature 
after the administration of quinine. Eppinger and Hess saw them in cases 
after the injection of atropine. Moreover cases of peracute Basedow’s disease 
are described that previous to death showed marked tachycardia with delirium, 
1 The editor regrets that he is unable to lay his hands onthe reference for this statement. 
Lueders states that in exophthalmic goiter there is creatinuria. Lueders (C. W.). The use of 
laboratory methods in the diagnosis of early hyperthyroidism. Arch. Int. Med., Vol. XXIV, 
Oct., 1919. basedow’s disease 
91 
associated with a rise of temperature to 4o-4i°C. (Friedr. Muller). Also 
Hirschlaf saw in a case a terminal rise of temperature to 40°. I have often 
seen in severe cases of Basedow’s disease transitory rises of temperature to 390, 
without finding a ground for them in the examination. After goiter operations, 
as is known, there have been observed marked rises of temperature that last 
for several days (Bergert, Reinbach, Kocher, Lanz). Riedel found them also after 
the operation for ordinary goiter, although those which occur after operations 
for exophthalmic goiter are essentially higher. Kostlivy found in all cases after 
operation pronounced neutrophilic hyperleucocytoses, but postoperative 
hyperthermia only in cases with thyrotoxic symptoms or in true Basedow’s. 
Kocher, Lanz, v. Bruns, and Schultze explain this hyperthermia as an absorption 
fever, as in operations on the throat there are present especially favorable 
conditions for the formation of hematomata. More probable is the explanation 
that in consequence of the manipulation of the gland more thyroid secretion is 
absorbed and perhaps also the cervical sympathetic is irritated mechanically. 
The objection of Schultze that the injection of extracts from such strumas calls 
forth no essential rises of temperature in other people does not seem to me ten- 
able, as normal individuals do not possess the lability of thermal equilibrium 
that exists in the Basedow’s patients. 
The skin in Basedow’s disease is usually delicate, pliable, moist, readily 
reddened, showing well a lively play of the vasomotors. Increased sweat 
secretion is almost constant and is mostly present from the beginning of the 
disease. As is the case with all the symptoms of Basedow’s disease, the sweats 
undergo great variations; sometimes they occur only at night, and often they 
are influenced greatly by psychic excitations. In rare cases, the sweats have 
an odor (y. Basedow, Dauscher, Observation V, previously reported). Many 
of the patients sweat more on one side. In consequence of the abnormal mois- 
ture of the skin due to the sweats there is found in most Basedow’s patients a 
reduction of the resistance to the passage of an electrical current; this was first 
described by F. Chvostek and Vigouroux and was more exactly studied by 
0. Kahler. On account of the marked excretion of sweat, miliaria sometimes 
occur; the formation of larger vesicles with elevation of the epidermis, as in 
Case K. (Observation V), seems to be a very rare occurrence. 
Pigmentations are found in about half of all cases, and indeed on the eye-lids, 
lips, throat, on the lines of constriction of the corset laces, on the nipples, in the 
axillae, on the linea alba, exceptionally on the mucous membranes, and also on 
the genitalia. In rare cases is found a diffuse brown coloration of the skin of the 
extremities, indeed even a bronzing. In many cases occur edematous swellings, 
especially of the eye-lids, but also on the extremities; they are firm and do not 
pit on pressure. They probably differ in nature. Trophedemas are apparently 
not very rare in Basedow’s disease. In many cases it seems as though we were 
dealing with a kind of lipodystrophy, as for example in the case reported by 
v. Schrotter, in which simultaneously with the emaciation of the upper half of the 
body there developed a considerable swelling of the lower half of the body, 
looking just like myxedema. Microscopical examination showed a lipomatosis 
with extraordinary large fat lobules. In this case there was found also a quite 
extraordinary pigmentation of the skin in the form of sharply circumscribed 92 
THE DISEASES OF THE THYROID GLAND 
surfaces. I shall refer later, in the discussion of the pathogenesis, to the myxede- 
matous swellings in this disease. There may be found also in certain cases 
hemorrhages into the skin and the mucous membranes. A common symptom 
in Basedow’s disease is the falling out of the hair, that sometimes may lead 
almost to baldness. Also the nails are sometimes fissured. 
Alterations of the osseous system occur mostly if the Basedow’s disease 
has developed in an individual who is youthful. Holmgren has pointed out 
that youthful Basedow’s patients show an accelerated growth in height and 
a somewhat premature closure of the epiphysial junctures. Very instructive 
is a case of Schkarine in a four and one-half-year-old girl who showed an 
abnormally rapid growth. Also Ballet reports a nineteen-year-old girl with 
Basedow’s disease and “gigantism.” The skeleton of the patient with Base- 
dow’s is mostly slender; the end phalanges are mostly pointed (Revilliod). 
v. Jaksch and Rotky describe in a case of Basedow's painful distentions at 
the distal ends of the forearm bones, and later also of the ribs, shoulder-blades, 
upper-arm, thighs, etc. Later the case developed kyphoscoliosis and para- 
plegia. The simultaneous occurrence of Basedow’s and rheumatoid arthritis 
has been frequently described {Jones and others). 
The alterations in the genitalia are mostly more pronounced in man, and 
in severe cases there may sometimes be decrease of libido and impotence. 
In women there are usually alterations of menstruation—sometimes cessa- 
tion of menstruation is an early symptom. On longer duration of the disease 
there may come about an atrophy of the entire genital apparatus (Clieadle, 
Askanazy, et al.). In the case of Kleinwachter there occurred, in addition to 
a pronounced atrophy of the external and internal genitalia, even an atrophy 
of the mammae. The relation between the genital sphere and the thyroid 
gland is found also in the fact, known for so long, that there is an increase of 
the volume of the thyroid at the time of puberty and during pregnancy. 
There may also occur during the period of pregnancy a development of a 
goiter {Lawson Tait), which disappears after labor and recurs during the next 
pregnancy. Vermorel refers the tachycardia and the cardiac palpitations 
that sometimes occur at the time of puberty to a light grade of hyperthy- 
roidism. At any rate it is noteworthy from this point of view that Base- 
dow’s disease is not at all rare. During pregnancy the Basedow’s symptoms 
mostly become exaggerated {Cholmogorojf and others). As the tendency to 
Basedow’s disease is sometimes inherited and as in the decline of Basedow’s 
patient frequently other diseases—neuroses of the vegetative nervous diseases, 
diabetes, etc.—occur, matrimony is to be advised against to Basedow’s patients, 
or in it conception is to be avoided (/. Novak). 
Basedow’s disease can naturally be combined with many other diseases. 
We should mention the not rare combination with the trophoneuroses, espe- 
cially with scleroderma. Such a case was first reported by Leube. Since 
that time numerous cases have been reported. An accurate compilation has 
been made by Sattler. Basedow’s disease may be added to an already exist- 
ing scleroderma, or sclerodermic symptoms may develop in the course of a 
Basedow’s disease. Observers have often found that an improvement of the 
Basedow’s disease is associated with an improvement of the scleroderma. basedow’s disease 
93 
There are, however, cases that take another course. Also complications of 
Basedow’s disease with tetany have often been observed (see Chapter IV). 
Pathogenesis.—Before I enter into the consideration of the individual 
forms of Basedow’s disease, I should like to make a few remarks as to the 
theory. The observation of Filehne and of Dourdouji and Bienfait that in 
animals after the transection of the restiform bodies there occur tachycar- 
dia, exophthalmus, and hyperemia of the thyroid gland (unilateral opera- 
tions are attended with these phenomena on one side only), for a long time 
attracted many adherents to the bulbar theory, which attributed all the 
Basedow’s symptoms to alterations in the brain stem. Actually many symp- 
toms point to a bulbar origin, as for instance the glycosuria that sometimes 
occurs, the alterations of the voice, and eventually the pareses of the various 
cranial nerves (Saltier). It is indeed true that in certain cases alterations 
are found in the medulla oblongata (.Mendel and others), but in the majority 
of cases these findings are absent. The French school, especially Charcot, 
Trousseau and Gauthier, and in Germany Gerhardt and Buschan, have regarded 
Basedow’s disease as a neurosis, assuming that the entire nervous system 
is diseased. Then Mohius, as has already been mentioned in the beginning, 
placed the thyroid gland as the central figure in the pathogenesis, assumed 
a poisoning of the body by the copious production of a harmful secretion, 
and expressed the thought that all forms of Basedow’s disease (goiters that 
have become associated with Basedow’s symptoms, formes frustes, and the 
fully developed Basedow’s disease) all depend on a uniform basis. Mohius 
first pointed out the opposition between the symptom picture of Basedow’s 
disease and the disease condition that ensues after extirpation of the thyroid 
gland. Mohius’s teaching gained ground rapidly, the predominant place 
of the thyroid gland in the pathogenesis of Basedow’s disease finding gen- 
eral recognition; but on the contrary the views as to the kind of functional 
disturbance diverged greatly. The view first advocated by Notki and later by 
Blum, that certain poisons existing in the body were rendered non-toxic (i.e., 
detoxicated) in the thyroid gland and that in Basedow’s disease this detoxi- 
cation is incomplete, may to-day be regarded as untenable. It was displaced 
by the secretion theory, which maintained that from the thyroid gland a specific 
active secretion is given off to the blood path that is necessary for the reten- 
tion of certain body functions, or, according to the supposition of others, to the 
rendering inert of certain poisons circulating in the body. The detoxication 
theory, although in an essentially modified form, again greets us in the view 
last-mentioned. In this form, however, there is as little evidence for it as in 
its older form. The known experiment of Reid Hunt, according to which the 
resistances of animals to methyl cyanide is somewhat raised, is not evidence for 
the detoxication theory since, as Reid Hunt himself emphasizes, the heightening 
of resistance can be called forth by the heightening of the metabolic processes 
that ensues in consequence of the administration of the thyroid. 
Oswald, Minnich, and others assume that in Basedow’s disease the thyroid 
furnishes a less active secretion (hypothyrosis or dysthyrosis); Mohius believes, 
as already mentioned, in the increased secretion of a substance that is quali- 
tatively altered; while most authors, especially Fr. Kraus, advocate the mere 94 
THE DISEASES OE THE THYROID GLAND 
increase of the thyroid function without qualitative alteration (hyperthyroid- 
ism). For this supposition, which I also advocate, speaks: 
1. The opposition in the symptom picture of Basedow’s disease and 
myxedema. 
2. The fact that on exothyropexy (conduction of the secretion of the 
thyroid gland to the exterior) the thyroid gland in Basedow’s disease fur- 
nishes more secretion than the thyroid of the ordinary strumas. 
3. The results of surgical treatment (diminution of the secreting paren- 
chyma) . 
4. The aggravation of Basedow’s disease on the administration of thyroid 
glandular substances and finally, 
5. Artificial thyroidism. 
Against these points many objections have been raised of which I shall 
mention only the most important. Against point 5 has been objected that 
while it is true that most of the symptoms of Basedow’s disease may be pro- 
duced on the administration of thyroid gland, they remain much behind 
those of true Basedow’s disease in intensity, and some of them, for instance 
the eye symptoms, are not produced in artificial thyroidism at all. As far 
as the eye symptoms are concerned, I must again mention that Kraus and 
Friedenthal observed exophthalmus after the injection into the blood of rabbits 
of the thyroid glandular juice,1 as did Heinecke on long-continued treatment 
with large amounts of thyroid glandular substance. In addition to-day 
exophthalmus can be produced in dogs on the use of juice expressed from 
human strumas (.Lampe, Liesegang, and Klose, Baruch). 
Lampe, Liesegang, and Klose, on the intravenous injection into certain 
breeds of dogs of fresh juice expressed from Basedow strumas, have found 
marked increase of the temperature and pulse rate, exophthalmus, glyco- 
suria and albuminuria. Death occurred in convulsions. Expressed juices 
that were obtained from normal thyroid glands or ordinary strumas had no 
effect, or very little effect. The authors regard these experiments as evidence 
that in Basedow’s disease there exists no hyperthyroidism but a dysthyroid- 
ism. The experiments are very significant, but I do not regard them as 
furnishing evidence for a dysthyroidism. It will not do to leave altogether 
unconsidered the long-known fact that, as stated above, through the feed- 
ing with normal thyroid glandular substances all the symptoms of Base- 
dow’s can be produced in a more or less well-pronounced manner. Also 
Baruch, who experimented in a manner quite analogous to that of Lampe, 
Liesegang, and Klose, and had similar results, does not agree with these authors’ 
interpretation. 
Much cited is the case of v. Nothafft, which I shall describe in detail on 
account of the interest that it has attracted. It was that of a forty-five- 
year-old man with a corpulency that had been increasing for several years. 
In the course of about five weeks he took almost 1000 thyroid-gland tablets. 
In a short time there developed a complement of Basedow’s symptoms of which 
1 Presssaft.—Falla states thyroid gland juice taken up by serum, but I cannot elicit any such 
meaning on reference to the original article.—Editor. basedow’s disease 
95 
I will mention irritating cough, tachycardia, acceleration of respiration, 
slight increase of temperature, bilateral exophthalmus, tremor of the whole 
body, even of the tongue, increased strangury, glycosuria (up to i per cent.), 
morose mood, excitement, and finally swelling of the thyroid gland. The 
irritating cough disappeared eight days after the onset of the thyroid glandu- 
lar therapy, as did also the sugar, without alteration of the diet; the tremor 
disappeared after four weeks; the struma, the exophthalmus, and the rest 
of the eye signs lasted nearly one-half year and then retrogressed almost 
entirely. Although here almost the entire symptom-complex of Basedow’s 
disease developed, the case is however not entirely convincing. We shall 
see later that in many persons often relatively small amounts of iodine are 
sufficient to occasion an enormous increase of the function of the thyroid 
gland. Also in the case of v. Nothajjt the amounts of iodine contained in the 
administered thyroid gland material may have sufficed for the purpose, as 
speaks also the transitory development of a struma. This objection might 
very well be raised to an artificial hyperthyroidism, unless the thyroid gland 
in the affected individual were absent. Now in myxedema after thyroid 
operation we may indeed frequently observe an extraordinarily high toler- 
ance for thyroid-gland substances, but on the other hand, symptoms of 
hyperthyroidism may be elicited after the administration of enormous amounts. 
At all events, we must not forget that we do not know anything as to the 
amount of thyroid-gland secretion given off to the blood in Basedow’s disease. 
Probably it is very large. We should further consider that on the peroral 
administration of large amounts the absorption would soon suffer harm. 
Although I therefore do not recognize the arguments advanced up to the 
present time as convincing, I shall have to acknowledge that artificial thyroid- 
ism has not as yet furnished complete evidence for the opinion here advo- 
cated. The greater intensity of the symptoms in true Basedow’s always admits 
of the possibility that hyperthyroidism is only a partial phenomenon of an altera- 
tion of the central nervous system and that the organism of the Basedow’s patient 
reacts to hyperthyroidism in a different manner than the normal. The foundation 
for this can perhaps he seen in a constitutional alteration, of which the cause 
lies in the associated involvement and perhaps in a functional increase of other 
ductless glands. The final cause of all the manifestations may well he regarded 
as lying in the central nervous system. 
It has been pointed out that the multiplicity of the Basedow’s symptoms 
cannot well be explained by the functional increase of the thyroid gland alone, 
and that therefore also on this ground a qualitative alteration of the secre- 
tion must be supposed. This objection does not hold in this general inter- 
pretation. All the symptoms of Basedow’s disease may be produced, at 
least in miniature, after the administration of normal thyroid gland. What 
syndrome will develop all depends on the constitution of the affected individual 
(Falta, Newburgh, and Nobel). 
Objections have been raised to point 4. It is true that in the most cases 
we observe under thyroid medication distinct aggravation of the Basedows’ 
symptoms such as increase of the tachycardia, arrhythmia, sleeplessness, 96 
THE DISEASES OF THE THYROID GLAND 
excitement, profuse sweats, gastrointestinal disturbances, severe prostra- 
tion, etc. But there have been reported cases in which the thyroid medication 
acted favorably. Quite complicated theories have been advanced for the 
explanation of these cases; thus, for example, Mobius believes that the increased 
activity of the thyroid gland retrogresses if through the administration of 
thyroid glandular substance the gland is given time to recover itself. Such 
cases may be explained without overdrawing by the observation that in many 
cured cases of Basedowr’s disease the counter-regulations develop strongly. 
I previously mentioned a case in which, after the cure of the Basedow’s, thyroid- 
gland tablets even in large quantities would bring forth no distinct relief. If, 
therefore, thyroid medication takes place in the declining stage of the disease, 
slight favorable results may be readily induced. 
The most important point is point i, the opposition in the symptom 
picture of Basedow’s disease and of myxedema. I here reproduce the excellent 
table of Kocher: 
Cachexia Thyreopriva 
Absence or atrophy of the thyroid 
gland. 
Slow, small, regular pulse. 
On application of cold to the skin, all 
vasomotor changes are absent. 
Listless quiet gaze without expression 
and animation. 
Narrow palpebral fissures. 
Retarded digestion and excretion, poor 
appetite, few demands. 
Slowed metabolism. 
Thick, nontransparent, folded, dry to 
scaly skin. 
Short, thick fingers often broadened 
at the ends. 
Sleepiness and tendency to sleep. 
Retarded sensation, apperception, and 
action. 
Deficiency of thoughts, listlessness, and 
loss of emotivity. 
Awkwardness and clumsiness. 
Stiffness of the extremities. 
Remaining behind of bone growth- 
bones short and thick, and often deformed. 
Constant feeling of cold. 
Retarded, heavy, breathing. 
Increase of body weight. 
Senile appearance, even when the 
patients are young. 
Morbus Basedowi 
Swelling of the thyroid gland—mostly 
of a diffuse nature, hypervascularization. 
Frequent, often tense, rapid, now and 
then irregular, pulse. 
Extraordinary irritable vascular nerv- 
ous system. 
Anxious, unsteady gaze which is chol- 
eric on fixation. 
Wide palpebral fissures, exophthalmus. 
Abundant evacuations, mostly abnor- 
mal appetite, increased demands. 
Increased metabolism. 
Thin, transparent, finely injected, 
moist skin. 
Long, slender fingers with pointed end 
phalanges. 
Sleeplessness and disturbed sleep. 
Accelerated sensation, apperception, 
and action. 
Flight of thoughts, psychic excitement 
as far as hallucination, mania and melan- 
cholia. 
Constant unrest and haste. 
Trembling extremities, increased mo- 
bility of the joints. 
Slender skeletal build, now and then 
weak and thin bones. 
Unbearable sensation of heat. 
Superficial breathing wdth deficient 
inspiratory expansion of the thorax. 
Reduction of body weight. 
Youthful luxuriant body development, 
at least in the initial stages. basedow’s disease 
97 
A. Kocher distinguishes, in addition to these opposed symptoms, symptoms 
that are similar in both diseases and reckons under these certain forms of 
edema, dryness and becoming gray of the hair, pigmentations, and the diminu- 
tion of the secretion of the salivary and lachrymal glands that is observed 
in many cases of Basedow’s disease. One may add to these symptoms 
the dryness of the skin seen in rare cases of Basedow’s disease and the gly- 
cosuria of quite rare cases of myxedema. These “exceptions to the rule” 
will hardly suffice to limit essentially the opposition in the symptom picture 
of the two conditions. For the explanation of many of these exceptions, 
constitutional differences may be called into account; for example, they may 
suffice for the explanation of the dryness of the hair and of the skin, and for 
the diminution of the salivary secretion. Eppinger and Hess regard 
the cause of the opposed behavior of the sweat formation in different 
cases of Basedow’s disease as a different tonus of the sympathetic or of the 
autonomous nerves; surely such behavior does not furnish sufficient argu- 
ment against the hypothesis of hyperthyrosis, because also in artificial hyperthy- 
roidism we saw, in certain cases, a diminution of the sweat formation under the 
influence of the thyroid medication. As far as the behavior of the hair is 
concerned, in Basedow’s disease the hair indeed may be dry but is also thin, 
while in myxedema it tends to be coarse, loose, and brittle. The explanation 
of other “similar” symptoms may be attributed to the pathological correla- 
tions; for instance, the rare glycosuria in myxedema may well point to a simul- 
taneous insufficiency of the pancreas. I would enter more fully only into a 
discussion of one of the symptoms detailed, as it is regarded by the adherents 
of dysthyrosis as an especially important argument. It is the combination of 
Basedow’s and myxedematous symptoms in the same patients. In Sattler’s 
work will be found a compilation of such cases. The observation that a fully 
developed Basedow’s may gradually go over into a myxedema has nothing 
striking about it, for an overfunctionating thyroid may degenerate and become 
functionally insufficient. Such a case was first described by Joffroy and 
Achard. In a twenty-three-year-old woman there first developed a typical 
Basedow’s disease, then great weakness, swelling of the feet, legs, trunk, 
the upper extremities and the face, apathy, great fatigability. Autopsy 
showed a sarcoma of the pleura and disappearance of the thyroid parenchyma, 
in the place of which was found connective tissue. Confer also the case of 
Gauthier. 
Concerning the cases of simultaneous occurrence of Basedow’s disease 
and myxedema, I would remark that in many of these cases the diagnosis myxe- 
dema seems to me very doubtful indeed. I call to mind the case of v. Schrotter, 
mentioned above, which microscopical examination showed to be lipomatosis. 
Perhaps something analogous is to be seen in the case of Hirschl, in which the 
skin of the ankle-joint was entirely normal and the swelling of the leg ended in a 
sharp ring. In this case, too, the swelling of the face was limited to a pad-like 
thickening on the lower border of the lower jaw. The circumstance that the 
skin was dry is no evidence for myxedema; otherwise there was a typical Base- 
dow’s disease. Also in both of Loew’s cases—otherwise typical cases of Base- 98 
THE DISEASES OF THE THYROID GLAND 
dow’s disease—there existed a thickening of the extremities that involved the 
backs of the feet little if at all. Thyroid medication had no influence on this 
thickening. 
It seems to me further noteworthy that almost all the cases that Sattler 
quotes show peculiar complications. In two cases (cases of Mobius and of 
Ilirschl) there existed at the same time osteomalacia. In the case of Sollier, 
the myxedematous swellings occurred especially at the time of menstruation, 
in the case of Ulrich there were choreiform twitchings, in the case of Kowalewsky 
epilepsy since youth, in the case of Ilolub there was marked Chvostek’s sign, 
and in OsleUs case there later occurred under thyroid medication marked glyco- 
suria. Moreover, I consider it possible that cases that stand on the border-line 
of thyroid glandular insufficiency would under certain conditions show lowered 
tolerance for thyroid-gland preparations. As example I cite the following case: 
Observation X.— Mrs. B., forty-eight years, has had five confinements. After the last 
confinement there was a gradual taking on of body weight, until she weighed about 125 kg. 
About twenty years ago she underwent a reduction cure, in the course of which she rapidly 
lost 14 kg. At the time, also, thyroid-gland tablets were administered. After the treat- 
ment marked excitability, cardiac oppressions, diarrheas, sweats, and tremor occurred. 
These symptoms lasted a long time. Then they retrogressed and the body weight again 
increased. Three years ago after inunction of an iodine salve, there was a gradual in- 
crease of the Basedow’s symptoms. The thyroid gland had formerly been large, and now 
enlarged still more. Two years ago the right lobe of the thyroid gland was extirpated. 
After the operation there was a gradual increase of body weight, about 12 kg., sensation of 
cold (can scarcely warm herself), skin dry and cold, mental sluggishness, constipation. 
For several months thyroid medication. The skin again became moist, cardiac manifesta- 
tions, tachycardia, and arrhythmia again appeared, the patient was excited, the constipation 
disappeared. Body weight decreased. When the thyroid medication was discontinued, 
the weight increased again and the myxedematous symptoms reappeared. Since that time, 
periods of thyroid administration were many times introduced, and regularly after the 
use of only two or three tablets a day for a short time Basedow’s manifestations appeared. 
At present after a three weeks’ thyroid treatment, there is a slight tachycardia and especially 
marked arrhythmia. The heart is dilated, the pulse is poorly filled, the skin is moist, there 
are stary eyes and a very slight fine-waved tremor. 
Later, in the section on myxedema, I shall cite similar cases. The slight 
tolerance toward thyroid preparations is in this case certainly remarkable, as 
high tolerance is characteristic for typical cases of myxedema. To my mind 
there is in this case no necessary basis for the assumption of a dysthyrosis. It 
is well known that a degenerated heart muscle is extraordinarily sensitive 
toward thyroidin. It can very well be conjectured that a slight excess of thy- 
roidin would already damage the heart muscle, if the myxedematous symptoms 
have not as yet altogether disappeared. Finally, it remains to be investigated 
whether in similar cases the myxedematous swellings of the skin are always 
dependent exclusively on the thyroid glandular insufficiency. Much speaks for 
the fact, as above indicated, that in such cases frequently also other ductless 
glands are degenerated. Especially frequently there occurs a simultaneous 
affection of thyroid and hypophysis. As is known, there is found an insuffi- 
ciency of the pituitary gland, alterations of the skin, and trophic disturbances 
that are similar to those of myxedema. In many Basedow’s cases with myxede- basedow’s disease 
99 
matoid symptoms, and in cases of myxedema that react to thyroid treatment 
with only partial improvement and that may even show signs of hyperthyroid- 
ism rapidly, it is quite probable that these myxedematoid manifestations depend 
on a hypophysial insufficiency (see also the chapter on the hypophysis). 
Many authors are disposed to ascribe to thymus hyperplasia an important 
role in the pathogenesis of Basedow’s disease. Already v. Hansemann was 
of the opinion that the cases of “thymus Basedow” could be distinguished also 
clinically. Hart refers the cardiac manifestations in Basedow’s disease to the 
thymus hyperplasia alone and sees in such cases thyroid hyperplasia as some- 
thing secondary. On the other hand, Gebele regards the enlargement of the 
thymus gland as a compensating process that serves to weaken the hyperthy- 
roidism. Especially worthy of notice are the reports of Garre and of Capelle 
and Bayer, concerning the extirpation of the thymus gland in Basedow’s disease. 
In the case of Capelle and Bayer, thymectomy seemed to have no influence on 
the struma, the exophthalmus, or the bulbar symptoms, but the cardiac symp- 
toms seemed to improve. After some weeks the mononucleosis had disap- 
peared. Gebele, however, does not regard the thymus in this case as enlarged, 
and points out that five months after the thymectomy an operative procedure 
on the thyroid was necessary on account of pronounced symptoms of Basedow’s. 
According to E. Bircher, implantation into the abdominal cavity of dogs of 
thymus gland that came from an individual who died from thymic death at 
operation called forth temporary tachycardia, conditions of excitement, and 
tremor, and also a struma. Clinical and experimental contributions to this 
subject seem to me far inadequate to ascribe to the thymus gland a significance 
at the present time great enough to warrant the delimitation of a thymogenic 
Basedow’s. 
Just a few words as to the place of iodine in the physiology and pathology of 
the thyroid gland. Iodine is found in very many organs, in the skin, the 
lungs, the ovaries, the small intestines, the blood, the liver, the bile, the hairs, 
and the glandular part of the hypophysis {Blum, Bourget, Heffter, Drechsler, 
and others). The iodine-contents of the thyroid gland is, however, much larger 
(according to Justus eight to ten times) than that of the other organs relatively 
rich in iodine. The normal thyroid gland of man contains according to Magnus- 
Levy about 0.3-0.9 mg. of iodine for 1 kg. of dry substance. The entire gland 
contains about 2-9 mg. {Baumann, Oswald). The thyroid glands of fetuses and 
new-born children are iodine-free. The thyroid glands of herbivora have very 
high iodine-contents, while the thyroid glands of carnivora have the lowest 
iodine-contents {Baumann, Roos, Oswald). Copious feeding of meats to dogs 
makes the thyroid gland very poor in iodine. The activity of the thyroid 
glandular substance is bound with its iodine-contents and parallels these. As 
is known, all the symptoms of deprivation after extirpation of the thyroid gland 
may be alleviated by the administration of iodine-containing thyroid glandular 
substance. The iodine-containing protein substance obtained by Oswald from 
the thyroid gland, iodthyroglobulin, contains about 1.75 per cent, of iodine. 
The iodothyrin obtained by Baumann by splitting with acids contains about 9.3. 
per cent. Oswald obtained from thyroglobulin by splitting with acid a still 100 
THE DISEASES OF THE THYROID GLAND 
richer iodothyrin with 14.29 per cent, of iodine. While the iodothyroglobulin 
seems to possess the complete action of dried thyroid-gland substance, iodo- 
thyrin is less active, even though it possesses a greater heightening power on 
metabolism and a greater action on the cardiovascular apparatus than artifi- 
cially iodized protein bodies. Its action is, however, much less than that of 
dried thyroid glandular substance. [Thyroxin contains 60 per cent, of iodine.— 
Editor.] While, for example, we could obtain with 2.7 gm. of Bourrough, 
Wellcome, and Co.’s tablets distinct tachycardia and other slight symptoms of 
thyroidism in three days, later twenty-one Bayer’s iodothyrin tablets daily, 
administered for a long time, were without effect (experiment of Dr. Fleming). 
The iodothyrin is also incapable of alleviating the manifestations of deprivation 
that occur in youthful animals after thyroidectomy {Pick and Pineles). Just 
as after splitting with acids, the thyroid-gland substance, after exposure to 
digestive ferments, loses in activity. Exposure of short duration to peptic and 
tryptic digestion does not seem to alter the specific substances, as we are able 
to bring about the complete action even on peroral administration. All 
experiments point to the fact that the thyroid gland carries iodine in a specific 
organic combination, perhaps iodothyroglobulin. [Thyroxin.—Editor.] 
The iodine-contents of pathological glands varies greatly. The purely 
parenchymatous Basedow strumas contain almost no iodine; strumas rich in 
colloid are also rich in iodine. Investigations by Oswald, A. Kocher, and others 
have shown that the iodine-contents of strumas rich in colloid is really not 
absolutely greater than in the normal thyroid-gland, but that relatively, that is, 
taken in relation to the amount of thyroid-gland substance, it is less. On 
the contrary, the holding in thyroglobulin is absolutely and relatively greater; 
in colloid goiters there is found, therefore, either an iodothyroglobulin poor in 
iodine or less iodothyroglobulin and more thyroglobulin. Probably in the Base- 
dow struma the formed iodothyroglobulin reaches the circulation immediately 
in consequence of the increased permeation with blood. 
The function of the thyroid gland, if the organ is altered pathologically, 
may be influenced by the administration of inorganic iodine. Individuals with 
normal thyroid glands separate out again the excess of iodine rather promptly, 
without any disturbance of the iodine equilibrium. Strumous individuals, 
according to the investigations of A. Kocher, behave very diversely; in strumas 
with abundantly functionating parenchyma more iodine is excreted than 
introduced, so that thyroid-gland tissue is melted down and symptoms of thyroid- 
ism may appear. In strumas with relatively iodine-poor colloid this is first 
iodized; there therefore occurs an iodine retention, but on continued treatment 
with iodine there may come about melting down of the colloid and thyroidism. 
Administration of the phosphates should favor the action of iodine and keep 
back the melting down of tissues. This experiment renders intelligible the old 
experience that in certain forms of struma the administration even of very 
small amounts of iodine leads to manifestations of thyroidism. 
Kocher’s investigations stand in the most intimate relation to the older 
experience as to the so-called iodine Basedow’s. Coindet, in Geneva, introduced 
iodine into therapy in 1820. Shortly afterward it was reported by Coindet basedow’s disease 
101 
himself and by Gautier, d’Espine, Relliet, and others that after the administration 
of iodine there often occurs a series of symptoms that are sharply distinguished 
from those of pure iodism (acne, catarrh of the mucous membranes, etc.). These 
symptoms (tachycardia, tremor, emaciation, etc.) could develop in strumous 
individuals after the administration of minimal amounts of iodine, and long 
outlast the medication. Already Lehert advocated the opinion that in such 
cases the administration of iodine led to rapid absorption of thyroid glandular 
substance and the symptoms mentioned could be referred to this. Breuer 
explained the contradiction that these observations met with in Paris by the fact 
that only certain forms of struma, as those for example in Geneva or Vienna, 
reacted to the administration of iodine in this manner. The regional difference 
in the sensitiveness toward iodine can be elicited from the large series of experi- 
ments of Fleischmann. Fleischmann after the administration of iodine to the 
persons under investigation in Basel saw acceleration of the pulse in 68 per 
cent., in Berne in 23 per cent., in Berlin in only 3.7 per cent. In Heidelberg, the 
use of iodine was warned against by Krehl. According to the statements of 
Breuer, Kocher, Mohius, Ortner, Goldflam (the last on the injection of iodipin 
into a person with tabes), a typical morbus Basedowi may develop, especially 
in the younger individuals, even in cases in which no struma existed before the 
treatment with iodine; or in cases of cured Basedow’s there may occur a severe 
relapse with a new enlargement of the thyroid gland. Case B. (Observation 
X), previously reported, furnishes a good example of this; or an existing Base- 
dow’s disease may be considerably aggravated by iodine therapy (compare 
case S. Schm). In Vienna, according to my observations, conditions are such 
that one must directly warn young persons with diffuse soft strumas against the 
use of iodine. Pineles has seen especially frequently, after the use of iodine, 
the occurrence of the manifestations of thyroidism in goitrous individuals in 
families in which Basedow’s disease or diabetes has occurred or in which a 
neuropathic disposition has existed. This was the case even when the iodine 
was given in very small quantities. 
It would really be correct to separate the cases of simple iodothyroidism 
from those of iodine Basedow’s, although there are transitions between the two 
groups. In the first group of cases administration of iodine brings about a 
rapid melting down of thyroid-gland tissue and hence the manifestations of 
thyroidism. After the discontinuation of the iodine medication the manifesta- 
tions for the most part rapidly retrogress, the thyroid gland remaining the 
same in size or becoming smaller. In the cases of iodine Basedow, on the 
contrary, the thyroid gland increases in volume, and the Basedow’s manifesta- 
tions can long outlast the iodine medication. 
As to the etiology of Basedow’s disease we do not know anything definite. 
The goiter noxus can play only a subordinate role, as just the fully developed 
forms of Basedow’s disease are rare in goiter districts. Neuropathic predisposi- 
tion is to be regarded at the most as a predisposing factor; psychic and bodily 
traumata as well as iodine and thyroid glandular medication are to be regarded 
as determining factors. Frequently Basedow’s disease develops at the close 
of acute infectious diseases (acute articular rheumatism, angina, typhoid fever, 102 
THE DISEASES OF THE THYROID GLAND 
scarlet fever, etc.). In some cases an idiopathic thyroiditis passes over into it. 
Finally, Kahn and myself in several cases of declining tetany saw occurrence of 
thyroid glandular swelling and distinct Basedow’s symptoms. As furthermore 
the true Basedow’s struma shows accumulations of lymphocytes and as the 
parathyroid glands in such cases are swollen, many authors have thought of an 
infectious etiology of Basedow’s disease. This assumption is not however 
satisfactory, as many cases of Basedow’s disease develop in complete health and 
are entirely fever-free. Hence the acute infection is regarded by Mobius, de 
Quervain, and others only as the connecting link. As I have already mentioned, 
the assumption of a thymogenic Basedow’s disease seems to-day to have but 
little foundation. Even those who refer all the symptoms of Basedow’s disease 
to an increase of function of the thyroid gland must recognize that the cause 
proper of this increase of function is as yet unknown. As the secretion of the 
thyroid gland is regulated by the central nervous system, lately nervous centers 
have again been assumed (Wiener), constituting, in a manner, a revival of the 
bulbar theory of Charcot and Geigel (Oppenheim). According to this theory 
many of the Basedow’s symptoms, above all the eye symptoms which are so 
hard to produce by artificial thyroidism, are coordinated with those of the 
thyroid glandular swelling. This theory would at least explain the rare ob- 
servation that the exophthalmus may occur unilaterally (Fr. Muller, Roasenda, 
Kocher, and others). 
The statements as to the theory and etiology of hyperthyrosis bring to 
recognition the fact that the cause of Basedow'* disease is not as yet explained. 
Most of the symptoms can be referred to the hyperthyroidism; the cause of the 
hyperthyroidism is possibly conditioned centrally, and thus perhaps a series of 
symptoms and alterations in the function of other ductless glands are coordinate 
with the hyperthyroidism. Finally, we should point out that the not unusual 
combination of the trophoneuroses (scleroderma) with symptoms similar to 
those of Basedow’s disease or even typical hyperthyrosis obtain some value in 
this connection (see Chapter I). 
Forms of Basedow’s Disease.—In consequence of the great variability 
which Basedow’s disease presents in its manifestations and in its course, there 
has existed from former years the attempt to bring forward certain symptoms 
as cardinal symptoms and to lend to certain apparently more remote symptoms a 
greater nosological independence. Originally the symptoms of the so-called 
Merseburg triad—exophthalmus, goiter, and tachycardia—were taken as the 
cardinal symptoms. However, exophthalmus is wanting in a not inconsider- 
able part ot the cases of this condition and, moreover, Pierre Marie added a new 
cardinal symptom—the tremor. The fact that the exophthalmus is often 
permanently absent led Pierre Marie to the establishment of the formes frustes, 
the effaced, or better, the incomplete forms, while formerly Charcot understood 
by forme fruste the residual condition after improvement of the classic form. 
Gautier and Buschan distinguished true Basedow’s disease and the pseudo- or 
secondary Basedow’s disease, regarding the former as a general neurosis with 
the predominance of the psychic and vasomotor sphere, while the latter is 
brought about by other changes in the organism among others also a distur- basedow’s disease 
103 
bance of function of the thyroid gland. Mobius distinguished primary and 
secondary Basedow’s disease according as to whether the alteration of function 
developed in a previously normal or in a goitrously degenerated thyroid gland. 
Secondary Basedow’s disease ordinarily pursues a chronic course and is often 
incomplete; the primary is often acute and rich in symptoms. The secondary 
form corresponds to the goitre basedowifie (Revilliod and Pierre Marie). Mobius 
does not however ascribe so very great a significance to this distinction, as he 
regards the alteration of function of the thyroid gland as the central figure. 
“The cardinal symptom is just the tachycardia.” Th. Kocher distinguishes 
between the fully developed forms and the so-called hyperthyrotoxic equivalents. 
Fr. Kraus has separated out the so-called goiter heart as an especial 
independent form. Apart from those cardiac disturbances which come about 
through mechanical obstruction to the circulation or respiration, there exists 
additionally in goiters, according to Kraus, a cardiac disturbance associated 
with other hyperthyroidal symptoms, which cardiac disturbance is produced 
bv the thyroidal secretion acting at a distance. 
Eppinger and Hess distinguish between sympathicotonic and vagotonic 
forms, according to whether the symptoms of excitation predominate on the 
part of the autonomous or of the sympathetic nerves. Characteristic for 
the vagotonic cases would be “a relatively slight degree of tachycardia, with, 
however, markedly pronounced heart oppressions, distinctly marked v. Grdfe, 
and wide palpebral fissures, absent Mobius, slight protrusion of eyeballs, 
marked secretion of tears, outbreaks of sweats, diarrheas, distresses that 
are to be referred to hyperacidity, eventually eosinophilia, and disturbances 
of the rhythm and mechanism of respiration, absent alimentary glycosuria;” 
in the sympathicotonic cases, Eppinger and Hess found “marked protrusion 
of the eye-balls, greatly increased cardiac activity with slight accentuation 
of the subjective disturbances, absence of sweats and diarrheas, marked falling 
out of the hair, inclination to increase of fever, absence of eosinophilia, no 
disturbances of respiration, alimentary glycosuria.” 
The position of many of these symptoms as sympathicotonic or vagotonic 
is as yet quite insecure. Thus, for example, the interpretation of the sweats 
as vagotonic is not sufficiently founded, because as yet we have known noth- 
ing as to the course of autonomous nerves of the skin. The significance of 
the individual phenomena is rendered the more difficult because there exist 
both sympathetic accelerator [fordernde] and inhibitor and autonomous 
accelerator and inhibitor fibers. I cannot look upon the alimentary glycosuria 
as sympathicotonic, as according to our investigations the alimentary factor 
is to be sharply separated from the nervous factor, and for the former the 
functional breadth of the pancreas is the determining factor. Moreover, 
there are undoubtedly cases, as Eppinger and Hess and recently v. Noorden, 
Jr., bring out, in the course of which at times the sympathicotonic, at times 
the autonomotonic, symptoms predominate. Before everything else, how- 
ever, the tachycardia is evidently to be regarded as the cardinal symptom 
'of Basedow’s disease; and, on the other hand, the sweats or the marked mois- 
tening of the skin is so extraordinarily frequent that almost never can we THE DISEASES OF THE THYROID GLAND 
104 
speak of a purely sympathetic type in the sense of Eppinger and Hess. In 
my opinion everything speaks for the fact that in Basedow’s disease the entire 
nervous system is in a condition of overexcitement and that the pictures pre- 
sented by the vegetative nervous system are uncommonly manifold and 
always changing. 
Recently Stern has entered the list for the greater independence of 
certain forms of Basedow’s that he regards as Basedowoid. In a certain 
sense there is in this a reversal to the views of Gautier and Buschan. Stern 
divides the classic form into true and degenerative Basedow’s disease, accord- 
ing to whether the disease develops in a previously normal or in a neuropathic 
individual. From the great group of formes frustes Stern separates out 
Kraus's goiter heart; the remaining forms are based regularly on an original 
degenerative neuropathic foundation. Basedowoid and Basedow’s ac- 
cording to this view are distinguished from each other essentially by 
their beginning, course, and prognosis. According to Stern, they never pass 
over into each other. Chvostek agrees with Stern on the whole, except that 
he would regard as formes frustes the relatively abortive cases of true Basedow’s 
that pursue a light course. Langelaan regards Stern's Basedowoid as Base- 
dow’s on an asthenic basis. The practical significance of a clinical differen- 
tiation of the individual forms is obvious, if through them deductions as to the 
prognosis and therapy can be given. On the other hand, I would point out 
with emphasis the danger that exists in the fact that through the accentuation 
of the distinguishing features, the painstakingly wrought-out conception of the 
pathogenetic unity, the hyperthyroidal syndrome, is relegated too much to the 
background. The same is true as to the statement as to which symptoms must 
be present, if we wish to establish the diagnosis of hyperthyrosis, that is, Base- 
dow’s disease in a wider sense. It seems to me suitable to approach this ques- 
tion from another direction, and to establish what symptom or what symptoms are 
constant in artificial thyroidism and the earliest to appear. According to our 
investigations on this subject it appears that without doubt the cardiovascu- 
lar symptoms, especially the tachycardia, here predominate. To the tachy- 
cardia may be added sweats, or mononucleosis, or psychic excitability, or 
headaches, etc. The symptom that occurs twice as frequently is accord- 
ing to our observation the greater moisture of the skin, which is absent only 
in rare cases. If other symptoms are added to this, we obtain syndromes 
such as tachycardia, sweats, headaches, or tachycardia, sweats, tremor, or 
tachycardia, sweats, mononucleosis, etc. Hence by this route we come back 
to the conception of Charcot and Mobius that just cardiac or vascular distur- 
bances are to be regarded as the cardinal symptom, to which is added in most 
cases the increase in metabolism; with somewhat longer action of the hyper- 
thyroidism, tachycardia, mononucleosis, and tremor may well be regarded 
as cardinal symptoms. From these symptoms to pronounced exophthalmus 
is indeed a wide stride; probably there is added an enormous flooding of the 
blood with thyroid secretion; and perhaps other constitutional factors whose 
nature is unknown to us. In the fully developed cases we have always before 
us a marked condition of excitation of almost the entire vegetative nervous system. basedow’s disease 
105 
This way of looking at the subject brings us back to Mohms’s view that all 
the syndromes of Basedow’s disease have a common nucleus. The classic 
form of Basedow’s is characterized only by the more pronounced accentua- 
tion of the eye symptoms, by a more considerable increase of the metabolic 
processes, and by its rapid origin, while Stern’s Basedowoid ordinarily shows 
from the beginning an insidious course. 
From both these forms—the classic form and the forme fruste—is to be 
delimited sharply only the Kraus-Minnich goiter heart. The newer investi- 
gations show that here the cardiac disturbances are not of pure hyperthy- 
roidal origin, but that the goiter noxus is involved in their coming about. I 
shall therefore speak of this form under cretinic degeneration. 
[About the time of puberty there occurs in females especially an enlarge- 
ment of the thyroid gland which should be regarded as more or less physiologic. 
The occurrence of this has been dwelt on by many authors. It is doubtful 
whether these enlargements are not to be considered simple goiters, to be 
treated with small doses of iodide as recommended by Marine and Kimball 
(see addendum to the chapter on goiter). Of course if some of the symptoms 
of hyperthyroidism are superadded, basal metabolism work is called for. 
But these goiters may be treated much more conservatively than goiters in 
older persons.—Editor.] 
Course.—The classic forms of Basedow’s disease as well as the formes 
frustes show the greatest variability in their course. The classic form may de- 
velop in the midst of complete health, often in a peracute manner, for example, 
during swimming {Pribram) or a few hours after a tonsillotomy (.Patterson); 
the condition may again return to normal, with a disappearance of the eye 
symptoms, or may lead to death under stormy manifestations (delirium, 
premortal increase of temperature), or may go over into a chronic form with 
remissions and renewals. It can, however, after several years show a sur- 
prising turn toward amelioration, and may eventually heal with the reten- 
tion of the exophthalmus, which has now become definite; relapses of this 
form are frequent; in other cases it leads to severe irreparable cachexia. The 
classical form may also begin gradually both in previously normal and in 
neuropathically affected individuals, or may show quite the picture of a forme 
fruste, and only later develop fully under any determining factor or without 
ascertainable cause. 
Among the formes frustes are slight abortive cases ot sudden onset. 
The cases with fat stools and glycosuria are mostly cases of abortive formes 
frustes (without eye symptoms). Many of the cases that I observed set in 
after trauma, but in the great majority of formes frustes a quite gradual 
beginning is the rule; especially in those forms existing on a neuropathic 
basis, the forms that Stern designated as Basedowoid, the beginning goes as 
far back as youth, and decades may lapse before the disease is to any degree 
distinct. In such characteristic cases the trophic disturbances are mark- 
edly prominent. It is Stern’s great service to have shown that in these cases 
there is quoad sanationem a very favorable prognosis. On the contrary 
I cannot agree with Stern that “Basedowoid” cases never go over into the 106 
THE DISEASES OF THE THYROID GLAND 
classic form of Basedow’s. It seems to me that the typical Basedow’s on 
a degenerative foundation (Stern’s degenerative Basedow’s) can hardly be 
anything else than a Basedow’s with acute exacerbations. 
The diagnosis of the classic form is easy, differential diagnostic diffi- 
culties presenting only in the formes frustes. Alcoholism and nicotinism 
may produce tachycardia and tremor; the history or finally the demonstra- 
tion of a central scotoma will set the diagnosis right (Chvostek). Fr. Muller 
has pointed out the similarity of chronic lead poisoning to the formes frustes. 
Here the lead line and the granular erythrocytes will set matters clear, although 
I have seen a case of the combination of the two conditions [lead poison- 
ing and Basedow’s]. Difficulties may also attend the decision of the question 
whether such Basedow’s symptoms as tachycardia, pigmentations, lability 
of the vascular system which often accompany such trophoneurosis of the 
vegetative nervous system as scleroderma, depend on a simultaneous hyperthy- 
rosis or the fundamental disease as such. Cassirer further points out that 
a slight grade of exophthalmus is often simulated by the sclerodermic mask. 
The presence of a Basedow’s struma in four such cases enables us to speak 
with probability of a combination with Basedow’s disease. Most difficult 
is the differential diagnosis from the cardiovascular neurosis of Chvostek in 
which occur tachycardia, dermographism, inclination for sweats and fine- 
waved tremor. Great lability of the heart manifestations speak for neurosis, 
enlargement of the thyroid gland and slight eye symptoms, heightening 
of the [metabolic] exchange (v. Noorden) and especially a mononucleosis 
speak for hyperthyroidism. In many cases, as Chvostek emphasizes, a certain 
diagnosis can be first established from the course of the disease. In persons 
that come to the physician with complaints as to slight emaciation, nervous- 
ness, cardiac palpitations, and psychic excitation, light will often be thrown 
on the matter by the fact that they have been using iodine. For the judgment 
of the fat stools the evacuation of unsplit neutral fats and the predomi- 
nance of finely divided soap balls and fatty acid needles is decisive. Evi- 
dence for the diagnosis of a complicating glycosuria is afforded by the fact 
that the true thyrogenic glycosuria usually is of slight intensity and that 
with the improvement or the retrogression of the Basedow’s symptoms it 
not only disappears, but high or normal tolerance for carbohydrates reappears 
very rapidly. [The study of the basal metabolism is an invaluable aid in the 
diagnosis of Basedow’s disease and hyperthyroidism. It is probably better 
to take more than one basal metabolic rate in doubtful cases, and always 
the clinical symptoms should be correlated with the basal metabolic findings.— 
See addendum.—Editor] 
Prognosis and Treatment.—Since the beginning of the operative era in 
the treatment of Basedow’s disease the question of especial interest has been 
whether surgical treatment should supersede the medical treatment. One 
has but to consider the great variability in the course of Basedow’s disease 
to understand that this question can be solved only by much statistical material. 
We must therefore bring up the question as to the prognosis of the cases of 
Basedow’s disease treated purely medically. The greatest difficulty lies basedow’s disease 
107 
in the fact that the internist publishes only the severest, because 
interesting, cases, and that further, this material comes especially from 
clinics and dispensaries, hence from the poorer classes of the population; 
and yet v. Noorden mentions the fact that the course of Basedow’s disease 
is to a great extent dependent on whether the patient for a long time can 
be placed under favorable living conditions until he has had time to regain 
his health. The material of the individual statistics is therefore very 
dissimilar. All statements by the internists agree on the one point that 
in mild forms of Basedow’s disease, recovery is the rule, as far as the patients 
can spare time for a proper treatment (y. Noorden, Oppenheim, Pribram 
Chvostek, Mackenzie, Murray, Quine, and many others). Special statements 
as to curability are concerned only with the slight and severe forms together. 
I mention A. Kocher's statistics (internal cases) 18 per cent., Syllaba's 26 
per cent., Stern's (of 19 cases, 9 almost cured), Mackenzie's 50 per cent, (very 
good result), Quine's 60 — 70 per cent., Klemm's 25 recoveries among 32 
cases. Just as difficult is any idea as to the mortality (death from Basedow’s 
disease itself, not from intercurrent affections). Sattler has collected the 
literature that is not too one-sided, and arrives at n per cent., Kocher states 
22 per cent., Leischner and Marburg, 12-25 Per cent., Mackenzie estimates 
the mortality in the acute cases as at 30 per cent., in cases in which icterus 
develops, the prognosis is extremely grave. Between these two extremes 
—recovery and death—lie the chronic and more or less improved cases, con- 
cerning the relationship of which to each other the figures again vary widely. 
Thus Kocher states 33 per cent, uncured, 27 per cent, improved; Syllaba 
36 per cent, improved, Stern, of 19 cases of classic morbus Basedowi, 6 with 
slight improvement, 3 uncured. Stern mentions that the improvement 
may set in even after years. Stern's work is of great practical importance 
in so far as it shows that cases on a degenerative-neuropathic basis 
progress to full height, rarely die of Basedow’s disease itself, and on the 
contrary, very rarely recover entirely. [For remarks on treatment, see 
addendum.—Editor.] 
In spite of the quantity of the material, its dissimilarity, as previously men- 
tioned, gives no certain result, at least not until according to v. Noorden's 
proposition there are separate statistics as to the disease in the well-to-do 
and the poor classes. Before I go into the question of internal treatment I 
would like to make a few remarks as to the results of operation. Concern- 
ing the method of operation, it should be mentioned that the ligation of arter- 
ies of the thyroid gland has to-day for the most part been discarded, because 
unsafe, and that enucleation methods are mostly practised, and sometimes 
excision and ligation are combined. The resection of the sympathetic, 
introduced by Jaboulay, practised especially by Jonnescu and by Abadie, has 
found but little vogue. Lately Berard has stated that among 40 operations, 
there were 8 complete cures, 5 died at operation, 16 retained a small goiter, 
5 were improved, and 5 remained uninfluenced. The latest statistics of 
Kocher include 376 of his own cases, of which 76 per cent, were cured (in one- 
fourth of these the exophthalmus was retained). The mortality was 3.9 per 108 
THE DISEASES OF THE THYROID GLAND 
cent., the rest was improved or not cured; one-third of these cases were oper- 
ated on more than once before the desired result was obtained. Leischner 
and Marburg report 45 cases (without compression symptoms) from v. Eisel- 
berg’s clinic, of which there were 6 cases of death (3 of the first 4 cases oper- 
ated on died), 18 cured, 8 improved. Mayo has 4.75 per cent, mortality 
in 405 cases and 70 per cent, cures; Schultze (Riedel) reports among 50 cases 
72 per cent, cured, 12 per cent, improved, 2 per cent, poor results, 12 per 
cent, deaths. Landstrom reports among 38 cases 52.6 per cent, cured, 18.4 
per cent, improvement, 29 per cent, poor result, among which 5.5 per cent, 
death. I shall not enter into the older compilations, they are less valuable, 
as the methods of operation have improved since their time and also the 
indications for operation have changed somewhat. [See the tabulated list of 
operative results in the addendum to this chapter.—Editor.] 
If we consider that among the cases operated on just the mild cases seem 
to be rare from the better situated classes, and that therefore the surgical statistics 
contain the especially severe cases, there is no doubt that all the surgical 
treatment in general surpasses the medical. To this should be added that 
after the operation the tachycardia usually diminishes; in a relatively short 
time, the body weight rapidly increases, even without hospital care, and 
working capability is rapidly attained. The difficult point of the question 
to-day is concerned with the indications for operation. Mild cases among the 
better situated classes should indeed not be recommended operation, nor 
should the chronic formes frustes on a degenerative-neuropathic basis (Stern’s 
Basedowoid). Also Kocher points out that the results in these cases are less 
satisfactory. Operation is indicated in cases with compression symptoms. 
In the cases of pure Basedow’s the social status should be decisive, because, 
as already mentioned, without doubt, operation leads more rapidly and 
certainly to working capability. A certain risk is always associated with 
operation, especially if a status thymico-lymphaticus is present. According 
to the statistics of Capelle, already mentioned, nearly 100 per cent, of the cases 
of Basedow’s disease that died at operation had a hyperplastic thymus. Hotz 
therefore proposed to avoid operation if the X-ray transillumination shows 
a shadow [indicating an enlarged thymus gland]. The demonstration of 
an enlarged thymus gland by means of the Rontgen procedure is however 
very uncertain. Kostlivy believes that the operation is especially dangerous 
in the cases without mononucleosis. This does not however meet with my 
view, because mononucleosis in the one and the same case may vary greatly 
(vide ante). All these questions have not as yet been worked out fully. 
Another question is as to whether one should operate early, or should await 
the results of internal therapy. A long period of awaiting is at all events 
unsuitable if the cardiac manifestations are well pronounced, as operation 
represents so much the less result the broader the cardiac dilatation and the 
more advanced the degenerative alterations of the cardiac muscle and of the 
other organs. On the other hand Kocher recommends a medical pretreat- 
ment as preferable, as far as no indicatio vitalis does not make an immediate 
operation necessary. basedow’s disease 
109 
Of late a lively discussion has arisen concerning the reliability or the value 
of the irradiation of the thyroid gland with the X-rays. This was discovered 
by Beck, first used in Germany by Gorl, and is warmly recommended in Vienna 
by Holzknecht and G. Schwarz. Schwarz has reported 40 cases in which after 
the irradiation the nervous symptoms always disappeared, and the tachycardia 
almost always; in two-thirds of the cases there were gains in weight, in about 
half the cases the exophthalmus retrogressed; only in one-third was the struma 
decreased in size. The cases that Holzknecht later reported showed a similar 
good result, v. Eiselsberg points out, however, that in three of the cases that 
had been treated with X-rays and that he operated on later, he found adhesions 
of the thyroid gland to the neighboring parts; on account of this the operation 
was essentially more difficult. Also Hochenegg reports three similar cases. It 
does not seem to me a priori that such adhesions are to be referred exclusively 
to the X-ray therapy. Kocher mentions especially that the operations of 
Basedow’s strumas are made especially difficult through an especial density of 
the peristrumal connective tissues, by adherence of the external goiter capsule 
to the struma, in short by alterations that are similar to those of a chronic 
inflammation and are often found in strumas after a long treatment with iodine 
salve; on the other hand it is to be expected that there are tissue reactions to 
X-ray illumination that especially favor the development of such adhesions 
and that the fragility of the blood-vessels constitute a danger. In the discus- 
sion that followed Holzknecht’s presentation in the Wiener Gesellschaft fur Arzte 
[Vienna Association of Physicians], v. Noorden and v. Strumpell assumed an 
expectant attitude with regard to X-ray therapy, while v. Wagner and Chvostek 
condemned it. In a number of cases that I published from the first medical 
clinic since that time I have seen a fairly good result as the consequence of 
X-ray therapy. [See addendum.] 
I quote the following example: In one case the spontaneous glycosuria disappeared 
from the day of the first irradiation, in another case the weight curve, which in spite of 
week-long hospital treatment had continually sunk, began to rise only a few days after 
the first irradiation, the diarrheas disappeared, and after a few weeks the patient could 
again resume his studies as technician. 
As far as the internal treatment of Basedow’s disease is concerned, it must 
be sorrowfully said that all attempts to find a specific method of treatment 
have up to the present not led to certain results. Ballet and Eniquez first 
used for therapeutic purposes the serum of thyroidectomized animals, Bunghart 
and Blumenthal the serum of myxedema patients, Sorgo the meat of thyroidless 
herbivorous animals. Mobius used the serum of thyroidless animals (anti- 
thyroidin, Merck’s preparation) or thyroidectin {Parke, Davis & Co.), Lanz used 
the milk of thyroidless animals (Rodagen-milk powder of thyroidless goats’ 
milk sugar). Lepine obtained an “immune serum” from the feeding of thy- 
roidin to goats. Finally we must mention the thyrotoxic serum of Beebe, 
v. Mikulicz recommended the feeding of thymus substance. All these thera- 
peutic propositions were for the most part greeted in the beginning with enthusi- 
asm, but improvement was seen only in the light cases, in which the amelioration 110 
THE DISEASES OF THE THYROID GLAND 
could not be attended with certainty by the means employed. In recent years 
to have the statements as to favorable results become always sparser. The 
scepsis is the more justified for the reason that all authors who have investigated 
the influence of thymus, rodagen, or antithyroidin serum on the metabolism 
have been able to elicit only negative results (Magnus-Levy, Stuve, Salomon).— 
A. Kocher recommends neutral sodium phosphate (up to 6 gm. per day), which 
should prevent the dissemination of the iodine-containing substance from the 
thyroid gland. Views do not agree as to the value of this means of treatment. 
Otherwise medical treatment seems to fail almost always. All authors are, for 
example, of the opinion that digitalis rather aggravates the cardiac conditions. 
Also the diarrheas and vomiting are but little influenced by drugs. 
v. Muller and Saxl proceeding from the experimental elicitation of Loeb, 
and of Frohlich and Chiari that calcium exercises a dampening influence on 
certain conditions of irritation of the nervous system, have used in Basedow’s 
disease intramuscular injections of calcium chloride gelatine (5-7 cc. of Merck's 
preparation “Kalzine”). They found in the typical cases mostly an essential 
improvement, while the treatment usually seems to fail in the case of an 
heredito-neuropathic basis. 
The dietetic and physical treatment of Basedow’s disease still occupies the 
central place of internal therapy. Most important is rest, in the severest 
cases rest in bed and the avoidance of every excitement, combined with the 
dietetic treatment; beneficial is the action of slight hydrotherapeutic procedures, 
such as were first recommended by Winternitz, eventually slight galvanization 
and faradization of the sympathetic, especially in strumas rich in blood-vessels, 
and the air of heights (600-1000 m.). Now a few words as to dietetic treat- 
ment. In the first place this must tend to prevent loss of weight and to enable 
gain in weight. Since in Basedow’s disease there exists an increased metabolism, 
it was believed that this could be made up by an abundance of protein food. 
On the basis of our own investigations we were however compelled to accept 
the idea that administration of protein increases the secretion of the thyroid 
gland. With this stands in harmony the fact that on administration of meat 
in experiments, we can make the thyroid gland extremely poor in iodine, thus 
bringing the stored secretion into the circulation on account of the greater 
need. I refer once more to the experiments of Rudinger carried out on the basis 
of these convictions, which showed that on almost protein-free diet, very rich, 
however, in carbohydrates, we can depress the increased metabolism to the 
normal. When therefore we administer abundant nitrogen-free energy carriers, 
we do not have to fear a loss of protein. From such a diet should be expected 
not only a favorable influencing of the body weight, but also a certain mitigat- 
ing influence on the hypersecretion of the thyroid gland; to which must be added 
that such a diet oppresses very little the gastrointestinal tract. As important 
as must be our endeavors to increase the body weight in Basedow’s, not the 
less important is the avoidance of overfeeding (v. Noorden), as the improvement 
of the cardiac activity does not keep pace with the increase of weight, and cases 
are known in which the increased demands on the heart, in consequence of the 
increase of weight, led to a sudden collapse. ATHYROSIS OR HYPOTHYROSIS 
111 
b. Athyrosis or Hypothyrosis 
Historical.—The first experiments as to the influence of extirpation of the 
thyroid gland on the animal organism originated with Schiffi. To about the 
same time belong also the first clinical descriptions of myxedema on the part 
of Gull, Ord, and Charcot. Gull, in 1873, described five cases of “A Cretinoid 
State supervening in Adult Life in Women.” Ord, in 1878, was the first to 
designate such cases as “myxedema.” Charcot, in 1879, called the attention 
of the French to this clinical picture, terming it “cachexie pachydermique.” 
The demonstration of the connection of this disease with the absence of thyroid 
function was furnished in 1882 and 1883, by Th. Kocher and Reverdin. In the 
period that followed this, thought was rendered confused by the fact that 
the symptoms following upon the removal of the parathyroids together with the 
thyroid were attributed to the absence of the thyroid. Investigation dis- 
tinguished between acute and chronic cachexia thyreopriva. Only at the end 
of the nineteenth century did the clinical pictures of athyrosis assume stabile 
forms, through the detachment of the symptoms due to the absence of the 
parathyroids (Gley, Vassale and Generali, Erdheim, Pineles, Biedl). About 
this time, too, Hertoghe called attention to the mitigated forms of athyrosis. 
To-day one of the hardest problems is the relation of myxedema to cretinic 
degeneration. Although the fact that congenital absence of the thyroid as 
well as a severe disease of this organ in early life (infantile myxedema) had been 
established by animal experimentation and the recognition of the significance 
of thyrotaplasia by Pineles in 1902, the careful analysis of the clinical manifesta- 
tions between sporadic and endemic cretinism permit a recognition of far- 
reaching differences. Among these is the fact that in the first condition thyroid 
therapy is always successful, in the latter it sometimes fails. While we must 
ascribe certain of the important symptoms of endemic cretinism to thyroid 
insufficiency, many facts speak for the separate position of this illness. 
I shall first describe those clinical pictures that develop through the failure 
of the thyroid gland function in the fully developed organisms because here 
the relations may be supervised more readily. 
i. Myxoedema Adultorum or Cachexia Thyreopriva Adultorum 
Definition.—This condition, resulting from the absence or insufficiency of 
the function of the thyroid gland in the adult organism, is characterized by the 
diminution of all vital processes and by certain trophic manifestations. The 
diminution affects the vegetative junctions as well as the psychic life. There is 
found slowing of the entire metabolism and diminution of the excitability of the 
whole vegetative nervous system. The trophic disturbances affect especially the 
ectodermal tissues, skin, hair, nails, and teeth, although almost all organs may show 
regressive metamorphoses, especially the vascular system, which tends to be the seal 
of a premature arteriosclerosis. 
Occurrence.—Spontaneous myxedema oi adults is a rare disease that is 
found somewhat more commonly in England and Holland [than on the conti- 
nent]. In goiter districts typical myxedema seems to be relatively rare. 112 
THE DISEASES OF THE THYROID GLAND 
Hereditary and familial occurrence is described by some authors (Maclllwaine, 
Ewald, et al). 
Symptomatology.—I begin with the description of the alterations in the 
skin, the most important of which has furnished for the disease its name myxe- 
dema. The myxedematous swelling may affect the skin of the entire body; it 
shows, however, a predilection for certain sites, the cheeks, lids, nose, supra- 
clavicular fossae, neck, backs of the hands and feet. The cheeks become yellow- 
ish in color, but on account of small venectases are colored bluish-red in the 
middle. The nose and lips are also of this bluish-red color. On account of the 
swelling of the eyelids the palpebral fissures are much narrowed, and the defi- 
cient play of the features makes the expression of the face rigid and sleepy. In 
the supraclavicular fossae develop thick cushions or pads that feel granular to 
palpation. The cushion-like swelling of the backs of the hands and feet make 
the extremities appear claw-like. 
For the most part the swelling invades also the mucous membranes, the 
mucous membrane of the mouth assuming a whitish color, while the participa- 
tion of the mucosa of the larynx leads to alterations of the voice; this becomes 
harsh and, according to Magnus-Levy, singing becomes impossible. The 
swelling of the uvula and the tonsils makes nasal breathing impossible; the 
patients breathe with open mouth and snore at night. The Eustachian tube 
and the tympanic cavity may also become involved by the swelling, causing a 
diminution in hearing-ability; and finally the female genitalia and the anus 
may become swollen. The tongue increases greatly in volume, so that it 
becomes visible between the rows of teeth, and shows impressions of the teeth. 
The increase in volume depends not only on the swelling of the lingual mucosa 
but also on alterations in the more deeply lying parts. Histological examina- 
tion shows alterations of the muscle fibers and increase in connective tissue; 
the latter contains numerous nuclei and numerous new formed capillary vessels. 
The tongue papillae, too, become hypertrophic (Maccone). 
The myxedematous skin looks like alabaster. It feels elastic, pressure 
with the finger evinces no pitting. It is dry and scales very much; the scales 
are mostly clayey. Stevenson and Halliburton ascribe the clay-like texture of 
the skin to the increased contents in mucin. They found the mucin-contents 
also increased in the salivary glands and tendons. Halliburton found that in 
the blood and in the parotid of thyroprivic. monkeys the proteid bodies pre- 
cipitating to acetic acid amount to 3 per cent., while they were not demonstrable 
in the blood of normal monkeys. Munk also found mucin in the parotid secre- 
tion of a case of myxedema described by Mendel. But other authors found that 
the mucin-contents of the myxedematous skin was not increased, while Bourne- 
ville maintains that in the investigations just mentioned it is not certain that the 
substance dealt with was mucin, as in his investigations no reducing substance 
was yielded by decomposition by means of acid. The microscopical investiga- 
tion of the myxedematous skin shows nuclear proliferation and new formation 
of connective-tissue fibrils, especially around the sweat-glands and sebaceous 
glands and around the hair follicles (English Myxedema Commission, Virchow). 
Unna found in skin of myxedemics substances that stained similarly to mucin, MYXEDEMA 
113 
while v. Wagner and Schlagenhaufer found them in the skins of endemically 
cretinoid dogs and thyroprivic goats. A substance similar to mucin could also 
be observed (Halliburton and Scholz) in other organs, such as the kidney, the 
muscles, and the brain. That presence of this substance similar to mucin was 
missed by certain authors has perhaps its explanation in the fact that the accu- 
mulations oi this substance are subject to much variation, and in cases of long 
Fig. io.—Postoperative myxedema. 
standing they sometimes disappear. The skin then regains a flaccid, lax, 
texture, and, in contradistinction to typical myxedematous skin, can be moved 
about on the underlying tissue. 
Pigmentations of the skin occur relatively rarely. 
The hair of the head and beard, the eyebrows, the axillary and pubic hairs 
become dry and brittle, and often, in part, fall out. On the skull then develop 
large bald spots, that may lead to complete baldness. The nails become dry 114 
THE DISEASES OF THE THYROID GLAND 
and cracked, the teeth become carious and fall out, and in the case to be 
described (Observation XII) the crowns of the teeth, in the course of the year that 
the myxedema had existed, had ground off entirely. The incisor teeth con- 
sisted of only short stumps provided with broad grinding surfaces. 
The circulation is sluggish, the body temperature reduces, the patients are 
chilly, and can warm themselves' with difficulty. The pulse is small and wTeak 
and slow—often only 50 to 60 beats a minute are observed. On body move- 
ments, dyspnea readily occurs. 
The excitability of the entire vegetative nervous system and especially that of 
the nerves regulating the heart is diminished. 
I here quote the clinical history of two myxedema patients in whom 
experiments were made as to the excitability of the vegetative nerves. 
Observation XI.—Karoline K., sixty-four years, single. Entered clinic Nov., 1913. 
One uncle and one aunt on the mother’s side suffered with struma. As a young girl the 
patient had a large neck, and of late years this has increased, producing difficulty in swal- 
lowing, difficulty in breathing, and indeed attacks of suffocation, on which account the 
patient was operated on in June, 1909. Nine days after the operation the patient was 
entirely well. In March, 1910, the hands and feet began to swell, the condition being 
taken for rheumatism. In the summer of 1910, myxedema was diagnosed, and an order 
given for thyroid tablets. Under this treatment the swellings retrogressed, but the patient 
became thin (loss of weight of 9 kg. in five weeks) and developed a marked tremor. 
At present are seen swellings of the backs of the hands and feet, of the supraclavicular 
fossae, and also of the face, especially in the vicinity of the eyes. The pulse is about 70. 
The skin is dry to the touch. 
0.01 gm. pilocarpine subcutaneously; after one-half hour slight flow of saliva, no 
sweat. 
100 gm. grape-sugar, no dextrose in the urine. 
150 gm. grape-sugar, no dextrose in the urine. 
Leucocytes, 6200, of which: 
Polymorphonuclear neutrophiles, 62.6 per cent. 
Eosinophiles, 5 per cent. 
Lymphocytes and large mononuclears, 32.4 per cent. 
After the instillation of homatropine into the eye, mydriasis occurs after about forty- 
eight hours. 
A fully normal sella turcica to Rontgen examination. 
In addition to the myxedematous manifestations are present slight signs of a primary 
chronic articular rheumatism (dry form). 
Moderate constipation. 
Observation XII.—Schw. F., thirty-eight years, entered September, 1910. First men- 
struated at twelve years of age. The flow was always regular and abundant. Two labors; 
since the last (eight years ago), which was followed by a hemorrhage, the menses have 
ceased. Since this time very poor appetite, patient always constipated. For one year 
the hands and feet often seem as if asleep, sensation of cold, formication in hands and feet. 
Speech has become slower. Often vertigo. Status: Skin pale, thickened and dry to the 
touch, hands cool, hairs thinned out and dry. Teeth small and loose, the chewing surfaces 
much worn down, so that the teeth are reduced to about one-half their length. In the 
axillze and on the pubis the hairs are entirely absent. The facial expression is slightly 
catatonic, both lobes of the thyroid are palpable, internal genitalia atrophic, blood-pressure 
very low (between 60 and 70, Gartner). 0.001 gm.1 adrenalin subcutaneously; no glycosuria, 
no increase in blood-pressure. 
1 German edition states mg. [ = milligram]; evidently gm. is intended.—Editor. MYXEDEMA 
115 
ioo gm. dextrose by mouth and at the same time 0.002 gm.1 adrenalin subcutaneously; 
no glycosuria. 
0.01 gm. pilocarpine; no salivation, sweating very slight. Slight increase in blood 
pressure. 
Erythrocytes, 3,500,000. 
Hemoglobin, 70 per cent. 
Leucocytes 7000, of which: 
Polymorphonuclear neutrophile, 52 per cent. 
Lymphocytes and large mononuclears, 42 per cent. 
Eosinophiles, 6 per cent. 
After the instillation of homatropine, mydriasis occurs after about thirty-six hours. 
From the middle of October, thyroid tablets. At the beginning of November swelling 
of the face has disappeared, the skin about the eyes and on the clavicles very loose, facial 
expression very much livelier, hands now warm and less cyanotic. 
A diminution in the excitability of the vegetative nervous system is 
demonstrated also by the experimental investigations in thyroidless animals. 
v. Cyon found a diminution of the excitability to electrical stimulation of 
the vagi nerves in such animals. The hyperexcitability ol the accelerator 
nerves that he asserted to be present could not be confirmed. It is far more 
likely that the excitability of the sympathetic nerves is diminished. For 
this view speaks the failure of the glycosuric action of adrenalin in thyroid- 
ectomized animals and in myxedema patients. As regards the diminution 
of the pressor action of adrenalin we (Eppinger, Falta, and Rudinger) did not 
arrive at a certain result; while on the contrary, later investigations of Bertelli 
and myself show definite alterations in the reaction of the vascular system 
of thyroidless dogs against adrenalin. 
As I regard the experiments important, I shall quote them in extenso.. 
15 kg. dog, ten days ago total extirpation of the thyroid gland with avoid- 
ance of the parathyroids. Electrical excitability remains unaltered. 
Erythrocytes 
Hemoglobin 
Specific gravity 
Before the injection 
4,900,000 
45 per cent. 
i°54 
5 hours after the infusion of 3.69 mg. adrenalin. 
4,100,000 
45 per cent. 
1050. 
24 hours after this 
3,936,000 
45 per cent. 
105E 
Dog, 16 kg., total extirpation of the thyroid six weeks ago. Electrical 
excitability remains unaltered. 
Erythrocytes 
Hemoglobin 
Specific gravity;' 
Before the injection 
5,056,000 
60 per cent. 
1050 
hours after infusion of 3.69 mg 
5,932,000 
65 per cent. 
1055 
5 hours after 
5,680,000 
63 per cent. 
i°SS 
72 hours after 
5,016,000 
55 per cent. 
1052 
According to investigations of Bertelli, Schweiger, and myself, the erythro- 
cyte count in normal dogs after the injection of adrenalin increases extra- 116 
THE DISEASES OF THE THYROID GLAND 
ordinarily rapidly; after ten minutes it may reach 40 per cent., after five 
hours 70 per cent. In an experiment in which 4.36 mg. adrenalin was injected, 
it reached 100 per cent, after twenty-four hours; in another experiment after 
3.69 mg. the hyperglobulia was indeed distinct, but had already begun mark- 
edly to decline. Although of course there occurred individual differences 
in the intensity and duration of the reaction, there was to be observed in all 
normal dogs a distinct rise. The hemoglobin contents showed a very much 
less increase. The specific gravity regularly showed a slight increase. 
While, then, normal animals show after injection of adrenalin a high- 
grade hyperglobulia, in the production of which there is surely concerned, 
in addition to alterations in the permeability of the endothelium of the blood- 
vessels, also the pressing out of plasma on account of the long-continued 
contracted condition of the vessels, this manifestation was absolutely lacking 
or was .essentially weaker in the thyroidless dogs. In this respect, individuals 
without thyroids show similarity to individuals with cachexia, who, as is 
known, do not react with hyperglobulia to the use of the lung suction-mask, 
or to sudden transference to great heights. 
The autonomous nerves too show a diminution of their tonus and their 
excitability, v. Cyon observed, as already mentioned, a diminution of the 
electrical excitability of the vagi. The miotic action of pilocarpine in thy- 
roidless dogs lasts for a shorter time (Eppinger, Falta and Rudinger). The 
observations of Asher have already shown that in dogs with thyroid insuffi- 
ciency the mydriatic action of atropine lasts for an abnormally long time. 
Hence the autonomous nerves are more readily paralyzed than under nor- 
mal relations. Also in blood-pressure investigations on thyroidless dogs 
Rudinger and / observed that ruling out of the vagi through atropine lasts 
extraordinarily long. Finally, in some cases of myxedema I could estab- 
lish an abnormally long mydriatic action on the instillation of homatropine 
into the eye (confer the analogous experiments in sporadic cretinism). Fleisch- 
mann observed that the blood of normal animals destroys the activity of 
added atropine more rapidly than the blood of strumous animals. 
[Barlow1 by using the Bdrdny tests in myxedema has shown that in this 
disease there is a definite clinical vestibular picture which can be demonstrated 
—a delayed response to stimuli. The degree of this does not bear a relation- 
ship to the basal metabolic rate.-—Editor.] 
The previously mentioned alteration in the reaction of the vascular endo- 
thelium to adrenalin depends perhaps on the disturbances in nutrition, and 
these could be the cause of the premature arteriosclerosis of thyroidless ani- 
mals, such as Eiselherg, Pick, Pineles, and others have described. Also in 
myxedema patients we frequently find striking grades of arteriosclerosis 
and depositions of lime salts, the latter even in other organs, such as the 
kidney, liver, etc. (Abrikosojf). Finally also in thyroaplasia has high-grade 
atheroma been found in the aorta and other vascular territories (Bourneville, 
Maresch, Machand, Heyn, and others). The occurrence of arteriosclerotic 
1 Barlow (R. A.) The study of vestibular nerve function in myedema. Am. J. M. Sc. 
Vol. CLXIV, No. 3, Sept., 1922, pp. 401-414. MYXEDEMA 
117 
alterations in thyroid-gland insufficiency has been brought forward as the 
explanation of the senile degeneration. Horsley first pointed out that the 
thyroid gland in old age becomes atrophic, Vermehren compares old age with 
a chronic myxedema, while in more recent times Lorand has elaborated on 
this view. In opposition to this, Ewald has already shown that in maras- 
mus senilis there is initiated not only an atrophy of the thyroid (and the 
other ductless glands) but also a degenerative atrophy of the other organs, 
especially the gastrointestinal tract. At all events, we should not use thy- 
roid medication in old age uncritically (v. Noorden). 
The diminution of the tonus or the excitability of the vegetative nerves 
is spoken for also by the failure of the sweat secretion in myxedema patients. 
The secretion of sweat may fail entirely on bodily movements, or even when 
there exists high external temperature. Mann observed that in myx- 
edemics infusion of jaborandi did not bring about secretion of sweat. I, 
too, observed, in the above-mentioned cases, after pilocarpine injection only 
slight salivation and no or only minimal sweating. In myxedema there is 
also a diminution of the function of the sebaceous glands (deficient oiling 
of the skin and hair). I have not been able to find in the literature statements 
as to the secretion of gastric juice or pancreatic juice. 
To a slight tonus of the autonomous nerves points the high-grade atony 
of the intestines that is the cause of the well-known obstipation of myxedema 
patients. Defecation in well-developed cases, if purgatives be not employed, 
may not occur for two or three weeks. 
Almost constantly alterations of the psychic functions accompany myx- 
edema. The English Myxedema Commission found the apathy charac- 
teristic of myxedema absent in only three of one hundred and nine cases. 
This may develop relatively early, and in the light cases may consist only 
in a sluggishness of the previously mentally and bodily active patients, in 
a retardation of the psychic functions, in an inability to form rapid conclu- 
sions and in a slowing and monotony of the speech. According to Magnus- 
Levy, in light cases the “capability of reacting to strong stimuli” is for the 
most part not lost. In more well-developed cases there is a complete dullness, 
the patients brood, and there exists marked desire for sleep. The speech 
may be markedly slowed “als ob die Sprachwerkzeuge eingefroren waren’ ’ 
[as if the speech-mechanism were frozen in] (Meltzer). Charcot compares 
such patients to hibernating animals. In such individuals, too, the intellect 
tends to deteriorate and the memory, especially that for recent occurrences, 
is lost. 
In such high-grade cases there are rarely lacking, in addition to this 
decided apathy, signs of'a more deeply seated mental disturbance. Already 
at the beginning of the myxedematous disease or in the formes frustes are 
hallucinations commonly present, concerning which, as Murray says, the 
patient does not willingly speak. 
The English Myxedema Commission found among the myxedema patients 
investigated by them illusions 18 times, hallucinations 16 times, and a frank 
psychosis 16 times. The psychoses belong to various types, although the 118 
THE DISEASES OF THE THYROID GLAND 
melancholoid conditions predominate; and may of course consist only of 
a combination with myxedema. Very commonly, however, they stand in an 
intimate relation with myxedema in this respect—that through the myxedema 
a previously existing predisposition becomes manifest. In these cases the 
symptoms of the psychosis develop simultaneously with those of the myxe- 
dema and vanish after thyroid therapy has been instituted, to reappear again 
when the therapy is discontinued. Such a case has been described by Pilcz. 
In many cases, especially at the beginning, the inhibition is suddenly inter- 
rupted, and the condition may transitorily go as far as excitation. Horsley 
distinguished between a neurotic stage that occurs at first, and a myxede- 
matous or cretinoid stage, although this distinction may have been influenced 
by the tetanoid manifestations after thyroid-gland extirpation which at that 
time were ascribed to the absence of the thyroid. 
Other coarse disturbances that are routinely looked for on the investiga- 
tion of the nervous status are not as a rule found. The reflexes are for the 
most part normal, only rarely are they increased or diminished. Not rarely 
the patients complain of paresthesias and of rheumatic pains. The test 
for sensibility for the most part normal, at the most it has been stated that 
slowing of conduction is present, although this finding is by no means con- 
stant. It has been recognized that testing of sensation is hard to carry out 
in heavily apathetic patients. The same holds good for tests of the smell, 
taste, and hearing. Most common of these disturbances are those of hear- 
ing. These were found by the English Commission in almost half of the 
cases it investigated. The cause for them has not as yet been certainly ascer- 
tained. Wagner v. Jauregg assumes that they are produced by myxedema- 
tous swelling of the mucous membrane of the tympanic cavity and the tube. 
It is, however, often very hard to determine what part the lessened power 
of apprehension of the central apparatus and the lacking apperception plays 
in this; in any case it is significant that the disturbances of hearing react 
promptly to thyroid medication. 
[The eye changes in hypothyroidism have been dealt with by Fridenberg 
and by Zentmyer1 and the nose and throat changes by Fridenberg, Wieder, 
and Schatz.2 (See references in footnotes, p. 74.—Editor.] 
1 We quote Zentmyer as follows: 
“In myxedema, in which the changes in the thyroid are chiefly atropic, edema of the lids with 
the consequent narrowing of the palpebral fissures is the most marked ocular phenomenon. The 
edges of the lids are hyperemic, the eyebrows are elevated, and the hairs and lid cilia are sparse and 
brittle. Subconjunctival hemorrhages may occur. Lacrimation, asthenopia, neuroretinitis and 
superior-temporal contraction of the visual fields are occasionally met with. The oculocardiac 
reflex has been found enormously intensified. This, according to Petzetakis, results from the sym- 
pathetic being deprived of the normal stimulation of the thyroid.” 
2 And Schatz has this to say [with bibliography]: 
“In the hypothyroid patients noises in the head are due to infiltration of the nerve; even hallu- 
cinations of hearing, as of sight, may occur, simulating various sounds, due to lost vascular tone and 
imperfect circulation. Vertigo, loss of equilibrium, even falling on slight provocation may occur. 
“ The auricles in myxedema are enlarged, the auditory meatus narrowed by its thickened walls, 
causing more or less deafness, vertigo, tinnitus. Also in the cretin the ears are swollen, erect, and 
deafness occurs from adenoids or middle ear disease. Swelling of the mucosae of the pharynx and 
ear are considered the cause of deafness and tinnitus in myxedema by G. Dock and others. MYXEDEMA 
119 
The conductivity of the skin for the electric current is diminished on 
account of the high degree of dryness. Authorities also state that in many 
cases there is diminution of the electrical excitability of the nerves and muscles. 
In one case Erb found it normal. Rudinger and myself found an appreciable 
diminution of the galvanic excitability of the nerves in thyroidless dogs. 
The investigation was conducted three months to one and one-half years after 
extirpation of the thyroid. Instead of the normal value of 1.2-1.5 milliamperes 
we needed 2-3 milliamperes in order to produce (test ot the sciatic nerve) 
a cathodal closing contraction. In one case of myxedema Erb found a slow 
twitching of the muscle to mechanical irritation. The motor processes, too, 
are conducted slowly. The movements are extremely slowed, the gait heavy, 
slow, and slightly staggering. One of the early symptoms is a rapid tiring, 
only on the longer duration of the disease is the motor power diminished. 
The cause of all alterations in function of the central and vegetative nervous 
system lies in nutritive disturbances. Walter, and Marinesco and Minea found 
in thyroidless dogs a slowing of degeneration and regeneration of the nerves. 
There is not much known concerning alterations in the osseous system 
in myxedema. Stubenrauch describes in a case symmetrical changes of the 
bones and joints of the feet. Both first, interphalangeal joints were destroyed, 
the middle and end phalanges showed in part abnormal transparence and in 
certain places direct loss of substance. In the absence of further observations 
we should be cautious about bringing such alterations into relationship with 
myxedema. 
The examination of the blood shows decrease of the red cells, and espe- 
cially of the hemoglobin, the latter to 60 per cent, or even 40 per cent.; also 
decrease in the dry residue and increased coagulability (Bultschenko and 
Drinkmann, Kottman). The leucocytic formula is altered, consisting in 
mononucleosis and mostly hypereosinophilia (Bence and Engel, and the author). 
[Deusch1 has recently ascertained that in myxedemics the viscosity of 
the blood serum is increased, but not that of the entire blood, and that the 
blood contains more protein that in normal blood.-—Editor.] 
In many cases are observed erythroblasts and slight poikilocytosis, 
in others also Turk’s irritation forms and myeloblasts. In one of the cases 
herein quoted were found indeed isolated myeloblasts. Similar blood changes 
are also found in thyroprivic animals (v. Eiselsberg, Zitschmann, Kishi, Esser, 
Bertilli’s investigations on our own dogs). The anemia quickly amelio- 
rates on the administration of thyroid-gland substance, and there occurs 
a “paradoxical” reaction of the leucocytes, i.e., the leucocytic formula 
approaches the normal, while in healthy individuals it is known that thy- 
roidin produces mononucleosis (Falla, Newburgh, and Nobel). More recent 
Lynah is quoted as advocating thyroid extract in chronic catarrhal otitis media in elderly patients. 
Sajons considers the nerve deafness of old age and of acute infections as due to thyroid and adrenal 
deficiency, and he advises thyroid extract grain i with calcium lactate grains v, t.i.d. after meals. 
Gordon thinks he found normal hearing (the tests admittedly unreliable) in all of his fifty-five cases 
of hypothyroid children.” 
1 Deusch (G.). Serumkonzentration und Viscositat des Blutes beim Myxodem und ihre Beein- 
flussung der Thyreoidin. Deutsches Archiv. f. klin. Med., Dec., 1920, pp. 342-351. 120 
THE DISEASES OF THE THYROID GLAND 
investigations of Fonio agree with these; interruption of the thyroid-gland 
therapy for the most part brings about a recurrence of the mononucleosis 
(von Korczynski), while the poverty in hemoglobin also is essentially amelio- 
rated by the thyroid-gland therapy. 
The metabolism of myxedemics is reduced to a marked degree. We are 
indebted to Magnus-Levy for the discovery of this. He found a reduction 
of the basal metabolism to 58 per cent. Treatment with thyroidin brings 
the basal metabolism to normal or supernormal figures. 
If the thyroid-gland therapy be interrupted, the amount of oxygen con- 
sumed gradually sinks as the clinical symptoms recur. Also the twenty- 
four-hour exchange is reduced, that is, myxedemics maintain an equilibrium 
with a much less amount of calories and take on fat more readily than does 
the normal individual. 
Sometimes accumulations of fat are found at entirely abnormal sites. 
Thus Abrikosojf found in a fifty-two-year myxedematous woman accumula- 
tions of fat in the lingual mucous membrane and in the submucosa of the 
intestine. If myxedemics are nourished abundantly, the twenty-four-hour 
exchange does not necessarily have to be below normal, and thyroidin admin- 
istration will then produce an enormous increase in the caloric production. 
Steyrer found in his case an increase of 83 per cent, (investigation in Voit- 
Pettenkofer’s apparatus). Especially fat is concerned, while the number of 
calories from protein is rather less than normal. Again, the protein metabolism 
lies low, the protein requirements are light, and there may be an addition 
of protein to the body. The relations in investigations as to the hunger 
protein metabolism are very clear. In thyroidless dogs we found this 
distinctly reduced. 
The time consumed in the protein destruction in thyroidless dogs is, 
according to the investigations of Pari, not altered. Administration of 
thyroidin leads, in the wake of the consumption of myxedematous tissue, at 
first to a significant increase of the nitrogen excretion, this giving place to 
normal relations. The relations of the salt metabolism in myxedemics is 
not as yet fully explained; it is to be expected that the need for salt is slighter 
and that less calcium is cast off in the feces, as the administration of thyroidin 
allows more calcium to pass out through the intestine. The amounts of urine 
in myxedemics as a rule are very small. Often slight albuminuria is found, 
which may probably be attributed to nutritive disturbances in the kidneys. 
The assimilation limits for grape-sugar, in myxedemics, is raised (.Hirschl, 
Knopfelmacher). Hirschl found no glycosuria even after the administration 
of 500 gm. of dextrose. Also in thyroprivic dogs the administration of sugar 
(up to 200 gm.) does not lead to glycosuria, although in dogs the assimilation 
limits lie relatively low. In thyroprivic dogs the glycosuric action of adrenalin 
is reduced (Eppinger, Falta, and Rudinger, Pick and Pineles).x Myxedemics 
show the same relation. 
JThe alimentary glycosuria that is observed in thyroparathyroprivic dogs (Falckenberg, R. 
Hirsch) is to be ascribed to the absence of the function of the parathyroids. (Confer also 
Falta and Rudinger.) MYXEDEMA 
121 
In a case of Herz’s the administration of dextrose with the simultaneous 
injection of adrenalin did not lead to glycosuria. I found the same thing in 
the case described above (Observation XII) (ioo gm. dextrose together 
with the simultaneous administration of 2 mg. adrenalin subcutaneously). 
After a long-continued thyroidin medication the relations become normal 
again. In the case of Herz, after successful thyroidin treatment, traces of 
sugar appeared in the urine after only 100 gm. of dextrose. Adrenalin now 
again produced glycosuria. 
The inclination to glycosuria can also remain after the withdrawal of 
thyroidin treatment. As example I quote the following case: 
Observation XIII.—Rosa L. Entered the clinic June, 1895, then fifty-two years old. 
From the history taken at the time, three confinements, first menstruation at the age of 
fifteen years. After the confinement the menses were irregular and sparse, and ceased 
three years ago. Then abdominal pains, jaundice, followed by a marked swelling of the 
Fig. ii.—Case of myxedema with tendency to glycosuria. 
neck that gradually retrogressed again. Since that time there has gradually developed, 
especially since the winter of this year, the following disease-condition; great languor, 
rapid fatigability, rheumatoid pain, swelling of the upper and lower extremities, the face, 
the eyelids, hoarseness of the voice, constipation and distention of the abdomen, bloated, 
condition of the face, swelling of the lips, tongue, and eyelids. The swelling of the tongue 
and lips is so intense that it hinders eating. There are subjective sensations of cold, especially 
on the back. Often severe headaches, sensation of vacancy in the head, and feeling of 
anxiety. 
From the status: Skin of the extremities and on the abdomen thick, cool, and cyanotic. 
There are present on the upper and lower extremities, and in part on the trunk, signs of 
ichthyosis. The face, and especially the eyelids, are swollen out, so that the skin in the 
vicinity of the eyes is markedly wrinkled. The facial expression is exquisitely sleepy, 
the forehead transversely wrinkled so that an astonished expression is produced; the hairs 
are dry and very much thinned out (of late years especially have fallen out). Face some- 
what markedly pigmented, lips protruded in a somewhat snout-like manner, the teeth for 
the most part are missing or are loose. In both supraclavicular fossae slight cushion forma- 
tion. On the left the lateral lobe of the thyroid somewhat palpable. Great drowsiness, and 
slowness of all movements. Speech very slow. Weakness of memory. Gait awkward, 122 
THE DISEASES OF THE THYROID GLAND 
dragging. Great fatigability. The patient was given at times thyroidin tablets, which 
however produced cardiac palpitations and turned the constipation into diarrhea. However, 
under this treatment the swellings disappeared very rapidly. In 1897 she tried thyroidin 
tablets, without deleterious effects. She took them ordinarily for about fourteen days, dur- 
ing which time she lost weight rapidly, then she would discontinue them for about four weeks, 
until the pockets on the eyelids and the thickenings on the abdomen appeared again. In 
1895 the patient was almost bald; later the hair grew again and at present she has a growth of 
hair about usual for a woman of her age. She perspires hardly at all. For two months she 
has again discontinued the thyroidin medication, and all the above-mentioned manifestations 
have recurred to an exaggerated degree. After 100 gm. of grape-sugar the patient shows a 
distinct although not very strong glycosuria; sharply delimited cyanosis of the cheeks. 
There is indeed no doubt that since the year 1895 the patient has suffered from a typical 
myxedema. Perhaps at that time a thyroiditis appeared together with the jaundice, which 
gradually led to insufficiency of the thyroid gland. The combination with ichthyosis had 
been often described by French authors. From the beginning, the case showed no high 
tolerance for thyroidin, although there was already present a myodegeneratio cordis. I can 
readily appreciate that in such cases palpitations can occur even when the doses are not too 
high. 
The observation that the alimentary glycosuria resulted positive, in spite of the two 
months’ cessation of thyroidin medication, points to the fact that here, in addition to the 
thyroid gland, the pancreatic insular apparatus is also degenerated. 
In this case I prescribed small doses of thyroidin, and at the same time hypophysis 
tablets, as I suspected a degeneration of the glandular portion of the hypophysis also. 
I need only mention the fact that this medication was borne for several months without 
calling forth the previous cardiac distresses, and that thereby the recurrence of the myxe- 
dema symptoms was prevented. The puffiness on the neck and face had disappeared, 
the scaling of the skin which has existed for eighteen years has disappeared, the skin has 
become smooth and elastic, the itching has ameliorated; only the brittleness of the nails 
has remained unaltered (communication by letter). 
The explanation for the simultaneous existence of myxedema and an 
inclination to glycosuria that I sought in this case would serve also for any 
case that under thyroid therapy proceeded to spontaneous glycosuria (Mac fie 
Campbell, Bramwell, Ewald, Osier, et al), or that without thyroid therapy 
showed a tendency to glycosuria (Gamier and Lehr el). Also combinations 
of myxedema and diabetes are observed, but indeed appear to be very rare. 
The case of Apert was that of sporadic cretinism with distinct myxedema- 
tous manifestations. In this case growth ceased only at the age of thirty- 
six years. Later, diabetes appeared. I believe that it is intelligible that 
absence of insufficiency of the function of the thyroid leads to hyperfunc- 
tion of the pancreatic insular apparatus only when this is capable of function- 
ating. If the pancreas itself is diseased, diabetes may occur, even when the 
thyroid fails. This is shown by the experiments of Eppinger, Rudinger, and 
myself on the pancreatic diabetes of thyroidless dogs. If, however, myxe- 
dema is superadded to an already present glycosuria, the glycosuria tends 
to disappear. Thus v. Noorden reports fourteen cases of endogenous obe- 
sity, of whom seven formerly excreted slight quantities of sugar. With 
the development of the formes frustes of myxedema the sugar disappeared, 
and even a high tolerance for carbohydrates commenced. Only in one case 
did the glycosuria persist, in mild form, during the myxedema. MYXEDEMA 
123 
The diminution in the general metabolic processes in myxedema expresses 
itself also in hypothermia; this belongs to the commonest symptoms of the 
fully developed forms. The rectal temperature varies between 36° and 370 
Celsius, and may even be below 36°. It stands in relationship with the 
sensations of cold complained of by the patients. Myxedemics feel com- 
fortable only when the external temperature is high; their condition becomes 
aggravated in the cold season of the year; it has even been stated that in sum- 
mer time we may need to administer smaller doses of thyroid-gland substance 
in order to compensate for the deficiency, and must increase the dose in winter. 
Strong stimuli, as for example, infectious diseases, may, however, also bring 
about hyperthermia, as numerous examples in the literature bear witness. 
In severe cases of myxedema there regularly develop disturbances in 
the sphere of the genitalia. Women develop irregularities of menstruation; 
either the menses cease or there occur profuse floodings. In the long-stand- 
ing cases premature climacteric occurs, and often a high degree of atrophy 
of the genital apparatus (Landau, Szanto). In two women with distinct 
cachexia strumipriva, Langhans found pronounced small-cystic degenera- 
tion of the ovaries. Allen Starr, Kirk, Schotten, and after them many others 
have testified to the occurrence of menorrhagia. In men, libido is lost. 
Very instructive in this connection is a case of Magnus-Levy, in which a fifty- 
four-year-old man lost libido completely, and regained it after cure of his ill- 
ness. Herz observed a similar case in which a forty-five-year-old man regained 
erections and ejaculations two weeks after the beginning of treatment. Treat- 
ment by thyroid gland also affects favorably the menstrual disturbances 
in women. These do not signify sterility, as there are cases of myxedema 
that become normally pregnant. It is shown also by animal experimenta- 
tion (Halsted) that partial extirpation of the thyroid does not prevent normal 
carrying of young. In such cases the thyroids of the fetuses seemed to act 
compensatorily. In other words, Halsted observed in the new-born pups 
an enormous hypertrophy of this organ. The thyroids were about twenty 
times as large as in a normal new-born pup. In cases with a long-standing 
high-grade deficiency of thyroid function, there occurs atrophy of the ovaries. 
In this case the disturbance seems to be irreparable. 
In cases of myxedema the hypophysis is commonly described as altered. 
Boyce and Beadles found enlargement of this organ, as did also Ponfick in a 
case. In a case of Ahrikosojf’s the glandular portion of the hypophysis was 
enlarged, and indeed the chromophilic cell-columns were increased, the cells 
enlarged, their protoplasm showing colloid degeneration. Comte earlier 
observed a similar condition and considered the enlargement of the hypophysis 
as a compensatory hypertrophy. In other cases there has occurred a pro- 
nounced sclerotic degeneration of the glandular hypophysis (2nd case of 
Ponfick) or cystic degeneration (Sainton and Rathery, and others). In both 
the cases of myxedema above reported sella turcica as shown by X-ray was 
normal. 
An enlargement of the hypophysis after extirpation of the thyroid has 
been observed on animal experimentation. In grown animals, Bertelli and THE DISEASES OF THE THYROID GLAND 
124 
myself (reports not published in detail) could not find anything similar after 
a one and one-half years’ duration of the thyroprivic condition. I think 
that the findings described are overestimated as to their significance for the 
reciprocal action between thyroid gland and the glandular hypophysis. The 
vicarious action of the hypophysis for the thyroid gland, as Comte assumed, 
need not be considered in this connection. It is just as if in contracted 
kidney the liver acts vicariously for the kidney. In myxedema adultorum 
the hypophysis sustains mostly changes of a strumous character, or simultane- 
ously with these, changes of a chronic inflammatory nature (as for example 
in the cases of Ponjick, Sainton and Rathery, et al.), such as we shall meet 
with again in the consideration of multiple ductless glandular sclerosis. 
Simultaneous disease of the thyroid gland and the glandular hypophysis 
(pathological correlation) is very rare. I shall deal with it in detail in the 
chapter on the hypophysis. Often in such cases thyroid-gland medication 
causes a disappearance of only a portion of the cachectic symptoms. We 
shall deal later with the alterations in the hypophysis in infantile myxe- 
dema. The combination of myxedema with tetany is considered in the 
fourth chapter. 
Etiology and Course.—We to-day possess a complete explanation of the 
etiology of myxedema operations. Total extirpation of the thyroid gland 
always leads to myxedema, which in very rare cases may be only slight 
and may heal spontaneously, this manifestation being due to the compen- 
satory hypertrophy of accessory thyroids (cases of Vollmann and Reverdin). 
It is very noteworthy that in cases of accessory struma of the base of the 
tongue, extirpation of the tongue struma led to myxedema. Seldowitsch 
and Chamisso have each reported such a case. After operations for struma, 
mitigated forms of myxedema operations often appear, forms that show, for 
example, only disturbances of growth, or only fat deposits, or only apathy. 
Among thirty-eight cases of cachexia strumipriva, Kocher saw the miti- 
gated form only nine times; here recurrences of the goiters developed. If 
a thorough continual treatment with thyroidin be not instituted there is 
shortening of the thyroidectomized individual’s life. Total thyroidectomies 
are to-day still performed only on malignant degenerations of the thyroid 
gland. Mitigated operative myxedema may also occur to-day where there 
is intense degeneration of the part left behind. 
The pathologico-anatomical finding in the thyroid in so-called spontane- 
ous myxedema is ordinarily sclerosis with destruction, or a high-grade goitrous 
degeneration. In many cases of spontaneous myxedema only fat and con- 
nective tissue (Abrikosojf) is found on the site of the thyroid. Only in rare 
cases is the etiology of the inflammatory cirrhosis clear, as for example in 
Kohler's cases of syphilis and actinomycosis respectively of the thyroid, the 
first yielding to the effects of potassium iodide, the latter to operation, v. 
Wagner observed two cases of formes frustes in the eruptive stage of syphilis; 
in the later stages of syphilis infiltrates and gummata are present. Tuber- 
culosis of the thyroid gland is relatively not very common. Also miliary 
tuberculosis has been observed. Primary tuberous tuberculosis seems to be MYXEDEMA 
125 
very rare. In certain cases of multiple sclerosis of the ductless glands there is 
found in the thyroid, in addition to diffuse chronic processes, also, in some 
places, tuberculous foci. In most of the cases of spontaneous myxedema 
there were perhaps other infections than those stated. The territory has 
not as yet been explored bacteriologically. An index is furnished by those 
cases of myxedema that appear after cases of infectious diseases. Thus 
Reinlinger reports a case of an individual, twenty-two years old, who after 
a gastric fever (typhoid?) developed cachexia, myxedema of the skin, apathy, 
dementia, and falling out of the axillary and pubic hair. Thyroid therapy 
produced good results. Marfan saw myxedema develop after an acute articu- 
lar rheumatism with angina. Sometimes, as previously mentioned, the 
hyperplasia of Basedow’s disease goes over into atrophy. The investigations 
of Roger and Gamier, de Quervain, Sarbach, Bayon, and others have shown, 
however, that in severe infections diseases there regularly develop in the 
thyroid inflammatory processes, and in chronic intoxications cirrhotic processes. 
The reason that myxedema is commoner in women than in men should 
be sought in the fact that the normal sexual processes in women determine 
an important affection of the function of the thyroid, and that an exhaustion 
of this is produced the more easily by damages to the parenchyma due to 
common infections or intoxications. For this assumption speaks the fact 
that mitigated forms of hypothyrosis tend to become worse during pregnancy 
and that not rarely the myxedematous symptoms disappear at the sexual 
involution. 
Finally, it should here be mentioned that sclerotic processes are found 
in the thyroid in numerous cases of scleroderma (Singer, Hektoen, Roux, 
Leredde and Thomas, and others). Eventually, in many cases of sclero- 
derma are found also symptoms that remind one of myxedema (Gresset, 
Osier, and others). As scleroderma involves in sympathy the most diverse 
organs, we readily see that we should best regard the alterations in the thyroid 
as a partial phenomenon of the fundamental processes (see Chapter I). 
[.Jaensch1 has studied the capillary net-work of the skin with E. Weiss’s 
capillaroscope, and finds that in cretins there are marked deviations from the 
ordinary hair-pin type of capillary loop. He regards as deviations from the 
normal type as a myxedemoid characteristic, or at least a characteristic that 
indicates hypothyroidism. Jaensch’s observations are suggestive, but 
should be checked by statistics of the basal metabolic rate.—Editor.] 
Differential diagnosis is concerned first of all with nephritic edema. 
Slight presence of albumin [in the urine] may also occur in myxedema. We 
should especially consider the density of the swellings, the failure of hyper- 
tonia, and the presence of psychic alterations. Also, in myxedema, the 
swellings are often more distinct in the morning than in the evenings. 
Stabile erysipeloid edema, indurative syphilitic edema, and pachyderma 
are distinguished from myxedema by normal psychic relations; nor do they 
react to administration of thyroidin. Thyroid medication may affect favor- 
1Jaensch (W.). Ueber psychophysische Konstitutionstypen. Munch, med. Wchnschr., Vol. 
LXVIII. No. 35, Sept. 2, 1921; pp. 1101-1103. 126 
THE DISEASES OF THE THYROID GLAND 
ably scleroderma (stimulation of metabolism, Ewald); the same holds good 
of certain cases of lipomatosis dolorosa (Dercum). In many such cases 
alterations are found in the thyroid, in others in the hypophysis (see Chapter 
XIV). 
The incomplete forms of myxedema are of difficult diagnosis. Hertoghe 
first drew attention to these, designating them chronic benign hypothyroid- 
ism. They are much commoner and more multiform in women. They often 
begin with chronic muscular pain, which may disturb sleep. Rachialgias 
are especially frequent, to which may be added great lassitude, especially 
in the morning hours, menstrual disturbances, menorrhagias or amenorrhea, 
sensation of cold, even shiverings, hoarseness of the voice, and, especially 
often, rather obstinate constipation. The picture becomes clearer when 
the hair begins to fall out, especially the hairs over the occiput, and when 
apathy and depression are added. Sometimes many persons in the same 
family are found with the signs of chronic mitigated thyroid insufficiency. 
Hertoghe mentions that pronounced signs of myxedema in children first 
drew his attention to the signs mentioned in the mother, and that thyroid 
treatment of the mother brought about good results. Gluzinski remarks 
that such abortive forms of myxedema in women occur not rarely in the 
years just before the climacteric and retrogress when the climacteric has 
been completed. The last statement has also been mentioned by Hertoghe. 
Kocher and Fr. Kraus agree with Hertoghe concerning the frequency of such 
forms. Kocher mentions that manifestations of chronic rheumatism that 
are associated with pains, stiffness, and heaviness of the extremities not 
infrequently depend upon a larval hypothyrosis. The diagnosis may also be 
made more difficult by the fact that distentions of the joints develop. Parhan 
and Papiniam have described a case of chronic rheumatism which they 
regarded as dysthyrogenic. Rothschild and Levi have tried thyroid therapy 
on a large group of cases of chronic articular rheumatism. There were 
twenty moderately severe and light cases among thirty-nine cases varying 
from twelve to fifteen years of age. Of these, eighteen were cured or essen- 
tially improved, while of the severe cases, two were cured and thirteen im- 
proved. One should be very careful about regarding these forms of articu- 
lar rheumatism as thyrogenic, as it is not unlikely that good results may be 
brought about solely by the stimulation of the metabolism through the 
thyroid medication. 
Hertoghe certainly goes too far when he brings myomata, retroflexion 
of the uterus, emphysema, congestion of the liver, and gall-stone formation 
directly into relation with the thyroid gland insufficiency (Kocher, Fr. Kraus). 
That on the other hand we were justified in ascribing, in many cases, the 
above-cited manifold disturbances to a chronic light thyroid insufficiency 
speaks the fact, quite apart from therapeutic results, that Kocher not rarely 
saw such “thyroprivic equivalents” occur after strumectomy. 
The diagnosis of such benign forms of thyroid-gland insufficiency can, 
as can readily be understood, present great difficulties, especially when only 
a few of the manifold symptoms are present, for instance, increased heavi- SPORADIC CRETINISM 
127 
ness of the nasal breathing, hoarseness of the voice, or a slight degree of 
deafness. Especial attention is to be directed in these cases to the presence 
of pseudolipomata in the supraclavicular fossae or to transverse folds in 
the forehead (y. Wagner). Often the diagnosis can only be made tentatively 
ex juvantibus. 
An especial form of mitigated thyroid insufficiency is thyrogenic obesity. 
In contradistinction to so-called dietary obesity there are cases in which 
obesity develops in spite of slight supply of calories, and remains present 
when the supply of calories is so restricted that normal individuals of the 
same size, of the same weight, and under the same living conditions would 
rapidly lose in bodily weight under such conditions. The cause of endoge- 
nous obesity is of very diverse nature (see also Chapter VI, on the hypophysis, 
and the various forms of obesity, Chapter XIV). But it can hardly be 
doubted that one of these causes is a slight grade of thyroid insufficiency. 
The thyrogenous obesity may depend on inherited predisposition or may 
follow infectious diseases (v. Noorden). Also it may be preceded by a Base- 
dow’s disease. I refer to the cases of Basedow’s disease in which the initial 
emaciation is followed by a progressive increase in weight. For the diagnosis 
of thyrogenous obesity, important also are other symptoms such as phlegma 
and constipation, especially if they have existed before the development of 
obesity. Such cases belong in the domain of thyroid treatment; restriction 
of calories in such cases can, especially in older persons, lead to a marked 
exhaustion and cardiac collapse, without lessening the amount of fat, while 
administration of thyroid gland reduces the body weight with amelioration 
of the general condition (v. Noorden). 
The cause of the manifoldness of the hypothyroidal syndrome may be 
regarded, as in the hyperthyroidal syndrome, as differences in the constitutions 
of the individuals affected. 
The course of myxedema in untreated cases may be progressive and give 
rise to a cachexia; then intercurrent affections often occur, and lead to death. 
Spontaneous improvement may also occur, not rarely with the develop- 
ment of a goiter, in rare cases with hypertrophy of the accessory thyroid 
glands. 
The treatment of myxedema will be considered after the description of 
sporadic cretinism. 
2. Sporadic Cretinism 
Definition.-—In the preceding section we drew disease pictures that 
originate in an organism already fully developed, when the thyroid becomes 
insufficient or loses its function entirely. When the disturbance in thyroid 
function develops in an organism as yet unfinished, there occur in addition 
profound developmental disturbances that are the more intense the earlier 
the disturbance begins. The conception of sporadic cretinism as hypo- 
thyrosis or athyrosis of the youthful organism is decisively proved in the first 
place by the sad experiences that were sometimes met with in strumectomies 
on children at a time when the functions of the thyroid were not known, and in 128 
THE DISEASES OF THE THYROID GLAND 
the second place by the fundamental researches (of Hofmeister and of v. Eisels- 
berg) on total extirpation of the thyroid in animals. The thyroprivic animals 
of v. Eiselsberg that were kept under the same conditions as the control ani- 
mals showed after a few weeks, as against the control animals of the same 
brood, a considerable remaining behind in size and in body weight. The dis- 
turbance in growth affected the long bones more than the trunk. The bones 
became coarse and showed decrease in solidity. After a longer time the 
body weight of the control animal often attained to three times that of the 
thyroprivic animal. In addition were found distention of the abdomen, 
anemia, atheromatous degenerations of the great vessels, atrophy of the geni- 
talia, reduction in temperature, curving of the bones, trophic alterations of 
the hair, dryness of the skin, senile marasmus, and pronounced idiocy, in 
short the picture of idiotic dwarfism. The changes in human beings when the 
function of the thyroid becomes deficient in early life are entirely analogous. 
The lack of thyroid may be either congenital (thyroaplasia or thyrohypoplasia) 
or the same changes that cause myxedema of adults may affect the thyroid in 
early life (spontaneous infantile myxedema), or, as already mentioned, a 
surgical procedure may lead to thyroid insufficiency (postoperative infantile 
myxedema). 
Pineles, who was the first to separate thyroaplasia from the entire group 
as an etiologically unitary form, wished to avoid the expression sporadic 
cretinism and to distinguish only between thyroaplasia and infantile myx- 
edema. It seems to me, however, that this sharp distinction is not prac- 
ticable. It is true that infantile myxedema makes its first appearance in the 
fifth or sixth year of life, while in thyroaplasia the inhibition of develop- 
ment begins gradually to manifest itself already in the first year of life. 
Infantile myxedema may, however, also develop at the earliest age. If 
the damage to the thyroid in these cases is material, the intensity of the 
inhibition of development is the same as in thyroaplasia, and as the find- 
ing on palpation when negative is not decisive, a differentiation between these 
two conditions is hardly attainable in vivo, especially if the individuals first 
are examined carefully at a later period of life. I therefore wish to retain 
the name sporadic cretinism for the entire group. Siegert embraces all the 
cases of lack or deficiency of the thyroid gland in children, together with 
endemic cretinism, under the name myxidiotie [myxidiocyj. As I do not 
regard endemic and sporadic cretinism as entirely of similar nature, I cannot 
subscribe to this designation. 
In his excellent work on thyroaplasia, Pineles collects from the older litera- 
ture twelve cases in which the thyroid was absent microscopically at autopsy. 
Almost all the individuals affected died at an early age; in the fewer older 
individuals who had attained the age of puberty it seems that the demonstra- 
tion of a complete aplasia of the thyroid was not certain, or the cases had been 
treated with thyroid tablets (MacCallum and Fabyan). Also Thomas Erwin 
remarks this. In the case of Fletcher-Beach, that concerned a fifteen-year-old 
girl, a certain intelligence had developed. She had learned to write and use 
figures, and had menstruated two or three times. The autopsy indeed SPORADIC CRETINISM 
129 
showed absence of the thyroid gland, but as such a development is hardly 
possible with a complete thyroaplasia—the publication of this case occurs 
before the era of thyroid-gland therapy—it is possible that here accessory 
thyroids were present, which could not, however, fully compensate the 
deficiency. Pineles then cites seven works of a more recent date in which an 
exact microscopical examination failed to find any remnants of thyroid gland 
(Kocher-Langhans, Muratov, Maresch, Peucker, Aschoff, Erdheim, Knopfel- 
macher). The case of Maresch was that of an eleven-year-old girl whose 
brothers and sisters were perfectly well; according to the statements of the 
parents, growth ceased almost entirely at one and a half years of age. At 
eleven years of age, the girl was 77 cm. tall, the skull had a circumference of 
49 cm., the abdomen 53 cm., the great fontanelle measured cm. by 1H 
cm. The girl could not walk, could not sit, and could speak only a few 
syllables. The skin was myxedematous (also on microscopical examination), 
the hypophysis was of normal size, the thymus gland corresponded with the 
age. Pancreas and suprarenals were of normal size. 
The contribution of Maresch was of fundamental importance, because 
Maresch established for the first time in his case the presence of the parathy- 
roid glands. Also later investigators found the parathyroid glands intact. 
Only in a few cases was the simultaneous absence of parathyroid glands 
reported (Quincke, Case I, Rocazet Cruchet, two cases of Siegert). Here, how- 
ever, no serial sections were made. 
Very exactly studied are the cases of Aschoff, of Erdheim, and of Dieterle. 
The case of Aschoff was that of a half-year-old child of 53 cm. length. 
The hypophysis was very much enlarged (0.5 gm.). Aschoff found at the root 
of the tongue a cystic tumor that he regarded as the remnant of the lingual 
duct. In addition, there was found at the site of the lateral thyroid lobe a 
half-pea-sized vesicle that he regarded as the remnant of the branchial pouch. 
The case of Erdheim was a thirteen-month-old child, the thirteenth child of 
healthy parents. High-grade constipation had been present (palpable fecal 
tumor). Here also was found the vesicle as in the case of Aschoff; micro- 
scopical examination showed that it consisted of an ectodermal formation, 
as to the origin of which from the fourth branchial pouch there could be no 
question, as Erdheim found the same cysts on this side in two cases of uni- 
lateral thyroaplasia, in which cysts on the normal side were absent. 
Very recently have been added the cases of Ungermann (vicarious tongue- 
struma), MacCallum and Fabyan (cysts in the neighborhood of the superior 
parathyroids), and finally three cases of Schilder. In all cases exactly inves- 
tigated up to the present these cysts have been found at the site of the lateral 
lobe of the thyroid. Dieterle could demonstrate in his case the absence of 
the rudiments of the superior thyroid arteries. 
We are therefore justified in the assumption that in these cases an ano- 
maly of formation is present that consists in an agenesis of the lateral rudi-' 
ments of the thyroid. The vesicles found at their site consist in indifferent 
rests of the postbranchial bodies, in which under circumstances isolated thyroid 
follicles may be imbedded. At the root of the tongue are found, at the site 130 
THE DISEASES OF THE THYROID GLAND 
of the median rudiment of the thyroid gland, analogous indifferent rests with 
traces of thyroid-gland tissue, which not infrequently give occasion to tumor 
formation. The cases described affect children who have reached the elev- 
enth year of life at most. The girls were far in the majority; they were all 
well developed at birth. Only in the second half of the first year of life 
did there gradually occur a standstill in the development. Among the 
numerous cases of sporadic cretinism described in the literature a large 
number certainly belong to thyroaplasia. Dieterle counts, among others, also 
the two cases of Kocher and the known case of Bourneville {Pacha de Bietre). 
Also two cases of Magnus-Levy belong to this group. The above-mentioned 
case of Bourneville attained an age of thirty-six years. As I have said before, 
I would rather not take up the question whether pure cases of thyroaplasia 
can reach so old an age, especially if they have not been previously treated. 
In any case it is established that also in complete absence of the thyroid 
gland, life and a certain degree of development is possible. 
Symptomatology.—I shall now describe the clinical picture of sporadic 
cretinism without regard to the etiology of special cases. We must in every 
respect consider that only those cases which show the fully developed clinical 
picture can belong to the thyroaplastic form, while in the incomplete forms 
there is only a relative insufficiency of the thyroid function which must have 
begun later in life. 
I would like to describe three cases of sporadic cretinism that Herr Hofrat 
Wagner v. Janeregg kindly allowed me to examine. 
Observation XIV.—Margerete H., two and one-half years. Entered the psychiatric 
clinic (of Wagner) Nov. 4, 1909. Father has a goiter, avowedly from blowing the bugle- 
horn. Otherwise no goiter in the family. Her mother’s mother was insane. Parent, 
have never been away from Vienna. A five-year-old child of the parents is entirely normals 
The birth of the patient was normal; she was nursed by the mother until the end of the 
second year. From birth lusty and lively; large, well developed; from the eighth month on 
the parents first remarked that the child did not take on more weight and since that time has 
remained at a standstill. The child has had an umbilical hernia since birth. It has never 
spoken. 
Height 62 cm. 
Circumference of skull, 42 cm. 
Breadth of shoulders, 45 cm. 
Circumference of breast, 45 cm. 
Pulse, 120. 
Rectal temperature, 36°. 
Panniculus adiposus soft, lax; myxedematous texture of the skin; walking and standing 
impossible. Forehead arched forward, root of the nose somewhat sunken in; no teeth 
as yet. Eyelids enormously swollen, tongue thick, abdomen markedly arched forward; 
umbilical hernia. Body weight 7.1 kg. From Dec. 2, 1909, on thyroidin tablet every 
third day. 
Nov. 10, 1910.—71 cm. long, weighs 9.1 kg. Treatment discontinued. 
Entrance into the first medical clinic on Oct. 15. Can only stand when it holds fast 
on a support, cannot speak, is, however, otherwise lively and busies itself. All fontanelles 
closed. 
Circumference of skull, 46 cm. 
Circumference of breast, 50 cm. 
Circumference of abdomen, 48 cm. SPORADIC CRETINISM 
131 
Anterior superior spine to internal malleolus, 30 cm. 
Acromion to olecranon, 13 cm. 
Olecranon to styloid process of radius, 12 cm. 
Skin somewhat dry, no distinct myxedema. Root of nose sunken in only a little. 
Tongue always protudes from the mouth; left anteriorly below, one tooth nucleus pal- 
pable, otherwise no teeth. Hearing apparently entirely normal. Thyroid gland not 
palpable; abdomen distended, liver is palpable, indication of umbilical hernia; the tickling 
Fig. 12.—X-ray picture of a hand of a sporadic cretin (Observation XIV7) 
reflexes of the external auditory meatus are present. Does not tell when she wishes to 
pass feces or urine. Nervous status, as far as elicited by tests, normal. 
Patellar reflexes somewhat lively. 
Oct. 15.—30 gm. dextrose, no sugar. 
Nov. 11.—50 gm. dextrose, no sugar. 
Oct. 24.—Erythrocytes, 4,560,000. 
Leucocytes, 6800, of which: 
Polymorphonuclear neutrophiles, 48.4 per cent. 
Large mononuclears, 8.3 per cent. 
Lymphocytes, 40 per cent. 
Eosinophiles, 3.3 per cent. 132 
THE DISEASES OF THE THYROID GLAND 
Nov. ii.—Erythrocytes, 5,250,000. 
Hb., 55 per cent. 
Leucocytes, 8200, of which: 
Polymorphonuclear neutrophiles, 38 per cent. 
Large mononuclears, 37 per cent. 
Lymphocytes, 54 per cent. 
Eosinophiles, 4.3 per cent. 
Nov. 26.—0.0005 gm. adrenalin subcutaneously and 50 gm. dextrose per os. After 
four hours 3.2 per cent, sugar. 
Nov. 29.—One drop homatropine in eye; twenty-four hours later, still slight mydriasis. 
Nov. 30.—Adrenalin, 0.0005 gm., no sugar. 
Nov. 20.—0.005 gm. pilocarpine subcutaneously, weak sweat, no salivation. 
From Dec. 2 on, two thyroidin tablets daily; 
from 6th on, three daily, from 8th on, five daily. 
Dec. 14.—Pulse that was formerly no, now 
130; thyroidin medication now reduced to one 
tablet. 
Summary.—We are dealing with a case of 
sporadic cretinism, probably depending on a con- 
genital aplasia or hypoplasia of the thyroid. 
Here are worthy of note the high assimilation 
boundary for sugar, the failure of adrenalin glyco- 
suria, the strong action of atropine and the weak 
action of pilocarpine; there is, however, found an 
unusually high glycosuria on combination of 
dextrose and adrenalin. There occurs in this case 
a somewhat high tolerance for thyroidin. 
Rontgen investigation of the skeleton of the 
hand, Nov., 1911: The bone-nuclei of the os 
magnum and the unciform bone are present. 
Those for the epiphysis of the radius and the basal 
epiphysis are still absent. The skeleton corre- 
sponds to that of a six- to eight-month-old child 
(Fig. 12). 
Sella turcica corresponding to the size of 
the skull. 
Observation XV.—Franz N. (see Fig. 13). Entered the psychiatric clinic of Wagner 
Oct. 6, 1909, four and one-half years old, from Rudoletz in Mahren. 
The fourth child of healthy parents. Birth easy, at the right time. Head at birth 
already large. Speech up to the second year of life consisted of the simplest words only; 
words were such as tata, mamma, and since this time the child has not spoken much other- 
wise. 
Parents and the entire family to the great-grandparents of the child have not suffered 
from goiter. Nowhere in the neighborhood does the father know of a similar case. 
Length of body 85 cm., weight 19.2 kg. Head extremely large without, however, any 
hydrocephalic formation. Bones of the head of hard consistency. Strong development 
of the skeleton of the face. Very low forehead, eyes stand wide apart. Saddle-nose, 
epicanthus; short, very broad cartilaginous nasal framework; cushiony lips; thick, broad 
tongue, that protrudes from the mouth. Cushiony ear lobes that lie close to the head. 
Cheeks very thick, throat thick and stubby. Thyroid not palpable. Thick lanugo hair on 
back. Skin of the body, especially in the supraclavicular grooves and on the backs of the 
hands and feet, springy elastic; hands and fingers chubby. Abdomen much distended. 
Circumference 65H cm. Reducible umbilical hernia. Reflexes, as far as can be tested, 
present. Noise tests were without any reaction. 
Fig. 13.—Sporadic cretinism. SPORADIC CRETINISM 
133 
From June 23 on was given one thyroidin tablet daily, until Oct. 24. Entrance into 
the first medical clinic. Now length of body 91.25 cm., weight 21 kg. Treatment is now 
discontinued. 
Circumference of the head now 56 cm., circumference of the abdomen 65 cm., cir- 
cumference of breast 49 cm. 
Anterior superior spine to internal malleolus 44.5 cm. 
Circumference of neck 36 cm. 
Heart dullness somewhat broadened (also by X-ray, heart of characteristic spherical 
shape). Heart sounds pure. 
Border of the liver palpable 10 cm. below the margin of the ribs in the mid-line, two 
fingers’ breadth below in the right mammillary line. 
Umbilical hernia about 3 cm. long, and its insertion 2.5 cm. in diameter. Penis very 
small, testicles have not descended. The child does not go to the toilet to void urine 
or feces. Slight heightening of the patellar reflexes, otherwise the reflexes normal. Nervous 
status, so far as can be tested, normal. 
The child often stares into space for a long time, but at times is right lively and cries 
loudly. No trace of speech. Puts all objects into his mouth, even his own feces. Im- 
pressions of hearing entirely absent, no reaction of the eyelids to sounds. 
Nov. 2.—50 gm. dextrose per os. no sugar. After several days 100 gm. dextrose of which 
he vomited a small amount, no sugar in the urine. 
Nov. 9.—Erythrocytes, 5,480,000. 
Hemoglobin, 70 per cent. 
Leucocytes, 9000, of which: 
Polymorphonuclear neutrophiles, 42.5 per cent. 
Large mononuclears, 8 per cent. 
Lymphocytes, 41 per cent. 
Eosinophiles, 8.5 per cent. 
A later count yielded: 
Erythrocytes, 5,400,000. 
Hemoglobin, 70 per cent. 
Leucocytes, 11,000. 
Eosinophiles, 12 per cent. 
Nov. 2i.—0.01 gm. pilocarpine. Sweat extremely slight, salivation negative. 
Nov. 22.—Homatropine evinces weak mydriasis only, which however is positive after 
twenty-four hours. 
Nov. 26.—0.001 gm. adrenalin subcutaneously and 50 gm. dextrose per os. After 
four hours 4.2 per cent, sugar. 
Nov. 29.—Weak mydriasis forty-eight hours after installation of homatropine. 
Nov. 30.—0.001 gm. adrenalin subcutaneously, no sugar. From Dec. 2 on, three thy- 
roid tablets a day; from Dec. 5 on, five tablets daily; from Dec. 8 on, seven tablets daily. 
Dec. 13.—Marked scaling of the skin, no trace of moisture, even of the palms. 
Dec. 22.—Pulse irregular, only 72 to the minute, although frequent abortive beats. 
The dose was reduced to three tablets and after some days, when the pulse had become 
entirely reg.ular again, five tablets were given continuously. 
Jan. 8—Leucocytes, 4800, of which: 
Polymorphonuclear neutrophiles, 61.5 per cent. 
Lymphocytes, 20.5 per cent. 
Large mononuclears, 12.5 per cent. 
Eosinophiles, 5.5 per cent. 
Jan. 19.—The examination of the hearing now shows certainly that the patient reacts 
to loud noises. Distinct lid-reflexes. 
March 29.—Thyroidin medication has now been continued in the large doses without 
producing manifestations of poisoning. The heating is still better, the enlargement of 
the liver has essentially diminished in size; otherwise there is no change. 134 
THE DISEASES OF THE THYROID GLAND 
December, igio.—The nuclei of the os magnum and the unciform bone are alone visible 
in the carpus, while at this time the nuclei of the entire skeleton of the carpus should have 
been laid down. The epiphysis of the radius is present. The skeleton corresponds to that 
of a one and one-half to two-year child. 
Summary.—The patient is from a goiter-free neighborhood. There exist no other 
grounds for the assumption of an endemic cretinism. We are indeed dealing with sporadic 
cretinism, probably dependent on aplasia or high-grade hypoplasia of the thyroid gland; 
Fig. 14. 
Fig. 15. 
Sporadic cretinism. 
and perhaps later there was added some other factor that we are not able to define that made 
the insufficiency still greater. 
Thyroid medication here succeeded less than in the preceding case. It was also intro- 
duced much later. Apparently the thyroid insufficiency is here very much greater. 
The investigation with adrenalin and pilocarpine several weeks after the discontinuation 
of thyroid-gland therapy show's slight or negative action. The test as to alimentary gly- 
cosuria results negative. It is very interesting also that in this case adrenalin plus dextrose 
leads to an entirely usual degree of glycosuria. SPORADIC CRETINISM 
135 
Worthy of note in this case is the enormous tolerance for thyroidin and also the action 
of thyroidin on the disturbance of hearing and on the enlargement of the liver. 
Observation XVI.—H. A., entrance into the psychiatric clinic (of Wagner) Jan. 21, 
1909. Fifteen years old, female dwarf (95 cm.); face puffy, skin of the entire body myxe- 
dematous, dry and scaly. Supraclavicular fossae filled with pad-like masses. Conjunc- 
tivitis eczematosa. Fundus normal. Circumference of skull cm. Root of nose sunken, 
tongue thick, also the lips; the teeth with transverse ridges, in great part carious, 
have remained very much behind in their development. Abdomen markedly distended, 
umbilical hernia. 
Fig. 16.—Sporadic cretinism, seventeen-year-old girl. In spite of a long-continued thyroid 
treatment the development of the skeleton of the hand is that of a normal girl aged ten years (see 
Fig. 17). 
Measurements.—Height, 95 cm. 
Circumference of skull, cm. 
Upper arm (acromion to olecranon), 19 cm. 
Arm proper, 13 cm. 
Lower extremity (spine [anterior superior] to heel), 46 cm. 
Intelligence that of a four-year child. Can speak, can understand questions and state- 
ments addressed to her; can, however, not write nor read, and can say, of a prayer, only 
the words at the beginning. Weight 20 gm. 
From April 27 on, 0.5 gm. sodium iodide, after which she became livelier; from June 
8 on, one thyroid-gland tablet a day. Body weight at the beginning of July had gained 136 
THE DISEASES OF THE THYROID GLAND 
16.9 kg. The bowel movements, which formerly frequently occurred only every two or 
three days, have gradually become entirely normal. Rapid mental development. Is 
much more active, plays much, wants a looking glass, a net for her hair, begins to sing. 
Jan. 18. 1910.—101 cm. Myxedematous texture of the skin much lessened, slight 
sweating of the palms of the hands. Dermographism. 
Oct. 13, 1910.—The patient, sixteen and three-fourths years old, now enters the medical 
clinic. Length no cm., weight 23 kg. The thyroid-gland medication is now discontinued. 
Circumference of the skull 57 Jlj cm. 
Hair soft, skin somewhat dry, only the palms of the hands moist, tongue not enlarged, 
teeth much behind in their development. Circumference of abdomen 62 cm.; there still 
remain indications of an umbilical hernia. Liver palpable two fingers’ breadth below 
the margin of the ribs. Pubis and axillae entirely devoid of hair. External genitalia hypo- 
plastic. Has never menstruated. The entire trachea is distinctly palpable, there is nothing 
to be felt of the thyroid. She gives correct information as to where she has been the last 
year. Cannot reackon, counting impossible. 
Oct. 15.—100 gm. dextrose, weakly positive. 
Erythrocytes, 4,540,000. 
Leucocytes, 11,200, of which: 
Lymphocytes, 49 per cent. 
Large mononuclears, 9.5 per cent. 
Lymphocytes, 51.0 per cent. 
Eosinophiles, 7 per cent. 
Oct. 25.—100 gm. dextrose, no sugar. 
Nov. 1.—Hands feel cool to the touch; patient has gained 1.7 kg. since here entrance. 
Nov. 3.—Leucocytes, 12,100, of which: 
Polymorphonuclear neutrophiles, 40.6 per cent. 
Large mononuclears, 4.6 per cent. 
Lymphocytes, 49 per cent. 
Eosinophiles, 5.8 per cent. 
Nov. 9.—Leucocytes, 11,500. 
Hemoglobin, 65 per cent. 
Nov. 10.—150 gm. dextrose, no sugar. 
Nov. 16.—Skin entirely dry. 0.01 gm. pilocarpine; no salivation, only slight sweating. 
Nov. 19.—Nervous status. Superficial abdominal reflexes increased and also plantar 
reflex lively; otherwise normal, as far as can be investigated. 
Only very slight mydriasis after homatropine. On Nov. 22, 0.001 gm. adrenalin sub- 
cutaneously and 100 gm. grape-sugar by mouth. Minimal increase in blood-pressure, 
lasting only for a very short time. Pulse only 84 to 92. In the first two-hour period, no 
sugar; in the second, 4.25 per cent, in 15 cc. urine; in the next twelve-hour period, Trommer 
still strongly positive. 
Nov. 26.;—0.001 gm. adrenalin, no sugar. 
Nov. 29.—Circumference of skull, 56H cm., total height, hi cm. Circumference of 
abdomen, 62 cm., circumference of breast (mammillae), 64 cm., circumference of neck, 28 
cm. Upper arm (acromion to olecranon), 21.5 cm., arm proper, 18.5 cm., lower extremity 
[anterior superior] spine to heel), 52 cm. 
Dec. 2.—Up to this time, pulse between 100 and no. Bowel movements not entirely 
regular, in that one bowel movement is wanting every three to five days. From now on, five 
thyroidin tablets a day. From Dec. 6 on, seven tablets a day. Dec. 8, nine tablets a day. 
During the next days the pulse rises up to 145 and sinks to its former count only on 
Dec. 22. 
Leucocytes: 10,200, of which: 
Polymorphonuclear neutrophiles, 67.2 per cent. 
Large mononuclears, 8.2 per cent. 
Lymphocytes, 22.6 per cent. 
Eosinophiles, 2 per cent. SPORADIC CRETINISM 
137 
X-ray examiation of the hand skeleton. The epiphysial junctures of the fingers 
and metacarpal bones are still open. The skeleton of the carpus is as yet laid out in the 
form of round bone-nuclei. At this age the carpal bones should be fully developed, and 
the epiphysial junctures should be closing up (Fig. 16). Sella turcica corresponding to the 
size of the skull. 
Fig. 17.—X-ray picture of the hand of a normal ten-year-old girl. 
Summary.-—Sporadic cretinism probably due to aplasia or high-grade hypoplasia of 
the thyroid gland. The thyroid-gland therapy instituted in the sixteenth year is able to 
affect the growth not inappreciably and to further intellectual development. We may 
readily comprehend that the marked inhibition of development that has existed for sixteen 
years cannot entirely be done away with. 
The investigation of the carbohydrate metabolism showed that after the year-long 
administration of thyroidin the assimilation limits for grape-sugar lay abnormally low. 138 
THE DISEASES OF THE THYROID GLAND 
It is very instructive that with the discontinuation of the thyroid medication the assimila- 
tion limits rose immediately, so that after several weeks as much as 150 gm. dextrose would 
be borne. Also adrenalin produces no glycosuria, while, on the contrary, adrenalin and 
grape-sugar produce abundant glycosuria. 
An over-loading test with thyroidin showed that the tolerance in this case was at any rate 
rather high, as symptoms of poisoning first occurred only with large doses. Under the test 
with thyroidin, the number of neutrophiles rose considerably, and the assimilation limits for 
grape-sugar again sank rapidly. 
In the clinical picture of sporadic cretinism the phenomenon most before 
the eyes is the disturbance in growth. Buschan collects from the literature 
thirty-four cases of sporadic cretinism that showed evident dwarfism. In the 
cases with high-grade disturbance of the function of the thyroid gland the length 
of the body was mostly below i meter. Siegert describes a two-and-a-half- 
year-old child of 50 cm. length; v. Eiselsberg a thirteen-year-old girl of 80 cm. 
length. In addition to the disturbance in the growth in height are found delay 
in the appearance of the bone-nuclei, and in the closures of the epiphyses 
(Hertoghe, v. Wyss, Kassowitz, Dieterle, Siegert, and others). The original state- 
ment of Virchow that the calcification appears prematurely was later found to 
be incorrect; the case investigated by Virchow was one of chondrodystrophy 
(Kaufmann). This was further confirmed by IVeygandt through the micro- 
scopical examination of Virchow's case. 
Already Argutinsky had mentioned that the development of the bone-nuclei 
in sporadic cretinism is even more intensely delayed than is the growth in height. 
If, for example, the size of a twenty-year-old cretin corresponds to that of a 
six-year-old child, the retardation in the deposition of the nuclei lies even 
farther behind. In the pure cases with complete lack of thyroid gland the 
epiphysial joints do not close. In the known case of Bourneville, autopsy, in 
the thirty-sixth year of age, showed epiphyses that were completely open. 
The closure of the fontanelles is markedly delayed. In the case mentioned the 
great fontanelle was still open in the twentieth year. At autopsy in the thirty- 
sixth year its place was tilled by a translucent bony plate. Also Kassowitz 
mentions cases of infantile myxedema with markedly delayed closure of the 
fontanelles; thus in a thirteen-year-old individual he found the frontal fontanelles 
still distinctly open. The measurements of the bones, with regard to their 
thickness and length, correspond to the relations of childhood; this is then a 
proportional dwarfism, deviating from the normal proportions of childhood only 
in the development of the skull. The circumference of the skull does not indeed 
correspond to the age of the individual, but is distinctly larger than would be 
represented by the rest of the body structure. In addition there is a remaining 
behind in the growth of the vomer, that results in a retraction of the root of the 
nose; this lends to the face the characteristic cretinoid expression, which 
does not, however, reach the extreme grade as seen in chondrodystrophy. In 
the four-month-old case, with pure thyroaplasia, of Dieterle, the measurements 
of the bones showed that they about corresponded to those of a new-born 
child. The disturbance in growth had therefore apparently first made its 
appearance after birth, and not already in fetal life. The histological examina- SPORADIC CRETINISM 
139 
lion of the hones in sporadic cretinism showed diminution in the size of the zone 
of cartilage proliferation, narrowing of the marrow cavity, abundant fat-con- 
tents of the marrow, and poverty of the marrow spaces in cells. According to 
Dieterle there also occurs a slowing of apposition and absorption, with normal 
calcification. This gives rise to a certain degree of sclerosis. With this agrees 
the observation of Kassowitz and of Dieterle, that the bones, when once formed, 
show an unusual hardness, thus differing from their condition in rachitis. The 
histological picture of the bones shows a certain senility; the disturbance 
depends on an equalized delay of the endochondral and periosteal ossification. 
It is further characteristic for the disturbance in growth in sporadic cretin- 
ism that it reacts to thyroid therapy in a pronounced manner, even when the 
therapy is first begun after the twentieth year. We shall speak of this in the 
consideration of the therapy. 
In the incomplete forms of sporadic cretinism the disturbances of growth 
are characterized by their slighter intensity. Here closure of the epiphysial 
junctures may occur, even in advanced years. I mention as example a case of 
Magnus-Levy, in which the treatment, instituted in the forty-fifth year—the 
patient was 132 cm. tall—failed to exercise any influence on growth, as the 
epiphysial junctures were already fully ossified. 
Disturbances in dentition go hand-in-hand with those of growth of the bones. 
When the thyroid gland is entirely absent the children during the first year 
remain completely toothless. In the later years the milk-teeth develop very 
slowly and finally remain partially retained. (Often in addition to the retained 
milk-teeth are found the rudiments of the permanent teeth.) Here thyroid 
therapy, as we shall see later, may elicit excellent results. 
Umbilical hernia is a constant finding in the higher grades of sporadic 
cretinism. Kassowitz observed it sixteen times in twenty-two cases of infantile 
myxedema. The eldest of these children was twelve years old. The hernia 
may attain the size of an apple. Therewith the abdomen is distended, the 
navel is markedly deep (Argutnisky), there is high-grade obstipation, which in 
the case of Maresch led to prolapse of the rectum. The myxedematous texture 
of the skin is for the most part distinctly evident; in the older cases, however, the 
skin is on the other hand rather atrophic, only the pad-like swellings of the supra- 
clavicular grooves and the slight puffiness of the face, especially the eyelids, 
remain. For the most part the limit of the hair zone is far back on the forehead, 
to which are added protuberance of the malar bones, retraction of the root of 
the nose, cushiony lips, protrusion of enlarged tongue all this lends the impression 
of something of an animal appearance to the face. 
Inspection of the mouth shows that the palatine arches are for the most 
part high, deepened with furrows, the tonsils enlarged; and often in the pharyn- 
geal space there are adenoids. The hypertrophic rhinitis which is present 
disturbs breathing; the children snuffle and snore; in most cases there is a dis- 
charge from the nose. In two of the above cases I found a distinct enlargement 
of the liver. In Argutinsky’s report of his case there is the statement that the 
border of the liver was palpable two and one-half finger-breadths below the 
margin of the ribs. 140 
THE DISEASES OF THE THYROID GLAND 
It should also be mentioned that in the fully developed cases, the breathing 
is extraordinarily slowed. A twenty-eight-year-old case of Magnus-Levy’s, who 
at the age of fourteen years had sustained a total strumectomy, breathed only 
six times in the minute. 
The sweat-inducing action of pilocarpine, in the three cases cited, was very 
slight; salivation failed entirely; the mydriatic action of homatropine lasted 
very long. 
The developmental disturbances of the genitalia are always very marked. 
In females the labia majora are stunted and do not cover the labia minora; 
uterus and ovaries are highly hypoplastic and the breasts fail to develop. In 
males the penis is very small, the testicles do not descend at all or descend very 
late, and in many cases are essentially smaller than in the normal individual 
The pubic and axillary hair does not develop. With the failure of sexual 
maturity in boys, there occurs also the failure of the change of voice. [Wollen- 
berg1 has recently reported a case in which an adult sporadic cretin menstruated. 
She conceived three times.—Editor.] 
The hematopoietic system also suffers in development. The hemoglobin 
contents is for the most part much reduced, more than the number of erythro- 
cytes. This behavior was very well illustrated in the three cases described 
although all three had been treated for a long time with thyroid tablets. For 
the most part the number of leucocytes is increased. The differential count of 
these shows an enormous reduction in the polymorphonuclear neutrophiles 
and a corresponding increase of the mononuclear cells, even when we consider 
that in children the number of neutrophile cells is smaller than in adults. The 
leucocytic picture shows the type of earlier stages of development (Meunacher.) 
Among the mononuclear cells are found a great number of granular cells. Also 
Turk’s irritation forms are observed (Esser). 
The number of eosinophile cells is mostly very much increased. In my 
three cases the percentage was 12 to 33. 
Thus the blood findings behave similarly to those of adult myxedemics, 
only the deviations from the normal are more strongly expressed. Also the 
pathologico-anatomical findings agree with this. While thyroidectomy in 
adult animals does not lead to a distinct alteration of the bone marrow, there 
has been observed by Kraus in young animals after thyroidectomy a lymphoid 
metamorphosis of the bone marrow; also Aschoff found in his case of thyroapla- 
sia a lymphoid metaplasia of the marrow of the femur. 
In sporadic cretinism, as in myxedema adultorum, there is found a para- 
doxical action of the thyroid substance on the leucocytic formula. While the 
administration of thyroid-gland substance in normal individuals increases the 
count of mononuclears at the cost of polymorphonuclear neutrophiles, we find 
in conditions of hypothyrosis under thyroid medication, together with the 
increase in hemoglobin and the number of red cells, also an increase in neutro- 
phile cells, with a decrease in mononuclears. The abnormal forms vanish from 
the blood and the leucocytic formula approaches its normal constitution. In a 
1 Wollenberg (H. IF.). Zur Frage der Sexualitat bei sporadischen Kretinsmus. Med. Klinik, 
Vol. XVIII, No. 5, Jan. 29, 1922, p. 144. SPORADIC CRETINISM 
141 
case of juvenile myxedema (complicated with symptoms of deficiency on the 
part of the other ductless glands), I observed that the count of neutrophiles 
increased from 54 per cent, to 84 per cent, during a two months’ thyroid 
treatment. 
Esser saw in a myxedemic child the count of neutrophiles increase under 
thyroid treatment from 19 per cent, to 41 per cent.; later, intoxication symptoms 
developed and with these the count of neutrophiles again sank to 19 per cent. I 
offered in explanation of this case, that at first the thyroid medication exercised 
its usual favorable influence on the blood picture of hypothyrosis, but that 
later with the appearance of the intoxication symptom it assumed the character 
of hyperthyrosis. 
In case N., Observation XV (sporadic cretinism), the neutrophilic count 
rose from 42.5 per cent. (Nov. 9) to 61.5 per cent. (Jan. 18); in case A., Ob- 
servation XVI, from 32.5 per cent. (Oct. 15) to 67.2 per cent. (Dec. 22), under 
treatment with large doses of thyroidin. 
Summarizing these observations, it may be said that on the absence or 
insufficient production of thyroid extract in the juvenile organism, the develop- 
ment of the hematopoietic system is severely inhibited. Agreeing with this is 
Dieterle’s observation that the disturbance in the growth of bone does not lie in 
the marrow of the epiphysial cartilage alone, but also in the bone marrow itself. 
Especially does the development of the neutrophilic cells suffer damage. There 
exists a slight grade of status lymphaticus that perhaps is in relationship with 
the faulty development of the chromaffin tissue. 
The metabolism of sporadic cretinism has been carefully studied in the 
excellent investigation of Magnus-Levy. I reproduce from the table of this 
author the following figures: 
Age, 
years 
Length, 
cm. 
Weight, 
kg. 
Cc., 
O2 
on 
Of 
Cc., O2 
per kg. 
Relation of the O2 excre- 
tion to that of a healthy 
individual 
Case I.... 
29 
98.0 
21 . I 
77-5 
54-5 
3-67 
48 per cent. 
Case II.... 
14 
84.0 
15-8 
72.6 
59-4 
4.62 
60 per cent. 
Case III.... 
46 
132.0 
42.5 
122.4 
104.9 
2.88 
S3 per cent. 
Case V 
(light) 
14 
131-5 
29-5 
I54-I 
137.0 
5.22 
96 per cent. 
In the fully developed form, the basal metabolism is therefore much 
reduced. 
With this agrees the experiment of v. Bergmann. He investigated the 
metabolism of a one-year-old child, employing the Voit-Pettenkofer apparatus. 
The child was put in equilibrium with a supply of calories that was far below 
that needed for a healthy child of like weight. Concerning the protein meta- 
bolism, I shall refer to the chapter on myxedema adultorum. The salt meta- 
bolism in infantile myxedema is dealt with in investigations of Haugardy and 
Langstein. These authors found that in their case the assimilation of calcium 
amounted to about one-third of that of a normal child the same age. In this 142 
THE DISEASES OF THE THYROID GLAND 
the intensity of the inhibition of bone growth finds expression in a pretty 
manner. 
As concerns the carbohydrate metabolism, I might mention that in the 
three cases of sporadic cretinism that we investigated the assimilation limits 
for carbohydrates lay rather high several weeks after the withdrawal of thyroid 
medication. Also injection of adrenalin did not lend to glycosuria, while on 
the contrary injection of adrenalin with simultaneous administration of sugar 
always yielded strikingly high sugar percentages in the urine. Perhaps we 
may seek the cause of this in the fact that in sporadic cretinism also the develop- 
ment of the other ductless glands suffer damage on account of the disturbances 
appearing in early youth, so that the simultaneous overburdening of the ali- 
mentary and the nervous factors bring about an appreciable insufficiency. 
The reduction of the metabolic processes expresses itself, here as in myxe- 
dema adultorum, in a hypothermia. For the most part the temperatures lie 
near 36°; also in my cases, the level of temperature was low. 
In his case Dieterle found during the last week of the life of the patient 
33.40. Then again an increase of temperature may remain absent when infec- 
tious processes occur. However, this is not usually the case. In the case of 
Bourneville, already mentioned many times, the temperature during a case of 
erysipelas rose to 40° Celsius. 
The statements as to the behavior of the hypophysis in sporadic cretinism 
do not agree. Extirpation of the thyroid gland in young rabbits leads to 
enlargement of the hypophysis (.Rogowitsch, Gley, and others). Microscopical 
alterations of an apparently degenerative nature have been many times 
described. Again, in many cases of sporadic cretinism the hypophysis or the sella 
turcica is enlarged. In my case, however, the X-ray examination of the skull 
showed no enlargement of the sella. Schilder likewise found in his three cases 
of thyroaplasia no enlargement of the sella; but no microscopical examination 
he found peculiar cells that approached near to the so-called “pregnancy cells” 
of the hypophysis. 
In sporadic cretinism the thymus gland often seems hypoplastic; Pineles 
found thyroaplasia and thymus aplasia combined. Bernheim-Karrer and 
Rucacz-Gruchet found only slight rests of the thymus. Other observers found 
the thymus normally developed. 
The marked inhibition in the development of the osseous and the blood 
systems and the ductless glandular system would lead us to expect that there 
would also be something wanting in the development of the central nervous 
system. This in the high-grade cases expresses itself not only in the absence or 
remaining backward of the mental and psychical development, but even in the 
inability to carry out the movements that subserve finer coordination. As 
Kassowitz observes, the children learn late to balance their heads, to sit, and 
to walk. 
Such cases, as for instance the case of N. described (Observation XV), 
have almost nothing human left about them. They give utterance to only 
some inarticulate sounds and almost every sign of mentality is absent. They 
do not go to the toilet to void urine or feces. N. always devoured.his feces SPORADIC CRETINISM 
143 
whenever he could get access to them. In lighter cases the disturbance of 
mental development is somewhat shorter. Usually the sense of smell is well 
developed. 
The statements as to disturbances of hearing in sporadic cretinism are very 
diverse. The assumptions as to the cause of these diverge greatly. It is 
certain that the absence or insufficiency to the function of the thyroid may lead 
to disturbances of hearing. I refer to the results of thyroid medication that are 
often attained in a striking manner in these cases. It is just as certain, how- 
ever, that with complete failure of the thyroid gland the organ of hearing may 
be completely developed from birth on. Siebermann examined the organ of 
hearing in Dieterle’s cases of congenital thyroaplasia and found entirely normal 
relationships in an anatomical sense. Even in a functional sense, disturbances 
do not necessarily have to be present,—for Maresch’s case of thyroaplasia showed 
no deafness. Hence what is under dispute is only how to explain the distur- 
bances that occur in many cases, v. Wagner was the first to express the opinion that 
myxedematous swelling of the mucous membrane of the tympanum, the Eusta- 
chian tube, etc., could furnish the cause of the hardness of hearing. On the 
contrary, Denker states that thyroidectomized animals after operation are 
completely deaf, show as the result of histological examination no myxedema- 
tous alterations of the mucous membrane and the organ of hearing, nor any 
degenerative alterations in the nervous organ of hearing or in the bulbar centers. 
The hypothesis of a dysthyric hardness of hearing {Bloch) is therefore denied. It 
is feasible to think, as many otologists assume,that central perception of the stimu- 
lus of sound suffers. There is then concerned a form of cortical deafness, or that 
form of deafness which Heller describes as psychical deafness, in which the 
perception of words does not come to consciousness, or as Gutzmann suggests, 
serious defects of attention or a high-grade weakness of memory for speech make 
their perception of words entirely impossible. Not entirely easy is differential 
diagnosis from sensory aphasia. The distinction is made possible only by the 
characteristic signs of feeble-mindedness. Only of my cases (case N.) seemed 
to be deaf-and-dumb. This was striking as otherwise complete hearing mutism 
[Horstummheit] does not seem to occur in sporadic cretinism. The ear tickling 
reflex was present. From the side of the specialists, hearing mutism [Horstumm- 
heit] was supposed to be present {Dr. Frdschels). The conception of hearing 
mutism is not, however, uniform among otologists. Gutzmann, Nadoleczny, 
H. Stern, and others speak of hearing mutism only when it concerns individuals 
(mostly children from third to seventh year) who are mute in spite of intact 
intelligence and intact hearing. These cases of pure hearing mutism are not 
common. In the case of N. there indeed occurred, after several months’ treat- 
ment with large doses of thyroidin (to seven tablets a day), a slight, but distinct, 
degree of ability to hear (lid reflex). Unclear however remains the circum- 
stance that also in complete absence of thyroid gland from birth, deafness does 
not always develop; as has already been mentioned, there occur cases of thyro- 
aplasia that heard. Also I should not neglect to mention that in the numerous 
dogs on which I myself performed thyroidectomy, and on which later exact 
investigation disproved any existence of accessory thyroids, there were never 144 
THE DISEASES OF THE THYROID GLAND 
to be observed perceptible mutism even after a period of observation lasting up 
to two years. The question still needs careful study. 
In cases in which the power of hearing is markedly affected or is absent, 
the development of speech is of course also slight; in the case mentioned, case 
N., it was limited to a few inarticulate sounds. 
We know nothing as to the etiology of thyroaplasia and thyrohypoplasia. 
Pineles states that there are sometimes malformations, tuberculosis, or alco- 
holism in the ancestry, but this statement does not explain much. For 
infantile myxedema, all those damaging influences come into consideration 
that were set forth for myxedema adultorum. Worthy of note is the state- 
ment of Spolverini, that sucklings who were nursed by women with goiter 
developed myxedema. All of Spolverini’s observations, however, do not seem 
to me to be free from objection. It seems well in this case for us to assume 
an expectant attitude, until more observations have been made. The thyroid 
secretion does not seem to go over in the milk, as according to many observa- 
tions {Lange and others) it was found that sucklings who were nursed by 
healthy women, might yet develop myxedema. 
Differential Diagnosis.—In the diagnosis of infantile myxedema all those 
points are to be considered that were mentioned in the diagnosis of myxedema 
adultorum. To these are added in infantile myxedema the ear marks of the 
remaining behind in the physical and the mental development. Among 
these the inhibition of ossification is especially important. Siegert is justified 
in emphasizing this. One should not forget, however, that in many vegetative 
disturbances, that have nothing to do with the thyroid gland, a delay in 
ossification may exist. As far as it affects only the closure of the epiphyses, 
as for instance in the case in eunuchoidism, it offers no difficulty from the 
standpoint of differential diagnosis, as in infantile myxedema the delay in 
growth and that in the appearance of the bone nuclei is very evident. On the 
contrary, there occurs in true infantilism and in hypophysial dwarfism an 
entirely similar, although in most cases not such a severe, delay in ossification 
as in infantile myxedema. It is true that growth in infantilism may some- 
times be hastened through thyroid medication, but not in such a manner as 
in sporadic cretinism. Hypophysial dwarfism tends to behave similarly (see 
Chap. VI). In both conditions, moreover, the assimilation boundaries for 
thyroidin lie essentially lower than in sporadic cretinism. 
The distinguishing of the etiologically different forms of cretinism in vivo 
is often difficult, and in many cases quite impossible. Light cases, or those in 
which the delay in development sets in at a later stage are to be counted as 
infantile myxedema. In the severe cases that occur quite early the assump- 
tion of a thyroaplasia is better warranted, but is not to be relied on in vivo, 
as the negative finding on palpation is valueless. 
We shall consider in the third chapter the delimitation from endemic 
cretinism. 
Light grades of thyroid insufficiency may heal spontaneously or under the 
use of thyroid-gland tablets (probably on account of the stimulating action 
Treatment of Athyrosis and Hypothyrosis TREATMENT OF ATHYROSIS AND HYPOTHYROSIS 
145 
of the iodine they contain on the thyroid and on account of the raising of 
all metabolic processes). In the severe cases, and especially those with com- 
plete absence of the thyroid, an ideal therapy would be the implantation of 
a new thyroid gland. 
Already A. Schiff tried to remedy the deficiency, in animals in whom the 
thyroid gland had been extirpated, by the implantation of a new thyroid. 
H. Bircher was the first, in 1889, to succeed in the implantation of a thyroid 
in a case of very severe cachexia strumipriva.1 He implanted with good 
results a human thyroid into the abdominal cavity; there soon, however, oc- 
curred a relapse. A new implantation brought about considerable improve- 
ment, indeed even there was a return of the menses, which had ceased for a year; 
but this result too was not permanent. Later Collins and Macpherson 
reported results in myxedema that lasted from one and one-half to two years. 
In these cases there were many renewed transplantations. Even more 
favorable results are reported by Gibson and others in sporadic cretinism. 
Horsley proposed that thyroids of monkeys or sheep be transplanted under the 
skin of the breast, Rehn under the skin of the throat. New hopes were aroused 
by the attempt of Payr to transplant thyroid tissue into the spleen, at first in 
animals, later in a four-year-old case of sporadic cretinism. In the case last 
mentioned the thyroid tissue came from the mothers. There occurred an 
essential improvement which affected, in addition to the myxedematous 
symptoms referable to the skin, also the intelligence and the growth of bone 
(12 cm. in five months). But also in this case the result was not permanent. 
Kocher suggested transplanting thyroid gland into the bone marrow. Mosz- 
kowicz implanted thyroid-gland tissue into the tibia of a six-year-old myxe- 
dematous child. Here too the result was good, but only transitory. (Per- 
sonal communication.) Also the results attained by Bramann seem to have 
been only transitory. 
New hopes have been awakened through the important investigations of 
Carrel on the suture of vessels. Stich and Makkas succeeded in doing auto- 
plasty on dogs; heteroplasty did not however succeed. Enderlen and Borst 
come, on the ground of their interesting experiments, to the conclusion that 
autotransplantation, that is, the transplantation of the thyroid gland from 
one part of the body to another of the same individual represents perma- 
nent results. Homiotransplantation, that is the transplantation of the 
thyroid gland of an individual to another of the same species, for instance, 
from dog to dog, or from goat to goat, remained without results even when 
the animals were from the same parents. The vessel suture indeed healed, 
the vessels remained patulous, the glands however underwent absorption. 
Experiments on cretins likewise led to negative results. The thyroid artery and 
vein from the upper pole of the thyroids obtained from struma operations 
on man were united to the axillary vessels of the cretins; but here also there 
came about a gradual absorption of the glands. Enderlen and Borst con- 
cluded that already the slight biochemical differences that exist between 
1 The experiments of v. Eiselsberg are of extraordinary interest for tetany and will be considered 
under that caption. 146 
THE DISEASES OF THE THYROID GLAND 
the tissues of different individuals of the same species are sufficient to prevent 
a permanent functionating of the engrafted organ. 
Therefore the sovereign method of treatment to-day is still the administration 
of thyroid-gland substance. 
Murray first proposed the treatment of myxedema with carbolated glyc- 
erin extracts from the thyroids of animals and practised this with good 
results. Also Kocher, Leichtenstern, Ewald, and others saw good results. 
Since that time, however, Fox, Mackenzie, and others found that they could 
succeed in inducing the action of the active principle also by administering it 
by mouth; this method superseded all others and to-day is alone practised. 
At the beginning one saw individual cases of severe acute intoxication. In 
many of these death occurred with profuse diarrhea after the ingestion of a 
very slight amount of thyroid-gland substance. Here the effect must have 
been due to putrefied preparations, as the symptoms deviated from those of 
thyroidin, and the latter appeared only after the ingestion of much larger 
doses. 
Of the numerous thyroid-gland preparations that are found on the market 
to-day the tablets of Burroughs, Wellcome & Co. [England] and those of 
Parke, Davis Co. [America] are characterized by the intensity and uni- 
formity of their action. They consist of dried sheep thyroid and come 
on the market in doses of o. 1-0.3 gm- 
Of other preparations I mention the thyreoidinum siccatum {Merck), 
thyraden {Kocher), in pills or tablets representing 0.0007 gm- iodine, and iodo- 
thyrin or thyroiodin {Bayer), igm. contains 3 mg. active substance or 0.3 
mg. iodine, representing the iodine content of 1 gm. fresh lamb’s thyroid. 
According to the investigations of Fonio, the action of thyroid prepara- 
tions on the metabolic processes (protein decomposition, diuresis, body 
weight, etc.) parallels their iodine content. This does not hold good for all 
actions of the thyroid-gland substance. For instance there occurred in my 
own experiments with iodothyrin in every dose (to 7 gm. daily) action on the 
metabolism much greater than that on the cardiovascular apparatus. Then, 
too, much larger doses of iodothyrin than of tabloids are needed to induce 
symptoms of hyperthyroidism. In his substitution experiments, Magnus- 
Levy ascribes to iodothyrin the same activity as that of thyroidin. It is quite 
undoubted that iodothyrin exerted a powerful influence on the basal metab- 
olism of Magnus-Levy’s patients—yet we cannot make out from Magnus- 
Levy’s protocols whether on long-continued administration also the influence 
on bone growth was the same. According to this it is not at all likely that, as 
Pick and Pineles state, in young thyroprivic dogs the symptoms of deficiency 
are not fully combated by iodothyrin, but that they are combated by the 
English tablets. 
Thyroantitoxin, potassium, iodide, and hypophysis substance are, as 
shown by the experiments of Mangus-Levy, entirely actionless. 
As far as the dose is concerned, it is well in every case to begin with small 
doses and gradually to increase. In adults we give one to two English tablets 
daily and can gradually increase to from three to five. If we have attained TREATMENT OF ATHYROSIS AND HYPOTHYROSIS 
147 
a favorable result, we may again decrease the dose to two or one tablet. 
Children are usually first given one-half tablet, which may be increased to 
from two to three tablets. In my cases of sporadic cretinism I went transi- 
torially as high as seven tablets, in one case indeed to nine. Kassowitz recom- 
mends thyroid elixir (Allen Hanbury, London), of which one coffee-spoonful 
represents about one-sixth of a sheep’s thyroid gland. Children under a half 
year should be given one-half coffee-spoonful daily, later increased to one 
coffee-spoonful. Only in children over twelve years of age did Kassowitz 
order up to two coffee-spoonfuls per day. 
[Thyroxin as a remedial agent is now on the market. Its use in cretinism 
by Goldstein has already been mentioned (see footnote, page 5). It should 
also be used in cases of myxedema. Among its advantages is the fact that its 
dosage and effect can be controlled by basal metabolism determinations. 
It can also be used in adolescent goiter when the basal metabolic rate shows 
that hyperthyroidism is not present (see New and Unofficial Remedies, published 
by American Medical Association, 1921, Chicago) the dosage is gauged by 
the amount of reduction of the basal metabolism (other things being equal). 
It can be given in doses of from 0.2 mg. to 2.0 mg. depending on the basal 
metabolism. 1 mg. increases the basal metabolism 2 per cent., 10 mg. 20 
(twenty) per cent. It does not have effect before 24 to 36 hours, its maximum 
effect is reached on the tenth day after administration and its effects last for 
three weeks. Remarkably small doses serve to keep up the good effects of 
the initial dose.—Editor.] 
The result of thyroid-gland medication in myxedema adultorum is in the 
most cases an immediate one. The myxedematous swellings may undergo 
an appreciable reduction even in a few days. Together with this there goes 
for the most part, a loss of the body protein, that for the most part depends 
on the rapid melting down of the myxedematous tissue. In the cases in 
which very marked swellings have occurred, the skin is lax and wrinkled. 
It acts very rapidly on the secretion of sweat, in that the previously dry 
skin becomes moist; then too, the marked scaling ceases. The action on 
the trophic disturbances naturally takes a long time, but are no less striking. 
The bald spots on the head cover again with new hair; the hair on the axillae 
and on the genitalia become thicker, the hairs again feel soft and pliable. 
The pulse becomes more rapid, the protein metabolism and the basal metab- 
olism rise to normal, the appetite increases, the beginning loss of weight super- 
sedes the gradual increase in weight. The diuresis becomes more abundant, 
the lowered temperature rises at first somewhat above the normal, and 
then remains normal. The action on the blood is usually slower; usually 
a medication of several weeks’ or several months’ duration is required before 
the red cells and the amount of hemoglobin come back to normal and before 
the differential counts of the white cells show normal values. The men- 
tal condition improves much more rapidly. The apathy may appreci- 
ably improve after only a few days, the patients become more active, they 
take a more active interest in their environment, and the memory improves. 
Also the mental disturbances accompanying the myxedematous condition 148 
THE DISEASES OF THE THYROID GLAND 
show a pronounced improvement and under the thyroid medication may even 
become entirely normal. In the case of Pilcz already mentioned the illusive 
ideas disappeared entirely; with the withdrawal of the medication the myxe- 
dema and also the mental disturbance recurred. A renewal of the therapy 
again brought about cure, that remained definite in spite of discontinuation of 
the treatment. This patient had a goiter. Pilcz supposes that in this case 
the thyroid gland regained its activities through the stimulating influence of 
thyroid medication. Also the hardness-of-hearing sometimes accompanying 
myxedema often shows a decided improvement. The English Myxedema 
Commission found that among one hundred and nine cases of myxedema, 
nearly the half showed disturbances of hearing; this disappeared under 
thyroid treatment. Also speech becomes livelier, even at the beginning 
of treatment, as Magnus-Levy states. In many of the cases stuttering appears 
at the beginning of the medication. Gutzmann explains this in the fact 
that the desire for speaking becomes rapidly increased, while there is a certain 
awkwardness of speech due to inhibition of the peripheral speech mechan- 
ism (swelling of the mucous membrane of the mouth, the nose, the throat, 
and slight mobility of the velum palati). Then, too, the disturbances in 
the sexual sphere improve, often astonishingly. The dysmenorrhea dis- 
appears, the long-absent menstruation may recur, in men potency may 
again return. Existing albuminurias tend to disappear. 
The results of thyroid medication in typical cases is to be regarded as 
almost certain. Already Heinzheimer has collected one hundred and fifty 
cases from the literature in which a complete favorable result was brought about 
by the treatment. Cure can occur even when myxedema has existed for a 
long time. In a case of Dunlop the myxedema had existed for twelve years. 
In the cases of formes frustes of myxedema the results are just as satis- 
factory. Especially in the cases of thyrogenic obesity, thyroid medication, 
as already mentioned, brings about, with diet freely chosen and with improve- 
ment of the general conditions, a rapid reduction in weight, while marked 
reduction of the caloric supply only produces conditions of weakness. 
Sometimes, indeed, the results of thyroid medication in myxedema are not 
so revolutionary. In the first place it may happen that on account of the long 
duration of the disease more deeply seated disturbances have developed, 
for example, high-grade anemia, which then furnishes a slight resistance to 
the administration of thyroid gland. In other cases symptoms of thyroidism 
rapidly appear, which call for the limitation or eventually the discontinuation 
of the agent. In such cases it may happen that the symptoms of myxedema 
are only a little influenced while tachycardia, insomnia, excitation, etc., make 
their appearance rapidly. Such a case was first described by Beclere. Here 
the myxedema gradually disappeared. There occurred, however, rapid loss 
of weight, tachycardia, insomnia, excitations, polyuria, albuminuria, partial 
paraplegia, sensation of heat, sweats, tachypnea, transitory tremor, and a 
slight grade of exophthalmus. 
Mabille believes that the simultaneous administration of small doses of 
arsenic prevents the occurrence of symptoms of hyperthyroidism. Ewald TREATMENT OF ATHYROS1S AND HYPOTHYROSIS 
149 
agrees with him. Magnus-Levy missed this action of arsenic. Hertoghe 
warns against the administration of alcohol or morphine during the thyroid 
medication. He recommends administration of sodium bicarbonate, or, when 
diarrhea occurs, of bismuth. 
In general we may well assume that typical cases of myxedema show a 
high tolerance for thyroidin. When manifestations of thyroidism occur, the 
cause of these may lie in a simultaneous degeneration of the heart muscle, that 
reacts more quickly to thyroid medication, or we are probably not dealing with 
typical myxedema, but with a combination of myxedema symptoms with 
symptoms of deficiency on the part of the other ductless glands (see multiple 
sclerosis of the ductless glands). 
The action of thyroid medication in sporadic cretinism deviates in many 
points from that just described. On the one hand, there here occurs a num- 
ber of other disturbances which relate to the existing disturbances in develop- 
ment (growth in size, dentition, sexual sphere, etc.); on the other hand, it is 
intelligible that with the long existence of the inhibition of development 
degenerative conditions have become established that are no longer reparable. 
Very significant results are hence to be expected only in light forms or when the 
treatment has been started early. Very significant seems to be the influence on 
growth. Already in 1896, Buschan collected from the literature thirty-two 
cases which showed rapid growth under thyroid medication. Latterly, 
statements as to this subject have considerably increased. 
X-ray examination shows that with the increased growth in height there 
occurs rapid appearance and growth of the bone nuclei, or rapid ossification of 
the epiphysial junctures. 
Hertoghe states that in myxedematous children under certain circum- 
stances, administration of thyroid may lead to such a rapidly increased growth 
in height that scoliosis or kyphoscoliosis develop. In the fully developed form 
of sporadic cretinism in which the epiphysial junctures are often fully open in 
the third and fourth decade, there may still occur under thyroid medication, 
appreciable growth in height and finally closure of the epiphysial junctures and 
the fontanelles. 
As is the case with ossification, the previously retarded dentition also shows 
a sudden acceleration. I cite from the reports of Kassowitz the following 
example: A twenty-two-month-old child had not a single tooth; after a six 
months’ treatment sixteen teeth had erupted. A similar accelerating influence 
is exercised on the formation of the permanent teeth. A ten-year-old girl had 
only remnants of the milk-teeth; after one year’s treatment she possessed six, 
after two years’ treatment eighteen permanent teeth. Very pretty examples 
of the stimulation of growth through thyroid medication are found also in 
Oppenheim’s text-book of neurology and in Siegert. 
Under the influence of the medication the umbilical hernias disappear, not 
rarely in a few weeks, sometimes after a month. These are almost constant 
in infantile myxedema, and often appreciably large. 
Finally, just as significant is the influence on the genitalia and the second- 
ary sexual characters. Magnus-Levy reports the case of a forty-five-year-old 150 
THE DISEASES OE THE THYROID GLAND 
cretin, in whom at the beginning of medication the pubic hair began to develop 
and the penis began to increase in size. In a case of cachexia strumipriva, in 
whom the struma had been totally extirpated at the age of fourteen, thyroid 
medication was begun in the twenty-eighth year. Already after two years 
there was noticed a certain sexual development, after seven years all sexual 
characters were present and sexual maturity was attained. In the fully 
developed form of sporadic cretinism it is not, of course, to be expected that a 
late-introduced treatment is able to bring about procreative capacity. 
Also the mental development takes part in this general impetus. 
In the severe cases of infantile myxedema permanent administration of 
thyroid substance is necessary; when the therapy is discontinued relapses occur, 
even when the administration of the larger doses have transitorially brought 
about symptoms of hyperthyroidism (Knopfelmachef). In slight cases the 
result is mostly a permanent one; in such cases we assume that under the stimu- 
lating influence of the therapy the thyroid gland has held fast to its develop- 
ment, or the less altered parts have recovered. 
Thyroid therapy has been tried in a great number of disease conditions that 
have nothing directly to do with myxedema and is often very much valued. I shall 
speak of its value in obesity in the consideration of the various forms of obesity 
at the end of this book. Its influence in diseases of the hypophysis, the sexual 
glands, infantilism, and multiple sclerosis of the ductless glands, I shall refer 
to in the appropriate chapters. Very much under discussion is the use of 
thyroidin in the treatment of scleroderma. Since Singer first reported as to the 
favorable results a series of good results have been published. In other cases 
there were soon manifested symptoms of thyroidism with only slight improve- 
ment of the sclerodermic symptoms, in still other cases, finally, the treatment 
failed entirely. The literature as to this subject is found in detail in Cassirer's 
communication, v. Notthaft is of the opinion that favorable results, where they 
have been obtained, depend only on the stimulation of the general metabolism 
(consult also the statements as to the ductless gland theory of scleroderma in 
the first chapter). As to therapeutic results in endemic cretinism see the next 
chapter. 
Addendum 
With regard to inflammations of the thyroid, cases of acute idiopathic 
thyroiditis have been reported by Dutrow and others. In Dutrow’s case, which 
was accompanied with a leucocytosis of 12,000, prompt relief was obtained on 
incision. In the majority of cases, such energetic treatment will not be neces- 
sary. The application of cold to the neck in this case is a means of physical 
treatment that must not be forgotten or dispensed with. 
The question of dysfunction in the cases of Basedow’s disease has by no 
means been disposed of, and in America has attracted Halsted,1 who has been 
much impressed with recent experiments of, among others, Klose, Larnpe, and 
Liesegang. Larnpe has been active in applying to the sera of Basedow’s patients 
1 Carlson also expresses himself as maintaining that there is evidence for the dysfunction theory. 
(J. Am. M. Ass., Vol. LXXIX, No. 2, July 8, 1922.) ADDENDUM 
151 
the Abderhalden reaction, with various organs as the objects to be acted on, 
with the result that he finds present in the sera ferments against ovaries, 
thyroid, thymus, and no other organs. Deutsch has also experimented along 
these lines and has found that thymus gland tissue is split up also by normal 
serum. The significance of these experiments would seem to point to some 
defect of thyroid secretions; whether or not the positive results of the expen 
ments mentioned above would tend to rule out simply a mere excess of thyroid 
secretion is not known to the editor. 
The fact that the sera act on ovaries in the Abderhalden test would point 
to some defect in ovarian action. It is well known that Basedow’s disease is 
often associated with, in addition to the menstrual disturbances that seem to be 
a part of the disease itself, pelvic disturbances, and that the disease is often 
considerably ameliorated, if not cured, with the remedying of these pelvic condi- 
tions. This fact has been repeatedly pointed out, and is mentioned among 
others by Porter. According to Lampe, dysfunction of the branchiogenic organs 
leads to dysfunction of the sexual glands. In some women, there is no doubt 
that the pelvic or the sexual trouble has led to marital unhappiness, this even 
when there is no gross gynecological lesion. According to Thomas, who in 
speaking of the subjects of exophthalmic goiter states that “nearly every 
married woman with whom I have discussed the matter has admitted some sort 
of incompatibility with her husband, and since it almost always appears during 
the active sexual life, I strongly suspect a distinct relationship.” 
The transition into the sexual sphere leads us once more into the confines 
of the Freudian hypothesis. Scarcely any of the most ardent of the advocates 
of Freud would venture the assertion that Basedow’s disease is the result of 
suppressed sexual experience of childhood, yet such a Freudian disciple might 
find evidence for it in a case of Basedow’s in a child fifteen years old, that I saw 
at the St. Agnes Hospital, Philadelphia. This child had been the victim of an 
attempt at rape, immediately after which it developed the classical symptoms of 
Basedow’s disease (I am not certain as to the presence of an enlarged thyroid) 
and almost utter inability to speak, which symptoms had persisted for some 
months. I do not know the ultimate fate of the child, as she had been referred 
to the hospital from a country district, and paid only one visit to the hospital. 
It is evident that in the above case the sexual element if present at all was 
subordinate to that of the factor of fright, which was present also in a case, seen 
by me at the St. Agnes Hospital. It was that of a highly religious, intelligent 
married woman, M. H., aged twenty-nine years, who during the strain of nursing 
a sick father, sustained a fright, during which she found that a burglar had 
entered her store. A few weeks later her father died. Since the time of his 
death she suffered from obsession of a religious and “immoral” nature, in the 
course of which she dared God to do his worst by her, and wished harm to 
people. Sometimes the obsessions were of a sexual nature, and objects in her 
environment suggested to her thoughts that she was ashamed of. The patient 
dreamed very much, but none of the dreams had a sexual content, at least so far 
as she stated. Her mental and physical conditions had improved somewhat 
recently, in consequence of a stay at a sanitarium. She had been happily 152 
THE DISEASES OF THE THYROID GLAND 
married for five years, acknowledged a moderate amount of libido (it increased 
very little during the earlier stages of her illness), but had had no children, 
not because she used means to prevent conception, but because according to a 
doctor her “womb is turned.” There was some evidence of hyperthyrosis, fine 
tremor, pulse 112, rather large thyroid, suggestion of exophthalmos, leucopenia 
of 2000 and various accessory signs (tendency to looseness of bowels rather than 
constipation, hair had become finer and more luxuriant). 
The factor of fright in the etiology of Basedow’s disease has been empha- 
sized by Crile, whose name is important in the ductless glandular diseases in 
general, not only because of the fact that he has developed an ingenious theory 
for the explanation of certain of these diseases (especially Basedow’s disease), 
but also because of his theory and practice of treatment in operating on Base- 
dow’s disease and in general (principle of anoci-association). Crile agrees with 
the author that Basedow’s disease is conditioned by a state affecting the central 
nervous system; in the course of this the nerve cells of the cerebral cortex 
become chromatolytic, at the same time that the cells of the liver and the 
suprarenals become less granular. These organs together with the thyroid 
gland, and the muscular elements constitute the kinetic system, the purpose of 
which in the organism is the conversion of potential energy into kinetic energy. 
The above changes, if I understand Crile rightly, are more or less theoretical for 
Basedow’s disease, but have been obtained by him in a number of conditions 
such as the various forms of traumatic, emotional, and toxic, foreign proteid, and 
anaphylactic shock, as well as in various forms of drug poisoning and anemia 
As has been stated, Crile has formulated on the basis of theory his principle of 
anoci-association upon which is founded a method of operating in which the 
deleterious effects of shock are minimized by a combination of local and general 
anesthesia. The method has been applied especially to operations on the 
thyroid gland. Whether or not the good results attest to the truth of the 
theory, or whether the combination of the two forms of anesthesia summate in 
some other way is of theoretical importance; practically, the good results speak 
for themselves, and are attested to by Frazier and Muller. The method is 
attended with a number of refinements of technique for the consideration of 
which the reader is referred to Crile’s work. One of the important factors is a 
sort of psychic treatment, consisting in the fact that the patient is gradually 
habituated on successive days to the method of general anesthesia, while under 
the impression that he is receiving treatments. As has already been stated at 
another place, Crile’s theory is based on observations on 40,000 nerve cells, and 
forms an interesting explanation for the role of the central nervous system in 
the etiology of Basedow’s disease. 
The effect of thyroid secretion on the central nervous system, the close 
connection of the central nervous system with the thyroid is instanced in the 
association of epilepsy with thyroid disease, especially exophthalmic goiter. 
This association which is acknowledged cursorily by Kocher and Cushing was 
pointed out by the translator some time ago. It is interesting that a short 
time after the translator presented his cases, through courtesy of Potts he 
presented the history of an adult female who developed an epileptiform convulsion ADDENDUM 
153 
for the first time after the use of double the prescribed doses of thyroid extract. 
It is probable that in this case, and in some of the cases previously reported by 
the translator, the thyroid-gland substance acted as a toxic agent on a central 
nervous system already predisposed to the occurrence of epilepsy. It is inter- 
esting, however, that the thyroid extract is one of the metabolic products that 
acts in this way. 
With regard to the laboratory symptomatology of Basedow’s disease, 
Kocher has corroborated his conclusions as to the blood picture in Basedow’s 
disease by over 670 cases that have been operated on. He regards the blood 
examination as of the greatest diagnostic importance in light and obscure cases 
of Basedow’s and myxedema. In 155 cases of myxedema there were only 
26 that did not show a leucopenia. The degree of absolute leucopenia is 
more considerable than in Basedow’s disease, lying between 3000 and 6000. 
Lymphocytosis lies between 30-40 per cent, less than in Basedow’s disease. 
The mast-cells are o. 2-0.4 Per cent. In myxedema the coagulation time is 
decreased, to as low as six minutes. This hastening of coagulation is very 
constant. The blood picture approaches the normal with favorable therapeutic 
procedures.1 
Cases of diffuse colloid goiter approach the type of blood picture of 
myxedema. Nodular goiters show, as a rule, a normal blood picture, or, 
occasionally that of hyperthyrosis. 
This blood picture has been much discussed, and is worthy of even more 
close study than it has received, especially in view of studies of the pathology 
of the thyroid gland in goiter by Wilson and by Plummer, stated below. 
Fonio’s experiments have shown that when thyroid or colloid goiter or 
Basedow’s struma preparations are administered to myxedemics there occurred 
an increased elimination of nitrogen, increased diuresis, and decrease of the body 
weight, and that the nitrogen elimination varied directly as the iodine content 
of the preparation administered. In the two cases he worked on, he was unable 
to substantiate a hyperleucocytosis or an eosinophilia. 
In passing, the editor would state that in Philadelphia the condition 
myxedema seems to be relatively rare, at least in its classic well established 
forms. Basal metabolism tests will be helpful in the diagnosis of the incomplete 
forms. The work of Jaensch, referred to in the text (p. 125) is suggestive 
along the lines of diagnosis. 
So far as the pathology of the thyroid gland is concerned, MacCarty, 
from a study of over 2500 thyroid glands removed at operation, divided these 
into the symmetrical and the asymmetrical or nodular. The symmetrical 
glands contain various combinations of an adult and a fetal type of tissue ele- 
ment or of hypertrophied acini containing colloid, or of acini that contain little 
or no colloid material, but that possess lumina almost completely filled with 
large hypertrophic or hyperplastic cells. The simple nodular or simple sym- 
metric thyroids contain nodules with a fetal type of cell, while the remainder 
of the parenchyma of the thyroid gland possesses various combinations of the 
tissue elements described under the symmetric thyroids. The complex non- 
1 See reference to the blood picture in the work of Plummer, quoted in the text.—Editor. 154 
THE DISEASES OF THE THYROID GLAND 
symmetric thyroids may show, in addition, various combinations of the tissue- 
element types in the nodules. 
Still more recent studies on the pathology of the thyroid gland have been 
made by Wilson and by Plummer, who base their conclusions on the enormous 
material of the Mayo Clinic. These authors divide goiters with symptoms 
of intoxication into, clinically, the exophthalmic and non-exophthalmic forms. 
In the first form only is there a true hypertrophy and hyperplasia of the gland 
tissue. The pathology of toxic non-exophthalmic goiter is one of increased 
parenchyma through regenerative changes in atrophic parenchyma, or the 
formation of new parenchyma of the fetal type with an increase in each instance 
of secretory activity and of absorption. The process is a chronic one, but one 
sufficiently active to cause the patient to consult a surgeon earlier than do the 
true exophthalmic goiter patients, in whom the disease is acute. 
Gilbride has examined the thyroids in six cases of exophthalmic goiter 
bacteriologically, and isolated a bacterium in one case only—micrococcus 
tetragenes. 
With regard to the treatment of Basedow’s disease, internists and surgeons 
occupy hostile camps. More and more has the opinion gained ground that 
the condition is an affection demanding surgical attention. Nevertheless 
border-line cases should first be given the benefit of properly directed medicinal, 
dietary, and physiotherapeutic measures. 
Very few medical men nowadays hold to the opinion that hyperthyroidism, 
at least in moderately severe stages, can be cured by medicinal methods alone, 
even when these are combined with the all essential rest. According to Mayo, 
some of the cases get well spontaneously. 
Psychotherapy must be used as an adjuvant in the management of the 
milder cases during a period in which it is justifiable to temporize. Of course, 
basal metabolism work is a guide to the immediate necessity for operation and 
to the possible use of the X-ray or radium. In spite of the fact that the increased 
attention to the nervous system and to the other ductless glands in hyperthy- 
roidism have led some authorities to regard it as a medical disease, its 
treatment continues mainly operative. It is true that although the X-ray and 
radium usurp the field that was formerly accorded to purely medical treatment, 
for the time being at least, the surgeons as opposed to the radiologists seem to 
have the better of the argument. 
For any primary nervous factor the methods of psychotherapy should be 
used as an adjuvant to all methods of treatment. This does not mean that 
establishment of confidence in a physician for the purpose of drawing-out a 
method of treatment that can result only in failure, or in instilling a belief in 
the individual that psychanalysis, for instance, is the proper means to be pur- 
sued in his case. But the success of some of the surgical methods even, as in the 
hands of a Crile, depends on the absolute freedom from fear on the part of the 
patient. 
From the earlier editions of this work the opinion of Cohen is quoted as to 
the drugs that are useful in hyperthyroidism. In view of the basal metabolism 
work that has been done since Cohen’s article was written, the basal metabolic 
rate as an indication for operation should be added:—• ADDENDUM 
155 
S. Solis-Cohen has a strong conviction that surgical measures are indicated 
only in a small minority of the cases of exophthalmic goiter that come under 
the eye of the alert physician. He recognizes the following indications for 
surgical treatment. 
1. When the disease has persisted and, despite proper medical and hy- 
gienic care, is advancing. 
2. When the disease is progressive or far advanced. 
3. When the patient’s means or social status is such that rest is impracti- 
cable, and the disease, although slight, has persisted under treat- 
ment for a year or more without signs of yielding. 
This author estimates the number of cases in which surgical intervention 
is necessary at about 5% of the total number. He recommends 
individualization in treatment, the keynote of which is rest. Correction of 
the eye conditions, fresh air, proper diet, the drinking of hot water for its 
diuretic and eliminative action, intestinal antiseptics, neutral quinine hydro- 
bromide (5 gr. or more thrice daily), ergot, picrotoxin, calcium chloride, digi- 
talis, strophanthus, and even cactus all have their place in the medicinal 
therapy. In addition hydrotherapeutic measures, electricity (ionic appli- 
cation of iodine to the gland or to the cervical sympathetic, or the high- 
frequency discharge to the neck or to the vertebra prominens) and the ice- 
bag or ice-coil to the heart or gland or spine. Among organic extracts the 
author recommends especially thymus extract (0.5-3 gm- Per diem) or a 
combination of thymus gland with adrenalin. 
Falta has in the text cited the fact that in many cases of Basedow’s the 
thymus gland is enlarged. The use of thymus extract in Basedow’s disease 
had better be dispensed with. The editor would advise against the employ- 
ment of adrenalin on account of the tendency to glycosuria in Basedow’s 
disease, except as emergency may dictate in complicating conditions. Obvi- 
ously the far advanced cases of exophthalmic goiter should at least await a 
favorable basal metabolism rate before operation is attempted. 
Abrams recommends for exophthalmic goiter stimulation of the vagus 
nerve by direct percussion or concussion over the seventh cervical spine. 
In addition, he recommends pilocarpine, hypodermically or in doses of Mo 
gr. three times daily by mouth. With regard to this treatment it may be 
said that Abrams uses it to give tone to the vagus nerve. If it is granted 
that this method of procedure really does stimulate the vagus nerve, the 
treatment is certainly not indicated in the so-called vagotonic forms of the 
disease. 
Stoney reports forty-one cases of exophthalmic goiter (various types) 
treated by X-rays. (The anode is 6 in. from the skin, which is protected with 
four layers of blankets. One-half to 1 milliampere of current is run through 
the secondary.) Of the forty-one cases fourteen were completely cured, some 
of these remaining well for over two years after the treatments, twenty-two 
more have improved very much, four were somewhat better, only one did not 
do well. Snow in a discussion of Stoney’s report stated that he had seen good 156 
THE DISEASES OF THE THYROID GLAND 
results from the application of the static wave current, and from the use of 
Abram’s percussion method. 
Pfabler has reported excellent results from the use of X-ray in the treat- 
ment of hyperthyroidism, in an article in which this subject is reviewed. 
(He reports also favorably on the use of radium, quoting Aikens). He also 
goes into the method of diagnosis of goiter speaking well of the quinine-hydro- 
bromide test of Bram, to supersede the better known adrenalin test of Goetsch, 
which he considers not devoid of danger. He seems to regard the taking of 
a basal metabolism test as more or less inconvenient to the patient, at least 
more inconvenient than the quinine test. (The Bram test is founded on the 
assumed relative hyposensitivity of the hyperthyroid patient to ordinarily 
toxic doses of quinine. Pfabler speaks well of the test. Sainton and Schul- 
mann have carried it out on io hyperthyroid cases and 2 controls and have 
failed to corroborate its usefulness.) 
Considering the fact that the portable Benedict apparatus has been 
adapted for office use, the amount of inconvenience to a patient is relatively 
small. Both the Bram test and the Goetsch test are certainly unnecessary 
in cases of well established hyperthyroidism, and as for the diagnosis of 
early cases, the basal metabolism test will corroborate any suspicion that 
a hyperthyroidism may be present. The chemico-physical test of Kottman 
provides interesting results in this field. 
As his results Pfahler reports a decrease in pulse-rate, a gain in weight, 
decrease in the nervous symptoms, attacks of diarrhea become less frequent; 
the thyroid enlargement and the exophthalmos are the last symptoms, respec- 
tively, to disappear. He alleges permanency of these results. For technique, 
the reader is referred to Pfahler’s article. 
Crile has recently acknowledged the use of the X-rays as a factor but 
he believes that surgery is preferable. See his article. This article is further 
referred to below. 
(.Kottman has recently devised a test based on physico-chemical principles 
by which hyperthyroidism can be distinguished from other conditions. It 
was tested out by O. Schmidt, who thought that he had found through it a 
way to distinguish between Basedow’s disease and “ thyroidism.” Peterson, 
II ’Doubler, Levinson, and Laibe have recently tested it in 400 sera and find 
it of distinct value in distinguishing the group of hyperthyroid cases from 
cases of other disease. To 1 c.c. of clear fresh serum (preferably drawn in 
the morning before food is taken) are added 0.25 c.c. of a 0.5% solution of 
Ag NO3. The resulting suspension is next exposed for 5 minutes to a 500 
watt Mazda lamp (or its equivalent) at a distance of 25 cm. Then 0.5 c.c. 
of a 0.25% solution of hvdroquinone is added and the color changes observed 
at 5 minute intervals. Peterson, II’Doubler, Levinson, and Laibe use a test 
tube 1.5 X 8 cm. The material under observation should be kept in a dark 
room preferably, although Peterson, H’Doubler, Levinson, and Laibe have had 
success when it was kept in diffuse daylight. A brown color soon develops 
in normal cases; in hyperthyroidism the coloration is retarded. Kottman 
found it accelerated in hypothyroid cases). ADDENDUM 
157 
Thus the treatment of hyperthyroidism resolves itself into a rivalry 
between the surgeon and the Roentgenologist. As has already been stated the 
surgeon has a trifle the better of the argument. 
The sad part about all treatment of thyroid conditions is that not all 
X-ray men have the technique of Pfahler, that not all surgeons have the 
technique of a Crile or of the May os. Many cases neglect treatment until 
even operative treatment is too late. The X-ray has its sphere of usefulness 
in the treatment of hyperthyroidism apart from the tender offices of the surgeon, 
although the surgeons still insist {Crile, Mayo) that preliminary X-ray treat- 
ment increases to some extent the difficulties of subsequent surgery.1 
As has been stated previously Aikens has reported favorably on the use 
of radium in the treatment of toxic goiter. It is his opinion that the effect of 
radium in toxic goiter of adolescence has been in some respects similar to that 
produced by the X-rays, but that the former has many advantages. He quotes 
Turner, Edinburgh M. J. Feb., 1919 to this effect: “As compared with X-rays in 
the treatment of this condition, radium has the following advantages: (a) Abso- 
lutely constant emission of rays, and therefore exact dosage possible; (b) for 
greater penetration of its rays, so that the deeper parts of the gland are reached; 
(c) no noisy exciting apparatus, so that the treatment can be applied at the bed- 
side without in any way disturbing the patient. The words cito, tuto, etjucunde 
can fairly be applied to the radium treatment of exophthalmic goiter.” The 
earlier articles of Turner and of Marine are referred to in our bibliography. 
In his earlier article Turner reported that results from local irradiation with 
radium were as favorable as those of the X-ray. 
Aikens uses large, flat applicators, 4 cm. X 4 cm. containing 10 mg. 
radium element, or smaller applicators containing the same or less radium. 
The plaques are screened with two thin aluminum screens or one fairly thick 
brass screen with a layer of felt. 
Crile reviews the entire subject of the use of surgery as against the 
Roentgen ray for the treatment of hyperthyroidism. He makes the interesting 
statement that in his experience he has never had a single case of hyperthy- 
roidism in which he had reason to consider an enlarged thymus a complicating 
factor. Crile states that interesting studies were made by Christie of the 
effects of the X-rays, of ligation, and of thyroidectomy on basal metabolism. 
Christie found that bilateral partial thyroidectomy reduces the metabolism 
more markedly and more promptly than either X-ray or ligation, and that 
X-rays reduce the metabolism more than ligation (however ligation is employed 
only as a preliminary step to thyroidectomy). 
The consensus of opinion among German surgeons is against the use of 
the X-ray. (See article by Melchoir, who refers to Verhandl. Chir Kongr. 
1921; Zentralbl. f. Chir., 1921. p. 752.) 
Lewi reports a series of thirty-four cases of exophthalmic goiter and 
perverted thyroid secretion [?] that he treated with high-frequency currents, 
with results that he considers exceptionally good. 
1 The editor has however heard Frazier in an as yet unpublished address refer to the value of 
irradiation before operation is resorted to. 158 
THE DISEASES OF THE THYROID GLAND 
The editor believes that no harm is done by expectant treatment with 
high-frequency currents, combined with rest and other rational methods of 
physiotherapeutics; and that such currents might be used as an alternative for 
the X-rays, or radium, or as a substitute for them before they are used. Tem- 
porizing with such methods should not, however, supersede surgical proced- 
ures in appropriate cases. 
After hearing what these internists and physiotherapeutists and Crile 
have to say let us turn our attention to the surgical side proper of the question. 
According to W. Mayo, the early operation of ligation cures many cases. Early as 
well as advanced cases can be cured by partial thyroidectomy. The mortality 
in these cases will vary from i to 4%. Combined operations are often indi- 
cated in bad cases: First ligating one or both superior vessel areas, and, later, 
doing a partial thyroidectomy. 
Local anesthesia is indicated in most ligations. Local or combined or 
straight ether anesthesia are the methods used for thyroidectomies, according 
to the preference or experience of the individual operator. 
Halsted in his article on thymectomy as a surgical procedure in the 
treatment of Basedow’s disease publishes the following instructive table, 
which he in turn has copied from Klose (Die Basedowsche Krankheit, Ergebn. 
d. inn. Med. u. Kinderh., Band X, 1913). 
Year 
Authors 
No. of 
cases 
Cures 
per 
cent. 
Considerable 
improvement, 
per cent. 
Slight 
improve- 
ment, 
per cent. 
No im- 
prove- 
ment, 
per 
cent. 
Deaths 
per 
cent. 
20 
90.0 
5 •0 
5.0 
Wolf 
9 
22.5 
6 
66.6 
1900 
Reinbach (V. Mikulicz) 
18 
66.5 
22.5 
5-5 
5-5 
1902 
Witmer (Kronlein) 
23 
40.9 
36.2 
9.2 
9.2 
9.2 
1902 
59 
76.0 
14.0 
3 • 3 
30 . O 
1904 
Mayo 
40 
67-5 
17-5 
15.0 
I9°S 
8 
50.2 
37-3 
12.5 
I9°S 
21 
87-5 
12.5 
1906 
K. Schultze (Riedel) 
50 
72.0 
12.0 
2.0 
14.0 
1907 
167 
93-7 
6.3 
1907 
7 
85.7 
143 
1907 
136 
78.2 
19.6 
2.2 
1907 
54 
50.2 
15-3 
29.0 
$. 5 
1908 
Moses (Garre) 
28 
16.9 
41.6 
24.9 
12.5 
4.1 
CO 
O 
O' 
M 
32 
93-2 
3 • 4 
3 • 4 
1908 
153 
98.7 
1 • 3 
1909 
MacCosh 
22 
14-5 
72.7 
8.2 
4.6 
4.6 
1909 
38.1 
42.8 
26 
84.6 
4.0 
4.0 
40 
72.5 
12 . < 
15 •0 
15-8 
44 
34 1 
4.0 
4° 
70.0 
20.0 
2.2 
2.2 
75 • 5 
9.8 
1.6 
I3 •1 
1912 
Weispfenning 
30 
60.0 
6.6 
23-3 
10.0 
Results of Operations for Basedow’s Disease ADDENDUM 
159 
In 900 operations performed on the thyroid in St. Mary’s Hospital, 
Rochester, Minn., during the first ten months of 1911, the mortality was 1 
per cent. 
Crile’s recent statistics show 500 thyroidectomies with 5 deaths; in 
a series of 500 ligations for thyroid disease there were but 2 deaths. Crile 
has done 476 successive thyroid operations without a death (331 thyroidecto- 
mies, 145 ligations); for exophthalmic goiter he did 227 thyroidectomies and 180 
ligations without a death. The Mayos also continue to operate on exoph- 
thalmic goiter with exceedingly low death-rates. 
In the Breslau Surgical Clinic 2 of 44 cases operated on died. (Melchior 
loc. cit.) 
Kiittner in a discussion tells of the results of his researches among old 
subjects of exophthalmic goiter, with results that speak immeasurably in favor 
of the surgical procedure. He stated that it was especially important to 
study the remote results of operation in cases of Basedow’s disease, and that 
we should not consider of such vital importance merely the immediate results. 
Of twenty-one well-marked cases treated conservatively, none had recovered 
health, nine having been treated for a period of at least fifteen years, 35.7% 
had died, and only one was able to work. Of the cases of the 
same series that were operated on only 17.3% had died, and of those living 
86.2% had either entirely recovered or were able to do their work. 
Pfahler reports that his end-results were good. End-results are what 
count after all, and considering this fact it is surprising how little the literature 
deals with them. Crile also believes that he has attained good end-results. 
Carlson notes that some cases do not give good end-results with any of our 
present methods of treatment. 
Halsted did about 650 operations in 500 patients with Basedow’s disease. 
A one-sided lobectomy resulted in an approximate cure in possibly 60% of 
the cases. For scientific purposes, to ascertain the role of the thymus in 
Basedow’s disease he recommends primary thymectomy, or secondary 
thymectomy where both lobes of the thyroid have been removed without 
proper effect. He states, however, that he is sorely tempted to remove 
a portion of an enlarged thymus when he meets with it in the course of an 
operation for Basedow’s disease. 
Halsted recommended removing an enlarged thymus when he met 
with it in the course of a Basedow’s disease. Crile does not meet with 
enlarged thymus glands often, and Melchior does not believe in removing 
them. 
Bram seems to have minimized the importance of surgery in the 
treatment of exophthalmic goiter. Incidentally he quotes opinions of various 
clinicians. It is not hard to quote authorities to any purpose whatever. 
We all know that we have not learned everything about the function of the 
thyroid gland, but it may be safely said that at the present time more 
harm is done by too late a recourse to surgery than by too premature 
an operation. Bram’s quotation of Charles H. Frazier, for instance, is very 160 
THE DISEASES OF THE THYROID GLAND 
apt, but Frazier does not stop operating for goiter because operation may be 
a transition to some better method of treatment in the future.1 
At present the creation of a general impression among the profession 
and the laity that operation is not indicated in exophthalmic goiter is to our 
mind not justified. The wise surgeon and the wise physician are they who 
appreciate the best method of treatment in the individual case. And of his 
judgment basal metabolism determinations are valuable aids to the formation. 
Articles too numerous to be quoted here have been written on the value 
of basal metabolism determinatious in hyperthyroidism, hypothyroidism, the 
goiters, and various internal diseases. One of the most recent of these is 
that by Peterson and Walter. Tests were made on about 1200 subjects, the 
number of observations being more than 2500. Tests were made with differ- 
ent instruments; it was found that the Benedict portable apparatus subserves 
all practical purposes. There was no cause and effect relation between weight 
and thyroid activity as evidenced by basal metabolism tests. The pulse 
rate is a fair test of the degree of basal metabolism, i.e. the rate in a resting 
condition. 
Another recent metabolism article, very excellent, with bibliography, 
is that of Rowe; reference to it will be found below. 
A good description of the instruments used in indirect calorimetry with 
pictures of the apparati will be found in the article by Fussell and Jonas. 
Frazier and Adler tested out the basal metabolism in their cases of goiter 
and found that there is a certain parallel between the clinical symptoms and 
the height of the basal metabolism. For practical purposes, they think 
that hyperplastic toxic goiter and cases of toxic adenoma should be treated 
alike. In rates from 10-40%, subtotal thyroidectomy may be proceeded with 
at once. In rates from 40-60%, they first do (usually) a subtotal ligation. 
In rates over 60 either unipolar or bipolar ligation is done. After ligation 
the average reduction in basal metabolism was 31.7 points, after thyroidectomy 
28 points. This obviously does not mean however that ligation as a curative 
measure is more effective than thyroidectomy. Much of the material of 
this paper is confirmed in the paper by Rowe. 
The latter author emphasizes the value of X-ray therapy, and the value 
of the basal metabolism as a check on this therapy. He calls attention to 
its value in the diagnosis of hypothyroidism and myxedema. Finally it is 
valuable as a guide to correct thyroid therapy. The subject of toxic non- 
exophthalmic goiter has been dealt with thoroughly from a clinical point of 
view by Boothby under the caption adenoma of the thyroid. This form of 
thyroid disturbance is not associated with exophthalmus and is identified by 
Boothby with the groups designated primary and secondary by Gauthier and 
Buschan, with the formes frustes of Marie, with goiter heart {Kraus, Gitter- 
man, and Stern), sympathicotonic and vagotonic (Eppinger and Fbess), 
rBut see foot-note, page 157. What is meant in the text is that Frazier does not hesitate to 
operate in suitable cases, although it is to be supposed that he gives them the benefit of irradia- 
tion and other measures before he decides that operation is indicated. Of course, judgment 
should be used in the individual case. ADDENDUM 
161 
Baseowoid {Stern), Basedowized {Kocher). The editor believes that if 
exophthalmus is absent in this group it is either because the toxin is not 
active enough or is accompanied by other metabolic products which combat 
the exophthalmus, or that the exophthalmus is caused by products other than 
thyroxin. 
From the fact that it has not been possible to produce exophthalmus 
by the injection of thyroxin alone, perhaps in the true exophthalmic type, 
additional substances circulate in the body. As a matter of fact the presence 
of intermediate groups between adenoma of the thyroid and exophthalmic 
goiter is acknowledged by Plummer (Boothby) and the basal metabolism 
rate is higher in true exophthalmic goiter {Boothby), Boothby says:—■ 
“In the differential diagnosis of adenoma with hyperthyroidism and 
exophthalmic goiter it is obviously necessary to exclude definitely cases 
presenting the syndrome of neurasthenia, usually of the cardiac type, with 
many of the earmarks of hyperthyroidism, but in which no hyperthyroidism 
or over-activity of the thyroid is actually present. The co-existence of an 
enlarged thyroid, often not distinguishable from those producing hyper- 
thyroidism renders the exclusion of many neurotic cases most difficult, and 
in certain instances impossible unless basal metabolic rate is known. Many 
of these patients with normal basal metabolic rates give a definite reaction 
to the epinephrin sensitiveness test, as pointed out by Goetsch and by Wood- 
bury. In our opinion a normal basal metabolic rate eliminates hyperthy- 
roidism.'’ (The last sentence should serve as a clinical aphorism, although it 
should be remembered that it probably admits of exceptions, as is pointed out 
indirectly by Carlson [J. Am. M. Ass. Vol. LXXIX, No. 2, July 8, 1922]; and 
conclusions as to basal metabolism in hyperthyroidism and hyperthyroidism 
should not be drawn from one determination.) 
The following figures (after Du Bois and his collaborators) taken from the Articles of Mosen- 
thal and Marks, and of Mohler show the basal metabolic rates in various diseases: 
Normal —15 to +15 
Obesity —14 to +10 
Diabetes mellitus, severe —19 to +23 
Diabetes mellitus, after fasting —36 (lowest observed) 
Diabetes mellitus, emaciated —37 to —10 
Cardiorenal with dyspnea +25 to +50 
Cardiorenal without dyspnea —10 to+10 
Nephritis with edema —40 to +14 
Nephritis without edema + 2 to +29 
Pernicious anemia + 2 to +33 
Leucemia +21 to +123 
Typhoid fever as high as to +50 
Tuberculosis (temperature about 104°) +15 to+35 
Tuberculosis, no fever — 33 to +15 
Prolonged undernutrition —30 to —10 
Exophthalmic goiter, very mild +15 to +30 
Exophthalmic goiter, mild +30 to +50 
Exophthalmic goiter, severe +50 to +75 
Exophthalmic goiter, very severe over 75 
Cretinism and myxedema —40 to —15 162 
THE DISEASES OF THE THYROID GLAND 
Interesting light on the pathology of the heart of exophthalmic goiter 
is thrown by Hashimoto, who fed albino rats with toxic doses of thyroid sub- 
stances and found myocardial changes in their hearts; the hearts of control 
rats did not show these changes. 
Dutrow (H. V.). Idiopathic nonpurulent acute thyroiditis; report of a case with complete 
recovery. Jr. Am. M. Ass., 1911, LVIII, p. 1761. 
Hoisted (W. S.). The significance of the thymus gland in Graves’ disease. Bulletin of the 
Johns Hopkins Hospital, Vol. XXXV, INo. 289, August, 1914, 223-234. 
Klose, Lampe, and Liesegang. Die Basedowische Krankheit Beitrage zur klinischen Chirurgie, 
XXXVII, 1912, p. 601-779. 
Lampe (A. E.). Basedowsche Krankheit und Genitale. Untersuchungen mit Helfe des 
Abderhaldenschen Dialysierverfahren. Monatsschrift fur Geburtshilfe und Gynakologie, 38, 1913, 
pp. 45-51. See also Lampe and Papazolu, Miinch. med. Wchsch., 1913; and Lampe, Fortschritte 
der naturwissenschriftlichen Forschung, herausgegeben von E. Abderhalden, Bd. 9, 1913. 
Dcutsch (II.). Erfahrungen mit dem Abderhaldenschen Dialysierverfahren I. Mitteilung. 
Abbau von Thymusgewebe durch normales Serum. Wien. klin. Wchsch., 38, 26, 1913, pp. 1492- 
1493- 
Porter (M. F.). Diseases of the thyroid in the female. Am. J. Obst., LXIV, pp. 781-790. 
Thomas (C. P.). The thyroid gland and some of its diseases. International Journal of Surgery, 
Vol. XXV, Jan., 1912, pp. 6-8. 
Crile (G. IF.) and Lower (IF. IF.). Anoci-Association. W. B. Saunders Co., 1914. 
Crile (G. IF.). The kinetic system. Cleveland M. J., Vol. XI, No. 4, Oct., 1913, p. 665. In 
connection with which, Hitchins (G. IF.), Sloan (H. A.), and Austin (J. B.). Laboratory studies of 
the activities of the brain and the adrenals in response to specific stimuli. Cleveland M. J., Vol. 
XI, No. 4, Oct., 1913, pp. 684-691. 
Crile (G. IF.). The kinetic theory of Graves’ disease. Am J. M. Sc., New Series, Vol. 
CXLV, Jan., 1913, p. 28. 
Miiller [and Frazier]. Discussion of Guthrie's article. Pennsylvania Medical Journal, Vol. 
XVII, No. 9, June, 19x4, p. 687. 
Cushing (H.). The pituitary body and its disorders. J. B. Lippincott Co., Phila., 1912. 
Kocher. “Surgery of Thyroid” in Keen’s System of Surgery. 
Meyers (M. K.). Epilepsy in adult life in association with thyroid disease, a report of seven 
cases. Monthly Cyclopedia and Medical Bulletin, Vol. V, No. 5, May, 1912, pp. 266-277. 
Meyers (M. K.). Report of a case in which epilepsy in adult life developed after the overuse 
of thyroid-gland extract. Monthly Cyclopedia and Medical Bulletin, Vol. V, No. 6, June, 1912. 
Kocher (Th.). Das Blutbild bei Cachexia thyreopriva (Myxodem. Cretinoide Zustande). 
Archiv fur klinische Chirurgie, 99, 1912, pp. 280-303. 
Fonio (A.). Ueber den Einfluss von Basedowstruma und Kolloidstrumapraparaten und 
Thyreoidin auf den Stickstoffwechsel und auf das Blutbild von Myxodem, unter Beriicksichtigung 
ihres Jodgehaltes. Mitteilungen aus den Grenzgebieten der Medizin und Chirurgie, Vol. XXIV, 
1911-1912, pp. 123-159. 
MacCarty (IF. E.). Pathological anatomy of goiter. New York State Journal of Medicine, 
Vol. XII, No. 10, Oct., 1912, pp. 595-599. 
Wilson (L. B.). A study of the pathology of the thyroids from cases of toxic nonexophthalmic 
goiter. Journal-Lancet, Minneapolis, Vol. XXXIV, No. 4, Feb. 15, 1914, p. 97. Also, the pathology 
of the thyroid in exophthalmic goiter. Tr. Ass. Am. Phys., Vol. XXVIII, 1913, pp. 576-586. 
Plummer (H. L.). The clinical and pathological relationship of simple and exophthalmic goiter. 
Am. J. M. Sc., Vol. CXLVI, Dec., 1913, p. 790. Also Tr. Ass. Am. Phys., Vol. XXVIII, 1913, 
PP- S87-594- 
Gilbride (J. J.). Cultures from the thyroid gland in goiter; a bacteriological study of fourteen 
cases. J. Am. M. Ass., LVII, 1911, p. 1988. 
Solis-Cohen (S.). The nonsurgical treatment of exophthalmic goiter. Am. J. M. Sc., New 
Series, CXLIX, July, 1912, pp. 13-20. 
Abrams (A.) Treatment of exophthalmic goiter. International Clinics, Series 22, Vol. IV, 1912, 
pp. 35-44- 
Stoney (F. A.). On the results of treating exophthalmic goiter with X-rays. Brit. M. J., 
Aug. 31, 1912, pp. 476-486. ADDENDUM 
163 
Pfahler (G. E.). Treatment of hyperthyroidism by radiation. M. Clinics N. America, Vol. 
V, Nov., 1921, pp. 853, seq. 
Bram (/). Diagnostic methods in exophthalmic goiter, with especial reference to quinine. 
Med. Record, Vol. XCVIII, Nov. 27, 1920, p. 887, seq. 
Sainton and Schulmann. Sur la valeur da test du Bram a la quinine comme moyen de diag- 
nostic du goitre exophthalmique. Bull, et mem. Soc. med. d. hop. de Par. 3s, April 4, r92i, 
1304-1306. 
Kottmann (K.). Kolloidchemische Untersuchungen liber Schildrusen-probleme Schweiz med. 
Wchnschr. Vol. XXX, July 22, 1920, pp. 644-651. 
Schmidt (0.). Ueber den Morbus Basedow i. Mitt. ad. Grenzgeb. Med. u. Chir. (Jena), 1921, 
XXXIII, pp. 512-532. (Quoted from Abstract in Endocrinology Vol. VI, No. 1, Jan., 1922.). 
Peterson (IF. F.), H’Doubler (F. T.), Levinson (S. A.), and Laibe (/. E.). The Kottmann reaction 
for thyroid activity. Jr. Am. M. Ass. Vol. LXXVIII, No. 14, April, 8 1922, pp. 1022-1023. 
Crile (G. IF.). Surgery versus Roentgen ray in hyperthyroidism. J. Am. M. Ass., LXXVII, 
Oct. 22, 1921, 132, seq. 
Aikens (IF. JL B.). Radium in toxic goiter. The Am. J. of Roentgenology, Vol. VII, No. 8, 
Aug., 1920, pp. 404-411. 
Turner (D.). Radium rays in the treatment of hypersecretion of the thyroid gland. Lancet, 
Sept. 27, 1913, pp. 924-925. 
Marine (D.). Some remarks on the thyroid gland in its relation to Basedow’s syndrome. 
Cleveland M. J., Jan., 1913, pp. 21-29. 
Lewi (IF. G.). Exophthalmic goiter and perverted thyroid secretion and their treatment with 
high-frequency electricity. Albany Medical Annals, Vol. XXXIV, No. 2, Feb., 1913, pp. 63-73. 
Mayo (C. H.). Diseases of the thyroid. Journal of the Michigan State Medical Society, Vol. 
XI, No. 1, Jan., 1912, pp. 1-2. 
Kiittner. [Discussion.] Annals of Surgery, Vol. LV, 1912, p. 148. 
Bram (/.). Exophthalmic goiter; the problem of recovery. Medical Record. Vol. Cl, No. 14, 
April 8, 1922, pp. 571-575- 
Melchoir (£.). JJeber den heutigen Stand des Basedowproblem in Theorie und Praxis. Berliner 
klin. Wchnschr., Vol. LXXXV, No. 50, Dec. 12, 1921, pp. 1453-1457 and No. 51, Dec. 19, 1921, pp. 
1500-1504. 
Mayo (IF.). The thyroid. Med. Record, Vol. C, No. 5, July 30, 1921, pp. 177-179 and Surg. 
Gyn. and Obst., Vol. XXXII, No. 3, March, 1921, pp. 209-213. 
Peterson (A) and Walter (IF.). Basal metabolisms and ideal weight and pulse ratios, etc. 
Jr. A. M. Ass., Vol. LXXVIII, No. 5, Feb. 4, 1922, pp. 341-343. 
Rowe (A. H.). The value of basal metabolism studies in the diagnosis and treatment of thyroid 
diseases. Am. Jr. Med. Sc., Vol. CXLII, No. 2, Aug., 1921, pp. 187-200. 
Fussell (M. H.) and Jonas (L.). Calorimetry in Clinical Medicine. M. Clinics of N. America, 
Vol. IV, Jan., 1921, pp. 989-1004. 
Mosenthal (H. 0.) and Marks (H. E.). The clinical value of basal metabolism. M. Clinics of 
N. America. Vol., IV No. 5, March, 1921, pp. 1403-1422, taken from the publications of Du Bois 
and his colloborators. Also quoted by Mohler (//.) Basal metabolism, its application to internal 
medicine. Therap. Gazette. Oct. 15, 1921, 3s. Vol. XXXVII, No. 10, pp. 690-693. 
Frazier (C. H.) and Adler (F. H.). Observations on the basal metabolism, estimations in the 
goiter clinic of the University Hospital. Am. Jr. Med. Sc., Vol. CLXII, No. 1, p. 10-12. 
Boothby (IF. M.). Ademona of the thyroid with hyperthyroidism and thyrotontic adenoma 
History of the recognition of this disease as a clinical entity. A study of the symptomatology with 
basal metabolic rates. Endocrinology. Vol. No. 1, Jan., pp. 1-20 [Bibliography]. 
Hashimoto (//.). Heart in experimental hyperthyroidism with special reference to its his- 
tology. Endocrinology, Vol. V, Sept., 1921, pp. 579-605. CHAPTER III 
THE CRETINIC DEGENERATION 
The enormous social significance of the cretinic degeneration in the countries 
affected by it may be seen by a glimpse at the following figures, which I 
take for the most part from the works of Ewald and E. Bircher. In Switzerland 
7.2% of the applicants for military service must be rejected on account 
of goiter, and 2% must later be discharged. In Cisleithania there 
occurred for every 100,000 inhabitants 71 cretins; in many strongly infested 
districts, for example, in Murrau, in the Steiermark, there are more than 1000 
cretins per 100,000 inhabitants. In France, in 1873, there were about 1% 
goitrous among the inhabitants and 0.3 per cent, cretins and idiots; in 
Piedmont in 1883 about 0.15% of cretins; in Lombardy 0.2 per cent., etc. 
The etiology of this affection is not as yet explained. The study of the geo- 
graphical distribution shows that goiter, goiter heart, endemic cretinism, and 
endemic mutism belong together. Typical Basedow’s disease is rare in goitrous 
districts. Manifestations of hyperthyrosis are commonly found there com- 
bined with those of goiter heart. The parallelism in the distribution of endemic 
mutism with that of endemic cretinism is convincingly shown by the investiga- 
tions of Bircher for Switzerland, and the statistics of v. Wagner for Austria. 
For lower France, there are the observations of Lohenhojfer. The group 
relationship of goiter and endemic cretinism is seen not only in the fact that the 
cretins are almost always goiter carriers, but also through the almost excep- 
tional occurrence of goiters in the ancestry of the cretins. This and other 
established facts point to a common etiological factor in the different forms of 
the cretinic degeneration. As to this all observers agree. On the contrary, 
there is as yet no agreement as to the question whether the manifold manifesta- 
tions of the cretinic degeneration are called into existence only by the mediation 
of the strumous degeneration of the thyroid gland, or whether a part of these 
are directly produced by the strumous noxus and thus are coordinate with the 
struma. 
The cretinic degeneration is found in Europe especially in the central 
Alps; in addition, large goitrous districts exist in the Carpathians, the German 
middle mountains, and the Pyrenees. In the other parts of the earth, also, 
the goiter districts lie in mountainous districts. The goiter districts change; 
localities that were formerly infested become goiter-free, and conversely. 
Sometimes there occurs an epidemiform breaking-out. When the affection 
retrogresses in one district, first the most severe forms of the cretinic degenera- 
tion disappear for the most part, while the goiter alone remains for some time 
(for example, in Baden and Thtiringen). Persons who come from a non-goiter 
neighborhood into a goiter neighborhood often develop goiter, or become 
164 THE CRETINIC DEGENERATION 
165 
affected with it after their return. E. Bircher here cites an instructive example: 
A family in a non-goiter neighborhood had healthy children. When they came 
into a goiter district, the parents themselves remained non-goitrous but had a 
cretin for a child. Kocher reports another example: The parents were healthy, 
and as long as they lived in a goiter-free district had nine healthy children. 
When they came into a goiter district, they had three cretin children, of which 
the first was the most pronouncedly affected. The thirteenth child was 
normal, but very small. Breitner has recently published a similarly instructive 
case. Enormous outbreaks of goiter have been often observed in regiments after 
their stationing in goiter districts. Families that remove from goiter districts 
can soon lose their goiters. Also the occurrence of goiters is not rarely observed 
in animals, after their transference to a goiter district. 
The noxus of goiter is bound in the drinking water. In the goiter territories 
there exist indeed especial goiter brooks; in the literature there are numerous 
examples of goiter communities becoming free of goiter after they had 
established drinking-water conduits from goiter-free vicinities. 
The occurrence of the goiter noxus in the water is bound together with a definite geolog- 
ical structure of the soil. This view has been especially promulgated by Bircher, Jr., on 
the ground of his penetrating studies and excellent observations. According to Bircher, 
cretinic degeneration is found only upon the marine deposits of the paleozoic ages, the 
triassic, and the tertiary ages, while the eruptive formations, the jurassic and fresh-water 
deposits, are free from the noxus. This view is not generally shared, but is, however, set 
upon a working basis by the works of Johannesen, and latterly by Bircher, Jr., and Lobenhofer. 
The practical significance of the investigations of Bircher, Sr., is seen at its best in that the 
community Rupperswill has become goiter-free since it has led its water from springs lying 
in jurassic deposits. A like example is furnished by the village Asp. 
Previously healthy animals may become goitrous on having goiter water 
furnished to them. The noxus of goiter goes through a Berkefeld filter; it is 
destroyed by temperature higher than 7o°C. (E. Bircher). Therefore it is 
likely, as Wilms first assumed, that the noxus is not a miasma, but a toxin or 
toxalbumin from an organic substance. 
It does not dialyze, thus behaving like a colloidal emulsion. The struma 
produced shows histologically changes that are degenerative, and on the use of 
weaker goiter water, also hyperplastic. The animals developed cardiac 
hypertrophy, and many remained behind in growth. 
[“If water is a factor, it would seem that it is the absence rather than the 
presence of some substance, which is to be considered, since goiter is associated 
with the purest of waters, chemically and bacteriologically, as, for example, 
in Portland, Ore. and in Seattle and Tacoma, Wash., where there has been a 
rapid increase in goiter since these cities began to take their water supplies 
from the Cascade Mountains.” (Marine and Kimballh) 
Marine and Kimball regard goiter as due to a relative or absolute deficiency 
of iodine.”—Editor.] 
1 Marine (D.) and Kimball (0. P.). The prevention of simple goiter in man. J. Am. M. Ass., 
Vol. LXXVII, No. 14, Oct. x, 1921, pp. 1068-1070. 166 
THE CRETINIC DEGENERATION 
1. Goiter 
We understand by this term a non-inflammatory, diseased alteration of the 
thyroid, mostly associated with enlargement of this gland, while the thyroid in 
most cases shows hyperplastic manifestations, and always degenerative manifesta- 
tions. The hyperplasia may affect the parenchyma as well as the vessels. 
The degenerative nature of the alteration is seen in the fact that the hyperplasia 
of the parenchyma is for the most part unaccompanied with increase in function. 
Therefore either the parenchyma must be less capable of functionating or the 
giving off of secretion is hindered by the sclerotic process. For the most part 
there is found sufficient parenchyma capable of functionating. According to the 
stronger or weaker participation of the hyperplastic or degenerative processes 
we distinguish parenchymatous, vascular, or fibrous—further, diffuse or cir- 
cumscribed—goiters; when the stagnation of the secretion is greater, we have 
colloid or cystic goiters. In goiter neighborhoods there also occur hyperplastic 
congenital goiters. There seems to exist a certain relationship between goiter 
and myomata of the uterus. At least it has been observed that in strumous 
women who also suffer with myomata, the struma also decreases in size with the 
retrogression of the myoma at the menopause (Ullmann). Concerning 
the further distinctions, the differential diagnosis, and the surgical treatment, I 
shall refer [the reader] to v. Eiselsherg’s monograph. Among the nonsurgical 
methods of treatment, I mention only the iodine treatment. This is the more 
effective the more the hyperplastic alterations and the less the degenerative 
alterations are present. That in certain neighborhoods iodine therapy often 
leads to manifestations of hyperthyrosis has already been mentioned in detail 
in the chapter on Basedow’s disease. The thyroid therapy recommended by 
Bruns is less used nowadays. Not much can be expected from the treatment 
of ordinary goiter by the X-rays. 
2. Goiter Heart 
The coincidence of goiter and cardiac disturbance is very common. The 
statistics of Schranz, which are based on an investigation of two hundred and 
sixty-four goitrous school children, one hundred and seventeen goitrous adults, 
and seven hundred and twenty autopsy protocols of the Innsbruck Patho- 
logico-anatomical Institute, show that after subtraction of the valvular defects, 
23% of the children and 49% of the adults suffered from heart trouble. Of 
the autopsied cases one hundred and eighty-eight showed degenerative altera- 
tions of the cardiac muscle, some with hypertrophy. While these figures 
can only partially stand ground against criticism (Wolfler, Fr. Kraus, 
Minnich) they are indeed, even when reduced, sufficient to show the common 
coincidence of goiter and cardiac disturbances. Rose showed, before Schranz, 
that the stagnation [congestion] in the lesser circulation caused by the large 
goiter can lead to dilatation and insufficiency of the right heart (so-called Rose’s 
goiter heart). When the embarrassment to respiration on account of 
the goiter enters more into the foreground we call the condition, following the 
lead of Kocher, pneumonic goiter heart. Conversely, primary stagnation in GOITER 
167 
the lesser circulation may lead to enlargement of the thyroid gland 
with greater or less manifestations of hyperthyroidism (Revilloid’s “goitre 
cardiaque”). 
Revilloid already mentioned that slight manifestations of hyperthyroidism 
may occur with this “goitre cardiaque.” This was later made intelligible by 
the experiments of Blum which showed that ligation of the thyroid veins leads 
to an eddying out of the thyroid-gland secretion and therewith to a slight hyper- 
thyrosis. Later, cirrhotic changes occur in such thyroids. 
Fr. Kraus first mentioned that there were numerous cases of cardiac dis- 
turbances in goiter in which all stagnation is absent, and in which, therefore, 
the mechanical factor as a cause does not come into consideration. In the 
light forms of these are found tachycardia, often dicrotism of the pulse, slight 
strengthening of the apex impulse, beating of the carotids, sometimes arrhyth- 
mia, glittering eye, sometimes indeed a slight degree of exophthalmus, inclina- 
tion to sweating, trembling, and eventually slight heightening of the basal 
metabolism, in short phenomena of a slight hyperthyrosis. In the severer forms 
are found, in addition, hypertrophy and dilatation of the heart and degenerative 
changes in the cardiac muscle. Also v. Mikulicz and Reinbach found similar 
symptoms in a great percentage of the goitrous that they examined. 
The fact that hypertrophy and premature degeneration of the cardiac 
muscle are found so frequently in the goitrous with cardiac disturbances indi- 
cates that we are here not dealing with the ordinary forms of hyperthyroidism. 
Fr. Kraus first championed the greater nosological independence of this form; 
the newer investigation, results of Minnich and E. Bircher seem fully to corrob- 
orate his contention. The opinions of Minnich, in his significant monograph, 
in so far as he regards these Basedow’s manifestations as the expression of a 
diminished thyroid-gland function, are not shared by the author. Entirely 
new views, however, are opened by Minnich in his description of cardiac dis- 
turbances in relatively young strumous individuals of both sexes, which mostly 
set in with new impulses in the growth of the goiter and lead objectively to 
enlargement of the heart, eventually with the gradual development of a pro- 
trusion of the precordium, and frequently also of accidental murmurs and 
subjectively to pains in the cardiac region, pricking pains, pressure, painful pre- 
cordial points of tenderness, and cardiac palpitations. Such cases may remain 
stationary a long time, or even become cured, or they may go over into tachy- 
cardia. This was the case in eleven of twenty cases. Here, therefore, we are 
dealing with a form of goiter heart in which, at least in the beginning, hyper- 
thyroidal symptoms were scarcely present. 
The fundamental significance of these observations is supported by the 
experiments of E. Bircher. Bircher saw enlargement of the heart almost 
regularly in the animals in which he artificially induced struma by giving them 
goiter water to drink. The weight of these hearts averaged one-third more 
than that of the hearts of the control animals. The heart muscle microscop- 
ically for the most part showed degenerative changes. Bircher refers the 
cardiac damage directly to the goiter noxus, and in agreement with Minnich 
sees in it a disease sui generis. 168 
THE CRETINIC DEGENERATION 
According to a personal communication from Prof. Scholz also the endemic 
cretins usually have bad hearts, but no hypertrophy; this fact may hang to- 
gether with the gradually and long-continued action of the goiter noxus, per- 
haps also with the slight “expressions of life” [Lebensausserungen] of such 
individuals. 
3. Endemic Cretinism 
Symptomatology.—The habitus of endemic cretinism shows a much greater 
multiformity than that of sporadic cretinism. Dieterle compares the 
photographs of seven youthful cretins of eighteen years of age from Bern with 
that of sporadic cretins from fourteen months to twenty-one years of age and, 
shows that despite the fact that the latter come from different countries, 
they show much similarity to one another, while the others resemble one another 
less strongly although they come from the same family. Dieterle cites the doc- 
trine of Majfeis, that there is no cretinic prototype. The skulls, too, in endemic 
cretinism show greater differences; in many endemic cretins the skull is small, 
the forehead low and receding; in others the skull is abnormally large. Regu- 
larly the root of the nose is retracted, although never to so great a degree as in 
chondrodystrophy; for the most part the eyes stand wide apart, the throat is 
short and thick, the lips are cushiony, the facial expression morose. Ordinarily 
the skeleton shows abnormalities—ankyloses, scolioses, etc. Scholz describes 
flattening of the head of the femur. The pelvis is often narrowed in all dimen- 
sions, and the bones are provided with swellings [Wiilsten]. Also there is differ- 
ence in the degree of dwarfism, v. Wagner observed individuals under 90 cm., 
although there are full cretins over 150 cm. in body length. E. Bircher of 
Aarau has kindly provided me with Figs. 18-22. Fig. 18 shows the multi- 
formity of the facial expression and the shape of the skull in endemic cretinism. 
The duration of life of the cretins is in most cases shortened, yet some 
cretins attain a very high age. Kocher reports about seventy-year-old and even 
one-hundred-year-old cretins. 
The figure is awkward, the gait inelastic, the muscles are poorly developed; 
individuals with completely developed forms can indeed not walk, but can 
only creep. This depends, however, not as much on the muscular weakness as 
on the want of every fine coordination. The skin of the face is often very lax, 
numerous transverse wrinkles traverse the forehead and lend to the face an old 
appearance. The development of the myxedema is very diverse. Magnus- 
Levy and v. Wagner found in many cases typical supraclavicular pseudolipo- 
mata, and also on other places of the skin very evident pad-like swelling 
and myxedematous alteration of the mucous membrane. Scholz found the 
skin only atrophic. In 60% of the cases investigated by E. Bircher the 
myxedematous swelling of the skin was absent. There are also cases that 
sweat profusely. The hairs are for the most part short and bristly, the nails 
torn, the teeth defective, the hair in the axillae and on the pubes may be absent 
or only sparsely developed. Umbilical hernia in children as well as obstipation 
and distention of the abdomen is just as frequent as in sporadic cretinism. 
Often conjunctivitides are found, and as a result of these, eczema of the palpe- 169 
ENDEMIC CRETINISM 
bral borders. According to Hitschmann, the conjunctivitides probably develop 
through disturbance in the leading off of the tears on account of the saddle nose. 
There mostly occurs a fairly high degree of anemia. The disturbances of 
intelligence of the cretins may vary from the slight grades of feeble-mindedness 
up through all the grades to the failure of all mental expression—the so-called 
plant man. In such cases all development of speech is also absent. In most 
cases, however, some psychical development is still present. The perception, 
Fig. 18.—Group of endemic cretins from Aarau. 
however, is somewhat slowed, the memory very poor; as for the emotions, the 
cretins show a certain clinging for the persons who feed them or hate against 
those whom they regard as enemies. 
The pathologico-anatomical findings in the brains of cretins are very 
diverse. Often they are only trivial; in most cases, however, there are found 
several alterations, and these of greater intensity. Scholz and Zingerle found 
at times chronic meningitic alterations and a slight grade of hydrocephalus. 
The brain may be smaller in toto—or in individual lobes; often it is highly 
asymmetric, sometimes there is found a persistence of the juvenile develop- 
mental stages, or in rare cases excessive development. The disturbances of 
development may affect the hemispheres as well as the brain-stem, the cerebel- 
lum, etc. The conformation of the surface of the brain is often pathologically 170 
THE CRETINIC DEGENERATION 
affected in that the convolutions are smaller or their number lessened. In 
abnormally small brains of cretins it may well be supposed that the smallness 
of the brain is primary, that of the skull secondary; as Bournevillve taught of 
idiots’ brains. The brain substance of cretins, according to Scholz and Zingerle, 
is often strikingly compact, the amount of gray matter relatively exceeding in 
mass the white.1 The disturbances of development may affect different parts 
Fig. 19.—Endemic cretinism. 
Fig. 20.—Cretins with myxedematous facial expression. 
in very different ways. The inhibition of the development of the sense organs 
is certainly to be ascribed, in part, to the faulty development of the central 
organs. 
The nervous status commonly shows increase of the reflexes, according to 
Scholz in 52%; the field of vision was found by Ottolenghi to be restricted, 
especially outward and upward. Hitschmann found the eye grounds normal in 
nearly all his cases; only in certain cases were crescents directed downward 
found, relationship of which with the cretinic degeneration was entirely ob- 
secure. The testing of sensibility, of the sense of taste and smell, naturally 
presents great difficulties. 
11 have here corrected the author’s error by reference to Scholz and Zingerle’s article. The 
German text here transposes “white” and “gray.”—Editor. ENDEMIC CRETINISM 
171 
The disturbances of hearing are of very diverse degrees. In many cases, the 
of hearing is fully intact. In others, there exists a slight or severe grade of 
hardness-of-hearing or mutism. Frightfully large is the number of mutes who 
are completely deaf. 
Endemic Mutism.—In all countries in which cretinism is endemic there is 
found a large number of deaf-mutes. According to the older statements of 
St. Lager, Switzerland possesses five thousand cretins and four thousand deaf- 
mutes. To the latter, of course, belong some cases of sporadic mutism, that is, 
those which depend on a meningitis in earliest youth, on otitides or formation 
anomalies of the brain, and which have nothing to do with the goiter noxus. A 
very great number, however, belong to endemic cretinism (according to E. 
Figs. 21 and 22.—Cretins with myxedematous facial expression 
Fig. 21. 
Fig. 22. 
Bircher, 80% in Switzerland). Also in Austria, and especially in the 
Stiermark, are found an enormous number of deaf-mutes. Scholz found among 
the cretins examined by him 29% deaf-mutes and 32% hard-of-hearing. 
The intensity of the disturbance of hearing does not go parallel throughout 
with that of the remaining cretinic symptoms. There are complete cretins that 
show only slight disturbances of hearing and speech. In others the mutism 
may be the chief symptom of the cretinic degeneration (larval form of v. 
Eiselsberg). 
The statements as to the functional disturbances or the pathologico- 
anatomical findings in the deaf cretins and in the endemic deaf-mutes diverge 
greatly. Hammerschlag, whom we have to thank for the first exact investiga- 
tions, found on the one hand alterations in the peripheral hearing apparatus, 
and on the other only disturbance of the perception of sound, as also found 
Scholz, Froschel, and others. Further, there was found in endemic cretinism 
incomplete ossification of the stapes, inhibition of development of the epithelial 
cells in the ductus cochlearis (Habermann, Alexander), shortening of the base 172 
THE CRET1NIC DEGENERATION 
of the skull and thereby disturbance in the development of the organ of hearing 
(Danzinger, Bircher), incomplete ossification of the organ of hearing with hyper- 
ostotic growths at other places (Moos and Steinbrugge). Anomalies of the 
malleus (Nager), myxedematous thickening of the tympanic mucous membrane, 
etc., have been regarded as the cause of the hardness-of-hearing. Recently, 
E. Bircher has strenuously criticised a portion of these findings or their signifi- 
cance. To-day we may safely assume that we may ascribe great importance 
to the degeneration in the cortical centers or the developmental inhibitions in 
the cortical centers, and that the different alterations are directly elicited by the 
goiter noxus and are coordinated with an insufficiency of the thyroid, which 
finally sets in (Pineles). 
The inhibition of the development of speech in endemic cretinism is extra- 
ordinarily different [in degree]; where hearing is entirely absent, of course, the 
development of speech is also absent. We do, however, see cases in which in 
spite of high-grade disturbances of hearing only relatively slight defects of 
intelligence are present. Of course, in these cases articulation is poor (Ham- 
mer schlag). In other cases, in spite of good hearing, intelligence and the 
development of speech are minimal. Here also we assume a developmental 
inhibition of cortical centers (Scholz and Zingerle). Where the endemic 
shows less intensity, defects of intelligence may be entirely absent 
(.H. Bircher). 
Investigations as to the metabolism in endemic cretins have been published 
only by Scholz. Scholz designates the metabolism as very sluggish. The 
amounts of urine were very slight, as well as the exchange of protein and of 
salts. The excretion of nitrogen, uric acid, creatinin, and sodium chloride 
was very slight, and that of urea, the xanthin bases, ammonia, and sulphuric 
acid showed corresponding proportions. There was further noted a tendency 
to retention of phosphorus and nitrogen. The metabolism therefore shows a 
relation analogous to that in myxedema.1 Very interesting are the results of 
feeding with thyroid gland. Diuresis increases. The nitrogen elimination 
was not, however, essentially influenced, while the body weight diminished. 
Therefore chiefly nitrogen-free substances must be consumed. 
As the cretins investigated showed no distinct myxedematous swellings, it 
was not to have been expected that the initial increase of the protein combustion 
observed in myxedema would be present. The experiments all show that the 
depressed protein metabolism in endemic cretinism cannot be stimulated so easily 
as in myxedema. I cannot see in this an analogy to Basedow’s disease, as 
Scholz does, as the absence of a further increase of nitrogen elimination through 
thyroid substance in Basedow’s disease may have its ground in the circum- 
stance that the excess of thyroid-gland secretion does not come distinctly into 
action, if in higher grades of hyperthyrosis the energy of the protein decomposi- 
tion has reached a great intensity. Scholz further observed in his experiments 
that under the influence of administration of thyroid gland, the calcium in the 
1 “Not however to experimental athyrosis proper.” This statement of Scholz is unintelligible 
to me, as according to my knowledge, an essential difference between the metabolism of myxe- 
dema and that of cachexia thyreopriva does not exist. 173 
ENDEMIC CRETINISM 
urine decreases markedly and that it increases in the feces, as we have also 
observed in normal individuals.1 
For the most part there is found in cretins a fairly evident hypoplasia of 
the genitalia. In women the labia and the uterus are mostly small, but it may 
happen that the external genitalia are relatively well developed; the ovaries are 
small and often show small cystic degeneration; the menses are absent or are 
scanty and irregular; the mammae are poorly developed and without glandular 
tissue. In men the penis is often very small, the testicles are not well descended, 
and on microscopical examination show spermatozoa very sparingly. The 
scrotum is lax. In both sexes the secondary sexual characters are for the most 
part very defectively developed; the sexual instinct is entirely absent or is very 
weak only; in many a light case, however, procreative power and conception 
are observed. E. Bircher reports concerning a cretin of the most severe grade 
who conceived; the fetuses, however, are not capable of living, even when, as 
in a case of Eppinger, they show no sign of cretinic degeneration. The genitalia 
can, however, like ossification, still show a late development. 
Worthy of observation are Schonemann’s investigations, which show that 
in neighborhoods where goiter is endemic strumous alterations are found very 
commonly in the glandular part of the hypophysis. Among one hundred twelve 
cases, the hypophysis was normal in only twenty-seven. These persons did not 
have a goiter. Among the cases with goiter, there was only one in whom was 
found a hypophysis that could be regarded as probably normal. “In persons 
with struma of the thyroid, there was always found enlargement of the hypo- 
physis, and indeed either proliferation of the connective stroma, also chromo- 
philic strumas, strumas with especially vascular development of the stroma a 
hyaline degeneration and swelling up of the columns of cells, and finally those 
with marked colloid formation.” v. Cyon found strumous alterations of the 
hypophysis very frequently in Bernese dogs. The goiter poison therefore works 
deleteriously on the hypophysis. 
As in sporadic cretinism, the disturbance in bone-growth consists of delay in 
the epiphysial closures and in retarded appearance of the bone-nuclei. Lang- 
hans first described, in the skeletons of five cretins, the remaining behind in the 
ossification and commented that also the cretinoids show a similar, although less 
marked, remaining behind. “The bones previously laid out in cartilage grow 
slowly in their length; the epiphyses remain low, the boundaries of ossification 
progress very slowly, the nuclei of ossification in the epiphyses occur very late, 
and the epiphysial discs are retained for long beyond the normal term. Rem- 
nants of these discs are still to be found in the forty-fifth year.” v. Wyss has 
confirmed the observations of Langhans by means of the X-ray examination of 
numerous cretins and cretinoids—and incidentally has finally contradicted the 
previous view that in cretins premature ossification of the epiphysial junctures 
occurs. This delay in the epiphysial closure makes intelligible, as v. Wyss 
emphasizes, the former observations of v. Wagner that in endemic cretins, even 
in late life, the growth in height may go on. To this extent the disturbance in 
the ossification agrees fully with that in sporadic cretinism, although on the 
1 See the chapter on hyperthyroidism. 174 
THE CRETINIC DEGENERATION 
other hand there are differences that are important from the point of view of 
differential diagnosis. Already v. Wyss pointed out that the retardation in the 
ossification for the most part lasts only a few years, so that only rarely are the 
epiphysial junctures found to be open after the twenty-fifth year. 
Dieterle mentions especially the extensive difference from thyroaplasia in 
this behavior of the epiphysial junctures, which in thyroaplasia, if thyroid 
therapy be not introduced, often remain open. In youthful age in endemic 
cretinism, however, the remaining of the ossification behind that of the normal 
individual is not inappreciable. Dieterle publishes a very instructive table in 
which he compares the ages of the cretins of v. Wyss as estimated from the 
radiograms of the hands with the actual ages of the individuals. He finds in 
eleven cretins between the ages of seven and eighteen years a remaining behind 
of ossification of from three to seven years. Breus and Kolisko state moreover 
that in six of the cretin skeletons examined by them never did all the epiphysial 
junctures remain open until an advanced age, therefore there did not exist in all 
bones the same degree of disturbance of growth, and that there resulted from 
this a dis pro portioned skeleton; the extremities are slender but shortened near 
the trunk, and there exists in this respect a difference between the cretinic 
dwarfism and the true dwarf described by A. Paltauf, in which all epiphysial 
closures remain behind, in like manner, as in a former child stage of develop- 
ment. In those cases of endemic cretinism in which the epiphysial closures are 
already ossified, thyroid therapy can naturally no longer lead to growth in height. 
E. Bircher has recently studied the disturbances in growth in endemic 
cretinism in a large number of cases (fifty-six) and has come to the same 
results as Breus and Kolisko. The inhibition of the ossification affects 
only the age of development. After thirty years of life the epiphyses and 
synchondrosis were found open only exceptionally. Also Bircher found 
throughout that the inhibition in the individual bones is quite dissimilar 
and leads to a disproportioned skeleton. Not rarely E. Bircher found a 
coxa vara or a humerus varus. 
Of quite a manifold nature are the findings as to the teeth of cretins. 
Kranz examined thirty cretins from the Knittelfeld Institute in Steiermark 
as to jaw and tooth formation, and found numerous anomalies of the jaws, 
retarded teething, and factors giving rise to anomalies of the position of 
the teeth. Further he commonly found alterations of the structure, defects 
of the enamel, hypoplasias and erosions and very frequently caries. That 
these anomalies were not produced by the experimental extirpation of the 
thyroid gland in animals is made intelligible by the conception that athy- 
rosis or hypothyrosis and endemic cretins are different conditions. 
Very frequently statements are made that endemic cretins are anemic; 
with this agrees the fact that Langhans found in a grown cretin much fat 
marrow and little functioning marrow in the long bones. I was unable to 
find statements as to the leucocytic formula in endemic cretinism. Mc- 
Carisson, however, reports on the basis of over one hundred blood examina- 
tions in endemic goiter a regular increase of lymphocytes and in most cases 
hypereosinophilia. ENDEMIC CRETINISM 
175 
The statements as to the thyroid gland in endemic cretins vary greatly. 
v. Wagner found not a single normal thyroid in inspection of the neck of two 
hundred cretins. Very commonly the thyroid is not palpable, but very little 
value can be ascribed to this statement. In the most cases are found goitrous 
degeneration with atrophy. DeCoulon found in the thyroid gland of five 
cretins, who died at the age of twenty-six to thirty years, very little normal 
thyroid-gland parenchyma. One of these cases was fairly well developed 
mentally. Hanau examined three thyroid glands that all were small and 
showed a marked disappearance of the parenchyma. Also Bayon and Get- 
zowa found high-grade degenerative processes, marked diminution of the 
functionating parenchyma, and enormous development of hyaline-degener- 
ated connective tissue. Getzowa found, however, similar alterations also in 
the thyroids of idiots and microcephalies who did not show dwarfism. On the 
other hand, Bircher, Sr., found abundant normal thyroid-gland tissue in the 
thyroid gland of one of the cretins that he operated on. Recently E. Bircher 
reports on the examination of over sixty cretins’ thyroids, obtained at autopsy 
or at operation. Degenerative processes were present in all, but were of 
extremely varying intensity, which often did not run parallel with the inten- 
sity of the affection. In all thyroids moreover were found large portions 
of normal thyroid-gland tissue. E. Bircher found similar conditions in a 
series of endemic deaf-mutes. Accordingly there were found in almost all cases 
sclerotic and atrophic processes, hut in addition always some functionating 
parenchyma. Hence there was no struma whose histological picture was 
characteristic for cretinism, v. Werdt arrives at the same conclusion on 
the ground of the examination of five strumas that histologically showed 
entirely the picture of a cretin’s thyroid, without there being any sign of 
cretinism whatsoever in the actual cases. 
No essential alterations have as yet been found in the parathyroid glands 
in cretinism (Scholz, Getzowa, E. Bircher). 
Treatment.—Before I consider the question as to the role that thyroid 
insufficiency plays in endemic cretinism, I should like to speak about the 
results of thyroid therapy. There are in the literature very contradictory 
statements as to this. v. Wagner saw very good results. They consisted in 
the disappearance of the myxedematous swellings, in the rapid development 
of the genitalia, which had remained behind, in the diminution in size of the 
enlarged tongue, and even in the disappearance of an umbilical hernia, in 
falling out of the bristly hair and development of new hair of normal texture, 
in acceleration of dentition, before all, however, in the diminution in size of 
the fontanelles that had remained open, in the acceleration of ossification and 
in increase in height. The least satisfactory were its results on the psyche; 
it is true that there was usually a decrease in the apathy and in the lack of 
movements, yet the increase in the intellectual capability was usually very 
slight. 
v. Wagner lays especial stress on the earliest possible beginning of the 
therapy. He also saw good results in individual cases from administration of 
small doses of iodine (through stimulation of the activity of the thyroid 176 
THE CRETINIC DEGENERATION 
gland?). Still better results were obtained by Magnus-Levy in fourteen 
individuals from three neighboring villages from upper Miinstertal in the 
Vosges. These individuals came from seven families. The cretinism had 
appeared in this neighborhood only a short time previously; goiters were 
usually present in the relatives, and also the parents showed symptoms of 
slight goitrous degeneration. In the individuals themselves the thyroid was 
in many cases not palpable, only in a few goitrously degenerated. The 
majority showed fairly well pronounced myxedematous symptoms. In the 
severest cases were present lordosis and pendulous abdomen, in all constipa- 
tion and faulty development of the genitalia. One case was highly deaf. 
It is further worthy of note that a case that had developed fairly normally up 
to the tenth year first showed signs of cretinic degeneration at the close of an 
attack of pertussis, and finally in the sixteenth year showed a rapid deteriora- 
tion with distinct signs of myxedema; in none of the cases did there exist com- 
plete dementia. In all these cases there was a distinct improvement already, 
four to six weeks after the institution of thyroid therapy. After one and one- 
half years only one case showed an increase in height as low as 4 cm.—all the 
rest n-17 cm. The myxedematous manifestations disappeared, and the 
intellectual ability improved considerably. Also v. Eysselt saw good results 
in forty-six cretins in the Littauer Amtbezirke [official district] in Mahren. 
In two the development of the genitalia was especially influenced. Also 
Sofer saw favorable influencing of the growth, and in addition also a severe 
loss in weight. In two later communications v. Wagner reports about numer- 
ous cases that were treated with very good results. Also in these communi- 
cations v. Wagner points out that the results were more favorable the 
sooner the treatment was begun. In certain light cases a cure may be obtained 
which persists even after withdrawal of the therapy. But even when the 
therapy is begun in late life good results can be obtained. In the severer 
grades of cretinism the result was indeed not so satisfactory. 
Also the hardness-of-hearing may become essentially improved. Many 
cases of hardness-of-hearing, however, do not improve. 
According to v. Wagner, cretinism for the most part is not congenital, but 
in the great majority of cases signs of cretinism first make their appearance in 
the first years of life. For an early diagnosis are important, first of all, the 
absence of disturbances of gait and speech, then the pale color of the face, the 
swellings of the skin, the apathy, the retardation of the closure of the fontan- 
elles and the dentition, the gradual retraction of the root of the nose and the 
remaining behind in growth. In such cases of acquired cretinism a much 
better result of thyroid treatment may be expected. 
As an especially pretty example of the increase in height, I shall quote the 
following case of v. Wagner. A fifteen-year-old boy is 105 cm. tall at the 
beginning of the treatment; after a four years’ treatment he has grown about 
43 cm. that is about 29 cm. more than corresponds to the average growth at 
this period of life. The typical saddle-nose and the apathy have disap- 
peared, he articulates fairly well, the hearing has improved, etc. On the 
contrary, cases in which the cretinism appears so early that we must assume a ENDEMIC CRETINISM 
177 
congenital cretinism are for the most part fairly refractory. In these cases an 
influencing of the disturbances of speech and intelligence is completely absent. 
But also in such cases a result seems possible when the treatment is instituted 
a short time after birth. Those cases of v. Wagner which after an initial nor- 
mal development first remained behind in body and mental development after 
an infectious disease could indeed in part also be classified with sporadic 
cretinism. 
On a still larger material is based the report of v. Kutschera as to the treat- 
ment of endemic cretinism in the Steiermark at the cost of the state. The 
treatment was given to one thousand eleven cretins; of these a great num- 
ber was treated for only a short time on account of the insufficient interest 
of the parents and could not be considered in the judgment of the result. 
Also there was found numerous individuals who could not be considered as 
cretins, and who were separated out at a later sifting. Only in 2.4% of all 
treated were the tablets not borne well. High-grade idiots and cases of 
pure mutism were rejected. Of great interest were the cases the growth 
of which could be followed for a long time. They were four hundred forty 
in number, of which only 10.2% showed only a less growth than corre- 
sponded with the age of life, 4.1% showed a growth corresponding 
with this age 85.7%, however, a growth that exceeded the normal at 
that age. Especially in the first years of life was the increase in height very 
significant, but it occurred, too, in individuals at the beginning of the third 
decade, in whom, under normal conditions, growth would have ceased. As to 
the total results, which also took into consideration other cretinic symptoms, 
among six hundred seventy-seven cases there was an appreciable improve- 
ment in 42.8%, a distinct improvement in 48.6%, and in 8.6% no 
improvement at all. 
Again, v. Kutschera reports light, previously treated cases, in which 
complete cure was obtained after a relatively short treatment. 
In rather sharp opposition to these good results are the bad results of 
Scholz and also of Lombroso. The bad results of Lombroso are concerned with 
old cretins. Scholz reports concerning a very large number of cases. Scholz 
treated with thyroid tablets one hundred cretinous children in the infirmary 
at Knittenfeld. He began with one tablet and gradually increased to three 
tablets, and in certain cases up to eight tablets, per diem. The results 
throughout were unfavorable. The body weights quickly sank (in certain 
cases as much as 36%). The children became extremely weak, even bed- 
ridden, the appetite diminished, vomiting and diarrhea occurred, apathy 
increased; three children died. Increase in height was not observed. Also 
there were observed other symptoms of hyperthyroidism, such as tachycardia, 
sweats, etc. v. Wagner believes that these unfavorable results of Scholz depend 
on too high dosage, v. Wagner and v. Kutschera gave only a half-tablet 
to small children and gradually increased to one tablet. Also older individ- 
uals were mostly given only one tablet a day. Scholz began with one 
tablet and increased apparently rather quickly to three tablets, in certain 
cases even higher. In my cases of sporadic cretinism, however, even much 178 
THE CRETINIC DEGENERATION 
larger doses were necessary over even a longer time before the first manifesta- 
tions of hyperthyroidism manifested themselves. Scholz later stated that he 
could not obtain any good results with small doses. Also v. Wagner stated 
that many severe cases, especially those which he regards as congenital 
cretinism, are either fully refractory, or that at least certain symptoms, 
especially the disturbances of intelligence and speech, can remain uninfluenced. 
The hypothesis that in such cases, in which the noxus has already done harm 
at a former period, already definitive irreparable damage has been done, 
especially in the central nervous system, can explain only a slight result, but 
not the complete failure of the thyroid-gland treatment, as these conditions 
also obtain in sporadic cretinism, and here thyroid-gland therapy is never 
entirely without [good] results. 
We now take up the question as to what role the disease of the thyroid 
plays in endemic cretinism. 
Pathogenesis.—Kocher and v. Wagner identify sporadic and endemic 
cretinism, referring all manifestations to a damaging of the thyroid gland. 
Bircher, Ewald, and Scholz ascribe to the athyrosis component only a cer- 
tain signification, and see in it only one manifestion of cretinic degeneration 
which is coordinated with other derangements. 
The following is a list of the factors that speak against the hypothesis 
of a thyroid disturbance alone: 
1. The action of thyroid therapy is not so constant as in sporadic cretinism. 
2. The myxedematous symptoms are wanting in many cases or are only very 
slightly expressed. 
3. The forms of the clinical manifestations of endemic cretinism are much 
more manifold. To it belong the frequent association with mutism, 
further the occurrence of mutism in cases that otherwise show only 
few signs of cretinic degeneration. In endemic cretinism there is an 
incongruence between the inhibition of the mental disturbances and 
the other signs of the cretinic degeneration; cases that on the one 
hand show struma and rather high-grade disturbance of growth are, 
however, well developed mentally; on the other hand, cases that are 
highly idiotic have remained behind in growth only a little. 
4. Further, there exists a quantitative and qualitative difference in the 
disturbance in growth. This in endemic cretinism is only delayed; 
even in the highest grades there occurs later closure of the most of the 
epiphysial junctures; the disturbance in growth is disproportionate 
{Breus and Kolisko). 
5. The hypophysis is often goitrously degenerated. 
I believe, therefore, that I shall have to concur in the opinion of those 
authors who ascribe to the noxus of cretinic degeneration a direct deleteri- 
ous influence on the central nervous system and other tissues, probably also 
on the other ductless glands. Also the independent position that according 
to the later investigations we must ascribe to goiter heart is embraced in the 
confines of this view. ENDEMIC CRETINISM 
179 
On the other hand, the significant results of thyroid-gland therapy in many 
cases of endemic cretinism force us to ascribe to the athyrosis components a greater, 
indeed in many cases an almost determining significance. The complete 
setting aside of this factor, as we see in the works of H. Bircher and Scholz, 
is not in my opinion correct. E. Bircher also surely goes too far when he 
explains the striking influencing of the inhibition of growth, which was 
observed in many cases of endemic cretinism under the thyroid medication, 
simply through the evidence that also the normal cartilages react to the 
administration of thyroid gland, and that Scholz and Zingerle favorably 
influenced the growth of rachitic dwarfs through thyroidin tablets. Such 
results, that are to be striven after in all cases, are not to be attained in all. 
I quote examples of this in the chapter on infantilism, in which the inhibition 
of the osseous growth behaves refractory to thyroid therapy. The cause 
of the divergence of views I would especially see in the fact that up to the 
present we have too little considered that a variable importance attaches to the 
athyrotic components in different individuals and in different epidemics. So, 
for instance, in the epidemic that Magnus-Levy described it stood entirely 
in the foreground; it is not without significance in this respect that the epi- 
demic that Magnus-Levy described had lasted only for a short time. Also 
in numerous cases of Kocher and of v. Wagner is the athyrosis predominant. 
However, v. Wagner states that the cases originating in Judenburg did not 
react at all to the administration of thyroid. The same is true of the severest 
forms of cretinism in the Steiermark that Scholz observed, and of the cases 
of Bircher. It is therefore to be supposed that at different places the noxus 
works with different intensity. Significant also is the fact as to whether 
the population has suffered from the affection for a long time; finally it is 
probable that bad living conditions, in-breeding, and many other factors 
contribute to the intensity and the clinical symptoms of the endemic. 
How complicated the question is, is shown by a communication of v. 
Wagner’s as to marine cretinism. It is known that the sea-coasts are almost 
free from goiter and cretinism. Now v. Wagner observed on the island 
Yeglia, belonging to the Guarneric Islands, fifteen dwarfs, mostly about 
ioo cm. tall. The closure of the fontanelles was delayed; in most, but not 
in all, the root of the nose was retracted, there existed more or less distinctly 
well-expressed myxedema of the skin, high voice; there was absence of hair on 
the pubic and in the axillary regions; the genitals showed high-grade infantil- 
ism, in men the mons Veneris was abundant in fat and, as is shown in the 
photographs accompanying v. Wagners’s publication, was limited above by a 
horizontal line; frequently there existed constipation, dentition was delayed, 
the intelligence in some was only very slight, in others there existed only 
slight apathy; many could not read and write; the hearing was well developed 
in all. The thyroid gland was not palpable in all of them. v. Wagner dis- 
cusses the question whether these cases are to be classified under endemic 
cretinism. As ground against such classification, v. Wagner adduces: The 
complete freedom from goiter of the neighborhood, the marked dwarfism of 
all individuals, the marked dysgenitalism, the normal development of hearing 180 
THE CRETINIC DEGENERATION 
and the relatively good development of speech, v. Wagner believes that 
the in-breeding that exists on this island—also albinism is indigenous here— 
perhaps plays a role in this, but that also the insufficiency of the thyroid 
gland is the decisive factor. Very striking seems to me the circumstance 
that in all individuals at first the development was entirely normal up to the 
third, the fifth, indeed even the tenth year and the inhibition of growth did 
not set in until this age; the accompanying photograph shows, in addition to 
the marked dysgenitalism, a form of obesity such as we are wont to find in 
dystrophia adiposo-genitalis and to refer to the insufficiency of the inter- 
stitial glands or of the hypophysis. The disturbance of growth seems to 
me to speak decisively for the hypophysis. A strumous degeneration of the 
hypophysis could perhaps have been demonstrated by an enlargement of the 
sella on X-ray examination; in other cases there did exist, however, undoubted 
myxedematous alterations. Such an endemic degeneration of the ductless 
glandular system with predominant involvement of the glandular hypophysis 
occurring in earliest youth is, at all events up to the present, unique. I 
cannot at first hand answer with certainty the question as to whether or 
not a variety of cretinic degeneration exists in such a case. 
Surveying once more the field covered in the preceding observations it 
seems to me that the separation of the cretinic degeneration from the chapter of the 
pathology of the thyroid gland is indeed possible and desirable, on the other hand it 
would be a mistake to relegate too far to the background the intimate connecting 
associations with the thyroid gland. The separate position depends on the locali- 
zation to certain territories, depending on the fact that the noxus contained in 
the thyroid gland produces very frequently, perhaps even regularly, alterations 
not only in the thyroid gland but also in numerous organs such as the heart and 
the central nervous system. 
But there are other attempts at explanation that I have not as yet men- 
tioned. v. Kutschera supposes an infectious noxus; he bases the assumption on 
the following observation: Dogs that have been brought up in the bed of a cretin 
remained behind in development and became typically cretinic. Of course it 
must be considered that these dogs were under the same external conditions 
as human beings and drank the same water. Very difficult to interpret is the 
observation of v. Wagner that a dog with typical endemic cretinism shows exten- 
sive retrogression of the cretinic symptoms after extirpation of the goiter. 
v. Wagner assumes that the manifold symptoms of endemic cretinism are 
produced by a poison emanating from the goiter, and therefore, as previously 
mentioned, places the thyroid gland as the central figure in the pathogenesis. 
Differential Diagnosis.—The differentiation between sporadic and endemic 
cretinism is often difficult and in certain cases may be impossible. The fact 
that the cretin comes from a locality in which cretinism is endemic naturally is 
not evidence, as sporadic cretinism may also occur in some infested neighbor- 
hood. The coming from a neighborhood where only goiter but not cretinism is 
endemic cannot, without other factors, be used against the diagnosis of endemic 
cretinism, as in such neighborhoods endemic cretinism may occur. I refer 
once more to the small endemic described by Magnus-Levy. Here too, seems to ADDENDUM 
181 
me, belongs the interesting observation of Eller. Eller describes three cases of 
cretinism in a Vienna family. The patients were goitrous and had never been 
out of Vienna; three sisters were entirely well; the cretins themselves had stru- 
mas. The result of the treatment with thyroid, which was not carried out 
perseveringly, was not satisfactory. 
The finding of a struma, slight or absent myxedematous consistency of the 
skin, incongruity between mental development and the rest of the symptoms, 
relatively slight inhibition of ossification and closure of the fontanelles, unequal 
remaining behind of the epiphysial closures, slight or absent results of treat- 
ment, impossibility of stimulating the metabolism with thyroidin, low tolerance 
or thyroid-gland substance speak for endemic cretinism. As far as the dis- 
turbance in ossification is concerned, it must be considered that this occurs in 
many vegetative disturbances that have nothing to do either with the thyroid 
gland or with endemic cretinism, v. Wyss already pointed this out; he found in 
four of seven individuals who, without showing striking symptoms of cretinism 
had remained behind physically and mentally, pronounced inhibition of growth 
and of ossification, which were in no wise different from those which are typical 
for endemic cretinism. We must therefore agree with v. Wyss that in a country 
in which cretinism is endemic the differentiation between cretins and idiots is 
extraordinarily difficult. The delay in ossification seems to be found regularly 
in cretinoids without mental defect. 
Addendum 
Goiter is not at all uncommon in the United States. A close study would 
perhaps show that goiter is confined in this country to certain districts. Clark 
and Pierce mention that there are certain districts of endemic goiter in the region 
of the Great Lakes and certain sections of West Virginia. W. Mayo is respon- 
sible for the following: “There is a tremendous amount of goiter in this country. 
Comparatively few of the cases occur in New England or in the Southern States. 
There were about three cases of goiter to each 1000 of draft recruits in the 
district of New York, seven cases to 1000 in the GreatLakes region, eight or nine 
cases to 1000 in Montana, and fourteen cases to 1000 in Oregon, Washington 
and Idaho. The incidence of exophthatmic goiter, three to 1000, as noted by 
some Western Draft Boards of the Army is too high for men in the third decade, 
since most exophthalmic goiters occur in women. ” It is to be noted in this 
connection that these statistics include all cases of enlarged thyroid gland, 
including the exophthalmic type of goiter. The various states of the Union 
would do well to study their incidence of goiter both from the standpoint of 
incidence and that of distribution. In this way much would be done for the 
study of the etiology and prophylaxis, although Marine and certain European 
investigators seem to have made headway in the solution of the problem. The 
editor has the impression that in Pennsylvania the so-called goiter-belt is not 
confined to the vicinity of the Great Lakes but that other belts are found in 
mountainous and hilly regions, including the western part of the State generally. 
Enlargements of the thyroid gland, perhaps not very marked, seem rather 182 
THE CRETINIC DEGENERATION 
common in Pittsburgh, for instance. It is remarkable that in spite of the fact 
that enlargements of the thyroid gland are not rare in the United States, there 
are no foci of endemic cretinism, at least so far as the editor knows. 
McCarrison was able to produce swelling of the thyroid experimentally in 
men by administering to them the filtrate of boiled water from a goitrous 
district. This author cites facts that make it very probable that the noxus of 
goiter exists in the soil, and may possibly be transmissible from individuals. 
Blood counts from seventy-three cases of goiter made under the direction of 
McCarrison showed a lessening of the polymorphonuclear leucocytes in 98.9% 
of the cases and increase of the small mononuclear leucocytes in 92.5% 
an increase of the eosinophiles in 88%, and an increase of the large mononu- 
clear cells in only 23% of cases. This author regards as mislead- 
ing and valueless Kocher’s blood count as a criterion of differentiation between 
exophthalmic and nonexophthalmic goiter. He treats goiter, with striking 
reduction of the goiter, by the use of intestinal antiseptics such as salol and 
thymol, milk soured by the bacillus bulgaricus and the injection of vaccines 
prepared from bacillus coli. His publication contains a map showing how 
goiter is distributed. 
Gilbride has made a bacteriological examination of the contents of eight 
cystic goiters, with negative results, save in one case in which he found the 
streptococcus vermiformis of Sternberg. McCarrison states that Hor and has 
reported the presence of a parasite in a goitrous cyst, but adds that in neither 
this work nor in that of Gilbride is there sufficient evidence to justify the suspi- 
cion that the organisms found are casual agents in the production of goiter. 
Chagas has determined that American trypanisomiasis, due to Trypanosoma 
Cruzi, which is transmitted by Triatoma magistus and perhaps by other species 
of Triatoma, is associated with goiter and with myxedema (Chagas’s disease). 
In view of Marine’s work the soil theory of goiter becomes improbable, 
unless indeed the soil is lacking in certain chemicals and thus affects the drinking 
water. 
As far as the prophylaxis of endemic goiter is concerned, Marine and Kim- 
ball distributed 2 gm. of sodium iodide in 0.2 gm. doses over a period of two weeks 
each autumn and spring to the individual pupils of the school population of 
Akron, Ohio. Only 5 of 2190 school girls among the 2190 pupils to whom the 
drug was administered developed goiter, while of 2305 pupils not taking it 495 
developed thyroid enlargement. The drug produced diminution in the size 
of the thyroids already present. Marine and Kimball report the figures of 
Klinger (1921) in Switzerland who also attained good results. Other European 
investigators must also be credited with having attained results along the same 
line, having used either iodine, the iodides, or some iodine preparation. Thus the 
subject of goiter becomes an important public health problem. It is to be noted 
that when adolescents do show a tendency to hyperthyroidism on the adminis- 
tration of iodine preparations, the use of these had better be discontinued in 
these individuals. Of course individuals who have passed through an attack 
of tuberculosis should not be submitted to the action of the iodides, although 
the prophylactic doses are probably too small to do harm. Marine and Kimball ADDENDUM 
183 
think that i gm. of sodium iodide over a longer period of time than two weeks 
would probably be more suitable than the dose they employed. 
Clark (T.), and Pierce (C. C.). Endemic goiter. Its possible relationship to water supply. 
U. S. Public Health Reports, April 17, 1914. 
Mayo {W.). The thyroid. Med. Record, Vol. C, No. 5, July 30, 1921, pp. 177-179 and Surg. 
Gyn. and Obst., Vol. XXXII, No. 3, March, 1921, pp. 209-213. 
McCarrison (R.). The etiology of endemic goiter. London, John Bale Sons & Danielsson, 1913. 
Gilbride (J. J.). Cultures from the thyroid gland in goiter. A bacteriologic study of fourteen 
cases. J. Am. M. Ass., Chicago, 19x1, LVII, p. 1988. 
Horand (R.). Examen a l’ultramicroscope du liquide du goitre kystique; presence d’un parasite. 
Rev. gen. de Clin, et de Therap. Par., 1911, XXV, p. 71. 
Chagas. Clinical and anatomical aspects of American trypanisomiasis. N. Orleans M. and 
S. J., Vol. LXXII, 1919-1920, pp. 631-660. (Translated by L. Ambrose). 
Marine (D.) and Kimball (0. P.). The prevention of simple goiter in man. J. Am. M. Ass., 
Vol. LXXVII, No. 14, Oct. 1, 1921, pp. 1068-1070. CHAPTER IV 
THE DISEASES OF THE PARATHYROID GLANDS 
(Glandulse Parathyreoidae) 
[Parathyroid Glandules, Epithelial Bodies, Epithelkorperchen] 
Anatomy.—The parathyroid glands are paired organs showing intimate 
spatial relationship with the thyroid gland. In man there are usually two 
parathyroid glands on each side. They have a length diameter of 3-15 mm. 
and a thickness or width of about 2 mm. According to Erdheim, the upper 
parathyroid glands (epithelial bodies) lie against the posterior surfaces of the 
Gl.pth 
Gl.pth. 
Fig. 23.—Parathyroid bodies of man (according to Zuckerkandl). Posterior view of organs of 
neck. Gl. pth. = parathyroid glands. 
lateral lobes of the thyroid gland about the middle of the height of the lobes, and 
the lower parathyroids lie toward the lower pole of these lobes; but not rarely 
there are exceptions with regard to both number and position of the para- 
thyroids. On one side there may be as many as three or four of these bodies 
(Schrieber et al.); the lower bodies may lie as low as against the upper pole of the 
thymus. Statements even exist that accessory parathyroids are pushed down 
to the pericardial fatty tissue (Vassale and Piano). The bodies, especially 
the upper, are bound to the thyroid gland by connective tissue, and the upper 
184 ANATOMY AND EMBRYOLOGY 
185 
may also in part be interpolated in the thyroid tissue. We find in the different 
species of animals great variations in the number and position of the para- 
thyroids. In the cat, the upper parathyroid is always imbedded in the thyroid, 
tissue; in the dog it is sometimes fully imbedded there (inner parathyroid,. 
Kohn), so that extirpation of the parathyroids alone may be attended with 
great difficulty. It is especially important, moreover, that in herbivorous 
animals the parathyroids are entirely apart, spatially from the thyroid gland. 
•F. C. 
eos.p_C. 
c. c. 
Fig. 24.—Parathyroid gland. F. C. = fat cells; eos. C. = eosinophilic cells; C. C. = chief cells 
The parathyroids are very abundantly supplied with blood. Between 
the individual cell groups are found numerous strikingly wide capillaries. 
The glands are supplied by the inferior thyroid artery. 
Histologically the parathyroids are characterized by great richness in cells. 
According to Welsh, large polygonal chief cells and smaller so-called oxyphilic 
cells are to be distinguished from each other. [According to Bergstrand,1 the 
deviations from the chief cells such as were described by Welsh are to be 
regarded as degenerated cells; the so-called granules in the chief cells are 
artefacts.-—Editor.] 
Embryology.—The parathyroids are entodermal glands (Verdun). Fig. 3 
shows how the parathyroids and the thymus gland originate from the bran- 
chial arches. 
The epithelial bodies (c3 and e4) come from the dorsal part of the third 
and fourth branchial pouch. The thymus gland comes from the ventral part 
of the third pouch. 
1 Bergstrand (H.). Acta Medica Scandinavica. Vol. LII, Fasc. vi, Feb. 20, 1920, pp. 791-848. 
[Bibliography on the anatomy, embryology, and histology of the parathyroid glands]. 186 
THE DISEASES OF THE PARATHYROID GLANDS 
If the bilaterally arranged thymus gland becomes pushed down the para- 
thyroids may come to rest on the thymus gland or even to be included in its 
substance. From the illustration it will be also seen that the relationship 
of the parathyroids to the thyroid is purely topographical. £4 represents 
the inner parathyroid gland which may eventually become included in the 
tissue of the thyroid. 
Historical.—It will be seen from the intimate spatial relationship between 
the thyroid and the parathyroids why for a long time the functional inde- 
pendence of the parathyroids was not recognized. As a sequence of the 
first attempts at total thyroidectomy, by Schiff, Kocher, Reverdin, v. Eisels- 
berg and others, there were observed, in addition to the results of the absence 
of the thyroid as described in Chapter II, severe acute manifestations that 
were uncommonly like the tetany that had formerly been observed in human 
pathology. The difference in topography of the parathyroids in different 
animal species, as just described, makes intelligible why in some species 
thyroid extirpation led to cachexia strumipriva, in others to tetany. The 
discovery of the parathyroids, in 1880, by Sandstrom, first made a change 
in this respect. Indeed Sandstrom at first regarded the bodies described 
by him as the embryonal stages of thyroid tissue that had remained at a 
standstill; Gley, who in 1891 first discussed the physiological significance of 
the parathyroids, believed that these bodies would assume the function 
of the thyroid on extirpation of that gland. A. Kohn first taught the anatom- 
ical independence of the parathyroids; Moussu, and Vassale and Generate 
their functional independence. Kohn also introduced the term “Epithel- 
korperchen.” The investigations of Pineles, Biedl, Erdheim and others 
to-day place the independence of the parathyroids beyond question. 
\Trautmann1 has recently published an article where this statement is well 
confirmed.—Editor.] The observations of aplasia of the thyroid with retention 
of the parathyroids, as detailed in chapter on the thyroid, showing the com- 
plete picture of deficiency of the thyroid with no symptoms whatever of 
tetany; further, the fact that the absence or deficiency of thyroid gland only, 
not however that of the parathyroids, is made good by thyroidin therapy, 
and finally, the fact established in animal experimentation that extirpation 
of the parathyroids alone leads to tetany but not to myxedema, make certain 
the teaching of the physiological independence of the parathyroids and have 
furnished the demonstration that tetany has nothing to do with the absence of 
thyroid gland, but depends on an insufficiency of the function of the parathyroids. 
It is only one step from this knowledge to the view that the different forms 
of tetany observed in human pathology (parathyroprivic tetany), idiopathic 
or occupation tetany, tetany of children, tetany of maternity, stomach 
tetany, tetany in infectious diseases and poisonings, etc., depend on a uni- 
form pathological basis, and that at the bottom of all is an absolute or relative 
1 Trautmann {A.). Zur Frage der Aenderung des histologischen Aufbaues der Thyroidea, 
Parathyroidea [Epithelkorperchen] und Glandula thyroidse accessorise nach teilweisen oder ganz- 
lichen Ausfall der Schildriisenfunktion Virchow’s Archiv., CCVIII, 1920, 345-365 [where references 
to the literature may be found]. TETANY 
187 
insufficiency of the parathyroids (Jeandelize, Pineles, Escherich, Erdheim, 
Chvostek, Jr., Rudinger, and others). 
A. Aparathyrosis or Hypoparathyrosis. Tetany 
Definition.—By tetany we mean an abnormally increased condition of 
excitement of the nervous system, which is demonstrable in a heightened excitability 
of the motor, sensible, sensory, and vegetative nerves, and under certain circum- 
stances, in paresthesias, and bilateral intermittent, for the most part painful, 
spasms, with intact consciousness, or which becomes manifest through phenomena 
of irritation on the part of the vegetative nerves. To the picture of tetany belong 
also trophic and certain metabolic disturbances. The manifestations are the 
result of an insufficiency of the parathyroid glands. 
Symptomatology.—Increase in the electric excitability is to be regarded, 
next to spasms, as the most important cardinal symptom of tetany. It 
affects in the first place the peripheral motor nerves (Erb), although the sen- 
sory senses (Hoffman), and the nerves of special sense (Sicusticus-Chvostek, 
Jr.), are overexcitable to electricity. This hyperexcitability is found espe- 
cially on the use of the galvanic current; the faradic excitability is most often 
normal. The ulnar nerve serves best for testing in adults; the peroneal 
nerve in children. We should use Stintzing’s normal electrode (3 sq. cm.) 
and Edelmann’s horizontal galvanometer. The hyperexcitability expresses 
itself if not only in a lessening of the irritation threshold against the cathodal 
closing contraction, but also in a definite alteration of the contraction formula. 
In normal individuals the lower limits for the C.C.C. lies at about 0.9 milli- 
ampere for the ulnar nerves, for the A.C.C. at about 1.5 to 2 milliamperes, 
for the A.O.C. about 2.5-3 milliamperes, for the C.C.Te about 5 milli- 
amperes, and the C.O.C. can hardly be obtained even with high amperage. 
Now in tetany the C.C.C. can fall to very low values (as low as 0.1 milli- 
ampere, and also the values for A.C.C. fall (even to 0.5 milliampere); it is 
important, however, that the value for the A.O.C. fall and eventually become 
lower than that of A.C.C. and even lower than that of C.C.C. Further 
C.C.Te occurs at very low values, and finally also C.O.C. may be obtained. 
Also A.C.Te and A.O.Te may be obtained sooner. The first statements 
as to the galvanic hyperexcitability came from Kussmaul and Benedict; 
the first exact measurements were made by Erb. In the tetany of children, 
first Escherich and Jauregg v. Wagner pointed out the galvanic hyperexcita- 
bility. Thiemich regarded the falling of C.O.C. below 5 milliamperes 
as conclusive for the diagnosis. It was shown, however, by v. Pirquet that 
this relation obtains only in the most severe cases and that the slight grades 
of tetany are first recognized in a falling of the value for A.O.C., in the 
so called anodal hyperexcitability. 
Erb’s phenomenon may be present in the most of the motor nerves 
accessible for the test. For the most part it is present in like intensity in 
symmetrical nerves, although there are exceptions to this rule. For instance 
v. Frankl-Hochwart found in the right ulnar in a case a C.C.C. of 0.3 milli- 188 
THE DISEASES OF THE PARATHYROID GLANDS 
ampere, in the left ulnar a C.C.C. of o.i milliampere. Erb’s phenom- 
enon, like all the symptoms of tetany, shows great variations. It is most 
distinct at the onset or during the acute exacerbations, less distinct, as a 
rule, during the intervals. In the chronic tetany that extends through many 
years the galvanic excitability can, during the interval free from attacks, ap- 
proach the lower limiting values of the normal, and may even show values as high 
as for normal individuals. As v. Frankl-Hochwart points out, this relation 
is beautifully shown in the tetany of maternity; here the galvanic hyper- 
excitability is seen only during pregnancy or lactation. Erb’s phenome- 
non is the most important symptom of tetany, because we as yet know 
of no other condition in which it occurs. It is also very frequent, v. Frankl- 
Hochwart says that he has not seen any acute case of tetany with normal 
electrical excitability; exceptions do, however, extremely rarely, occur. 
Kahn and / observed a case of chronic tetany with acute exacerbations, in 
which all the important symptoms of tetany were present pronouncedly, but 
Erb’s phenomenon, in spite of the presence of severe spasms, was absent 
during the first days. The condition ameliorated; Erb’s phenomenon was 
positive only on an acute exacerbation of the illness, which occurred after 
about two weeks. 
A heightened excitability to the electric current is shown by the sensory 
nerves also (Hofmann). We usually test the ulnar nerve. Paresthesias 
occur in its distribution even on very low values of the C.C.C. There occurs 
too an analogous change in the sensation formula. Finally the nerves of 
special sense may be hyper excitable. With relatively low current strengths, 
Chvostek, Jr., found sensory reactions in the acoustic nerve with analogous 
alterations in the formula of sensation in six out of seven cases of tetany, v 
Frankl-Hochwart found a similar relation to the galvanic current of the 
taste sensations. Occasionally, in testing the electrical excitability, when 
the electrode is placed over the mastoid process there occur with very low 
current strength, and often before the occurrence of contraction, ear noises 
and finally a bitter taste sensation (Falta and Kahn). These symptoms are 
subject to great variation. 
Another certain symptom of latent as well as manifest tetany is the 
mechanical hyper excitability of the motor and sensory nerves. Chvostek, Sr., 
first pointed out in this regard, that in tetany percussion of the motor nerve 
trunks and especially the facial trunk leads to lightning-like contractions in 
the muscles supplied. When the facial trunk is struck, the contractions 
rarely affect the muscles of the forehead, v. Frankl-Hochwart distinguishes 
three degrees of the phenomenon depending on the intensity. In Chvostek 
I, on percussion of the vicinity of the auditory meatus contractions occur in 
the muscles that close the eyelids, in those of the alae nasi, and in those of 
the corner of the mouth. They may even be brought about by slight strok- 
ing of the front of the ear with the handle of the percussion hammer (Schultze). 
In Chvostek II, there are contractions of the alae nasi and muscles of the 
corner of the mouth on percussion under the zygomatic arch. In Chvostek 
III, percussion here causes contractions of the corner of the mouth only. TETANY 
189 
As to the pathognomonic significance of the different degrees of Chvostek's 
phenomena for tetany, opinions are at variance. 
The phenomenon is certainly very frequent in tetany, yet it may be 
wanting in pronounced cases and often shows great variations. On the 
other hand slight degrees of it may occur in numerous cases of neurasthenia, 
hysteria, and epilepsy.1 v. Frankl-Hochwart and Schlesinger found Chvostek 
II and III in nearly one-half of patients with phthisis. However, other 
authors, for example Schonborn (Heidelberg), do not find this phenomenon 
so frequent. It is found commonly also in rachitis. Kahn and / found 
it several times in rachitis tarda. Mager found it very frequently in enter- 
optosis, v. Frankl-Hochwart in strumous individuals. It is especially fre- 
quent in all possible sorts of cachexia, especially when this is associated 
with much loss of water from the body. Curschmann especially has pointed 
this out. Kahn and I observed it also in severe diabetes, and also in almost 
all cases of Reichmann’s disease. It is probable that in a great number of 
such cases this phenomenon depends not so much on the mechanical excita- 
bility of the nerves as on that of the levator anguli oris muscle, as we tap 
too on the insertion of this muscle in the procedure. For this view speaks 
the fact that in the conditions named idiomuscular prominences were pro- 
duced regularly on the various muscles.2 
Chvostek II and III are also seen not rarely in entirely normal individuals. 
Hence they are not pathognomonic for tetany, although it should be noted 
that these phenomena are very frequent in the localities in which tetany is 
endemic at the season of the tetany, and that in cases of tuberculosis in 
which they were present they were not infrequently found associated with 
caseation of certain of the parathyroids. Chvostek I, when pronounced, 
is very indicative of tetany; although absence of the symptom does not 
speak against tetany, as it may be wanting in the acute stages, and like all 
symptoms of tetany, shows great variations. The mechanical hyperex- 
citability of the sensory nerves expresses itself in the occurrence of a burn- 
ing sensation on percussion of the nerve trunk or on pressure over it. I shall 
speak later about the mechanical excitability of the sympathetic nerves of the 
blood-vessels. 
Trousseau's phenomenon consists in the circumstance that pressure 
on a nerve trunk will bring about a typical tetanic spasm in its area of dis- 
tribution, or that the constriction of an extremity with a rubber bandage 
will also induce such a spasm. This phenomenon has nothing to do with 
alterations in the circulation, but depends on the excitability of the nerve 
itself (v. Frankl-Hochwart). However, it cannot be so simply explained by 
the increased motor irritability of the nerve alone, for v. Frankl-Hochwart 
saw bilateral spasms occur after pressure on the nerve plexus of one extremity, 
and Schlesinger shows that this phenomenon cannot be induced on the purely 
1 D. J. McCarthy has recently again called our attention to this point (unpublished article). 
2 It is quite possible that in certain of these conditions, alkalosis, circulating metabolic poi- 
sons, e.g. guanidin, or a defect in calcium metabolism may be at the bottom of the phenomena. 
See addendum^—Editor. 190 
THE DISEASES OF THE PARATHYROID GLANDS 
motor facial nerve, but only on the mixed nerves. Hence to the hyperexcita- 
bility of the motor nerves must be superadded that of the sensory nerves or of 
their spinal centers and their connecting links [SchaltstiickeJ. 
In similar manner would be explained the leg-phenomenon lately described 
by Schlesinger. On flexion at the hip-joint of the leg that is extended at 
the knee there can be induced under circumstances during the time of the 
freedom from attacks, a painful tonic spasm in the extremity, after from 
a few seconds to three minutes. Finally should be mentioned here the 
thermic hyperexcitabilty described by Kashida. This expresses itself 
in the occurrence of paresthesias and spasms on the application of cold or 
hot irritants. 
In tetany the tendon reflexes are mostly normal, in the attack not rarely 
diminished. 
Finally it should be mentioned that the patient frequently complains 
of pains in the hones or joints (Falta and Kahn), especially after severe tetanic 
attacks. I shall later report such a case. 
We now come to a symptom that in the full development of tetany makes 
it one of the most dreadful diseases, and that has furnished its name, i.e., the 
tetanic spasm. Here we meet with the greatest differences in the phenomena, 
and here the individual forms of tetany show the greatest variations in the 
localization of the spasm. In tetany of adults usually the upper extremities 
are involved symmetrically in the spasm, and indeed in the known obstetri- 
cian’s position, yet there sometimes occur fist-positions with extended thumbs, 
and spasms may occur unilaterally (v. Frankl-Hochwart, v. Jaksch, Cursch- 
mann, et al.). When the lower extremities are affected, they are extended, 
the foot is in a slight equinovarus position, the toes are bent plantarly, some- 
times, however, dorsally. The spasms are exquisitely painful. 
As example I cite the following case (Case VI of Falta and Kahn). 
Observation XVII.—-Augustine Sch.', four and one-half years old, from Vienna. Entered 
the clinic Nov. 24, 1911. For three weeks emaciation, and very poor appetite. One of the 
two children of the same parents died in 1909, in the first year of life, of spasm of the glottis. 
The patient herself had had spasms at two and one-half years, that lasted two days and were 
associated with fever. No rickets. Aug., 1910 to Jan., 1911 pertussis, then pneumonia 
with measles. Since that time frequent severe diarrheas for eight days; on Feb. 22 vomiting 
daily, since which six to seven bowel movements daily. Since this morning tonic spasms in 
the feet. 
The illustration shows the typical obstetrician’s position of the hands. Also there is 
distinct spasm of the left leg, as is to be seen by the tension of the tendon of the tibialis 
anticus muscle and by the dorsal flexion of the great toe. The diarrheas ceased on Feb. 
15 (administration of tanningen), and the tetanic attacks disappeared. 
In children there occurs the so-called carpopedal spasms in which the 
fingers do not, as in the previous case, assume the obstetrician’s position, but 
are spread out. In the involvement of the face, the tetany expresses itself in a 
tension of the muscles, in spasm of the lids, in slight pointing of the mouth 
(fish-mouth position, “tetany face” of Ujfenheimer), in spasms of the masse- 
ter, of the geniohyoglossus, and hyoglossus muscles (yawning spasms), in 
difficulty of speech on account of the tonic rigidity of the tongue, and eventu- TETANY 
191 
ally in convergence or strabismus with the occurrence of double vision. 
Sometimes the trunkal, nuchal, and abdominal musculature is involved. Fin- 
ally the diaphragmatic and the intercostal muscles may be affected, producing 
dyspnea. Bechterew could produce spasm of the diaphragm directly by 
pressure over the phrenic nerve. As is known, the involvement of the muscles 
of the larynx is very common in children. Here the laryngospasm often 
stands well in the foreground. Moreover, the rest of the respiratory muscles 
are mostly involved. There occurs inspiratory 
retraction, and even lightning-like closure of the 
glottis (tetanus apnoicus); more rarely expiratory 
apnea also (Escherich). Also in adults laryngospasms 
occur not at all rarely, as Pineles points out especially. 
Finally we must mention the rare retching spasms. 
In the tetany of animals in which the parathyroids 
have been removed, these occur not at all rarely; 
here it is associated with vomiting. The transversely 
striated sphincters of the bladder and rectum for 
the most part remain free, although difficulty in 
urinating is sometimes seen (v. Frankl Flochwart). 
The duration of the spasms is often very short, 
although at times it is hours along. The patients 
often sit for a long time with retracted abdomen, 
the extremities in the position described, incapable 
of movement. Sometimes there occurs only a single 
spasmodic attack; in other cases the attacks are 
repeated at longer or shorter intervals; in children 
are observed as many has eighty laryngospasmodic 
attacks a day. 
The most manifold factors may bring about the 
spasm. In acute cases a slight excitation, percussion 
of the abdominal musculature, may lead to a spasm. 
In latent tetany a febrile affection (angina, tuberculin 
injection, gastrointestinal indisposition, introduction 
of the stomach sound, pregnancy, an intoxication, etc.) may render the 
tetany manifest. 
Chvostek, Jr., observed the occurrence of spasms after injection of tuber- 
culin. Rudinger and I regularly saw spasms in the acute stages occur after 
injection of adrenalin. Kahn and / saw in the acute stage, also regularly, the 
occurrence of increase in intensity of the tetanic symptoms during the hours 
following the injection (as will be considered later). 
Fibrillary contraction of the muscles, which are constant in the tetany 
of parathyroidectomized animals, occur in human tetany rarely. The same 
is also true as regards the pareses, which occur very frequently in totally 
parathyroidectomized animals, especially in the hind extremities. 
Weakness of the extremities, especially after the spasms, may also occur 
in human beings. Also paralysis is observed in man (v. Frankl-IIochwart). 
Fig. 25.—Obstetrician’s posi- 
tion of the hands in tetany. 192 
THE DISEASES OF THE PARATHYROID GLANDS 
Chvostek, Jr., observed for instance a temporary paralysis in the ulnar terri- 
tory after a spasm that was long in duration, which he attributed to the long 
drawn-out extreme position of flexion. Also slight ataxias occur in human 
beings as well as in animals. Spastic contractures are rare. 
In adults, the sensorium is mostly uninvolved, in children it is very fre- 
quently clouded, although also in adults, in the severe cases, especially in 
the parathyroprivic tetany and in stomach tetany, there may occur clouding 
or indeed complete loss of consciousness. 
The coincidence of epileptic attacks with tetany is not rare (v. Frankl- 
Hochwart, Freund, Hirschl, Fries, Falta and Kahn, Redlich, et al). Redlich 
has collected seventy-two cases from the literature. Typical epilepsy may 
have existed for years, to which tetany is then superadded, or epileptic attacks 
may occur in the course of tetany, or may set in simultaneously with it. Espe- 
cially in parathyroprivic individuals have been observed severe unilateral or 
bilateral epileptiform convulsions with loss of consciousness and slowness 
or absence of pupillary reaction. Such cases may rapidly come to a lethal 
end; or the tetany may altogether subside, and death follow later in status 
epilepticus, or tetany and epilepsy may pass over into a chronic stage (cases 
of Westphal and of Redlich). In children severe eclamptic attacks may enter 
into the course of tetany, or may occupy a position in the foreground. In the 
discussion of the pathogenesis I shall take up the question of the relation of 
the two conditions. 
Finally it should be mentioned that in the severest forms of tetany, espe- 
cially in the parathyroprivic forms and in stomach tetany, myotonic symp- 
toms are observed not infrequently, v. Frankl-Hochwart designates them 
as intention spasms [Intentionskrampfe]; they express themselves in such 
a manner that on such an attempted intentional movement as closure of the 
hand for instance, the hand cannot be opened again for several seconds 
{Schultze, Hofmann, Bettmann, Kasparek, v. Foss, Schieferdecker and Schultze, 
v. Orzechowski, et al.). 
In such cases we also observe mechanical hyperexcitability of the muscles 
and formation of pits on percussion, indeed even typical myotonic reaction 
on testing with the galvanic and faradic currents. We shall consider this 
more fully in the discussion of the pathogenesis. 
I have already mentioned disturbances of the sensorium. In a series of 
■cases psychoses have also been observed (z>. Frankl-Hochwart, Kraepelin, 
Hirschl, and others). In acute cases, v. Frankl-Hochwart several times saw 
typical hallucinatory confusion or deep depression; he found abnormal 
psychical excitement and even depressive mental attitudes, fourteen times 
among thirty-seven cases. Erdheim saw characteristic conditions of excite- 
ment in parathyroidectomized rats. 
Finally it remains to be mentioned that in certain cases a slight grade 
of choked disc or neuroretinitis has been observed (v. Jaksch, Hanke). 
I now come to the description of the behavior of the vegetative nerves in 
this condition. In the literature there have appeared up to the present 
only a few scattered references as to this question; nevertheless I can find TETANY 
193 
ground for my statements in the work I did in collaboration with Eppinger 
and Rudinger and especially with Fr. Kahn; in addition, there is a detailed 
work on the subject of Ibrahim. The vegetative nerves show in tetany 
manifestations of increased excitability on one hand and long-continued 
heightening of tone on the other. 
Kahn and / in one case observed hyperexcitability of the sympathetic 
nerves accompanying the vessels. After application of the bandage for the 
elicitation of Trousseau’s phenomenon there occurred in addition to this 
phenomenon, pronounced anemia of the phalanges of the third, fourth, and 
fifth finger. Since that time I have seen this symptom once, in the case of 
E. C. to be described later (Observation XVIII). In this case there occurred 
regularly on application of the bandage to the upper arm or thigh, simul- 
taneously with Trousseau’s phenomenon, a pronounced anemia of the extrem- 
ity. Here also belongs the pronounced dermographism that we find so 
extraordinary frequent in the acute stage of the disease. 
The electrical hyperexcitability of the vegetative nerves in man is hard 
to demonstrate. On the other hand, we may readily show the chemical 
hyperexcitability as seen in the behavior of the patient on the action of 
adrenalin or pilocarpine. After subcutaneous injection of adrenalin in the 
acute stage of tetany there occurs almost regularly an abnormally strong 
action of the blood-pressure, on the heart action, on the contraction of the 
vessels of the skin, and also on the tetanic spasm. The increase in the blood- 
pressure and the pulse rate was especially rapid. To it were often added 
extreme paleness of the face and the skin of the entire body, strengthening 
of the heart action, subjective cardiac palpitations, and even extra systoles. 
In almost all cases there was an acute exacerbation of the tetanic conditions, 
together with paresthesias or spasms. In the declining stage of the disease, 
all these manifestations were very much less pronounced. 
An abnormally strong vascular action of the adrenalin could also be 
demonstrated on the parathyroidectomized dog. 
Later, in the consideration of the metabolism, I will take up the question 
of the glycosuric action of adrenalin in tetany. 
The sensitiveness to pilocarpine is essentially increased in the acute 
stage of tetany. There occurs abnormally strong outbreak of sweat or 
salivation, together with flow of tears, initial contraction of the erectores 
pilorum muscles (gooseflesh), later marked reddening of the skin of the body 
with sensation of heat and rushes to the head, abnormal increase of the 
secretion of gastric juice and relaxation of stomach tonus; further, symptoms 
that we hardly see on the administration of this pilocarpine; symptoms 
such as nausea, diarrhea, urinary and rectal pressure. Also pilocarpine 
induces frequent tetanic spasms in the various muscular territories. The 
manifestations of an increased tonus in the vegetative nerves in the first stage 
of tetany are of very manifold nature. Here I follow almost verbatim the 
expositions on the subject in the work of Kahn and myself. 
Spasmodic conditions of the smooth ciliary muscle seem to occur very 
rarely. Kunn and Fr. Muller saw mydriasis in the attack (spasm of the 194 
THE DISEASES OF THE PARATHYROID GLANDS 
dilatator pupillae?). Feer and also Escherich observed transitory differences 
in the size of the pupils, that Feer regarded as spasmodic conditions. A. 
Fuchs saw during the attack appreciable diminution in the time of pupillary 
reaction. Finkelstein saw pupillary rigidity. Ibrahim saw pupillary differ- 
ences in one case (unilateral spasm of the dilator pupillae). In this case the 
nuchal, pharyngeal, and ocular muscles were especially involved in the spasm, 
thus simulating the picture of a meningitis. The cerebrospinal fluid was 
clear, however. 
Little is known as to lachrymation in tetany; evidence as to the proba- 
bility of its occurrence is furnished in one case only, that of Kahn and myself. 
Here there existed slight redness of the conjunctiva and there was often an 
increase in the lachrymation simultaneously with the exacerbation of the 
tetany, as well as an increase flow of saliva. 
Marked sweats are frequently found in the acute stage of tetany. 
In tetany it is difficult to refer changes in the type of breathing to altera- 
tions in the tonus of the smooth musculature of the bronchi, as we must 
not overlook what part spasms of the diaphragm and of the intercostal 
muscles eventually play in its production. Ibrahim, Finkelstein and Popper 
report cases of tachypnea. We saw dyspnea occur very frequently. [Deep 
breathing itself will produce tetany.—See addendum.—Editor.] 
Disturbances of the action of the heart seem to be very frequent. Kahn 
and / could observe in almost all cases in the acute stage strengthening of 
the cardiac action, loud sounds at the apex, and even accentuated second 
pulmonic sound, in one case an accentuated aortic second. To this is added 
lability of the heart action, in other words, slight tachycardia on psychical 
excitement and abnormally high pulse rate on working. Complaints as to 
cardiac palpitations are frequent. In two cases we observed, toward the 
end of the stay at the hospital, occurrences of mitral systolic murmurs that 
surely were not there previously. 
Very noteworthy are the statements of Ibrahim. This author saw sudden 
death without spasm of the glottis in three cases of tetany of sucklings, 
without signs of suffocation showing at autopsy. Signs of status thymico- 
lymphaticus were in these cases absent or only slightly developed. In two 
of these cases the heart was relaxed in dilatation. In the third case the right 
ventricle was relaxed, the left unusually hard and forcibly contracted. Ibra- 
him thought of tetany of the heart, probably called forth by vagal or sym- 
pathetic excitement. We do not as yet know how far abnormal conditions 
of excitability of the autonomous heart ganglia or heart regulating nerves 
are responsible for the manifestations mentioned. 
In tetany of adults manifestations on the part of the vascular apparatus 
are very pronounced. In the acute stage all tetanies have pronounced vaso- 
motor disturbances. They all look pale, in spite of the fact that, as we 
shall see later, blood counts show high figures for red cells and a hemoglobin 
value not lowered. Emotions often call forth abnormally intensive variations 
of tonus in the vessels; and the edematous swellings that are observed not 
infrequently be regarded as angiospasmodic manifestations. Ibrahim TETANY 
195 
saw, in a suckling suffering with tetany, edema of the legs, with kidneys 
intact, and Kahn and I several times saw marked edema of the skin over the 
metacarpo-phalangeal joints after severe attacks. Curschmann described 
pronounced angiospasmodic manifestations, vascular spasms of the fingers 
and toes. Heat relieved the attacks. Here too would belong the char- 
acteristic puffiness of the face which was first described by v. Frankl-Hoch- 
wart and which we have also frequently observed. The face is pale but does 
not possess the livid coloration that tends to appear in myxedema. 
I now take up the question of the blood picture in tetany, for it stands in 
intimate relationship with the manifestations on the part of the vascular 
apparatus. Until the appearance of our work, the statements as to blood 
changes in tetany were concerned only with cases of so-called stomach tetany. 
In isolated cases there has been observed appreciable increase in the number 
of red cells, or increase in the specific gravity (F. Muller, Fleiner, Kuckein, also 
ourselves), and attempts had been made to refer these to the organism’s poverty 
in water, that might have been brought about by deficiency in absorption on 
account of pyloric stenosis, or on account of the vomiting of large amounts 
of gastric juice. Our investigations showed decisively that this polyglobulia 
is directly a tetany symptom. Above all, it could be shown that in the case 
of “stomach tetany” this polyglobulia existed only in the acute stages, and 
with the decline of the tetany it again made way for normal relations; the 
investigations also showed that the polyglobulia may be for a time appreci- 
ably increased during an acute attack, in one case rising from 5,106,000 to 
7,808,000 red cells; finally, the investigations showed that in the cases of 
occupation tetany the red-cell count is higher during the acute stages, and 
that it is raised temporarily even higher during an acute attack. As example, 
I cite the following case: 
Observation XVIII.—C. E. Entered the clinic May 14, 1912. Carpenter, forty 
years old. For about four years the patient felt a striking sensation of fatigue in the arms 
and legs, especially after heavy work and after long walks. He also had paresthesias in the 
arms and legs (formication, “going to sleep” of the left leg). For two years slight gastric 
disturbances, consisting in brief spasmodic pains, and in acid eructations, sometimes associ- 
ated with vomiting. For the last year, the patient has felt quite well. 
Two days ago he suddenly experienced nausea, acid eructations, vomiting, and a colicky 
pain in the region of the stomach. Some hours later he experienced spasmodic drawing 
together of the hands (according to the description, the typical obstetrician’s position), 
and formications in the tips of the fingers and twitchings of the muscles of the face. Later 
there were also spasms of the lower extremities, which became quite rigid. The spasms seem 
to have lasted three to four hours. The patient was conscious throughout the spasm. 
Since then the spasms have been repeated several times. 
Rather strong potator. Inclination to bronchitides. 
Rather vigorous, large, patient, pale color of the face, facial expression as if he were 
going to cry, skin moist, apical dullness on the left, vesicular murmurs sharpened, at places 
rhonical and whistling murmurs. Cardiac findings normal. Liver two finger-breadths 
below the margin of the ribs. Very well pronounced dermographism. 
Chvostek I and II strongly positive; also the frontal muscles twitch on application of the 
test; Trousseau markedly positive, Hof man markedly positive, Schlesinger markedly positive. 196 
THE DISEASES OF THE PARATHYROID GLANDS 
Electrical examinations 
Ulnar 
Facial 
c.c.c. 
I .O 
0.6 
An C.C. 
2-5 
1.8 
An O.C. 
3-4 
I .O 
C.C.Te. 
8.0 
I . 2 
An C.Te. 
not attainable 
not attainable 
Mechanical hyperexcitability of the muscles very pronounced. Idiomuscular ridges 
make their appearance. 
Patellar reflexes markedly exaggerated, suggestion of a patellar clonus. 
Coarse tremor of the fingers. 
Blood-pressure {Gartner), 125. 
In urine traces of albumin, reactions for urobilin and urobilinogen markedly positive. 
Tubercle bacilli in the sputum. 
Increase of temperature up to 37.30. 
May 14.—During the day and also during the preceding night many severe tetanic 
spasms in the upper and lower extremities, that always lasted for several hours. 
On elicitation of Trousseau’s phenomenon by means of the bandage fibrillary con- 
tractions occur in the musculature of the arms or feet respectively. Together with the 
spasm there regularly appears, on application of the bandage, a pronounced anemia of the 
extremity in question. 
May 15.—Severe attack this morning, at 10 o’clock, during which blood was with- 
drawn from the ear. The blood is dark red. 
Erythrocytes, 6,500,000. 
Leucocytes, 4200, of which: 
Polymorphonuclear neutrophiles, 63 per cent. 
Large mononuclear cells, 36 per cent. 
Eosinophiles, 1 per cent. 
May 16.—Blood findings during the attack-free interval. 
Erythrocytes, 5,600,000. 
Trousseau positive; after the decline, the patient complained of severe bone pains in 
the extremity affected. 
May 20.—No attack since the 16th. Face still slightly swollen, facial expression still 
somewhat as if the patient were going to weep. 
May 22.—Erythrocytes, 5,200,000. 
May 24.—Trousseau can no longer be elicited. 
May 25-31.—Patient feels well, no paresthesias; he has gained as much as 5 kg., appetite 
excellent, no gastric disturbances. 
In a case reported by Falta and Kahn the following values were found: 
At the beginning of the observation about 4,000,000 erythrocytes and 9 
gm. hemoglobin. Three weeks later during a long-continued severe attack 
7,808,000 erythrocytes and 14.86 gm.1 hemoglobin. The next day, during 
a period of almost free attacks there was 5,106,000 erythrocytes. Later 
after amelioration of the spasms 4,160,000. This was a case of tetany in 
the course of a Reichmann’s disease. In another case (Observation XXIII) 
that I report below, we likewise see a distinct agreement between the varia- 
tion of the erythrocyte count and the tetanic condition. I would suppose 
that the behavior of the erythrocytes furnishes a good criterion for the course 
of the disease, just as the leucocyte formula does in Basedow’s disease. 
1 In German edition “per cent.” This has been corrected to “gm.” on reference to the original 
article. —Editor. TETANY 
197 
In dogs, also, we have seen, after parathyroidectomy, the count of erythro- 
cytes in the acute stage rise to 7,000,000. Such polyglobulias occurring dur- 
ing the acute stage can be explained in no other way than that they are 
due to vascular spasm, analogous to those polyglobulias which are observed 
after injection of adrenalin (Bertelli, Falta, and Schweeger). But one is not 
justified in assuming, on this account, that during the tetanic attack there is 
an increased production of adrenalin; we should rather suppose that in analogy 
with all other conditions of excitement in tetany the seat of the hyperexcita- 
bility is to be found in the ganglia. We have noticed no increase of blood- 
pressure during the attack, which however does not speak against our 
supposition-—for vascular spasm need not occur in all portions of the body 
simultaneously and thus an equalization of blood pressure may occur very 
readily. The polyglobulia of the so-called stomach tetany is to be explained 
in the same way. 
The leucocyte count in tetany is mostly normal. Leastwise in individual 
cases, we saw, during severe attacks, transitory hyperleucocytosis up to 
19,000. Differential counts of the leucocytes showed, in the great majority 
of cases, a rather distinct lymphocytosis or a relative and absolute diminu- 
tion of the neutrophilic cells. In these cases there also were found, for the 
most part, swellings of the lymph glands at the portions of the body accessible 
to palpation, enlargement of the tonsils and of the papillae at the base of the 
tongue, hence a slight status lymphaticus. 
With more exact investigation, there could also be demonstrated in the 
great number of cases of tetany slight or severe disturbances in the function 
of the gastrointestinal tract. In this connection we could distinguish two cate- 
gories of cases. In one the tetany develops in individuals who have been 
sick for a long time with gastric and intestinal complaints, especially with 
those which lead to a high-grade stagnation of the gastric or intestinal con- 
tents. To this group I shall refer more in detail in the consideration of 
the individual forms of tetany. In the second category the gastrointesti- 
nal disturbances occur at or after the outbreak of the tetany. Many such 
cases have been observed by Kahn and myself. Of such disturbances I 
would mention: First, a certain hyperexcitability which, as already men- 
tioned, manifests itself in the experiment with pilocarpine in an abnormally 
marked laxity of the stomach and in a very pronounced stratification of 
the gastric contents, eventually in tenesmus and diarrheas. Second, mani- 
festations of increased secretion of the gastric or intestinal glands; in certain 
cases there is found for example a slight grade of hyperchlorhydria, such 
as has been described by Jonas and Rudinger. On increased secretional 
processes in the intestinal tract may depend the diarrheas we observed so 
frequently. In many cases the tetany is ushered in with diarrheas or vomiting. 
As example I cite the following: 
Observation XIX.—A. W. (Case of Falta and Kahn), twenty-seven-year-old woman 
from Vienna. Entered the first medical clinic March 16, 1909. Marked chlorosis at the 
age of sixteen. Menstruation from the age of eighteen on, regular. Three normal con- 
finements. Three days ago suffered with severe pains in the abdomen, that were associated 198 
THE DISEASES OF THE PARATHYROID GLANDS 
with fever, eructations, and constipation. On the next morning typical tetanic spasms 
in the upper extremities, hands in the obstetrician’s position, flexion at the elbows, upper 
arms drawn to the body. At least six such attacks each of about five minutes’ duration. 
The spasms were painful. The galvanic excitability was increased. Rapid recovery. 
Still more instructive is the following case, in which the gastric dis- 
turbance set in at the same time as the tetanic spasms: 
Observation XX.—L. E. (Case VIII of Falta and Kahn), twenty-year-old woman from 
Vienna. Entered the first medical clinic on March 23, 1911. One normal confinement. 
Present illness began six days ago with severe pains in the back and hypogastrium, with the 
vomiting of green-colored masses of bitter taste, and a painful spasmodic attack affecting 
the hands and legs. The hands were in typical obstetrician’s position. Two days later 
again severe pains in the abdomen, with vomiting, associated with typical attack of tetanic 
spasms in the upper extremities and later abdominal pains of a twitching character. Tempera- 
ture as high as 38°. Indican much increased. Rapid recovery. 
In other cases the gastric disturbances occur later, and are made worse 
by a later exacerbation of the tetany. We find likewise that in the cases of 
the first category the gastrointestinal disturbances may increase markedly at 
the time that the tetany is added to the clinical picture. 
In many cases, as seen by the fluoroscope, there is an abnormally rapid 
emptying of the stomach. In some cases there is a marked pyloric spasm, 
in the acute stage, that leads to acute dilatation of the stomach. The cases 
that belong here, which Kahn and myself have reported, are those of the 
first category, in which gastric disturbances existed previously. It is prob- 
able that the tetany increases the pyloric spasm, or in many cases directly 
brings it about. A short time ago, I saw also a case of typical occupation 
tetany that showed the same thing. The report of it follows: 
Observation XXI.—B., seventeen years old, shoemaker. Entered the clinic Ian. 14 
1913. First attack of tetany in winter of 1911. The convulsions then lasted with inter- 
ruptions throughout the winter, disappearing only in April. Throughout the summer, the 
patient felt quite well; two days ago spasms reappeared, especially in the upper extremities, 
and to it were added formications. The symptoms, varying in intensity, have lasted until 
to-day. 
The patient shows the typical crying facial expression of the tetanic. There exists 
great vasomotor excitability. All the typical symptoms of tetany are present. The 
galvanic excitability is much increased. The examination of the blood shows 6,250,000 
erythrocytes. There exist painful spasms, especially in the upper extremities, that are 
often repeated throughout the day. Temperature as high as 37.50. 
Jan. 18.—For three days no spasmodic attacks, the electrical excitability is less in- 
creased; in blood, 4,870,000 erythrocytes. Chvostek’s and Trousseau's phenomena no 
more elicitable. 
Jan. 23.—Fresh spasms, the symptoms of tetany present once more, 5,820,000 ery- 
throcytes. 
Jan. 24.—X-ray examination two hours after breakfast shows a dilated stomach filled to 
a marked degree with fluid; it reaches to three finger-breadths below the umbilicus; there exists 
lengthened time for emptying of the stomach, in short, signs of a hypersecretion with pyloric 
stenosis. 
Jan. 31.—Chvostek still positive, more spasms, 6,400,000 erythrocytes. 
Feb. 6.—No spasms any more, but there still exists paresthesias. Chvostek and Trousseau 
negative. TETANY 
199 
From now on the tetanic symptoms decline, the count of erythrocytes becomes normal 
(4,500,000-4,800,000), the X-ray examination of the stomach, that has been taken three 
times in the course of the last two weeks, now always shows normal relations; after a break- 
fast the X-rays show that the stomach reaches to two finger-breadths below the umbilicus. 
Peristalsis and time of emptying are now normal. 
Fig. 26.—Tetany face (Observation XXI). 
In this case, therefore, is to be found an “attack” of pylorospasmand 
hypersecretion and consecutive dilatation of the stomach occurring in the 
acute stage of tetany. Also Ibrahim is of the opinion that the pylorospasm 
can occur in the course of a tetany of childhood. 
Especially significant for this question are two observations that have 
been reported by Kahn and myself. I would therefore go into the question 
more accurately at this point. In the one case (Observation XXII—Case 
18 of Falta and Kahn), X-ray examination at the time that only slight signs 
of tetany existed showed an elongated but otherwise normal stomach. On 
a later examination, during an acute exacerbation of the tetany, there was 
found a retraction of the greater curvature, completely the picture of an 200 
THE DISEASES OF THE PARATHYROID GLAND 
hour-glass stomach (see Fig. 27). The tetanic spasms rapidly decreased 
in intensity, the stomach assuming normal relations after a few days. In 
the case there were no grounds for the assumption of an ulcus ventriculi. 
In a second case (Observation XXIII—Case 17 of Falta and Kahn) the 
stomach, as found on X-ray examination at the time of an acute exacerbation 
of the tetany and indeed during an attack, was small, markedly contracted, 
divided in two parts like an hour-glass stomach; in addition there was insuffi- 
ciency of the pylorus; there was present therefore a total spasm of the stomach, 
that affected also the longitudinal musculature. At the next examination, 
this phenomenon occurred again, gradually decreasing in intensity, how- 
ever, with the amelioration of the tetany; and later, when the tetany had 
Fig. 27.—Spasm of the stomach in tetany (Falta and Kahn, Ztsch. f. klin. Med., Bd. LXXIV) 
disappeared entirely, the stomach showed normal relations on X-ray exam- 
ination (see Fig. 28). We regarded these manifestations as conditions of 
tetanic spasms. 
Also in thyroprivic animals I several times observed that the spasm 
was ushered in with vomiting and bowel movement. 
All observations detailed point to the fact that in the acute stage of 
tetany the gastrointestinal tract may show symptoms of increased excita- 
bility and a heightened tonus, which later may increase up to a spasmodic 
condition. To which are added heightening of the secretory processes. 
Ibrahim further describes, in the case of suckling tetany, spasm of the 
sphincter of the bladder that led to marked retention of urine, and mentions 
similar observations of Sachs, Escherich, and Ilagenbach-Burckhardt. v. Frankl- 
Hochwart had mentioned still earlier a retention of urine in tetany of adults. 
Ibrahim further assumes involvement of the sphincter ani in the tetanic 
spasms as he often observed in suckling tetany an intense gaseous disten- 
tion of the abdomen (flatulent colic). After introduction of an intestinal 
tube there were emptied large amounts of gas—or even spontaneously there 
occurred an “ explosion-like expulsion of flatus with frequent clonic twitch- 
ings of the abdominal muscles.” Also Koeppe had already supposed, as TETANY 
201 
Fig. 28.—Spasm of the stomach in tetany (after Falta and Kahn, Ztsch. f. klin. Med., Bd. LXXIV)- 202 
THE DISEASES OF THE PARATHYROID GLANDS 
Ibrahim states, that the internal sphincter became contracted in the eclamptic 
attack. 
Finally we mention the disturbances of the regulation of heat. In para- 
thyroprivic dogs there often occur, during attacks, increases in temperature; 
in very intense spasms we even observed on several occasions values signify- 
ing hyperpyrexia. Such disturbances of heat regulation also occur in human 
tetany. In the attack-free interval, the body temperature, as v. Jaksch and v. 
Frankl-Hochwart have emphasized, is often abnormally low. In thirty-five 
observations on acute cases v. Jaksch saw more or less fever at the beginning of 
the disease nine times. Kahn and my observations agree with these. We 
frequently saw with the acute stage temperature as high as 37.8°, in one 
case up to 38.5°, without exact investigation affording any ground that 
there was any cause for the increase of temperature other than the tetany. 
Later, after decline of the tetany, the temperature sank to normal or slightly 
subnormal values. In certain cases we found in the acute stage transitory 
rises of temperature after the injection of substances that otherwise do not 
tend to induce fever (antithyroidin [Mdbius\, pituitrinum glandulare of Parke, 
Davis & Co.). This points to an especial lability of the regulation of heat. 
One could be tempted to regard the increase of temperature in the sense of 
those authors who consider idiopathic tetany as an infectious disease. The 
fact that it is found to still higher degrees in experimental thyroprivic tet- 
any has led Kahn and myself to the assumption that it is probably the expres- 
sion of a condition of excitability of the vegetative nerves. 
Summarizing again all observations that can be advanced for the vegeta- 
tive organs, we find that in the acute stage of tetany the hyperexcitability or 
the abnormal conditions of irritability are not limited throughout to the central 
nervous system and to the peripheral nerves, but that they involve also the vegeta- 
tive nervous system. With the decline of the acute tetanic condition there 
also occurs a decline of the condition of irritability of the vegetative nerves. 
Also the metabolism in tetany shows alterations. 
Disturbances in the carbohydrate metabolism are almost constant in the 
tetanic dogs. First a few remarks as to the glycosuric action of adrenalin 
in tetany. In the thyroidless dog it is known that the glycosuric action of 
adrenalin is reduced. In dogs that have had only their parathyroids removed 
it is mostly increased, so far as a tetanic spasm is not induced by the injec- 
tion (Eppinger, Falta, and Rudinger). In the idiopathic human tetany 
Rudinger and / never found in the acute stage glycosuria following injec- 
tion of adrenalin; but on the contrary, as already mentioned, almost always 
a strong reaction of the cardiovascular apparatus. This dissociation of 
the action of adrenalin has its foundation chiefly in the increase of sugar 
consumption through the enormous vasoconstriction and eventually in 
the attack induced by means of injection. In the declining stage of tetany 
we find, contrariwise, frequently a distinct glycosuric action due to adrenalin. 
In parathyroidectomized dogs the assimilation limits for dextrose are 
regularly reduced. Falkenburg and R. Hirsch, and also Frank P. Underhill 
and Tadasu Saiki, found this after thyroparathyroidectomy and referred it TETANY 
203 
to the absence of the thyroid gland. This, however, leads to a heightening 
of the tolerance boundary. According to the experiments of Eppinger, 
Rudinger, and myself the glycosuria after thyroparathyroidectomy depends 
on the absence of the parathyroids. In a dog almost completely parathy- 
roidectomized we found that when a diet rich in starch was administered 
very large amounts of sugar would appear in the urine for a long time. After 
the extirpation of the pancreas and three parathyroids we found in many 
experiments a higher D to N quotient than could be obtained on extirpa- 
tion of the pancreas alone. In human beings ill with tetany we never found 
reduction of the assimilation limits for dextrose, although Kahn and I can 
adduce an observation that shows that also in human beings the insufficiency 
of the function of the parathyroids exercises an indirect influence on the 
function of the pancreas. In a case of Basedow’s disease complicated with 
tetany the test for alimentary glycosuria immediately after the tetanic 
attack yielded 4.1 gm. of sugar. Later, after the acute tetany had subsided, 
many tests for alimentary glycosuria resulted negative. In the literature 
is found only a statement of Miller that he observed transitory glycosuria 
after an attack of tetany. 
MacCallum and Vogtlin, and also we, saw the protein metabolism in para- 
thyroidectomized dogs appreciably increased. There do not exist similar 
investigations on human beings. There also occur regularly disturbances 
of the intermediate protein metabolism. MacCallum and Vogtlin found in 
thyroparathyroprivic dogs increase of the elimination of ammonia in the 
NH3N 
urme and of the quotient > and in addition increased creatinin elimi- 
nation. In human idiopathic tetany Kahn and / found in the acute stage 
the elimination of ammonia for the most part relatively and absolutely 
increased. The amino-acid fraction was for the most part normal; on the 
contrary, the peptid-N in our experiments was often even appreciably 
increased. Administration of glycocoll increased this value mostly only 
unessentially. Immediately after the decline of the acute tetany this value 
for the peptid-N was mostly still high, but distinctly lower than in the acute 
stage, or it had already become normal. Also the heightening of the ammonia 
value can apparently outlast for some time the acute stage. The find- 
ings described are to be distinguished from those in lesions of the liver in 
that in the latter the amino-acid-N is ordinarily increased as much as, or 
even more, than the peptid-N, and the administration of glycocoll almost 
always causes an increase of these factors. Perhaps these disturbances of 
the intermediary metabolism in tetany are the expression of a condition of 
nervous hyperirritability of the liver. 
Systematic investigations as to the gaseous metabolism in tetany have as 
yet not been made. That the exchange of calories in the acute stage, and 
especially in the severe attack is markedly increased, needs no especial investi- 
gation. More interesting would be the investigation of the basal metabol- 
ism in chronic tetany. Partially parathyroidectomized animals often show 
a severe cachexia; and often in human idiopathic tetany, cachetic mani- 204 
THE DISEASES OF THE PARATHYROID GLANDS 
festations later make their appearance {v. Frankl-Hochwart). The cases 
of relapsing tetany that Kahn and I observed all showed more or less dis- 
tinct signs of cachexia (see later the relations to the thyroid gland). Here 
there must be a profound disturbance of metabolism, as has been mentioned 
by Segale and others. 
The behavior of the calcium metabolism in tetany has been much studied. 
Stimulating were the observations of Sabbatani and Loeb. Sabbatani found 
that application of calcium salts to the surface of the brain reduced the 
excitability, application of sodium salts increased it; Loeb found that sub- 
stances that precipitate calcium heightened the excitability of the nerves. 
This holds true also for the vegetative nerves (R. Chiari and A. Frohlich). 
MacCallum and Vogtlin as well as Parhon and Orechie have tried to influence 
favorably the tetanic spasms of parathyroidectomized dogs by the subcu- 
taneous or peroral administration of calcium. Magnesium salts work directly, 
as do the calcium salts, but show in addition strong toxic action. Potassium 
salts increase the irritability. Quest had already stated before this that the 
brain of new-born infants, which is relatively slightly excitable, is very 
rich in calcium, but that later the calcium-contents of the brain reduces. 
He further states that diet poor in calcium makes the animal hyperexcitable, 
and that the brains of children after they have died of tetany are very poor 
in calcium. MacCallum and Vogtlin found the calcium-contents of the 
brain of parathyroidectomized dogs lowered, as well as those of the blood. 
The elimination of calcium through the urine and feces was increased. This 
last fact was also found by us. The same was also observed by Cattaneo. 
Neurath, who estimated the so-called active calcium in the blood of children 
with tetany by Wright’s method, found very low values. Investigations as 
to the calcium balance in children with tetany frequently show increased 
elimination of calcium (L. V. Iddo and Sarle, and others). Aschenheim has 
recently pointed out that there does not exist so much an absolute calcium 
poverty of the tissues as there does [an increase of] the relation of alkalies to 
earthy alkalies. He found in children who had died of spasmophilia an 
increase of this quotient just as in parathyroidectomized dogs. Finkel- 
stein and Rosenstern arrived at similar views. According to Rosens tern the 
administration of common salt to children brings forth anodal hyperexcita- 
bility, and indeed even laryngospasm. 
Experimental investigations show also that the function of the para- 
thyroids influences bone formation. Morel and Canal found in parathy- 
roidectomized dogs that the healing of fractures is delayed and the callus 
formation slowed. Erdheim showed that such callus is remarkedly poor in 
calcium. Leopold and v. Reuss found the skeletons of youthful parathyroidec- 
tomized rats poorer in calcium than those of the control animals. To a loss 
of calcium in the parathyroid insufficiency points also the finding of Schuller 
that the bones in chronic tetany show in the Roentgen picture a characteristic 
rarefaction of the trabeculae and marked atrophy, an observation that we 
could confirm in almost all the cases, in which we paid attention to it. We 
found this, however, in cases that had never had tetany. TETANY 
205 
Summarizing that which has been said as to the metabolism, we find that 
in the acute stage of tetany there exists an appreciable increase of the metabolism, 
that is related to very many factors of the same. As most probable, we may sup- 
pose that only in experimental, but also in human, tetany there exists an 
increased breaking down of protein with disturbances in the intermediary pro- 
tein decomposition, increased metabolism of carbohydrates, increased produc- 
tion of calories, and apparently also increased elimination of calcium. A 
part of these alterations in metabolism may well depend on increased irrita- 
bility in the vegetative nervous system. We may expect in the chronic 
stages of tetany alterations of metabolism that to-day we cannot well define. 
The trophic disturbances in tetany affect epithelial parts exclusively, 
the hairs, nails, skin, enamel, and ciliary epithelium. In chronic tetany there 
are frequent statements as to a thinned-out growth of hair (Hofmann, v. 
Frankl-Hochwart, and others). An acute exacerbation may be introduced 
with rapid falling out of the hair. Adler and Thaler in their experiments on 
dogs found the falling out of hair a direct premonitory symptom of tetany. 
Also Pfeifer and Meier observed in ectomized animals falling out of hair 
as the direct symptom of tetany. Speigler in a case of chronic tetany found 
that the thinned-out and very thin hair was split at the point {trichorrhexis). 
Also the nails frequently show trophic disturbances, they become brittle and 
there may occur complete necrosis that leads to casting off of the nails; rapid 
substitution occurs, however, after subsidence of the acute stage. In a new 
attack the process may be repeated. An instructive case is reported by 
Hofmann. It is that of a woman who had passed through five normal 
deliveries. After the fifth pregnancy, she developed tetany with distinct 
edema of the hands. The finger nails fell out. A year later tetany recurred. 
This time the hair fell out. After a year, new pregnancy and tetany; after 
the delivery again trophic alterations of the finger nails. After a half year, 
at the time of a new pregnancy, again tetany, with which was associated loss 
of nails and hair. In the tetany of children loss of the finger-nails seems 
to be very rare. Pineles found in the literature only one observation by 
Hofmann, in a three and one-half-year-old child. 
The skin of the face and of the extremities shows in acute cases a pufy 
appearance (angiospasm[?], see what is stated previously), causing a character- 
istic expression of crying. 
Pigmentations of the skin are rare. Kocher states that after total exci- 
sion of the thyroid gland in many individuals there occur, if the tetany symp- 
toms predominate, marked pigmentations progressing as far as bronzed skin. 
Of greatest interest is the formation of cataracts. Already Meinert had 
observed in tetany a case of cataract, and the first exact investigations began 
with Peters. Important information was furnished by Erdheim, Pineles, 
Zirm, Sperber, Bartels, v. Frankl-Hochwart, Schonborn, and others. The 
cataract of tetany is characterized by its very rapid development. It is not 
at all rare in children. It is especially frequent in the tetany of pregnancy, 
and in women between the ages of eighteen and forty years, as observed by 
Zirm and Sperber. In youthful individuals it occurs more frequently as 206 
THE DISEASES OF THE PARATHYROID GLANDS 
nuclear cataract, in older individuals as cortical cataract. Peters was the first 
to show that the cataract formation was brought about by degenerative 
changes in the ciliary epithelium. This caused a molecular concentration of 
the water in the chamber, thereby damaging the lens. Erdheim produced 
tetany cataract by parathyroidectomy in rats. We are indebted to Pineles for 
the information that the cataract formation occurs in all forms of tetany. 
Ranke on histological examination of the globe of the forty-nine- year old 
man who suffered with chronic tetany and cataract found optic neuritis and a 
characteristic degeneration of the pigment epithelium of the posterior sur- 
face of the iris, similar to that observed in diabetes mellitus. Pineles had 
already attached theoretic value to the circumstance that cataract formation 
could occur in tetany as well as in diabetes. 
Of recent date are the investigations concerning the disturbances in 
tooth formation. Erdheim first observed that there occurred in rats, one and 
one-half to two and one-half months after the operation, opaque spots on the 
anterior surface of the incisor teeth which gradually advanced toward the 
points with the teeth’s growth. Either the tooth breaks off at this point or 
the defect in the enamel heals, leaving behind a shallow groove. The tooth 
may also break in the alveolus, in which case suppuration of the latter occurs. 
Erdheim observed a deficient calcification of the dentine. Even the short 
cessation of parathyroid function that occurs in autotransplantation of the 
parathyroid is sufficient to determine the appearance of stripes poor in cal- 
cium in the dentine of young rats. An especial clinical interest to Erdheim’s 
studies is given by the investigations of Fleischmann. This worker held the 
view that the defect of enamel so commonly observed was due, not as was 
formerly supposed to rachitis, but to tetany. He points to the dispropor- 
tion between the frequency of rachitis and hypoplasia of the enamel. In 
rachitis are regularly found alterations in the dentine; in tetany, however, 
one always finds hypoplasia of the enamel leading to the formation of hori- 
zontal transverse surfaces. When frequent exacerbations of the tetany 
have occurred, are found numerous furrows below one another. Fleisch- 
mann investigated ten children who had suffered from tetany and found in 
all the above-mentioned hypoplasia, and indeed this was present only on 
those teeth which had been present during the course of the illness. Nearly 
all of the children had also had rachitis. Fleischmann points out, however, 
that rachitis lasts much longer than tetany, and also attains its acme much 
later. Fleischmann also finds support for his view in the statement of Fuchs 
that children with lamellar cataract almost always show hypoplasia of the 
enamel. In individuals with hypoplasia of the enamel, in whom nothing 
is known of their having had tetany, there may have existed a latent tetanic 
condition in early childhood. Very convincing is an observation of Spiegler 
in a case of recurring tetany, who had an attack every spring during eight 
years. In this case it was known that the tetany had first made its appear- 
ance at the end of the second year of life. All teeth whose crowns must 
have been formed at this time were normal, while the teeth whose crowns 
developed later showed defects of the enamel. An entirely similar case TETANY 
207 
was observed by Kahn and myself (Observation XXIII). Here were found 
on the canine and incisor teeth punctiform defects of enamel often arranged 
in parallel rows; the upper parts of the molars were partly broken off. The 
patient’s mother stated definitely that already in the first year of life, but more 
especially in the second and third years, he had spasms of the glottis and 
spasms of the hands, while a severe rachitis was added to the picture only 
in the third year. 
The above illustration (Fig. 29) shows the defects of enamel observed by 
us in another case. 
The connection between tetany and defects of the enamel is by all this 
evidence put on a sound basis; and I shall not discuss the possibility of these 
defects being brought about by other causes. 
Fig. 29.—Enamel defect in tetany. 
Perhaps the conjunctivitis accompanying tetany may also be regarded as 
a trophic disturbance. De Quervain observed that parathyroidectomized 
dogs often suffer from severe conjunctivitis. I saw this almost regularly in 
parathyroidectomized dogs and cats. In the case previously mentioned (Ob- 
servation XXIII) it happened that the conjunctivitis regularly became exacer- 
bated with the aggravation of the tetany. 
Yet a few words with regard to growth disturbances in tetany. Schuller 
investigated five cases of rachitis tarda and found, besides pronounced Chvo- 
stek’s symptoms, remaining behind in growth, delayed ossification and dentition, 
and marked atrophy of the bones; the last was also found in an exactly investi- 
gated case of the chronic recurring form of tetany, and also in three juvenile 
cases of occupation tetany. On the contrary, a case of tetany after strum- 
ectomy, and some cases of tetany of maternity showed normal relations. 
Schuller points out that tetany may also occur in combination with osteomal- 
acia, and believes that tetany may induce rachitic alterations before the 
cessation of bone growth, and osteomalacia after it. A similar view is held by 
Erdheim on the basis of histological examination of the skeleton, and especially 
of callus formation in rats after parathyroidectomy. Kassowitz had before 
this supposed a casual connection between rachitis and tetany. 208 
THE DISEASES OF THE PARATHYROID GLANDS 
This view I would not subscribe to. It is to be expected that high-grade, 
and especially, long-continued, absence of parathyroid function in youthful 
life would lead to disturbances in growth of bones. We also saw certain cases 
of chronic recurring tetany, in which the individuals were remarkably small 
and showed retarded epiphyseal closure. The disturbance has certainly 
nothing to do with true rachitis. Sometimes, indeed, it is difficult to separate 
the two conditions, as combination of rachitis and tetany are extremely fre- 
quent, and according to Escherich, not less than 80-90 per cent, of all tetany 
in children is associated with rachitis. There are certainly, however, cases 
of tetany without rachitis, and cases of rachitis with tetany constitute only 
an extremely small percentage of the whole number of cases. Also the rare- 
faction of the bone trabecuke described by Schuller is not characteristic for a 
withstood tetany, for we have found them in individuals who have not had 
tetany. Experimental experiences speak, too, against a direct connection 
between rachitis and tetany. Iselin observed remaining behind in growth in 
parathyroidectomized rats; and similar observations have been made by 
Jeandelize, Moussu, and Vassale and Generali on other species of animals. 
Iselin’s animals remained well proportioned, however, and showed no bone 
perversions. 
I decline to subscribe to the doctrine of a connection between tetany and 
osteomalacia. The number of cases in which the diseases coexisted is not large. 
Blaziceck, Weber, E. Freund, Schultze, Hecker, have reported such cases. An 
exception in this respect is only the markworthy observation of Krajewska 
from Bosnia; she found tetany present among one hundred fifty cases of osteo- 
malacia no fewer than forty-eight times. All forty-eight cases affected puer- 
peral women. 
Hence there may be regarded as the symptom belonging to chronic tetany 
at most the rarefaction of the bone trabeculae and the atrophy. It is shown 
by the statistics of late years that a chronic tetany existing from earliest 
youth may damage the development of the entire body. Disturbances of 
the development of speech and of the intelligence are especially frequent 
(see prognosis). The development of the sexual glands does not appear to 
suffer; in isolated cases we can find at least no remaining behind in sexual 
development although tetany spasms may have existed for years, from early 
youth or from just at the time of puberty. 
The symptomatology of tetany would be incomplete were I to neglect to 
mention a series of symptoms that depend on a functional disturbance of other 
ductless glands, but are very frequently combined with tetany. 
As has already been mentioned, Kocher states that after total extirpation of 
the thyroid in human beings, there occur in individuals in whom the symptoms 
of tetany predominate, marked pigmentations progressing as far as bronzed 
skin. Probably in such chronic cachectic conditions there is a reduction in 
the activity of the chromaffin tissue. Oftenest occur symptoms that depend on 
an alteration of thyroid function. Not so very rare in chronic tetany are 
symptoms of myxedema, v. Frankl-Hochwart, in looking over his cases, found 
symptoms of myxedema as many as thirteen times among twenty-six cases. PATHOGENESIS OF TETANY 
209 
We saw this alteration once. These myxedematous alterations of the skin 
occurring in chronic tetany should not be confused with the puffiness of the 
face previously described, or with the edema of the backs of the hands that 
occurs in the acute stage, which phenomena are properly regarded as 
angiospasmodic. 
Kahn and / have reported an observation, which in the clinical sense is 
not of less significance. In a series of our own cases we saw develop in the acute 
stage or immediately at its close a slight hyperthyrosis. This consisted 
especially in tachycardia, headache, slight rise of temperature, increase in 
blood-pressure, sweats, slight tremor, and slight diffuse enlargement of the 
thyroid. The connection between our observations and those of Frankl- 
Hochwart is perhaps this: That in many cases of tetany at the conclusion of the 
acute stage or during an acute exacerbation there occurs an increase of thyroid 
activity and even an appreciable enlargement of the thyroid gland, which is 
succeeded, in the stage of chronic tetany, by a slight degree of thyroid insuffi- 
ciency (see the section on the idiopathic form of tetany). 
Pathogenesis of Tetany 
It seems to me suitable first to set forth in detail the pathogenesis of para- 
thyroprivic tetany; and then later in the exposition of the individual forms of 
tetany, to speak of their etiology separately. 
As I have already mentioned at the beginning, to-day we may regard as 
established that experimental tetany depends on the loss or marked damaging 
of the parathyroid glands. This holds good for all species of animals. The 
course of tetany in different animals is, however, different. In some after 
total extirpation of all the parathyroids there occurs an acute tetany, which 
after a short time leads to death. In others, for instance in monkeys, the course 
is chronic. Does the complete loss of parathyroid glands lead to tetany 
always ? 
Here should be mentioned that all authors are agreed that older animals 
resist the operative attack more readily than young ones. Important in 
this respect are the investigations of Iselin, who found that the young of par- 
tially parathyroidectomized rats are especially sensitive to the extirpation of 
the parathyroids, and die in a few hours with fulminating epileptiform seizures. 
Moreover, there are numerous statements that the simultaneous extirpation 
of thyroid gland and parathyroids is better borne than isolated parathyroidec- 
tomy. Many hypotheses have been advanced to explain this fact, a fact that 
our own investigations fully substantiate. The most natural of these seems 
to me to be the conception that on the simultaneous extirpation of the thyroid 
glands the metabolism and with it the excitability of the entire nervous system 
is reduced, so that the effect of the lack of the function of the parathyroid 
glands it then reduced in its action. On the other hand, we know that proce- 
dures of the most diverse kinds and conditions that make great demands on 
the nervous system accelerate the outbreak of tetany or allow latent forms to 
pass over into the acute forms. If we here recognize too that the influences 210 
THE DISEASES OF THE PARATHYROID GLANDS 
that may modify the course and acuity of the process may be manifold, we may 
well assume that the complete loss of all parathyroids leads to death in all species 
of animals, under the manifestations of an acute or more chronic tetany, hence 
that the loss of the parathyroid function is incompatible with the long continua- 
tion of life. I would not off-hand relinquish this assumption on account of the 
quite isolated contrary statements. Haberfeld and Schilder state that rabbits 
in which at first the four parathyroids are removed, and later the thymus gland 
with the accessory thyroid, continue to live. Continuous serial sections show 
the absence of any parathyroid tissue. Wiener even asserts that of forty-five 
parathyroidectomized animals, 20% did not show any manifestations of 
tetany. In my own numerous experiments on dogs, cats and rabbits, I have 
never seen an animal survive. The unconditional importance of the function 
of parathyroids for life is also held by Biedl, Hagenbach, and others. As long, 
therefore, as no further statements as to this question exist, I would still believe 
that in the experiments of Haberfeld and Schilder and of Wiener that have 
been mentioned, accessory parathyroids may have escaped demonstration. 
As regards the mechanism of parathyroid function, numerous opinions have 
been promulgated. In the foreground stands the views as to the detoxicating 
function. The parathyroids would seem to furnish to the blood-path a hor- 
mone which renders innocuous poisons that exist in the body. Originally the 
thyroid gland was looked upon as the organ preparing the poison ( Vassale and 
Generali). Lately Pineles, Pfeiffer and Meyer, Oni and Beste, Berkeley and Beebe, 
and most recently, especially Wiener, have turned attention from the thyroid 
and have assumed that in the bodies of animals with tetany there circulates a 
specific poison or one originating otherwise in metabolic processes. 
It is impossible for me to enter intimately into the numerous experiments 
that have been instituted for the establishment of the hypothesis. I would 
mention only the most important. Pfeifer and Meyer state that in the sera 
collected in the death agony, of seventeen dogs affected with tetany, they have 
found in six a toxic principle which injured partially parathyroidectomized 
mice, while the sera of normal dogs were inactive. The fact that animals with 
tetany are very sensitive to the various procedures tends to make one sceptical 
as to the value of these experiments. Ceni and Besta have tried to obtain an 
immune serum, injecting the serum of totally ectomized dogs into rabbits 
and goats, and reinjecting the sera of these into the tetanic dogs. Almost 
regularly they cured the acute manifestations, although none of the animals 
remained alive. H. Wiener followed a similar course for experimentation, 
except that he used cats both for immunization and for treatment. In some 
animals (not all) he succeeded in combating the tetanic symptoms permanently. 
The residual thyroid glands of these animals were examined and found to con- 
tain no piece of parathyroid tissue. The assumption of Wiener that in cats 
there are no accessory parathyroids must, in consideration of the importance 
of such experiments, first be shown by painstaking investigations. The 
doubt is increased by the statement of Wiener that in some experiments 
also the injection of entirely normal serum permanently set aside the 
tetanic symptoms. PATHOGENESIS OF TETANY 
211 
Although, up to the present, the detoxication theory of tetany cannot be 
refuted, it does not seem to me to have been satisfactory. The assumption 
of a detoxicating function has, up to the present, played a great role in'the 
pathology of all the ductless glands. However, it seems to me that up to the 
present there does not exist a single fact that strictly demonstrates this supposi- 
tion. As with the other glands, so with the parathyroids, another supposition 
seems plausible, a supposition that was first suggested by Rudinger and myselj 
and then further developed, with modifications, by Kahn and myself. 
The cardinal symptoms of tetany depend on increased excitability or abnor- 
mal conditions of irritability of the nervous system. As to the seat of the 
abnormal irritability we may say the following: Schijj had already shown that 
in tetany tremors and spasms ceased after the section of the peripheral nerves. 
Rudinger and / have repeated these experiments, and have modified them in 
various ways. When we had extirpated the parathyroids in cats and at the 
same time had cut the sciatic nerve, immediately below its exit from the pelvis, 
no hyperexcitability made its appearance in the nerve peripherally from the site 
of the section; much more did the nerve gradually become excitable to the gal- 
vanic current in about the same time as after the section in normal animals.1 
If, however, we first obtain our tetany through parathyroidectomy and then 
transect the nerve when it had already become hyperexcitable, we find that 
the hyperexcitability continues for some time, and then only gradually passes 
through a period of normal irritability (with normal electrical reaction) into 
the condition of non-excitability. In some experiments it takes nine days 
before this condition is reached. From this, in reliance on former experiments 
of Frdhlich and Lowi on nerve-muscle preparations of the octopod Eledona 
moschata, we have concluded that under normal circumstances the nerve is 
supplied [loaded, stored, ausladen] from its trophic center, the ganglion-cell, 
with an as yet unknown indefinite substance, and that separation from this 
center is followed by a gradual loss of this supply and by degeneration, and that 
in tetany there exists an abnormally high loading of the ganglion-cell or of 
whole neuron proceeding from it. Biedl had set forward to this experiment the 
objection that pressure on the nerve below the point of severance can no longer 
elicit muscular spasm. According to Schlesinger’s explanation of Trousseau’s 
phenomenon, however (reflex-process on account of irritation of sensory nerves), 
nothing else than this is to be expected. That, moreover, no muscular spasm 
appears any longer in the extremity in question is not remarkable, as every 
new impulse from the ganglion-cell, which is always storing anew, is lacking. 
Further investigations have shown, moreover, that an association of the 
ganglion-cells of the spinal cord with higher centers is not necessary to render 
possible in tetany or to obtain in it the abnormal loading of the ganglion- 
cells. Already Munk had stated that after transection of the spinal cord the 
spasms in the paralyzed hind-extremity persisted, and Horsley and Lanz have 
1 In more recent investigations MacCallum (Journal of the American Medical Association, 19, 
1912, p. 3T9) found that the peripheral part of the nerve also becomes hyperexcitable, if it had been 
cut off before the parathyroid had been excised. I cannot state off-hand the explanation for the 
divergence of our observations. 212 
THE DISEASES OF THE PARATHYROID GLANDS 
since ascertained that after extirpation of the cortical motor areas on one side, 
the tetany may persist on the other half of the body. 
Our own investigations showed that after section of the spinal cord in 
animals suffering with tetany the hyperexcitability in the paralyzed hind- 
extremities remained exactly as in the fore-extremities until death. BiedVs 
statement that there appeared in the paralyzed extremities lightning-like 
contractions and fibrillary muscular twitchings, but that all traces of a toxic 
rigidity were absent, are in direct contradiction to Muniz’s statement and our 
own. In addition we could most definitely assure ourselves that we saw in 
the paralyzed extremities, in certain cases, in cats and dogs, after complete 
section of the spinal cord, the occurrence of most intense spasms in the para- 
lyzed extremities in the acute attack. Moreover, the occurrence of such spasms 
was not at all necessary. The exact demonstration of the galvanic hyperexcita- 
bility of the nerves of the posterior extremities, which develop even when the 
transection of the spinal cord has been done at the same time with the extirpa- 
tion of the parathyroids, shows with certainty that the cause of the tetanic 
changes lies in the ganglion-cells of the spinal cord, and not, as MacCallum and 
Biedl believe, in the higher centers. By this we do not mean to assert that in 
tetany the higher centers do not likewise share in the condition of hyperexcita- 
bility, and that the course of the twitchings in the tetanic attack may not under 
circumstances be concomitantly influenced by the centers that lie higher. 
Just as the motor nerves maintain their hyperexcitability, we may assume 
that the same is true of the sensory and vegetative nerves. It is very probable 
that the neurons of different orders become involved in a definite sequence. 
In the slight grades of human tetany it is especially the neurons of the first 
order that are affected. Here the occurrence of, as a rule, bilateral spasms, 
convulsions, and pains, points to the spinal cord or to the medulla oblongata 
as the seat of the affection. In the acute stage the vegetative nervous system 
is also affected concomitantly. In the severe cases phenomena tend to occur 
that point to involvement of still higher centers. Forced movements point to 
the mid-brain, disturbances of equilibrium to the cerebellum, epileptiform 
convulsions to participation of the motor cortical areas, and psychoses that of 
the cortex in general. A similar train of thought was followed by de Quervain 
in 1893, and later by Ast, and others. In children we actually find a mounting 
from cord to cerebrum, with increasing intensity. Here, as Escherich empha- 
sizes, the higher centers are more frequently and more strongly involved. The 
retrogression of the condition tends to follow a reversed series of involvements. 
Here I quote verbatim the conclusions arrived at in the work of Kahn 
and myself. “In tetany there exists an abnormal irritability of the motor, 
sensory, special sensory, and vegetative ganglion-cells that from here as a 
starting-point involves the entire neuron. It is principally the peripheral 
neurons that are found in this state of hyperirritability. Neurons of higher 
orders may, however, be concomitantly involved. This abnormal state 
expresses itself chiefly in a heightened excitability to mechanical, electrical, 
or chemical irritants (latent tetany). Nevertheless the abnormal tension in 
the ganglion-cell, either per se or through any other occasioning factor, may PATHOGENESIS OE TETANY 
213 
lead to a heightened irritability in the organs supplied by it, and may become 
manifest in tonic spasms and fibrillary twitchings of the transversely striated 
muscles, in paresthesias, in tonic contractures of the smooth muscles, in height- 
ened secretional processes, etc. 
“ Thereby is found a partial unloading of the ganglion-cells, although 
apparently not in very great degree, so that the hyperexcitability is still present 
after the attack. This conception explains why at one time an occasioning 
factor may call forth a spasm, while a short time afterward it is inactive, per- 
haps becoming active again on the next day, and why the spontaneous condi- 
tion of hyperirritability in tetanies is subject to such significant rapid change. 
This behavior may be observed especially beautifully on animals that have been 
parathyroidectomized; these dogs and cats may be the victims of the most 
severe spasms, and yet a few hours later may play as vivaciously as ever. Only 
the exact investigation of the electrical and mechanical hyperexcitability now 
affords knowledge as to the latent tetanic condition. This view also makes 
appear intelligible the fact that certain nerve territories that have immediately 
met with numerous irritations (peripheral neurons) are especially preferred, and 
that the conditions of irritability in the different nerve territories are of differ- 
ent strengths, and may be subject to considerable change. 
“In what relation do the parathyroids stand to the hyperexcitability or 
to the condition of excitability of the ganglion-cells? ‘Everywhere where 
excitation is, is also present inhibition’ (Meltzer). According to Bechterew, 
the inhibitory processes are to be regarded as an indispensable protective 
arrangement of the central nervous system. The normal condition of irrita- 
bility of the ganglion-cells is guaranteed only by the finest regulation of increase 
of activity [Forderung] and inhibition. Falta and Rudinger have expressed 
the opinion that the parathyroid glands exercise inhibitory influences on the 
ganglia by a hormone, and that the diminution or complete withdrawal of this 
inhibition leads to an abnormal loading of the cell with energy. 
“We do not know anything more intimately as to the action of this hor- 
mone. It is not impossible, however, to bring this hypothesis into combination 
with that developed by MacCallum and Vogtlin, by our following the assumption 
of these authors that the parathyroid glands influence the calcium metabolism 
in the central nervous system by means of a hormone. The hormone of the 
parathyroid glands might thus be regarded as an assimilatory hormone, with 
the withdrawal of which there occurs loss of calcium in the ganglion-cells and 
hyperirritability of these.” 
The details up to the present confine themselves to the mechanism by which 
insufficiency of the parathyroids leads to tetany; they set forth that all forms 
of tetany depend on an absolute, or at least, a relative insufficiency of the 
parathyroids. The different causes of parathyroid insufficiency will be dis- 
cussed later, with the exposition of the different forms of tetany and of the 
pathological anatomy. 
We shall add a few words as to the relation of myotonia, epilepsy and 
eclampsia to tetany. The occurrence in tetany of symptoms similar to those of 
myotonia is, as already mentioned, not rare. The fact that they are also 214 
THE DISEASES OF THE PARATHYROID GLANDS 
observed in experimental tetany, ensures relationship to tetany. The inten- 
tion spasms may be explained by the fact that the will impulse furnishes the 
determining factor for a tetany spasm. In addition there often occurs, however, 
pitting on percussion and the myotonic electrical reaction. On the other hand 
there occur true cases of myotonia congenita to which are superadded the 
clinical picture of tetany. 
In these cases,as v. Orzechowski points out, the symptoms of tetany are 
only of a slight grade; with the decline of the tetany, the myotonia remains. 
This coincidence of tetany and myotonia has been sufficient for Lundburg 
and others to ascribe the cause of myotonia to an insufficiency of the para- 
thyroids. The assumption seems to me to be fully unsubstantiated, as in 
true myotonia all symptoms, that according to experimental experiences we 
have come to regard as the cardinal symptoms of parathyroid insufficiency, 
are absent. Myotonia is an affection of the muscles (Erb, Schultze and Schief- 
fendecker and others). The occurrence of symptoms similar to those of myo- 
tonia in tetany perhaps finds its explanation in a definite alteration of the 
metabolism. It is remarkable that just those animals in whom the thyroids 
and parathyroids have been removed show these manifestations. Further- 
more, there is a case of Hoffmann’s in whom the myotonic symptoms disap- 
peared on the administration of thyroid gland, and in whom they reappeared 
after withdrawal of the treatment, while the tetanic symptoms were not essen- 
tially affected. Perhaps there is a certain relation between myotonia and the 
high-grade mechanical hyperexcitability of the muscles such as is not rarely 
seen in cachectic conditions. 
As for epilepsy, we have already mentioned in the consideration of the 
symptomatology that tetany may develop on an epilepsy that has lasted for 
a long time, and that tetany and epilepsy may develop simultaneously in 
individuals not previously epileptic, and indeed may improve simultaneously. 
In many cases the epileptic convulsions occurring in severe tetanic attacks 
may remain the sole manifestation of epilepsy. It should further be men- 
tioned that Chvostek’s phenomenon is not rarely elicitable in epileptics, and 
that Fleischmann and Poetzl as reported by Redlich found twenty-eight times 
defects of the enamel among sixty epileptics, a fact that perhaps indicates that 
individuals who in early years have passed through tetany, later often become 
epileptics. Most important for the relationship between tetany and epilepsy 
are the cases of parathyroprivic tetany with epilepsy. Redlich has collected 
twenty such cases from the literature and adds a case of his own. The frequent 
coincidence of tetany and epilepsy shows that this combination is “no acciden- 
tal happening” (v. Frankl-Hochwart, Schultze, Redlich). As to the intimate 
connection we really know nothing certain. Westphal supposed that tetany 
and epilepsy depended on the same toxic cause, which, as Chvostek later elabo- 
rated, led both to alterations in the central nervous system and to functional 
disturbances of the epithelial bodies. Pineles supposed that the toxin of tetany 
produced a latent predisposition to epilepsy; Curschmann that it increased the 
excitability of the cortex and subcortex. Experimental pathology has as 
yet furnished no reliable evidence. In a cat in which Kreidl extirpated three PARATHYROPRIVIC OR TRAUMATIC TETANY 
215 
parathyroids, epileptic attacks regularly followed operations on different 
parts of the cortex. Redlich could not confirm the results of this experiment 
when he repeated it. Only in one experiment, an operation on the brain cortex 
after total thyroparathyroidectomy, did he notice the simultaneous occurrence 
of severe tetanic and severe epileptic attacks. 
Attempts have also been made to refer epilepsy without tetany to an 
insufficiency of the parathyroids. As was to have been expected, pathological 
anatomy did not substantiate this hypothesis. Erdheim examined the para- 
thyroid glands in two cases of status epilepticus; in one they were entirely 
normal and in the other they were lightly sclerotic. Claude and Schmiergeld 
found no constant change of tissue in thirteen cases. 
[Undoubtedly we should speak of the epilepsies rather than of epilepsy— 
but we might, by the same token, speak of the tetanies. It should be mentioned 
in this connection that there is scarcely a ductless gland in the body with 
which an attempt has not been made to bring epilepsy into relationship. (See 
addendum to chapter on the thyroid gland.) Thus one of the favorite glands 
found at fault in a certain kind of epilepsy is the pituitary body. Perhaps 
however at least the so-called “functional” (as opposed to “organic,” not 
connoting “hysteria” here) epilepsies, if not the “organic,” may be found to 
have at their base a disturbance of metabolism, in which blood-changes akin 
to those found in tetany may be revealed. Perhaps it will be found that in 
epilepsy the central nervous tissues especially show increased hyperirritability, 
in tetany, the peripheral nerve tissues.—Editor.\ 
The relationship of tetany to eclampsia has not yet been cleared up in a 
satisfactory manner. In the years of childhood tetany may occur under 
the guise of eclamptic attacks, as has been mentioned already. It has been 
held that children who have suffered with eclampsia, later become epileptic. 
Birk could not find this in his material, to which are opposed the statements of 
Potpetschnigg. The eclampsia of adults is as a rule to be separated from tetany; 
for in eclampsia the cardinal symptom of parathyroid insufficiency, the gal- 
vanic excitability, is absent. Erdheim could not corroborate the statements 
of Pepere and Zanfrognini, who found a lessened number of parathyroid glands 
in their cases of eclampsia. In four cases of eclampsia examined by Erdheim 
the parathyroids were normal, except for the fact that they were very hypere- 
mic and were permeated with small hemorrhages, which manifestations are 
certainly to be regarded as secondary. [It is interesting in this connection to 
record that Bergstrand1 has reported that in 10 of 60 cases of kidney disease, the 
parathyroid glands were enlarged. This fact is mentioned here without com- 
ment.—Editor.] 
FORMS OF TETANY AND PATHOLOGICAL ANATOMY 
1. The Parathyroprivic or Traumatic Tetany 
It was first noticed by Nathan Weiss that in Billroth's clinic that extirpation 
of the thyroid gland was often followed by tetany. Since that time the litera- 
1 Bergstrand (H.). The parathyroid bodies and Bright’s disease. Acta medica Scandinavica , 
Vol. LVIII, Fasc. VI, Jan. 14, 1921, pp. 644-649. 216 
THE DISEASES OF THE PARATHYROID GLANDS 
ture as to this subject has grown enormously. The question is handled with 
especial thoroughness in the publications of v. Eiselsberg and Kocher. v. 
Eiselsberg in his “Diseases of the Thyroid Gland” publishes a classic description 
of tetany after extirpation of the thyroid gland. In Vienna tetania “strumi- 
priva” was observed much more frequently than in Bern. Among forty cases 
of total extirpation of the thyroid gland, tetany was seen by Kocher only nine 
times, of which number only three were pronounced cases; among thirty 
cases of partial extirpation only six were acute tetany; among ninety-seven 
operations in Basedow’s disease, only five were tetany; one case of ligation 
of all four arteries supplying the thyroid gland led to peracute tetany. 
Epileptiform tetany has been observed by v. Eiselsberg, Kocher, and 
others, in the wake of partial extirpation [of the thyroid gland]. Originally 
tetany was attributed to the failure of the thyroid gland. With the awak- 
ening knowledge of the significance of the parathyroid function were heard 
loud voices referring thyroid-gland tetany to the simultaneous damaging or 
removal of the parathyroids. Fundamental for this view are the investigations 
of Pineles, and of Erdheim. The latter observed three cases that had died of 
more or less acute tetany after strumectomy. In the first case, which had 
shown a more chronic course, the entire throat portion was cut in the serial 
sections; it was found that all four parathyroids were missing, although two 
small accessory parathyroids were found in the midst of the thymus tissue. In 
both the other cases, which had pursued a more acute course, parathyroids 
capable of functionating were not to be found. Erdheim pointed out that the 
great frequency of strumiprivic tetany in Vienna had its explanation in the 
fact that there the operations on the thyroid gland were conducted according 
to the old methods, while Mikulicz’s wedge resection or Kocher’s resection 
enucleation are rather adapted to avoid the parathyroids. However, the genius 
loci must not be entirely overlooked in the explanation of the fact. 
To-day, when we are well informed as to the significance and topography 
of the parathyroids, tetany after operations belongs to the greatest of rarities. 
A preparatory search for the parathyroids is not necessary; sufficient is adher- 
ence to the propositions of Pineles and of Erdheim to let remain both the lower 
lobes; search for the parathyroids is directly indicated only when in malignant 
struma, it becomes necessary to remove the entire thyroid gland, v. Eiselsberg 
has reported a case in which the greater part of the thyroid gland was removed 
for malignant adenoma. Myxedema developed, and retrogressed after the 
appearance of metastases in the sternum. Extirpation of these metastases 
(healing by secondary intention) was followed by a recurrence of the myxedema- 
tous symptoms and by tetany. Erdheim explains this case by the fact that 
at the first operations there was left behind one of the lower chief parathyroids, 
and that this became sacrificed at the second operation. 
The etiology of the thyroprivic tetany is thus clear. This form of tetany 
depends on the loss or the damaging of the parathyroids at the operation. 
Proescher and Diller report a case of traumatic tetany in the adult. A 
young man developed typical tetany eight days after a severe blow. At 
autopsy there were found numerous small fresh hemorrhages in the parathyroids, TETANY IN INFECTIOUS DISEASES AND INTOXICATIONS 
217 
which were in addition hypoplastic. Belonging to traumatic tetany are also 
numerous cases of the tetany of sucklings, as we shall see later in the section 
on tetany in children. 
2. Tetany in Diseases of the Thyroid Gland 
Cases of tetany in myxedema are rare. They are strikingly frequent, 
combined with epilepsy (cases of Stewart, Schonborn, and myself). 
Cases of thyroiditis with tetany were observed by v. Eiselsberg, and Kocher. 
Although there are no pathologico-anatomical investigations, yet it may 
readily be supposed that acute inflammatory or sclerosing processes that attack 
the thyroid 'also involve the parathyroid in sympathy. In strumous degenera- 
tion of the thyroid gland the parathyroids associated with the capsule may 
become involved and thus are brought to atrophy. Such cases have been 
reported by Steinlechner, Fraisseix, Hirschl, Marinesco, Jacobi, and others. 
I shall speak in the consideration of idiopathic tetany of the triad described by 
v. Frankl-Hochwart—tachycardia, tremor, and Chvostek’s symptoms (II and 
III), with struma and vasomotor excitability. This condition was called 
“tetanoid” by v. Frankl-Hochwart (see above for the consideration of the hyper- 
thyrosis in tetany). 
3. Tetany in Infectious Diseases and Intoxications 
Tetany has been observed in the most diverse infectious diseases. Most 
quoted is the frequent association of tetany in epidemics of typhoid fever 
(Aran and Rabaud). Tetany has also been observed in angina, influenza, 
acute articular rheumatism, croupous pneumonia, and many other infectious 
diseases. For the most part these cases occur in places where tetany is common 
and during the time of the occurrence of tetany. Therefore it is very probable 
that in the majority of these cases the infectious disease constitutes only the 
determining factor, that no form sui generis is present, but that these cases 
belong to the idiopathic tetany to be described later. At all events it is not 
improbable that a generalized infectious process would affect also the parathy- 
roids, and lead to infiltration or at least to parenchymatous degeneration of 
these organs, thus temporarily deranging their function. 
In this category belong the cases of tuberculosis of the parathyroids. 
There have been already published numerous statements as to the occurrence 
of this condition (Benjamin, Carnot and Delion, Pepere, Konigstein, Stumme, 
Schmorl and Eggers). Carnot and Delion, and Pepere, observed typical tetanic 
symptoms in phthisis, in the days immediately preceding death. Stumme 
observed Chvostek’s phenomenon. These findings are certainly interesting in 
consideration of the frequent occurrence of Chvostek’s phenomenon in tubercu- 
losis, mentioned previously. 
We can regard the cases that occur in poisonings as a less independent 
group. The most diverse poisons, such as ergotin, phosphorus, carbonic oxide, 
spermin (Oppenheim), lead, morphine, chloroform, etc., may lead to an outbreak 218 
THE DISEASES OF THE PARATHYROID GLANDS 
of tetany. The assumption that the poisoning constitutes only the determining 
factor has a firm basis in the investigations of Rudinger. Rudinger first deter- 
mined that in cats the peroral administration of calomel, the subcutaneous 
administration of morphine, atropine, tuberculin, and ergotin, and the inhala- 
tion of ether does not influence in any way the electrical excitability. After 
these animals had been placed in the condition of latent tetany by a partial 
parathyroidectomy, the administration of these poisons led to spasms. 
4. Idiopathic Tetany (Occupation Tetany) 
In the description of this form I chiefly follow the exposition of v. Frankl- 
Hochwart. Idiopathic tetany shows the characteristic that it chiefly occurs in 
certain localities, and that it shows an epidemic-like increase during certain 
months. The last observation was first made by N. Weiss and v. Jaksch. 
The statistics of v. Frankl-Hochwart from the years 1880 to 1905 embrace five 
hundred and seventy-six cases (among which, however, only five hundred and 
twenty-eight were cases of occupation tetany). Of these occurred in 
Jan 66 Apr in July 12 Oct 10 
Feb 88 May 52 Aug 9 Nov 15 
Mar 137 June 36 Sept 9 Dec 31 cases 
The especial predisposition of the followers of various occupations was 
first mentioned by v. Murdock, later by von Jaksch, Mader, Hofmann, Schultze, 
and others. It is especially cobblers and tailors that become affected with 
tetany. Among five hundred twenty-eight cases of v. Frankl-Hochwart were 
two hundred twenty-three cobblers, one hundred seventeen tailors, thirty-eight 
carpenters, thirty locksmiths, thirty turners and the remainder were divided 
among the other occupational classes. In women, it is especially the maids 
[i.e., lady’s maids] that become affected (thirty-two of ninety-nine female cases). 
Also soldiers become affected with it not at all rarely (Mattauschek). 
Another characteristic of occupation tetany is as has already been men- 
tioned that it prefers certain cities. It is most frequent in Vienna, Heidelberg, 
and is not rare in Budapest; it is, however, especially the lead workers who be- 
come its victims (Jakobi). Moreover, its epidemic extension presents variations. 
For instance it was very frequent in Paris in the years 1830-1860. Since that time 
it has been very rare there. In Heidelberg also according to the most recent 
statement of Schonhorn has it become rarer. In the other cities that now harbor 
it, it shows a large increase in certain years. Thus Mattauschek observed an 
epidemic among soldiers of the Vienna garrison in the year 1896. Outside 
these cities, tetany is sporadic nearly all over. In several places, small epi- 
demics have been observed. 
Idiopathic tetany shows a great inclination for relapses. After the first 
attack it passes over in the latent stage, and tends to recur the next year at the 
time for tetany (acute relapsing form of tetany, v. Jaksch). There is in addition 
a chronic form in which the disease never entirely disappears. The first form 
may pass over in the latter (see prognosis). IDIOPATHIC TETANY 
219 
Concerning the etiology of idiopathic tetany we know nothing that is certain. 
The endemic-epidemic occurrence, as is intelligible, has a priori given occasion 
to the thought of an infection. This is supported by the increase in temperature 
that occurs in the acute stages; I mentioned before that this is rather due to 
disturbances in the regulation of heat, which may serve as a partial manifesta- 
tion of the irritable condition of the vegetative nervous system; it may be said 
it occurs to a much greater degree after parathyroidectomy. Recently A. 
Fuchs has pointed out the resemblance of the clinical pictures of tetany and 
ergotism (typical form of spasms, paresthesias, trophic disturbances, cataract 
formation, epilepsy, psychoses, etc.), and is inclined to refer occupation tetany 
to poisoning with bad corn. Biedl comments on this hypothesis, stating that 
there is formed in the putrefaction of histidin an amino-base (imidoazolylethyl- 
amin) that is identical with the active agent in ergotin. I shall assume an 
expectant attitude with regard to Fuck’s hypothesis, as insufficient facts are 
at our command. 
Very important for the etiology of idiopathic tetany appears to me a contri- 
bution by McCarrison. In certain valleys among the Himalaya mountains 
exists much epidemic tetany, and indeed just in those places where there is 
epidemic goiter. The disease affects most solely women, and the only man in 
whom McCarrison observed it was not affected with goiter. The epidemic of 
tetany takes on in numbers in spring, as with us, and is increased during preg- 
nancy and lactation. The goiter that predominates in this locality is of a 
marked degenerative character. Numerous cases of tetany observed show 
also signs of an incomplete myxedema; very noteworthy is also the statement 
that persons that suffer from tetany become free of this affection when they go 
into tetany-free districts, and finally reacquire the tetany when they return to 
the original spot. In the light of this observation seems to me important the 
fact that our localities for tetany, Vienna and Heidelberg, show an especial form 
of goiter in the clinical sense, further the fact already mentioned that v. Frankl- 
Hochwart has observed that a great number of cases of tetany later show distinct 
symptoms of myxedema, and finally the fact that Kahn and / have described 
the observation that manifestations of a slight hyperthyrosis and thyroid swell- 
ing can develop in the acute stage, or immediately at the close of the acute 
stage. As tetany is not frequent throughout in any goiter districts—in Steier- 
mark and Tyrol it practically is absent, and in Switzerland very rare—we may 
suppose that not every goiter noxus may bring about idiopathic tetany, but 
an especial goiter noxus or a noxus that is similar to the goiter noxus. But even 
such an assumption is, as I fully know, not satisfactory in certain directions. 
It does not explain why tetany is so frequent in the springtime nor why certain 
occupations are preferred in such a striking manner. I believe moreover that 
it would be worth while to pursue the problem further. 
5. The Tetany of Children 
The tetany of children is characterized by its great multiformity of manifes- 
tations. The assumption of the collectivity of these manifestations is of recent 
date. In 1887 Cheadle had already stated that laryngospasm, tetany, and con- 220 
THE DISEASES OF THE PARATHYROID GLANDS 
vulsions were only the varying expression of the same “ constitutional morbid 
state.” Since the year 1890 Escherich and v. Wagner, Ganghofner, and later 
especially the school of Escherich maintained the teaching of the belonging to- 
gether of laryngospasm and the eclampsia of childhood, and, in spite of much 
opposition, have held to these doctrines, by the demonstration of the increased 
electrical excitability and the delimitation from similar manifestations of 
another kind. The pathologico-anatomical investigations of Erdheim and 
Yanasse seem adapted for establishing this view on a safe basis. Tetany of 
early childhood occurs chiefly in the third to the twentieth month of life. This 
is the form that deviates from the clinical picture of tetany of adults through the 
multiplicity of its manifestations. The tetany that sets in from the third year 
of life on is essentially similar to the tetany of adults. The tetany of sucklings 
which often manifests itself only through increased galvanic, and especially 
anodic, hyperexcitability is extraordinarily frequent in rachitic children and 
especially also in children that have been fed artificially. This occurs almost 
always in the cold time of the year. It shows a preference, as does rachitis, 
for northern countries especially, but is distinguished from the tetany of adults 
by its uniform extension. 
The investigations of Erdheim and Yanasse, already mentioned, have fur- 
nished an interesting elucidation for the etiology of this form of tetany. 
Already in 1903 Erdheim had mentioned the finding of hemorrhage in the para- 
thyroids of new-born children, and in 1906 he reported like findings in two of 
the sucklings that had died of tetany. Yanasse then examined systematically 
the parathyroids of thirty-five children who had died at the age of fifteen 
months. He found that in cases in which the electrical excitability had been 
normal during life, the parathyroids were normal. In those children, however, 
in whom there had existed electrical hyperexcitability, he found almost con- 
stantly hemorrhages or the remains of hemorrhages (in 71 of the 104 cases 
investigated). The hemorrhages are demonstrable at about the twelfth month, 
and are very probably to be referred to trauma during birth. According to the, 
later investigations of Haberfeld, the damaging influence of the hemorrhages 
does not act so much on the destruction of the parathyroid parenchyma as on 
the inhibition in growth of these organs conditioned by it. Erdheim and his 
collaborators, on the basis of their investigations, adhere to the view that the 
tetania infantum depends on a hypoparathyroidism, and that the artificial 
nourishment constitutes only the occasioning factor. Erdheim is corroborated 
by Peters, Schmorl, v. Verebely and Strada. Auerbach, Grosser and Betke, Bliss, 
Raymond, Jorgensen, and others have pronounced against the assumptions on 
the ground of pathologico-anatomical investigations. Thus Escherich’s views 
in their universal form are to-day not generally shared. 
Heubner has grouped together the diseases mentioned under the less 
prejudicial name of spasmophilic diathesis. 
The etiology of the tetany of later childhood (puerile tetany according 
to Escherich) is as yet unknown; perhaps it is identical with that of the idio- 
pathic form. THE TETANY OF MATERNITY 
221 
6. The Tetany of Maternity 
Under this heading we understand the tetany observed in pregnant, 
child-bearing, or puerperal women, v. Frankl-Hochwart has collected fifty- 
three certain cases from the literature, and add to them twenty-three of his 
own. Of these twenty-eight women were pregnant, nineteen were affected 
after the delivery, and twenty-nine during the puerperium. The beginning of 
tetany in pregnant women occurs in the sixth to the eighth month [of 
pregnancy]. 
To-day maternity tetany can scarcely make a bid for the distinction of 
a form sui generis. A portion of the cases belong in the group of tetany 
after strumectomy, the rest in great part to the group of idiopathic tetany; 
these come from places affected with tetany and occur especially in the 
tetany months, and it seems to me noteworthy that there do occur epidemics 
chiefly in the form of maternity tetany. While for example, according to 
the summary of Adler and Thaler, maternity tetany is relatively rare in Vienna 
(at the first gynecological clinic at Vienna only nine cases of the tetany of 
maternity were observed among about 30,000 cases), a great number of the 
cases described by Krajewska and also by McCarrison belong to this group. 
In all the forms the pregnancy or lactation plays the role of the determining 
factor only. This has been established by numerous experiments on animals. 
At first Horsley, later V as sale, Pineles, Erdheim, and especially Adler and 
Thaler, showed that in partially ectomized animals that show no signs of 
tetany, the tetany comes to expression with the progress of the pregnancy. 
In cases of slight parathyroid insufficiency, this may occur only in the course 
of the second pregnancy, or, as has repeatedly been observed, there may even 
occur a normal pregnancy interpolated between pregnancies complicated 
with tetany. A very interesting case of this sort is reported by Meinert. 
In this case there had been two births that were normal, then in the third there 
was tetany; then there were two more normal births, to be succeeded by a 
sixth pregnancy in which the tetany recurred. A strikingly marked atony 
of the uterus has been observed after the delivery in women who have tetany 
(cases of Erdheim and of Neumann). The tetany during pregnancy tends 
to have a very unfavorable influence on the fetus. The birth of macerated 
fetuses has been reported several times {Pick, Neumann); or the statements are 
that the children indeed were delivered, but soon died in convulsions {Kocher, 
v. Frankl-Hochwart). These last statements are very important with respect 
to the investigations of Iselin. 
The question as to why pregnancy calls forth tetany in predisposed 
individuals is not as yet fully explained.1 We may readily conceive that preg- 
nancy makes increased demands on all the ductless glands and thus unmasks 
a latent insufficiency. Perhaps similar relations are to be found with respect 
to tetany combined with osteomalacia. In osteomalacia, Erdheim found 
hyperplasia of the parathyroids. He assumes that in osteomalacia there are 
1 The changes found by Bergstrand in the kidneys, as set forth on page 215, are suggestive in this 
direction.—Editor. 222 
THE DISEASES OF THE PARATHYROID GLANDS 
especial demands made on these glands. The statement of Erdheim has 
been often corroborated. Schmorl found the parathyroids normal in four 
cases of rickets, but in a case of osteomalacia the parathyroids were markedly 
hypoplastic. In three other cases the parathyroids were normal, although 
Erdheim points out that the islands were not examined with the use of the 
osmium stain. Strada found the parathyroids enlarged in a case of osteo- 
malacia, and unaltered in two cases; in one case Bauer found in one para- 
thyroid an adenoma, and foci of proliferation in three others. Finally the 
parathyroids of twenty-four individuals were examined by Todyo. He found 
hyperplastic processes as described by Erdheim four times. In seven cases 
of osteomalacia they were, however, absent only once, and in six cases only 
one parathyroid was examined. In eleven cases of senile osteoporosis he 
found, on the contrary, hypoplasia eight times. 
7. Tetany in Gastrointestinal Diseases 
Tetany is observed in the most diverse gastric and intestinal affections. 
I mention only acute dyspepsia, acute and chronic enteritides, and helmin- 
thiasis. Especially are those cases brought into relief in which on account 
of some obstruction there occurred a dilatation of the stomach, or (in rare 
cases) a dilatation of the intestine, and a stagnation of the gastric and intes- 
tinal contents. From the great group of gastrointestinal tetany a number 
of cases are to be singled out in which the gastrointestinal disturbances con- 
stitute only one symptom of the tetany. I would agree with Chvostek that 
these cases are not at all rare. This has been taken up in detail in the con- 
sideration of the symptomatology. In a further group of cases an indisposi- 
tion of the stomach or intestines may constitute the determining factor for 
the tetany. 
An especial interest attaches to that form which occurs when the gastric 
or intestinal disturbance has existed for a long time. Attention to this 
form was directed first by Kussmaul. Since that time there have been pub- 
lished numerous reports concerning it (Fleiner, Fr. Muller, Gerhardt, Bouveret 
and Devic, Ewald, Albu, Schlesinger, v. Frankl-Hochwart, Rudinger and Jonas, 
Wirth). The most various conditions have been found: Cicatrized ulcer of 
the pylorus or of the duodenum, hour-glass stomach, malignant processes 
(such as carcinoma or sarcoma) in the neighborhood of the pylorus, or tumors 
of the gall-bladder or of the pancreas that lead to stenosis, torsion of the 
stomach, acute paralytic dilatation of the upper small intestines, in children 
dilatation of the colon, etc. 
There has also been reported a group of cases of dilatation of the stomach 
without demonstrable stenosis. I mention from the newer literature only 
the cases of Ferrannini and of Fleiner. 
The tetany that occurs in all these conditions may be quite rudimentary. 
Not rarely, however, it is of the most severe forms, forms that are attended 
with universal spasms and loss of consciousness. 
Bouveret and Devic distinguish a simple form attended with paresthesia 
and typical spasms of the extremities, and a “tetanisme plus ou moin general- TETANY IN GASTROINTESTINAL DISEASES 
223 
ise” that may lead to dyspnea and death from asphyxia principally through 
involvement of the muscles of respiration, and a form attended with loss of 
consciousness and coma. These severe forms of stomach tetany leave the 
prognosis always somewhat doubtful. The present statistics show a mor- 
tality of about 60-70 per cent. 
Numerous hypotheses have been brought forward to explain this form. 
In a certain number of the cases perhaps an affection of the gastrointestinal 
tract may play the determining role. This may be likely through the cir- 
cumstance that, as the figures of v. Frankl-Hochwart show, a great number 
of these cases occur during the tetany months. On the grounds of this 
observation Rudinger and Jonas have upheld the supposition that the tetany of 
gastrodilatation is nothing more than tetany acquired in the course of a 
gastrodilatation. This explanation does not seem to me to be entirely 
satisfactory. Before everything else, it is striking that this form of tetany 
is less confined to the tetany districts. Kussmaul supposed that the tetany 
was caused by a thickening of the blood, due to the frequent vomiting and the 
diminished absorption of water. Fleiner has adopted this theory, pointing 
to the hyperglobulia observed by Fr. Muller and also himself. This hyper- 
globulia is, however, as we have already seen, not the cause of tetany spasms, 
but their effect. Gerhardt, Palliard, Ewald, Albu, and others have supposed 
that toxic substances bring about the tetany, their origin being due to the 
stagnation of the gastric and intestinal contents (autointoxication theory). 
The finding of diamines in the stomach contents and in the urine of such 
patients means nothing, as they are also found there in other diseases. It 
is certain, however, that in many cases, the tetany promptly disappears on 
combating of the stagnation (for example washing out of the stomach). 
The explanation of this subject has as yet received no elucidation from 
pathologico-anatomical investigations. Erdheim found the parathyroids 
entirely normal, first in a case of severe gastric tetany, then in a second case 
with slight gastric manifestations, and third in the case of tetany in the 
course of enteritis. MacCallum in a case of gastric tetany found five rather 
arge parathyroids whose cells showed abundant mitoses. This he regarded 
as hyperplasia. Kinnicutt found in a case of gastric tetany the parathy- 
roids normal. It seems, therefore, that in a group of these cases there is 
present only a relative insufficiency of the function of the parathyroids 
with, however, markedly increased demands on them; we should consider 
further the possibility that in high-grade stagnation in the gastrointestinal 
tract substances are formed and absorbed that increase the excitability 
of the nervous system so markedly that under circumstances the action 
of the parathyroids no longer suffice; we must also assume, however, a certain 
predisposition of the individuals affected, as conditions of stagnation in 
gastrointestinal conditions are rather frequent, while complication with 
tetany is very rare. 
If we pass in review what has been said concerning the individual forms 
of tetany and their etiology, we find that we cannot deny that the view that 
all forms of tetany may be grouped together from the point of view of rela- 224 
THE DISEASES OF THE PARATHYROID GLANDS 
tive or absolute insufficiency of the parathyroids is, as a result of patho- 
logical anatomy, not sufficiently proved. All the rest of the pathologico- 
anatomical findings that up to the present have been brought into relief 
in tetany, findings such as alterations .in the ganglion-cells of the spinal 
column, in the marrow, or in the nerve fibers themselves, have been incon- 
stant. As yet unelucidated as to its significance is the finding of a premature 
sclerosis of the fine and finest cerebral vessels, especially in the medulla 
of the cerebrum and in the cerebellum, such as A. Pick pointed out in four 
cases of chronic tetany. 
Differential Diagnosis.—We distinguish an acute relapsing and an acute 
recurring form of tetany. We should also appropriately distinguish between 
a manifest and a latent tetany unattended with spasms, and finally between 
fully developed form of the formes frustes (the expression tetanoid I regard 
as less to the purpose); it is the latter differentiation that is attended with 
differential diagnostic difficulties. In general, the diagnosis of tetany is 
easy, as its most important criterion, the galvanic hyperexcitability, has as 
yet been observed in no other condition. As has previously been mentioned, 
Erb’s phenomenon may be temporarily absent even in the acute stage. In 
such cases great value can be attached to Chvostek’s phenomenon only when 
it is pronounced. If in addition there are present paresthesias in the terri- 
tory of the ulnar nerve and complaints as the sensations of tension in the 
hands and feet, the diagnosis of tetany appears to be very likely; often there 
occur in the further course of the disease fibrillary contractions, or Trous- 
seau’s phenomenon, or only transitorially a slight degree of heightened 
galvanic hyperexcitability, thus making entirely certain the diagnosis. Not 
rarely, during the tetany season, Reichmann’s disease may be attended 
with quite rudimentary forms of tetany. 
v. Frankl-Hochwart, and Fleiner have regarded certain cases of gastric 
tetany described in the literature as spurious, as they showed only sensa- 
tion of tension in the hands, with the absence of Erb’s phenomenon. During 
the last few years I have observed six cases of gastric tetany (see also Falta 
and Kahn); in almost all I was dealing with a typical Reichmann’s disease 
with marked dilatation of the stomach and increased peristalsis, indeed even 
antiperistalsis, phenomena that retrogress in many such cases on appro- 
priate treatment. In some galvanic hyperexcitability, mostly of a slight 
grade, was present quite transitorily. However, the paresthesias and the 
sensation of tension outlasted Erb ’s phenomenon for a long time. Therefore, 
in the formes frustes we may miss Erb’s phenomenon, even on repeated 
examinations. We fully recognize its prominent importance for the diag- 
nosis; there do occur, however, isolated cases in which it is absent and in 
which the diagnosis tetany can be established in spite of this fact. 
Concerning diseases that may be confused with tetany I mention only 
the following: Tetanus is readily distinguished from it by the increase in 
reflexes, by the non-involvement of the hands, and by the absence of the 
typical symptoms of tetany. Also the delimitation from meningitis, from 
acroparesthesia in chronic poisonings and from occupational spasms is always TETANY IN GASTROINTESTINAL DISEASES 
225 
easy, as in these diseases the typical distinguishing symptoms of tetany 
are absent. Hysteria may occur combined with tetany, and in such a way 
that tetany spasms and hysterical spasms are present simultaneously, or 
the hysterical spasms may come to the fore on the retrogression of the tetany, 
or hysteria alone may exist simulating tetany (pseudotetany) (E. Freund, 
H. Curschmann, F. Chvostek). In this form, naturally Erb’s phenomenon 
is absent, but hysterical stigmata are present. The pseudotetany attacks 
may simulate the true tetany attacks in an illusory manner. The uni- 
lateral occurrence of the spasms would rather point to the thought of hys- 
teria. Yet it should not be forgotten that a few true cases of hemitetany 
have been known (H. Freund, v. Frankl-Hochwart, v. Jaksch, E. Freund, et 
al). Too, Trousseau’s phenomena is often simulated illusorily. Especially 
to be considered is the absence of the paresthesias usually attending tetany 
attacks, and of Erb’s phenomenon, and the presence of fibrillary contrac- 
tions. If these cases of pronounced hysterical symptoms are added to 
a true tetany, Erb ’s phenomenon is decisive. 
If the differential diagnosis between epilepsy and tetany it is especially 
important to determine whether epileptiform convulsions belong to tetany 
or whether there exists a true epilepsy in addition to the tetany. Especial 
attention must be directed to the aura, to the incontinence of urine and feces 
during the attack and to the postepileptic stupor. Loss of consciousness in 
tetany is very rare, in epilepsy it is the principal symptom. In similar 
fashion a case of tetany with symptoms of myotonia must be investigated 
with regard to the cardinal symptoms of true myotonia (myotonic reaction). 
The galvanic hyperexcitability is important, according to Escherich, 
for differentiation from eclamptic convulsions of the years of childhood. 
The prognosis for the different clinical forms of tetany is not the same, 
and in strumiprivic tetany the prognosis quoad vitam may be very unfavor- 
able. To-day such cases scarcely come into consideration. The prognosis 
of idiopathic tetany quoad sanitationem was formerly regarded as favor- 
able. Since v. Frankl-Hochwart has reviewed his cases the views as to this 
point have changed considerably. Of fifty-five cases only nine were entirely 
healthy, seven showed chronic tetany, general nervousness and chronic 
invalidism, nineteen showed slight tetany symptoms and trophic distur- 
bances, six showed chronic invalidism without symptoms of tetany, eleven 
had died four to eleven years after the outset of the tetany. Saiz furnishes 
similar unfavorable statistics. He states that of nine cases only one remained 
free of distress, and that also this individual had sustained a recurrence. 
Cases of death from tetany of maternity have been reported (Trousseau, 
Schundlechner, Blazicek, et al.). Also transition into chronic tetany has 
been observed, v. Frankl-Hochwart, Adler, and Thaler and Novak, in contra- 
distinction of Fellner, hold therefore the prognosis as doubtful. Especially 
unfavorable is the prognosis in tetania gastrica; here it happens that the 
stomach affection itself frequently influences the prognosis unfavorably. 
Also in the tetany of childhood the revisions of the more recent period 
have furnished rather unfavorable results as to the length of life and 226 
THE DISEASES OF THE PARATHYROID GLANDS 
especially as to the further development (Escherich, Thiemich, Birk, and 
Potpetschnigg). 
According to Escherich, 25% of the nurslings at the hosp'tals who 
are sick with tetany die, and Thiemich and Birk in Breslau and Potpetschnigg 
in Graz have concerned themselves with the later fate of children who have 
been sick with tetany. Both statistics come to the result that a not incon- 
siderable number of such children soon die. Those investigated were only 
rarelv quite normal. In the majority of cases they showed disturbances 
of the psychical and intellectual development and especially remaining behind 
in the development of speech. 
The treatment of tetany should be concerned first of all with efforts to 
replace the lacking parathyroid function or to improve the insufficient para- 
thyroid function. It is a pity that up to the present all attempts have been 
futile. The substitution therapy that was so valuable in thyroidin sufficiency 
has in this case up to the present led to no certain result. It is intelligible 
to-day why the thyroid medication formerly employed in tetany was without 
results. It is remarkable, however, that no decisive results are obtained by 
the administration of subcutaneous employment of dried parathyroid gland 
or of extracts of parathyroids. The favorable statements of a few authors 
(parathyroid tablets, Marinesco, Lowenthal, Wieprecht; parathyroantitoxin, 
Vassale) stand in contradiction to the negative results of the exact trials of 
Pineles and the statements of many other authors. 
Pineles found that neither stomachal, nor subcutaneous, nor intraperitoneal 
administration of parathyroid extract in large doses served to influence in any 
way parathyroprivic tetany. Again, the feeding of very large amount of the 
extract of the parathyroids of horses, remained without results in human beings. 
One is reminded of the negative results of pancreas feeding (islands of Langer- 
hans) in diabetes. The parathyroids are, like the pancreas, no storage glands. 
The attempts to transplant the parathyroids at first awakened great hopes; 
v. Eiselsberg and later Payr transplanted the thyroid land in the abdominal 
wall or in the spleen and (on account of associated transplantation of the para- 
thyroids) prevented the outbreak of the tetany. Enderlen first showed micro- 
scopically that the parathyroids transplanted with the thyroid gland remained 
capable of functionating, in that in part they regenerated. Since that time 
numerous transplantations have been undertaken by Biedl, Pfeifer and Meyer, 
Halstead, Harvey, Cristiani, Leischner, et al.); favorable results have also been 
reported in man (first by v. Eiselsberg); favorable results were reported by Pool- 
Kocher (transplantation into the bone marrow), v. Garre, Boese and Lorenz, and 
Danielsen. The clinic of v. Eiselsberg later met with unfavorable results. 
On this account, the question was restudied by Leischner and Kohler, who con- 
cluded that the parathyroids behave quite similarly to the thyroid, that is, 
that only autotransplantation is attended with favorable results; while on 
homiotransplantation it is true that the parathyroids functionate for a time at 
first, but later they become absorbed. 
The administration of calcium salts has been regarded by MacCallum and 
Vdgtlin as a casual therapy. Theoretically, the condition of excitability in TETANY IN GASTROINTESTINAL DISEASES 
227 
ectomized animals should become dampened. Improvement is reported by 
Curschmann in three cases of tetany in man, and by E. Meyer in a case of tetany 
of pregnancy. Kahn and / studied the excitability of the nerves at intervals 
of two to three hours, and, after the administration of even a large amount of 
calcium lactate never observed a distinct influence on the same. Also the 
intramuscular administration of “Kalzine” (y. Muller and Saxl) was ineffective. 
If the assumption that in tetany the assimilation of calcium in the nervous 
system is disturbed holds good, it seems to me that the negative results become 
intelligible; the person with tetany behaves against increased administration of 
calcium just as a patient with pancreatic diabetes behaves against increased 
administration of sugar. We should expect, on the contrary, in conditions of 
increased dissipation of calcium, a result from the calcium administration. 
Perhaps we may explain in this manner the favorable results of calcium treat- 
ment in Basedow’s disease. 
There therefore remains for the treatment of tetany only symptomatic 
therapy, a therapy that likewise is almost ineffective. Weak sedatives such as 
the bromides and valerian are especially ineffective. In severer cases we can 
occasionally ameliorate the condition by the use of chloral. Levi claims to 
have had good results through blood-letting, and Narhut through lumbar punc- 
ture. The means that have proved best are rest in bed, diet poor in meats, 
protracted warm baths, and roborants. The phosphorus liver oil had been 
especially recommended in cases complicated with osteomalacia. In the tetany 
of sucklings, Escherich recommends the interpolation of days with just adequate 
diet; it is especially important to substitute natural feeding for cow’s milk 
whenever possible. Worthy of notice is the statement of McCarrison that some 
cases of tetany disappeared when the patient moved to another place. In 
women conception should be prevented or even pregnancy interrupted. Cer- 
tain drugs, such as ergotin, are to be avoided in the tetany of pregnancy (Novak). 
Gastric tetany deserves an especial consideration. Here the question of 
operation (gastroenterostomy) has met with lively discussion. While Alhu 
recommends operation as soon as possible, Fleiner would first await the results 
of internal therapy. Also Chvostek favors internal treatment. The results of 
the surgical treatment now seem very much to encourage this method of treat- 
ment. According to the latest statistics by Wirth, of twenty-one operated 
cases, seventeen remained permanently cured, while according to older statis- 
tics of Alhu the mortality of cases treated internally reached 77%. The 
question is, however, rather more complicated than one would gather from these 
statistics. In case of assured pyloric stenosis, operation is indeed not to be 
rejected, the question is only whether operation should be undertaken immedi- 
ately or whether it should be postponed until we find that we can accomplish 
no good by attempts to improve through internal treatment. Much will 
depend upon whether gastric lavage can be borne. The chief difficulty is 
met with in the diagnosis of the pyloric stenosis. Cases of Reichmann’s disease 
may present all the symptoms of pyloric stenosis—increased peristalsis in 
front of a fluoroscope, indeed even antiperistalsis. Even in cases of true 
gastric tetany we saw not only a disappearance of the tetanic symptoms but 228 
THE DISEASES OF THE PARATHYROID GLANDS 
also a lessening of the size of the stomach and a cessation of the spasm of the 
pylorus—this as the result of gastric lavage every evening, and the administra- 
tion of a dry diet rich in fats and of enemas to satisfy thirst. In such cases 
perhaps operation would be without curative results. 
b. Conditions of Hyperfunction of the Parathyroids 
Certain cases of adenoma of the parathyroids are known, without there hav- 
ing been found conditions that would be regarded as those of hyperfunction 
(.Erdheim). Also the tumors, in size up to that of a child’s head, described by 
Benjamin, Hulst, and de Santi, were attended with symptoms that were purely 
local, and otherwise remained without symptoms. In paralysis agitans, which 
was brought into relation with the parathyroids by Ronssy and Clunet, Erdheim 
found the parathyroids normal in three cases. Lundborg and Chvostek ascribed 
myasthenia pseudoparalytica to hyperfunction of the parathyroids. Chvostek 
sought to establish that the clinical pictures of myasthenia and tetany were 
diametrically opposed to each other. Both would seem to affect the voluntary 
muscles with noninvolvement of the sphincters. The electrical behavior in 
myasthenia is directly opposite to that in tetany; and in the one is found fatigue 
of accommodation, in the other accommodation spasm. Each sometimes 
accompanies myxedema or Basedow’s disease. The finding of the collection 
of cellular infiltrations and of discontinuous fatty degeneration of the muscle 
fibers, that is extraordinarily frequent (for literature see Marburg), points 
rather to the fact that myasthenia belongs more to the diseases of the muscular 
system; moreover, Haberfeld recently has been unable to find any alteration of 
the parathyroids in the cases of myasthenia gravis (see also the first chapter). 
[The investigations of J. Ramsay Hunt would seem to point to the fact that 
paralysis agitans is due to disease of the so-called “pallidal system” of the 
corpus striatum—at least he found the globus pallidus diseased in a case that 
he considered “ juvenile” paralysis agitans. Hunt1 has been criticized by Hall2 
who does not acknowledge that the one case of juvenile paralysis agitans 
reported by Hunt bears much resemblance to ordinary paralysis agitans of 
adults;—and then again Hunt had an autopsy on but owe case of the juvenile 
form. In a review of the literature, Hall finds reason to believe that in paraly- 
sis agitans the corpus striatum is mainly involved although lesions have also 
been found in the thalamus, the basilar nuclei, the hypothalmus, the locus 
niger, and the nuclei of the pneumogastric nerves. It does not seem to the editor 
probable that the parathyroid glands play a part in the etiology.—Editor.] 
Addendum 
The author’s criticism that some of the negative results of thyropara- 
thyroidectomy may be due to the leaving behind of inaccessible parathyroids, 
1 Hunt (J. R.). Primary atrophy of the pallidal system of the corpus striatum. A contribu- 
tion to the nature and pathology of paralysis agitans. Archives Int. Medicine, Vol. XXII, No. 5, 
Nov. 1918, pp. 647-691. 
2 Hall (H. C.). La degenererescence hepato-lenticulaire; maladie de TFz/sow-pseudo-sclerose 
Paris, Masson, 1921. ADDENDUM 
229 
or portions of parathyroids seems also to the opinion of MacCallum, Thomson 
and Murphy. At all events it appears that adult herbivorous animals 
(sheep, Simpson) are capable of sustaining thyroparathyroidectomy without 
appreciable effect, although in Simpson’’s experiments the lambs that were 
operated on developed acute tetany and died. 
The results obtained by Mustard on transection of the spinal cord agree 
with Biedl’s and MacCallum’s in that they are diametrically opposed to Munk’s 
and to Falta’s as to noncontinuance of tonic contractions in the parts below the 
seat of cutting after transection of the spinal cord. 
Paton, Findlay and Watson (1917) as a result of their studies, conclude that 
the nervous symptoms following parathyroidectomy are due to the condition 
of the central nervous system; that the cerebral hemispheres are not directly 
involved in the production of spasticity, tremors, and jerkings; that these 
may develop independently of the cerebellum, but that the integrity of the 
cerebellum is essential for a sustained spastic tone; that the integrity of the 
spinal cord is not essential since tetany persists (thus agreeing with Falta’s 
work) after section of the spinal neurones; that efferent neurones are the struc- 
tures primarily implicated and that in advanced cases disturbed equilibrium 
suggests the involvement of the cerebellum. They do not believe that the 
increased electrical excitability can be taken as a measure of the severity of the 
condition and deny that the parathyroids exercise a direct controlling influence 
on the central nervous system. 
Hoskins and Wheeler have tested the effects of the injection of nicotine, 
adrenalin, and pituitrin in parathyroidectomized dogs, and have found that 
in these dogs there is a marked increase of vasomotor irritability affecting all 
components of the vasomotor mechanism, sympathetic cells, myoneural junc- 
tions, and musculature. 
Underhill and Blatherweck show that during the tetany which develops after 
thyroparathyroidectomy, glycogen disappears entirely from the liver and the 
sugar content of the blood is markedly lowered or may even be reduced to 
zero. It is probable that this action may be ascribed to the lack of parathyroid 
tissue, since the phenomena may be observed when all the parathyroids are 
removed and some thyroid tissue remains. 
Boothhy has admirably collated the literature on the parathyroid glands. 
Credit is given to Falta’s presentation of the clinical and theoretic considera- 
tions with the literature supporting the hypothesis of an underlying parathyroid 
insufficiency in these various tetanic conditions. A complete bibliography is 
appended to Boothhy’s review. He summarizes as follows: 
1. In many species of animals the removal of all parathyroid tissue causes 
death from tetany, within a few days in most instances, the herbivora are less 
liable to tetany than the carnivora, age appears to have a definite influence on 
the frequency and severity as probably also do pregnancy and lactation. 
There is some evidence of late trophic changes in those animals that survive 
parathyroidectomy and have few or no tetanic symptoms. 
2. The preservation of very small amounts of parathyroid tissue prevents 
or renders the tetany less intense. 230 
THE DISEASES OF THE PARATHYROID GLANDS 
“3. From the evidence at hand, the function of the parathyroids appears to 
be distinct and separate from that of the thyroid, their only relationship seems 
to be anatomic and not functional, the parathyroids are not embryonic thy- 
roid tissue. 
‘ '4. There is some evidence that their function is in some way concerned with 
calcium or guanidine metabolism or with both, they may play some part in the 
regulation or maintenance of the acid-base equilibrium in the body. 
“5. The experimental evidence pointing to the parathyroids as the primary 
cause of idiopathic tetany, unassociated with operative procedures on the 
thyroid, is very limited. 
“6. The only definite clinical entity which has yet been proved experiment- 
ally to be of parathyroid origin is the tetany seen after operations on the 
thyroid. In these conditions calcium in large doses usually ameliorates the 
symptoms. The reports as to the benefit obtained by parathyroid transplanta- 
tion or feeding are not convincing.” 
Kramer, Tisdall, and Howland have determined that in infantile tetany 
the inorganic phosphorus of the serum shows a marked variation; in about half 
the cases the concentration is normal or slightly above normal. Owing almost 
wholly to a decrease in the concentration of calcium the ratio sodium and potas- 
sium to calcium and magnesium is increased. The increased irritability of the 
neuro-muscular mechanism is due to the diminution of the concentration of 
calcium in the serum. 
The subject of tetany has been dealt with in a comprehensive fashion by 
Freudenberg and Gy orgy, who distinguish between blood tetany and tissue tetany. 
Phosphate, acetate, nitrate, and bicarbonate anions in the blood serum inhibit 
the binding of calcium to the brain tissue, and under certain circumstances also 
to cartilage colloid. Substances with few amido groups of the character of 
protein deviations inhibit the binding of calcium to colloids—such substances 
are the amino-acids, peptids, methylamine and trimethyamine, guanidine, 
methylguanidine, creatinine, betain, etc. as well as urea and ammonium salts. 
The regulation of the binding of calcium in the body is brought about preemi- 
nently by the C02 tension in the blood, by the bicarbonate and phosphate ions, 
as well as by organic substances as mentioned above. Calcium exists in the 
blood in three forms—as protein combinations of calcium, as undissociated 
calcium salts, and as calcium ions. In this article reference is made to the 
work of Grant and Goldman, who showed that all the essential symptoms 
of tetany could be produced in the human subject by voluntary forced 
respiration. Goldman has recently written an article in which cases of tetany 
occurred under various conditions and during various diseases,—but all due to 
forced respiration (eleven cases in all). He states that they are the first clinical 
cases of tetany due to involuntary forced breathing to be reported; that over- 
breathing sufficient to produce an alkalosis and tetany may occur during an 
acute disease, such as cholecystitis or influenza, in hysteria and gastric dis- 
orders, during and following physical exertion, and questionably during early 
anesthesia; that the tetany resulting from forced respiration produces hypes- 
thesia to pain; and that the type of breathing in all cases should be carefully ADDENDUM 
231 
observed. Barker and Sprunt report a case of tetany during an attack of 
epidemic encephalitis. 
Poll and Turnure have transplanted a parathyroid into the preperitoneal 
tissue behind the sheath of the rectus muscle, in a case of tetany due to sup- 
posed operative removal of the parathyroids, with apparent good results, 
including cessation of the tetany. 
Eiselsberg, who has transplanted parathyroids eight times in seven cases, 
agrees that much can be done by means of medication. He mentions parathyroid 
tablets, 3 or 4 thrice a day, calcium lactate up to thirty grams a day, afenil (cal- 
cium chloride-urea) one tube intravenously to be repeated if necessary, enemata of 
chloral hydrate, meat-free diet. Transplantation should be done only in 
case this medication fails. Transplantation of glands of living individuals is 
not without danger to the donor. The glands of individuals killed by accident 
suffice. Eiselsberg states that records in the literature exist of more than twenty 
transplantations with healing-in of the gland twenty times. Eiselsberg regards 
as interesting the transition of tetany into epilepsy. 
Following the idea suggested to him by Meltzer’s experiments, Berend treats, 
with unusual success, cases of tetany with subcutaneous injections of magnesium 
sulphate solution (0.20 centigrams magnesium sulphate per kilogram of body 
weight). The electrical hyperirritability and the carpopedal spasm diminish, 
and there is a shortening of the disease’s duration. The treatment is combined 
with salt-free diet. An 8% solution of magnesium sulphate should be used, 
and the water for dissolving it should be freshly distilled. 15 to 20 c.c. of this 
solution is the usual dose for a young infant. 
Freudenberg and Gyorgy have treated manifest (not latent) tetany in suck- 
lings with ammonium chloride three to seven grams per day with good results. 
They have also obtained good results from its use in a case of post-operative tetany. 
Simpson (S.). The influence of age following thyroparathyroidectomy. Proc. Soc. Experim. 
Biol, and Med., Vol. IX, 1911-1912, pp. 2-4. 
Mustard (H. J.). A study of certain tonic and reflex nervous impulses as factors in parathyroid 
tetany. Am. J. Physiol., 1911-1912, XXIX, 311-3x6. 
Paton (D. N.), Findlay (L.) and Watson (A.). The parathyroids: Tetania parathyreopriva; its 
nature, cause, and relations to iodopathic tetany—7 parts—Quarterly Jr. of Physiol. Vol. X, 1916, 
1917, pp. 203-382; also Paton (N.), Findlay (L.), et al. Tetany and the functions of the parathyroids. 
Brit. M. J., May 5, 1917, pp. 575-577- 
Hoskins (R. G.) and Wheelan. Parathyroid deficiency and sympathetic irritability. Am. J. 
Physiol., Vol. XXXIV, No. 3, June 1, 1914. 
Underhill (G. P.) and Blatherweck (N. P.). The influence of thyreopurathyroidectomy upon 
the sugar content of the blood and the glycogen content of the liver. J. Biol. Chem., Vol. XVIII, 
No. 1, June, 1914, pp. 87-90. 
Boothby (W. M.). The parathyroid glands; a review of the literature. Emdocrinology, July, 
1921, Vol. V, pp. 403-440. 
Freudenberg (E.) and Gyorgy (P.). Ueber Kalkbilding durch tierische Gewebe, VI. Biochem. 
Zeitschr. Bd. CXXIV, Heft. 1 to 6, 1921, pp. 299-310. 
Freudenburg (£.) and Gyorgy (P.) Salmiakbehandlung der Kindertetanie Klinische Wochen- 
schrift Vol. I, No. 9, Feb. 25, 1922, pp. 410-411. 
Kramer (B.), Tisdall (F. F.), and Howland (/.), Observations on infantile tetany. Am. J. Dis. 
Children; Vol. XXII, No. 5, Nov., 1921, pp. 431-437. 
Grant (S. B.) and Goldman (A.). Tetany following forced respiration in man. Am. J. Physiol., 
Vol. LII, June, 1920, pp. 209, et seq. 232 
THE DISEASES OF THE PARATHYROID GLANDS 
Goldman (A.). Clinical tetany by forced respiration. J. Am. M. Ass., Vol. LXXVIII, No. 16, 
April 22, 1922, pp. 1193-1195. 
Pool and Turnure. Annals of Surgery. Vol. LVI, 2, 1912; Vol. LVI, Nov., 1912, No. 2, pp. 
804-807. 
Eiselbergs (A.). Ueber die Behandlung der Tetania parathyeopriva. Wiener klin Wochen- 
schrift. Vol. XXXV, No. 1, Jan. 5, 1922, pp. 1-2. 
Berend (N.). Die Magnesiumsulfatbehandlung der spasmophilic Krampfe. Monatschrift 
ur Kinderheilkunde Bd. 1-2. Originalien. 1914, pp. 269-331. Also, Verhandlungen der Gesell- 
schaft deutscher Naturforscher und Artze. Pt. 2, 2nd half, 1913, p. 596-398. CHAPTER V 
THE DISEASES OF THE THYMUS GLAND 
It has not been long that the thymus gland has been classed with the 
hormonopoietic system. Originally it was regarded as a constituent of the 
lymphatic apparatus. 
Anatomy and Embryology.—The thymus gland develops as a paired 
organ from the ventral part of the third branchial cleft. (See illustration 3, 
p. 53). The pairs unite very early; at birth the organ lies behind the ster- 
num, backward as far as the pericardium, reaching above somewhat higher 
than the jugular notch. In the human being there may occur accessory 
lobes of the thymus which may be either independent, or be united with 
the thyroid gland, or even the thymus gland itself. The thymus gland 
is of entodermal origin; although at present there is no unity of opinion 
with regard to the origin of the pictures resembling lymphocytes found 
in the completed thymus and especially in its cortex. Since the inves- 
tigations of Hammar the entodermal origin of the polymorphic fixed reticu- 
lar elements lying chiefly in the medulla, and of the so-called Hassal’s 
corpuscles stands assured. Stohr regards the origin of the thymus lympho- 
cytes as due to division of the epithelial cells while recently Hammar and 
Maximow, following the older assumption of His and Stieda, adhere to the 
assumption of a secondary ingrowth of mesodermal pictures. According to 
the latter view, the thymus gland therefore belongs to the lymphatic appa- 
ratus; there is found in it a “symbiosis of cells of the different germinal layers;” 
it is concerned with the production of lymphocytes. According to Nagele 
it is indeed the principal site in the formation of the lymphocytes in early 
life. The same author states that this view is also favored by phyloge- 
netic factors, for in the amphibians the thymus is the source of lymphocytes 
when the lymph glands are still absent. The statement of Ivar Bang that the 
thymus gland contains at least five or six times more nucleinate than the 
lymphatic glands does not speak unconditionally against this assumption, 
as the analysis included the epithelial elements. 
The weight of the thymus gland increases after birth, according to the 
statement of Hammar, v. Sury, Schridde, Ronconi, Pappenheimer, and others, 
the growth ceasing only with the beginning of sexual maturity; the thymus 
tissue gradually atrophies and is partly replaced by fat, although appreciable 
remnants of thymus tissue are retained until late life. In late life too were 
found, by Hammar, mitotic proliferation of lymphocytes and new formation 
of Hassal’s corpuscles. In addition to this involution of age an accidental 
involution also occurs; Hammar and Jonson have shown that in fasting ani- 
mals the weight of the thymus gland reduces very rapidly, especially through 
loss of lymphocytes. Also in the melting down of the thymus gland on 
233 234 
THE DISEASES OF THE THYMUS GLAND 
irradiation with X-rays, the reticulum shows itself much more resistant than 
the lymphocytes. The accidental involution is found among chronic dis- 
eases that lead to marasmus. It is especially well expressed in pedatrophy 
(Farret). Also, according to Hammar, accidental involution may occur in 
older people, an evidence that glandular tissue capable of functionating has 
still been present. 
Physiology.—The question as to whether the thymus gland is an organ 
important for the life of the organism has not until recent times received 
a uniform answer. Friedleben, Langerhans, and others saw animals in which 
the thymus gland had been removed remain undisturbed in their development, 
while other authors on the contrary, of whom I here mention only Tarulli 
and LoMonaco, Ghika, Cozzolino, Basch, Sommer and Florken; Ranzi and 
Tandler saw occur in dogs, rabbits, cats, and other animals, temporary 
serious disturbances of growth which later disappeared. The most recent 
investigations are those of Klose and Vogt, and of Matti. The investigations 
make it very likely that the disturbances mentioned can no longer disap- 
pear when the extirpation of the thymus gland has been done on very young 
animals only a few days old. 
Klose and Vogt operated on twenty-five dogs. The phenomena observed 
are brieffy as follows: After the latent stage of about fourteen days the ani- 
mals gradually showed a spongy, soft skin, a “pasty habitus.” They began 
to remain behind in growth on account of a lessened growth in length of the 
extremities. The bones were distinctly more flexible. In agreement with 
Basch, Klose and Vogt found that the ossification is retarded and that if 
the bones are fractured callus formation is very poor or does not occur at 
all. The ash contents of the bones is essentially diminished. Basch also 
found that in this stage the elimination of calcium is essentially increased. 
The hyperexcitability to galvanism which Basch found in thymectomized 
animals is to be referred to the associated extirpation of the parathyroid 
bodies imbedded in the thymus tissue. 
According to Ranzi and Tandler, the dentition is also delayed in this stage; 
the dogs take on abundant fat (stadium adipositatis, according to Klose and 
Vogt). This is followed by a stadium cachecticum; in spite of increased 
hunger the animals gradually lose weight, muscular tremors occur, the hemo- 
globin contents and erythrocyte contents of the blood reduce, and chemotactic 
irritants, such for examples, injection of nucleinic acid, remain inactive. The 
animals become indolent and tired, begin to suffer with disturbances of coordi- 
nation and finally die in a coma-like condition. Feeding with thymus gland 
or injection of it only aggravates the condition. 
H. Matti describes the condition after thymectomy in very young animals 
as somewhat different. After the latent period of about four weeks, during 
which the animals remain behind in growth, manifestations occur in the osse- 
ous system that are very much like those of high-grade rachitis. There occur 
a high-grade softening and bowing of the bones and a rosary formation; there 
are found a deficient apposition of calcium in the bones, a hyperemia of the 
bone marrow and a slowing of the metaplasia in the fat marrow. The epiphy- PATHOLOGY AND SEMIOLOGY 
235 
sial junctures are several times broadened. The examination of the blood 
shows only that the decrease in lymphocytes and the increase in neutrophilic 
elements which normally occurs with increasing age is slowed. Matti found 
a broadening of the suprarenal medulla and a slight enlargement of the 
thyroid gland and of the pancreas. The gray substance of the spinal cord 
shows, as Klose and Vogt have already stated, signs of an increased break- 
ing up. At the close the animals lose the ability to walk and there ensues 
marked cachexia that leads to death. The muscles show high-grade atrophy 
of inactivity, with transitions to degenerative atrophy. 
In thymectomy in somewhat older animals these manifestations occur 
only temporarily, yet when the extirpation was associated with removal of the 
spleen, the animals, according to Klose and Vogt, for the most part died. 
This would signify that the spleen takes over at least a part of the function of 
the thymus gland. Matti could not find this. 
[Elaborate experiments were conducted by Park and McClure1 on young 
puppies. They subject the earlier work to a thorough-giving critique. They 
concluded that the thymus gland is not essential to the life of the dog; that 
extirpation of the thymus gland produces no detectable alteration in the 
hair, teeth, contour of the body, muscular development, strength, activity, 
or intelligence of the animal under experimentation; that extirpation of the 
thymus gland does not influence growth or development, although the possi- 
bility exists that it may cause retardation in development and delayed closure 
of the epiphyses; the procedure probably produces no alterations in the 
organs of internal secretion; although they may possibly have been affected 
in the period immediately following thymectomy.—Editor.] 
It should be mentioned further that castration in young animals essen- 
tially delays the involution of the thymus gland and that increased sexual 
activity accelerates it (Calzolari, Henderson, N. Paton, and Goddall, and others). 
With this agrees the fact that Tandler and Grosz found the thymus gland 
of eunuchs hyperplastic. 
Svehla’s experiments on hyperthymization have in part lost their signifi- 
cance, for it has been shown by Popper that the depressor action of thymus 
extracts intravenously is not specific, but is dependent on clots in the blood path. 
Pathology and Semiology.—Our knowledge as to the significance of the 
thymus gland in clinical medicine is extremely deficient. As far as symptoms 
in the absence of the thymus in human beings is concerned we know next 
to nothing. 
In the autopsy of new born and very small children aplasia of the thymus 
gland has sometimes been found. The first statement is that of Bischof. 
Clark described an eight-month-old child that remained well up to the sixth 
month. Then there developed hydropic swellings. Autopsy showed left- 
sided hydronephrosis and aplasia of the thymus gland, v. Sury describes a 
case of congenital total defect of the thymus gland in a three-month-old child 
who died of pneumonia. Aplasia of the thymus gland seems very frequently 
1 Park (E. A.) and McClure (R. D.). The results of thymus extirpation in the dog, etc. Am. 
J. Dis. Children, Vol. XVIII, No. 5, Nov., 1919, pp. 317-521. 236 
THE DISEASES OF THE THYMUS GLAND 
to be associated with other malformations, especially developmental defects 
of the brain (Winslow, Borneville, Katz, and others). On the other hand, 
G. Anton shows the simultaneous occurrence of thymus hyperplasia and 
brain hypertrophy. [This brain hypertrophy has probably been borne out 
by other authors.—How does this fact square with the so-called “ constitu- 
tional inferiority” that is supposed to be associated with status thymicus and 
status lymphaticus?1 See addenda to this chapter, to the chapter on status 
lymphaticus, and to that on infantilism.—Editor.] 
Lately total extirpation of the thymus gland has been carried out on 
account of stenosis of the trachea (see below). Very worthy of note is the 
statement of Koenig, that after resection of the thymus gland such as was 
undertaken in a nine-month-old child on account of dyspnea, breathing 
became normal; and that afterwards a severe rachitis developed on account of 
which the child first learned to walk as late as the age of four and one-half 
years. In the rest of the cases there are no statements as to the further course. 
According to the experiences in animals, total extirpation of the thymus 
gland in very young children is to be advised against. [But see the experiments 
of Park and McClure, just summarized.—Editor.] 
Up to the present the entire clinical interest has been turned to the cases 
which have shown a hyperplasia of the thymus gland and a persistence or 
reviviscence of it.2 Kopp in 1855 first attracted the interest of the medi- 
cal world to the cases of sudden death in early life which occurred with cyano- 
sis and stridor and which on section showed nothing but hyperplastic thymus 
gland. The extensive investigations of Friedleben, which culminated in 
the aphorism “ there exists no thymic asthma,” for a long time suppressed 
this teaching. First in the year 1888 Grawitz on the evidence of two cases 
pointed out the forensic significance of thymic hyperplasia. Up to this 
time only purely mechanical factors in these cases of death had been con- 
sidered. Then, in 1889, A. Paltauf, noting the frequent combination of 
thymic hyperplasia, status lymphaticus, and narrowing of the vascular system 
regarded the cause of death not as a mechanical factor but as a vegetative dis- 
turbance; this he designated as lymphato-chlorotic constitution. Among 
others, Ortner reported congenital narrowing of the aortic system in these cases 
of sudden death, v. Kundrat reported status lymphaticus with more or less large 
thymus gland in cases of sudden death in narcosis, Schnitzler and others reported 
narcotic death in cases of Basedow’s disease with persistence of the thymus and 
status lymphaticus. With Pott originated an excellent description of the cases 
of sudden death in the years of childhood. Most authors agree with the view 
of A. Paltauf, in that they regard the mechanical factor as without signifi- 
cance and place in the foreground the lability of the organism or of the 
cardio-vascular system that is dependent on toxic factors. Especially interest- 
:I am however aware that greater brain weight does not necessarily mean greater intel- 
ligence. 
2 Persistence of the thymus gland is, properly speaking, an incorrect expression as every human 
being possesses a thymus gland for his whole lifetime. Better than “persistence” is higher parenchy- 
mal value than corresponds to the age; also a reviviscence is really not certain, as we do not possess a 
criterion for it. PATHOLOGY AND SEMIOLOGY 
237 
ing are the observations of the familial occurrence of this kind of sudden 
death {Perrin, Hedinger, and others). Certain authors, however, hold fast 
to the mechanical cause through compression of the trachea by the thymus 
gland. 
The question is not completely cleared up at the present day although the 
direction in which we may expect the clarification is indicated. What makes 
the question especially difficult is the circumstance that status lymphaticus and 
enlarged thymus gland occur so frequently in associationship. Apparently, 
however, they stand to each other in a conditioned relation. As we shall see 
later in another paragraph, the finding of an intumescence of the lymphatic 
apparatus, eventually with a mononucleosis in the blood, is very frequent 
indeed. We find this in numerous diseases of the ductless glands, in chronic 
infectious diseases, in neurosis of the vagus nerve, etc. These hyperplasias 
deviate markedly from one another histologically. In addition, it is per- 
fectly clear that not every chronic swelling of the lymphatic apparatus is 
associated with increased chemic function. Also the thymic hyperplasia or 
thymic persistence or reviviscence is extraordinarily frequent just in these 
diseases of the ductless glands. If we accept the view that the thymus 
gland is in part of mesodermal origin, therefore in part belongs to the lym- 
phatic apparatus, this frequent combination of enlarged thymus gland and 
status lymphaticus would not be inexplicable. There certainly exists, 
however, an abnormally large thymus gland without status lymphaticus, 
hence a status thymicus. 
Recent investigations seem to have furnished a significant differentiating 
criterion. Wiesel and Hedinger have shown that status lymphaticus is asso- 
ciated with a hyperplasia of the chromaffin tissue. Thus Hedinger found in 
five cases of pure thymic hyperplasia entirely normal development of the 
suprarenals and the entire chromaffin tissue, even on microscopical exami- 
nation. Again, v. Sury points out that in the so-called thymic death of the 
new-born the chromaffin tissue is always well developed and that the hypo- 
plasia of the chromaffin tissue sets in only with the development of status 
lymphaticus. In cases of pure thymus hyperplasia the lymphocytosis of the 
blood would seem to be absent.1 
Let us now turn again to the question of thymic death, v. Sury has 
treated this subject in an elucidative exposition, one especially adequate on 
account of its rigid critique. He bases his conclusions on the material of two 
hundred medicolegal autopsies in which the thymus gland was taken into 
account, v. Sury shows first that the thymus gland varies extraordinarily 
in size and that therefore the diagnosis of a thymus hyperplasia is often very 
arbitrary. He mentions further that in the cases of sudden death in apparently 
healthy children there exists very frequently capillary bronchitides which 
are very common and which are very easily overlooked. In spite of this we 
can hardly deny the significance of the mechanical factor in the cases of 
1 Often in pure status thymicus the epithelial thymic tissue, that is, the reticulum and its deriva- 
tives, is found hyperplastic while the small thymic cells do not necessarily have to be increased, in 
contrast with status lymphaticus (Wiesel). 238 
THE DISEASES OF THE THYMUS GLAND 
“thymic asthma” published in recent years—cases which after partial or 
complete extirpation of the thymus gland became greatly relieved of their 
oppressive symptoms. Klose and Vogt have collected eight such cases. The 
first case was operated on by Rehn (reported by Parucker). [Rehn’s sign is 
the appearance of a swelling in the jugulum during expiration of air from the 
lungs.-—Editor.] It was that of a two-and-a-half-year-old child. Since 
that time a series of other cases have been operated on (see the literature in 
Wiesel). Especially to be mentioned is the case of Ilinrichs in which the 
hyperplastic thymus gland led, in addition to a hindrance of breathing, to a 
high-grade disturbance of the ingestion of food. Lately the action of the 
X-rays has also been recommended (Friedlander, Myers, Rachford, Rihideaur 
and Weil). The case of Ribideau was that of a two-month-old child with 
marked need for air on account of hyperplasia of the thymus. After extensive 
irradiation with X-rays the dyspneic manifestations disappeared within two 
days; somewhat later the child died from measles. The autopsy showed 
fibrous atrophy of the thymus gland. 
The attacks of dyspnea, cyanosis, stridor, and eventually hoarseness, that 
were observed in all these cases speak indeed for a purely mechanical factor. 
Whether in the pure cases of status thymicus in addition to this mechanical 
factor there exists a toxic factor on account of hyperthymization we must for 
the present leave undecided; although I have hardly been able to discover any 
grounds for this assumption. Up to the present the cases of Basedow’s dis- 
ease in which death occurred suddenly in narcosis regularly showed in addi- 
tion to thymus hyperplasia a pronounced status lymphaticus and were in 
addition complicated by other factors. 
It should be mentioned further that the thymus gland can also be the seat 
of malignant tumors or of inflammatory processes. The numerous thymic 
tumors thus far observed have not furnished any information as to the physi- 
ology of the gland, v. Neusser described a case of sarcoma of the thymus 
gland; a twenty-five-year-old patient was remarkably large and showed 
hyperplasia of the genitalia. A short time ago we observed a case of carcinoma; 
here also there existed gigantism; the development of the genitalia was, 
however, entirely normal. There should also be mentioned the case of 
Bramwell in which was found, in addition to the sarcoma of the suprarenal 
gland, a carcinoma of the thymus. Finally in numerous, but not all, cases of 
myasthenia gravis there were found hyperplasia of the thymus gland and 
alterations in the muscles that were regarded as lymphosarcoma. This 
interpretation is not however certain, as Hassal’s corpuscles occur in the 
muscle metastases. In these cases we are dealing rather with reticulum, 
tumors. 
If on our trying to draw a resume out of the facts detailed, we find that it: 
cannot be denied that in spite of the enormous labor that up to the present 
has been spent on this subject, the physiological significance of the thymus, 
gland is still unclear. The destruction of the organ through tumors or 
inflammatory processes which have otherwise furnished us with so much 
important information in the pathology of the other ductless glands is here ADDENDUM 
239 
apparently entirely without significance. Operative extirpations of the gland 
in earliest childhood have, except in the single case of Konig previously 
mentioned, furnished no symptoms of absence. However, we should not for- 
get that we mostly deal with cases of resections and that also in most of the 
cases statements as to the further course are absent. Then again in such 
cases we must consider the presence of accessory lobules of the thymus. 
Just as little clarified appears to me the significance of thymic hyper- 
plasia for pathology. In many cases only the significance of the mechanical 
factors remain certain; this is however quite without significance for the ques- 
tion of hyperthymization. For the rest we really only know that in a great 
number of very diverse conditions we find thymus glands with supernormal 
parenchymal values. Especially is this true for diseases of the ductless glands. 
We find thymus hyperplasia very frequently in Basedow’s disease, apparently 
also in acromegaly, in hypophysial dystrophy, in myxedema, in eunuchoidism, 
etc. It therefore occurs as well in conditions of glandular hyperfunction as in 
hypofunction. I believe, therefore, that we should exercise great scepticism 
concerning theories that would explain the frequent coincidence of Basedow’s 
disease and thymic hyperplasia. On the same ground I regard as at present 
quite hypothetical the correlations that according to the views of many modern 
authors exist between the thymus gland and the other glands of internal 
secretion. 
[It should be remembered in this connection that the histological make-up 
of the thymus is quite as important as whether or not the gland is larger than 
“normal” or not—See addendum.-—Editor.] 
Also the attempts to produce hyperthymization artificially have up to 
the present seemed scarcely satisfactory. The old experiments of Svehla are, 
as has already been mentioned, not of value as evidence. The fewer experi- 
ments of Hart with injection of powdered Basedow’s thymus and those of Bircher 
with implantation of Basedow’s thymus in animals are worthy of notice but 
do not furnish sufficient grounds for the support of a teaching of hyperthymiza- 
tion.1 Also the hypothesis that Wiesel provides at the end of his unusually 
well-prepared work on the pathology of the thymus seems to me on the face 
of it as still too little supported. Wiesel supposes that the thymus gland fur- 
nishes to the blood path a secretion that acts vagotonically, and he regards 
especially the eosinophilic cells present so abundantly in the thymus gland 
as the seat of origin of this principle that acts antagonistically to adrenalin. 
In this respect Wiesel identifies status thymicus and status lymphaticus, 
although he does take pains to separate the two conditions from each other in 
an anatomical sense. 
Addendum 
Boggs points out, without regards to the dullness due to enlarged thymus 
is partially higher and more superficial than that due to diseased mediastinal 
lymph glands or other forms of mediastinitis; that it is constantly much more 
1 Concerning the “thymogenic” Basedow’s disease see chapter on thyroid gland, pp. 83 and 
99. 240 
THE DISEASES OF THE THYMUS GLAND 
marked on the left of the sternum than the right, and the dullness is movable, 
the lower border rising as much as an interspace when the head is shifted from 
extreme flexion to extreme extension, with the patient in the sitting position. 
“In some cases of persistent or enlarged thymus there may be no dullness in 
the first interspace, but only in the second and below it. In such instances a 
shift in both upper and lower borders of dullness may be made out.” 
The movement of the dullness of the thymus is explained by this author as 
due to the movability of the thymus itself. He found the thymus to be enlarged 
or persistent in thirty-five of sixty-six colored girls, between the ages of five 
and eighteen years, fourteen of whom had suffered from measles. He remarked 
that lymphatic hyperplasia seems more common in the colored race. Jacobi, 
in the discussion on Bogg’s article, recommends percussing with the child in the 
prone position. 
Park and McGuire, however, on the basis of twenty-nine autopsies, have 
determined that the thymus gland is a relatively immobile organ and that the 
methods of percussion used by Jacobi and by Boggs bring out a movable 
dullness that is due to other factors, probably to the upward advance of the 
lung margins. 
Of cases of apparent thymic death, it is probable that death in the cases of 
Ginsburg and of Kennedy was due to mechanical factors, while in Veeder’s case, 
it is not at all certain that the thymus had anything to do in the matter. 
Christeller does not believe that the so-called thymus death has a unique 
cause. He ascribes it either to pressure of a hyperplastic thymus on the 
trachea, or to pressure of the hyperplastic thymus on the great vascular trunks, 
leaving to heart-failure. (Bibliography and review of the literature). See 
reference to work of Ryser below. 
Noback as the result of anatomical studies determined that in live-born 
infants the thymus changes its form from the cervicothoracic type to the elon- 
gated and moulded type as the effect of respiration, and that in the infant it 
may extend posteriorly and compress the structures there; this is due to an 
unusually large thymus or to a very narrow thoracic aperture. 
In a review, Ricketts mentions the various surgical procedures on the thymus 
gland, and points out that in case of impending suffocation due to enlarged 
thymus, intubation or tracheotomy may be done. 
According to Halsted, Klose warns against X-ray irradiation of the thymus 
region in young children, because of the marked susceptibility of the gland to 
the influence of the X-ray. On the other hand we regard <it as well established 
that the X-ray is of use in treating a really demonstrable thymus gland of child- 
hood which is producing symptoms. 
In spite of the fact that certain authors ascribe an important function to 
the thymus gland in disorders of the endocrine system, as in the pluriglandular 
syndrome of Timme, the function of the thymus gland is as yet unknown. For 
instance in the X-ray plate furnished by Kay and Brock in their well-studied 
case which they report as a hyperfunctioning of the thymus and suprarenal 
glands counterbalancing a hypopituitary state the thymus gland is said to 
furnish a distinct shadow. It is not even known whether the thymus gland ADDENDUM 
241 
furnishes a hormone. None has to our knowledge been demonstrated. Per- 
haps the gland responses to hormonic and general metabolic action without 
furnishing an internal secretion of its own. The work of Park and McClure, 
referred to in the text, would seem to indicate that its function, whatever it 
may be, is limited so far as importance to life is concerned. This view is shared 
by competent observers, investigators, and experimenters. Thus M. M. 
Hoskins has performed extirpation and transplantation experiments in larvse 
of rana sylvatica practically with negative results. In these larvae, complete 
thymectomy did not affect the spleen of the larva or frog, nor any 
of the other organs with the possible exception of the hypophysis; this ap- 
peared abnormally large in some of the specimens after thymectomy, although 
the difference in size was probably not a true compensatory hypertrophy. 
The grafting of thymic tissue into a tadpole did not affect the size or structure 
of the normal thymus, the spleen, or any other organs. 
Downs and Eddy have injected desiccated thymus substance subcutaneously 
into rabbits and have observed some increase in the weight of the thyroid gland 
and of the spleen and a decrease in the weight of the thymus gland to follow 
such injection; but no muscular spasms or convulsions were observed in the 
animals operated on. 
Hammar has recently summarized our knowledge as to the thymus gland. 
The effects of intravenous injection of thymus extract us as well as experiments 
which show that amphibian larvae show marked growth and delayed metamor- 
phosis when fed thymus gland substance, are subjected to a critique. Hammar 
is of the opinion that the thymus gland does not function by means of secretion 
and quotes Hoskins (1918) and Dustin (1920) as sharing his opinion. He 
regards the thymus as “ antitoxic ” in function. So far as the lymphoid structure 
of the thymus gland is concerned, the lymphocytes seem to obey the same rules 
as usually regulate the total lymphocyte constituent in the organism. The 
Hassall corpuscular apparatus is subjected to both excitor and depressor factors 
(an increase in their number has been shown in Graves’ disease, and acute infec- 
tions of various sorts). 
It will be remembered that the thyroid gland was at one time considered 
“antitoxic” in its action. In the case of the thymus gland however the views 
of Hammar are not without justification, especially in the present stage of our 
knowledge. If he is right, it is probable that in the so-called pluriglandular 
affections the thymus may hypertrophy to compensate for increased or pre- 
verted ductless glandular or metabolic secretions, rather than be the antecedent 
factor of changes in the rest of the endocrine system. 
The subject of thymus gland conditions has been well dealt with by Symmins 
in his article on the subject in Nelson’s Loose-Leaf Living Medicine. The follow- 
ing is an extract:— 
“The function of the thymus gland is unknown. From its inception the 
organ exerts no detectable influence on growth or metamorphoses, and at no 
stage of life is it indispensable, nor does its removal seem to cause any note- 
worthy deficiency in metabolism or in the development of other members of the 
so-called endocrine series. In spite of its colorless position in the physiological 242 
THE DISEASES OF THE THYMUS GLAND 
scale, the thymus is of clinical interest, notable in connection with the condition 
known as status lymphaticus.” 
Symmins points out that in status thymo-lymphaticus is not the only cause 
of sudden death in children and adults, but that sudden death can also occur 
from anaphylaxis. The susceptibility of these thymo-lymphatic children is 
dwelt on. The childhood stage of the Timme syndrome may be recognized in 
the following:—“In the clinical conglomerate of scrofula, the elder Gross long 
ago recognized the so-called angelic type of child, whom he described as well- 
nourished and beautifully proportioned, with velvety skin and silk-like hair, 
shapely, arching limbs and narrow waist, and in whom he pointed out an unusual 
susceptibility to infection.” He points out that there is a recessive type in 
whom the thymus is partially or completely replaced by fat. Also, “Schridde 
and others have pointed out that those patients in whom there is a lymphocy- 
tosis or over are dangerous operative risks.” 
There is no doubt that status lymphaticus and status hypoplasticus and 
certain types of infantilism are often associated with status thymicus—perhaps 
indeed there is no true isolated status thymicus—but this would tend to rob the 
thymus gland of some of the importance attached to it. According to Brugsch 
a primary hypoplasia of the blood-vessels is associated in a constitutional way 
with a response in the formation of an abnormally large quantity of lymphoid 
material. This affects especially the lymphoid follicles at the base of the tongue. 
This was shown in a clinical way by Pribram who in observing supposed cases 
of status lymphaticus at autopsy found that more constant than any other sign 
of the status lymphaticus including enlarged thymus gland was an enlargement 
of the lymphoid follicles of the root of the tongue. 
Ryser deals in a comprehensive way with the subject of sudden death in so- 
called status thymo-lymphaticus. He mentions the mechanical factors, the 
supposed chemical factors (hyperthymization, insufficiency of adrenalin) and 
calls attention to the work of Riesenfeld and of Ceelen in demonstrating a 
lymphatic infiltration of the heart muscle in cases of so-called idiopathic heart 
hypertrophy in children. Riesenfeld observed five such cases and Ceelen 
described in these cases at autopsy leucocytic collections among the fibers of the 
heart, atrophy, and fattening of the fibers. The author (Ryser) thinks that 
perhaps there is a constitutional inferiority of the heart muscle, which perhaps 
may be correlated with the hypoplasia of the vascular system. Otherwise 
why not cases of sudden death in lymphatic leukaemia?—(Editor). The 
phenomenon is likened to sudden death in convalescense from influenza and 
other infectious fevers. 
Yamanoi noticed in 24.42% of cases of individuals between 25 and 50 years 
of age who had died from “grippe” a persistent thymus gland; in a third of 
another series of 60 cases between 25 and 50 years of age who had died of acute 
poisoning or suddenly of accident there was a persistent thymus. It is true 
that Yamonoi worked with cases that came from a goiter district, and many of 
whom had an enlarged thyroid. His idea however that persistence of the 
thymus gland is more common than is usually thought was worked out 
previously by Groll who used bodies of individuals who had been killed in the ADDENDUM 
243 
World War. Groil’s work was concerned especially with the lymphatic system 
in general as is also the more recent work of Heilman who by observation in 
rabbits and in man has shown that lymphatic tissue in general is much more 
wide-spread in the body than is usually supposed. 
Considering the fact that Emerson’s work on the thymus gland of alcoholic 
individuals was not controlled [see addendum to the chapter on infantilism] 
may it not be that the so-called constitutional inferior is not so inferior when 
it comes to the matter of the thymus gland. As Richter says in Miinchener 
medicinische Wochenschrift, in writing that the normal size of the thymus 
gland is larger than it is usually supposed to be,—-“ein Irrtum ist schwerer zu 
bekampfen als hundert Wahrheiten” (An error is harder to fight against than 
a hundred truths). 
Years ago Richter expressed himself concerning the enlargement of the 
thymus gland in young adults thus:—“In every vigorous young individual who 
has died of not too consuming a disease there will be found a well developed 
thymus gland, which on section is found to consist not only of fat tissue, but of 
greyish red thymus tissue. This may be found as late as the twenties. Nobody 
has demonstrated pressure of such a gland on the air passages, the bronchi, 
the innominate artery and vein, the right heart or the various nerves [in adults—- 
Editor] . . . any such assumption that seeks in the enlargement of the thymus 
gland a partial manifestation of a special inferior constitutional tissue composi- 
tion is it seems to me, in view of the regular finding of a large thymus gland in 
vigorous youthful individuals to be too poorly founded to be of value in medical 
practice.” 
Boggs (T. R.). Percussion signs of persistent or enlarged thymus. Tr. Ass. Am. Phys., Vol 
xxvi, 1911, pp. 353-356. 
Park (E. A.) and McGuire (W. C.) A criticism of two percussion methods for the diagnosis of 
enlarged thymus. Arch. Int. Med., Vol. X, No. 3, Sept., 1912, pp. 214-218. 
Ginsburg (N.). Thoracic viscera in a case of thymic enlargement. Proc. Path. Soc. Phila., 
N. S., Vol. XIV, 1911, p. 82. 
Kennedy (A. M.). Enlargement of the thymus; a remarkable case. Glasgow M. J., Vol. 
XXVII, Jan., 1912, pp. 31-37. 
Veeder (B. S.). Hemorrhage into the parathyroid glands in a case of “thymic death.” Proc. 
Path. Soc. Phila., N. S., Vol. XIV, 1911, p. 83. 
Christeller (£.). Entspricht dem sogenanntes Thymustode ein einhelltliches Kransheitsbild? 
Archiv. fur path Anat. und Physiol, etc., Vol. CCXXIV, 1919, pp. 277-304. 
Noback (G. J.). Contribution to topographic anatomy of thymus gland. Am. J. Dis. Children, 
Vol. XXII, Aug., 1921, pp. 120, seq. 
Halsted {W. S.). The significance of the thymus gland in Graves’ disease. Bulletin of the 
Johns Hopkins Hospital, Vol. XXV, No. 282, Aug., 1914, pp. 223-228. 
Timme (IT.) see page 50. 
Kay {W. E.) and Brock (S.). Unusual endocrine distuances; their associated myopathiqes. 
endocrine balance and metabolism in findings. Arch. Int. Med., Vol. XXVII, Jan., 1921, p. 1, seq. 
Hoskins (M. M.). Extirpation and transplantation of the thymi in larvae of rana sylvatica. 
Endocrinology, Vol. V, Nov., 1921, pp. 763, seq. 
Downs (A. W.) and Eddy (N. B.). Effect of subcutaneous injections of thymus substance in 
young rabbits. Endocrinology, Vol. LV, July-Sept., 1920, pp. 420-428. 
Hammar (J. A.). The new views as to the morphology of the thymus gland and their bearing 
on the problem of the thymus. Endocrinology, Vol. V, No. 5, Serial No. 21, Sept., 1921, pp. 543-573, 
and Vol. V, No. 6, Nov., 1921, pp. 731-760. 
Hoskins (E. R.). Is there a thymic hormone? Endocrinology, Vol. Ill, 1918, pp. 241-257. 244 
THE DISEASES OF THE THYMUS GLAND 
Dustin (A. P.). Recherches d’histologie normale et experimentale sur le thymus des Amphi- 
biens anoures. Arch, de Biol. Liege, Vol. XXI, pp. 601-693. 
Symmins. The thymus gland. Nelson Loose Leaf Living Medicine, Vol. Ill, pp. 319-327. 
Brugsch (T.). Allegemeine Prognostik, (etc.), Berlin, Urban, 1918. 
Pribram (H.). Klinische Beobachtungen zur Kenntnis des Status lymphaticus und Beziehungen 
desselben zur pluriglandularen Erkrankung. Ztschr. klin. Med., Berlin, 1914, Vol. XXXI, pp. 
120-128. 
Ryser(H.). Zur Erklarung der plotzlichen Todesfalle beim Status thymo-lymphaticus, Schwei- 
zerische Med. Wochenschrift, No. 24, June 16, 1921, pp. 554-557. 
Riesenfeld. Ueber primare Herzhypertrophe im fitihen Kindesalter und ihre Beziehung zum 
Status thymico-lymphaticus. Jahrbuch f. Kinderheilkunde Bd. 86, Heft 6, 1917, pp. 419-441. 
Ceelen. Ueber Herzvergrosserungen im friihen Kindesalter. Berlin kl. Wochenschift, No. 9, 
March 1, 1920, pp. 197-202. 
Yamonoi (S.). Die Bedeutung der Thymus persistens Schweizerische med-Wchnschrift, No. 24, 
June 16, 1921, pp. 557-560. 
Groll (H.). Die “Hyperplasie” des lymphatischen Apparatus bei Kriegsteilnehmern Miinch. 
m. Wchnschr., Vol. LXVI, No. 30, July 25, 1919, pp. 833-835. 
Heilman (T.J.son). Studien uber das lymphoide Gewebe. LV, Zur Frage des Status lympha- 
ticus. Zeitschrift f. Konstitutionslehre, Band VIII, Heft 5, 1921, pp. 191-219. 
Emerson (H.). Status lymphaticus in adults, its clinical diagnosis and importance. Arch. 
Int. Med., Vol. XIII, 1914, pp. 169-176. 
Richter IM.). Die “Hyperplasie” des lymphatischen Apparates bei Kriegsteilnehmern, Munch, 
med. Wochrschr., Vol. LXVI, No. 32, Aug. 1, 1919, p. 890. 
Richter (M.). Gerichtsarztliche Diagnostik and Technik. Leipzig, Herzel, 1905. CHAPTER VI 
THE DISEASES OF THE HYPOPHYSIS [Pituitary Gland] 
Since Pierre Marie delineated the clinical picture of acromegaly and 
placed it in an etiological relationship to the hypophysis, the literature on 
the experimental research and clinical study of the hypophysis has grown 
enormously. In spite of this fact there as yet prevails in our views as to the 
pathogenesis of the clinical pictures concerned with the hypophysis very 
little uniformity. The chiefest cause of this is that as yet we know but little 
as to this organ’s physiological significance, at least much less than we know 
about the thyroid. The blame resides principally in the difficult accessibility 
of the gland for experimental purposes, and further the fact that here we 
have to do with two organs intimately bound together and enclosed in a rigid 
bony cavity. A certain physiological independence of these two organs might 
be expected from their morphological and embryological independence. 
Hence we may speak of a hypophysial apparatus showing certain analogies 
with the thyroid apparatus (thyroid gland and parathyroid glands) and with 
the corresponding suprarenal apparatus (cortex and chromaffin medulla), 
hereafter to be described. The differentiation of the pathological mani- 
festations accruing to the two systems is made more difficult than that of the 
pathological manifestations affecting the other ductless gland groups because 
on account of the enclosure in a rigid cavity an affection of one of the organs 
seldom leaves the other entirely uninvolved. 
In an attempt to delimit and to explain the clinical pictures presented 
by the hypophysial apparatus the following four points seem to begin to be 
important, (i) The characteristic typographical relations, (2) the embryo- 
logical development, (3) a certain physiological independence, and (4) the mani- 
fold analogies that exist between the glandular hypophysis and the thyroid 
gland. 
Anatomy and Embryology.—The normal hypophysis of man weighs on 
the average somewhat more than 0.5 gm. It consists in a glandular anterior 
lobe and a nervous posterior lobe. Both lie in the sella turcica, into which 
cavity the dura penetrates through the foramen sellae turcica? and surrounds 
them both in common. From the anterior lobe a small process projects 
forward in the so-called peduncle of the hypophysis while the posterior lobe 
is directly in communication with the brain by means of the infundibulum. 
A tapering cleft, the recessus infundibuli, in communication with the third 
ventricle, penetrates deeply into the peduncle. 
The following scheme after Erdheim shows these relations: Ch. = 
chiasm; V.L. — anterior lobe; H.L. = posterior lobe; PI.eh = accumu- 
lations of squamous epithelium; R.C. = Rathke’s cyst; F = process; E = 
245 246 
THE DISEASES OF THE HYPOPHYSIS 
terminal enlargement of process; r.i. = recessus infundibuli; /. = infun- 
dibulum; D. = dura; D2 = diaphragma sellae; A. — arachnoid. 
The anterior lobe is supplied by small branches of the internal car- 
otid artery, the posterior lobe by vessels 
of the pia. The veins end in the sinus 
circulosus Ridleyi. Anterior and pos- 
terior lobes are surrounded by a capsule 
of the dura mater, which capsule over- 
hangs the entrance to the sellae in the 
form of a diaphragm that is perforated 
by the infundibular peduncle. 
The anterior lobe for the most part 
consists in epithelial columns. Here 
are found chromophilic cells in which 
Benda by the employment of a specific 
stain has demonstrated eosinophilic 
and basophilic granules. Here are also 
found cells that are non-granular: the so-called principal cells, which during 
pregnancy, according to Erdheim and Stumme, develop into the so-called 
pregnancy cells. 
Fig. 30.—Diagram of the structure of the 
hypophysis (after Erdheim). 
Fig. 31.—Anterior lobe of the hypophysis. E.C. = eosinophile cells. B.C. = basophile cells. 
C.C. = chief cells. 
Posteriorly the anterior lobe is delimited from the so-called pars inter- 
media by a poorly vascularized layer of connective tissue. The especial ANATOMY AND EMBRYOLOGY 
247 
histological character of the pars intermedia has been emphasized by Her- 
ring. Here are found follicle-like pictures filled with colloid. This cellular 
layer has also been called the cork layer or Peremeschko’s medullary layer. 
Here lies also the so-called Rathke’s cyst. 
The posterior lobe is made up of glial tissue and scattered cells, the 
character of which has not as yet been established, and of nerve fibers. 
The hypophysis of man undergoes characteristic alterations during 
pregnancy. First Comte, in six pregnant women, found enlargement of 
the hypophysis and multiplication of all the sorts 
of cells. Later Erdheim and Stumme made a 
careful study of the alterations. According to 
both these authors the enlargements affect only 
the anterior lobe. The differences in size are very 
appreciable. While the weight of the hypophysis 
in a nullipara is about 61.8 cgm. on the average, 
Erdheim and Stumme found it to be on the average 
84.7 cgm. in primiparae and 106 cgm. in multiparae. 
[Hibernation in animals produces changes in 
the cells of anterior lobe, as may also brooding 
in the hen {Bell)} The essential change in the 
pars anterior of all animals during pregnancy is 
towards greater activity, and this may be repre- 
sented by increased eosinophilia of the epithelial 
elements or by chromatophobia {Bell). That 
hibernation is a condition of pluriglandular in- 
activity is the opinion of Gemelli2 and Cushing 
and Goetsch}—-Editor.] 
Through its position the hypophysis shows 
special relations to the chiasm of the optic nerves 
and to the third and sixth cranial nerves. 
The embryological development of the hypo- 
physial apparatus is shown in the following three 
sketches, which are taken from the works of Erdheim and of Mihalkovic. 
Fig. 32.—Development of the 
hypophysis. 
i = infundibulum. 
h — Rathke’s pouch. 
x — boundary between epithelium originating from the primary 
ectodermal oral diverticulum and the entodermal head-gut. 
Pi = solid process (anterior lobe). 
g = hypophysial duct. 
x = original insertion of the hypophysial duct. 
1 Bell (W. B.). The pituitary; etc. New York Wm. Wood & Co., 1919. References to the 
subject matter of the above paragraph are quoted by Bell. 
2 Gemelli (A.). Su l’ipofisi delle marmotte durante il letargo e nella stagione estiva. Arch. p. 
le Sci. Med., 1906, Vol. XXX, No. 6, pp. 341-349. 
3 Cushing (II.) and Goetsch (£.). Hibernation and the pituitary body. J. Exper. Med. Sc., Vol. 
XXII, 1915, pp. 25-47. 248 
THE DISEASES OF THE HYPOPHYSIS 
pi = process of the grown-out [ausgewachsen] normal hypophysis. 
x = collection of accumulations of squamous epithelium, probably 
remnants of the hypophysial duct originating from the epi- 
thelium of the oral diverticulum, while the epithelium of the 
hypophysial duct is cubical. 
The nervous lobe of the hypophysis originates from the diencephalon. 
Here there develops a pouch-like protrusion (processus infundibularis), which 
during the fourth week adjoins a similar pouch originating from the epithe- 
lium of the oral diverticulum (Rathke’s hypophysial pouch). In the lower 
classes of animals there exists an intimate spatial relationship between the 
two, due to the fact that the infundibular peduncle, which in these animals 
is much better developed, is overlain in a cup-like manner by the epithelial 
part (see Edinger, Bau der nervosen Zentralorgane des Menschen und der 
Tiere, 2, Bd. 7 Edition, 1908). In man this intimate relationship between 
anterior and posterior lobes is by no means so extensive. Here principally 
the posterior lobe is very much less well developed. 
The question as to whether the pars intermedia belongs to the anterior 
or to the posterior lobe seems to me, according to what I can find in the 
literature as to this subject, as yet not cleared up. At all events the facts 
are important that on separation of the anterior lobe from the posterior the 
pars intermedia always remains with the posterior—a fact also mentioned 
by Cushing—and that, as had already been mentioned, the anterior lobe and 
the pars intermedia are always separated by a layer of connective tissue. 
This question seems to me to be a very important one from the clinical stand- 
point. As is known, the posterior lobe and the pars intermedia contain 
a substance that increases blood-pressure and acts as a diuretic, a substance 
that in its action shows a certain similarity to adrenalin. It is, therefore, not 
impossible that the pars intermedia possesses in its relation to the nervous 
system similar embryological relations to those which have been demon- 
strated for the chromaffin tissue. 
[A clear description of the anatomy and histology of the pituitary gland 
has been written by Atwell. He calls attention to the fact that the oral 
part of the gland consists in the pars intermedia, the anterior lobe, and the 
pars tuberalis, a thin layer closely applied to the infundibulum and the 
tuber cinereum, often completely surrounding the infundibular neck and 
extending forward to the optic chiasm. The pars tuberalis is characterized 
by its paired origin from two buds, which appear early at the ventral end 
of Rathke’s pocket, near the attachment of the epithelial stalk. As develop- 
ment proceeds they fuse and spread out to form a thin layer under the floor 
of the diencephalon and hypothalamus. It lies imbedded in the pia mater 
of the diencephalonic floor and except where it surrounds the neural stalk 
is separated from the main body of the gland by the arachnoid spaces and the 
dura mater forming the diaphragma sellae. It is distinctly more vascular 
than the part of pars intermedia which borders the residual lumen. One 
of its most striking characteristics is its acinic structure. It never invades ANATOMY AND EMBRYOLOGY 
249 
the neural tissue as does the pars intermedia, and unlike the pars intermedia 
contains no ectodermal supporting cells. It is believed that it is incapable of 
producing the effects on uterus, intestines, and blood-vessels characteristic 
of the posterior lobe complex. When fed to rats it does not produce the 
growth effects of the anterior lobe proper (Marinus). 
Although the pars intermedia belongs with the glandular 
part of the hypophysis, anatomically it is closely related to the neural lobe; 
with which it forms a physiologic unit and with which it is extracted to form 
the usual posterior lobe extracts. 
Atwell1 regards it established that some of the secretions at least, of the 
pars intermedia, pass through the posterior lobe. He does not regard as 
definitely demonstrated that these enter the cerebrospinal fluid directly. 
He points out that Bell combats Cushing and Goetsch’s view strongly. At 
all events it is not necessary to suppose that the secretion must pass through 
the cerebrospinal fluid before it enters the blood stream.—Editor] 
The analogy in the development of the glandular lobe of the hypophysis 
with that of the development of the thyroid is apparent. Both originally are 
glands with external secretion. Just as is the case with the hypophysial 
duct, the ductus thyreoglossus undergoes atrophy; this also leaves behind cell 
accumulations which consist chiefly of stratified plaster epithelium. Accord- 
ing to the recent investigations of Haberfeld the hypophysial duct may persist, 
especially when there are malformations of the skull. This has also been 
observed in acromegaly (Ettore Levi). It is of especial significance for the 
pathogenesis of acromegaly, as we shall see later, that accumulations of 
typical glandular epithelium may be found on the roof of the pharynx as well 
as along the persistent craniopharyngeal canal, from which accumulations 
may be formed adenomata. 
The glandular anterior lobe of the hypophysis is a true ductless gland. 
The opinion has been expressed that its secretion streams off through the 
posterior lobe. Against this speaks first the separate blood supplies, then 
the fact that the posterior lobe may be removed without the anterior lobe’s 
losing its function (Crowe, Cushing and Homans), and finally the observation 
of v. Cyon that in hypophyses of cattle and sheep the anterior and posterior 
lobes may be separated from each other by small plates of bone. It may well 
be supposed that, as is true for the external secretion of the thyroid, the exit 
channel for the internal secretion of the anterior lobe is formed by the lymph- 
vessels or the blood-vessels. 
The secretion of the posterior lobe would seem to pour out into the third 
ventricle through the recessus infundibuli. Cushing and Gotsch in animal 
experiments found that the cerebrospinal fluid increases the blood-pressure 
in a manner analogous to the action of infundibular extract. I would like 
to see demonstrated the fact that the cerebrospinal fluid acts as a diuretic as 
does pituitrinum infundibulare. [See remarks on Atwell’s article a few para- 
graphs above.— Editor.] 
1 Atwell (W. J.). Anatomical considerations of hypophysis cerebri. N. Y. M. J., Vol. CXIII, 
March 2, 1921, pp. 366-370 [Bibliography]. 250 
THE DISEASES OF THE HYPOPHYSIS 
a. Acromegaly 
Hyperpituitarism. Marie’s Disease 
Definition.—By acromegaly we understand a disease that is characterized by 
the gradual enlargement of the peaked [gipfelnde, i.e., peaked, acral] parts {nose, 
lips, tongue, lower jaw, hands and feet) and by hyperplastic alterations in the 
entire osseous system. There mostly develops an appreciable enlargement of the 
hypophysis, which leads to broadening of the sella turcica. Associated with this 
is localization of corresponding symptoms of brain pressure. To this are added 
very frequently alterations of the thyroid gland of a hyperplastic character, 
marked accentuation of the function of the interstitial glands; also, very frequently, 
loss of function of the genital glands after preliminary transitory increase of 
function, and, apparently frequently, hyperplasia of the suprarenal cortex. 
Also the condition of excitability of the vegetative nerves is sometimes increased 
in manifold ways. Very frequently there occurs rapid withering away of the 
body and manifestations of degeneration of manifold nature. The pathological 
anatomical finding in the hypophysis is an adenoma or adenocarcinoma of 
the anterior lobe. To-day we refer acromegaly to an increase of function of the 
glandular hypophysis. 
Occurrence.—Acromegaly is not a very rare disease. It does not seem to 
give preference to any country or to any race of people. It usually begins 
between the ages of twenty and forty years, most frequently between the 
twentieth and thirtieth year of life (Sternburg). According to this author 
it usually occurs in women later than in men. There are also rare cases 
of acromegaly that begin in the years of childhood or adolescence. These 
are of special importance. I shall refer to them in greater detail in the 
consideration of the pathogenesis. Hereditary or familial occurrence seems 
to be very rare. I have found very few statements as to this question in 
the literature and all these are very indefinite. Thus Arnold in 1891 described 
in detail a case of acromegaly that began in the eighteenth year of life. One 
of the patient’s brothers was affected with the same disease earlier in life. 
Also Frdntzel describes a case in which the affection began in boyhood; in 
the eleven-year-old daughter of which patient the disease was also recognizable. 
In this family were many individuals who were very tall. We find a state- 
ment of Schwoner’s that the mother of the female patient who was seventy- 
three years old apparently became sick with acromegaly at the age of fifty; 
the father of the patient was also very large. Frankel, Stadelmann and Benda 
state that the father of two blood relations of the case described by them was 
said to have shown the same anomaly. In the case reported by II. Salomon, 
we find the statement that the mother of the patient seems to have suffered 
with acromegaly and diabetes. 
Symptomatology.—I begin with a description of the alterations in the 
bones and soft parts. The alteration of the face in fully developed cases can 
be so marked that the individuals actually become unrecognizable. The nose 
is monstrously thickened, the superciliary arches and malar bones protrude 
markedly; this is chiefly dependent on an increase in volume of the pneu- ACROMEGALY 
251 
matic cavities. I refer to the X-ray illustration of Observation XXV in 
which the large frontal cavity is to be seen as a light space. Such an enlarge- 
ment may bring about narrowing of the auditory passages and of the orbits. 
In the case of youthful acromegaly described by Schultze and Fischer there 
occurred almost complete deafness probably due to the thickening of the 
internal ear. Also the cranial skull may increase essentially in circumference, 
so that the hats no longer fit. The sutures often close prematurely. The 
external occipital protuberance is in most cases enormously developed. The 
narrowing of the orbits may bring about exophthalmus although this may be 
also brought about by other causes such as enlargements of the eye-balls and 
stagnation in the cavernous sinuses {Benda). In many of the cases associated 
with symptoms of Basedow’s disease the cause of an existing exophthalmus 
may be due also to a heightened tonus of the Midler-Landstrdm muscle. The 
great variation that the exophthalmus shows in such cases may be as well 
explained in this manner as by the cause assigned by Benda. 
Very characteristic is the spreading apart of the teeth on account of the 
enlargement of the upper jaw, especially of the lower jaw. [See Fig. 33.— 
Fig. 33.—Showing separation of teeth mil. I. Goldstein's case of acromegaly and lymphatic leukemia 
(The left side of the mouth is too dark.) 
H. I. Goldstein’s case of acromegaly and lymphatic leukemia.—Editor.] On 
account of the marked prognathia of the lower jaw, and on account of the 
oblique position of the alveolar process due to this, chewing becomes almost 
impossible. The mucous membrane of the oral cavity is for the most part 
thickened, the tongue can so increase in size that in spite of the enlargement of 
the jaws it projects over the teeth. The mucous membrane of the tongue 
becomes thickened, the papillae are enlarged, the microscopic examination 
showed enormous proliferation of the interstitial tissue, while the muscle fibers 
show, at least in the later stages, signs of atrophy and degeneration. On 
account of the thickening and the weight of the tongue articulation may be 
affected. The larynx is often considerably enlarged, the voice is deep and, on 
account of the resonance in the enlarged pneumatic spaces, abnormally loud. 
This is true for both male and female individuals. The clavicles, especially, 
are enlarged. Often there develops rather quickly a pronounced kyphosis of 
the lower cervical and upper thoracic spine and a lordosis of the lumbar spine. 
Then, too, there may occur ankylosis of the vertebral bodies. The ribs 252 
THE DISEASES OF THE HYPOPHYSIS 
are thickened and broadened. Very characteristic is the tremendous thicken- 
ing of the places for the insertion of the muscles, the widening of the vascular 
foramina and the deepening of the vascular furrows (Sternberg); the entire 
osseous system can be enlarged in all dimensions as in the cases of Schultze 
and of Fischer. 
On the hands only the soft parts are considerably thickened, the thicken- 
ing occasioning a spreading apart of the metacarpal bones. The' hands 
become paw-like. The X-ray picture does not show anything especially 
beyond a slight thickening of the places of muscular insertion (type en large, 
Pierre Marie), (see St, Observation XXX, reported later). In other cases 
there is in addition to this an increased growth in length, leading to a true 
giant hand (type en long see Ti, Observation XXV). Here are found both 
lengthening and broadening of the hands and feet. Launois and Roy find the 
type en long in acromegalic gigantism. The feet may behave similarly. 
Fig. 34.—Before acromegalic changes occurred. (H. I. Goldstein’s case.) 
X-ray examination of the skeleton shows a thickening of the walls of the 
skull, enlargement of the pneumatic cavities, increase in size of the lower jaw 
and broadening of the epiphyses of the long bones, formation of osteophytes 
on these, thickening of the phalanges of the fingers and toes (Schuller); in the 
later stages of acromegaly there is found considerable atrophy of the osseous 
structure; on section Deitrich found especially the spongiosa atrophic. He 
regards this as neuropathic atrophy. Frdnkel, Stadelmann, and Benda in 
each of four cases found pronounced atrophy, in one case distinct porosis and 
always formation of osteophytes. 
As in the later stages the muscles of the arms and legs are for the most 
part markedly atrophic, the amorphic condition of the extremities becomes 
that much the more conspicuous. 
As example of the skeletal alterations in acromegaly I cite the following 
case:—[See also the pictures of H. I. Goldstein’s case of acromegaly and lymph- 
atic leukemia.'—Figs. 34 and 35.—Editor.] ACROMEGALY 
253 
Observation XXIV.-—-V. U., thirty-two years old, entered the clinic Jan. 10, 1912, car- 
penter. No hereditary predisposition to disease, no similar sickness in the family. Married 
seven years. One year after the marriage a child was born that died soon after birth. One 
illegitimate child is ten years old. 
The present disease began seven years ago with a feeling of furriness in both hands, 
formications, and a characteristic sensation of stillness especially in the morning. For 
some months severe pains in the hands and forearms so that the patient had to get up often 
at nights and walk about the room. Soon afterward the patient noticed gradual enlarge- 
ment of the hands, and a short time after this the chin became larger so that chewing was 
done only with the lateral teeth, as also the jaw was pushed forward. The pains and pares- 
Fig. 35.—Showing acromegalic face, thick lips, heavy jaw, long hands of the paw-like type. 
{II. I. Goldstein's case of acromegaly and lymphatic leukemia—Note hairiness is not marked, as 
is also the case in Figs. 36 and 37.) 
thesias were always worse in summer than in winter. For five and one-half years gradual 
loss of libido, and later loss of credibility of the penis. Entirely impotent for jive years. The 
acromegalic alterations greatly increased in intensity. The patient denied headache and 
disturbances of vision. Lately there have reappeared drawing pains, especially in the knees 
and ready fatigability; in addition to these, severe sweats. Alcoholism; patient denies 
lues. 
Status.—168 cm. tall, coarsening of the facial features, cushioning of the lips, circum- 
ference of the skull 58 cm. Marked protrusion of the orbital borders and the frontal pro- 
tuberances. Circumference of the skull from the point of the chin to the top of the occiput 
74 cm. Nose coarse, large, lower jaw markedly protruding, lower row of teeth is 1.5 cm. 
anterior to the upper row. The lower incisor teeth gape 3 mm. Tongue markedly thickened 
and broadened and on account of the thick tongue, articulation is poor. Uvula broad, 
tonsils enlarged, neck broad and compressed 34U2 cm. in circumference. Submaxillary 
glands palpable. Thyroid enlarged, left lobe more enlarged than right. 
The skin and visible mucous membranes somewhat pale. The skin rather thick but 254 
THE DISEASES OF THE HYPOPHYSIS 
may be readily raised from the underlying tissues in great thick folds. The hair of the 
head rather abundant, the hairiness of the genitalia rather marked and also the thigh and 
legs are rather pronouncedly covered with hair. 
Distinct kyphosis of the upper dorsal part of the vertebral column, slight lumbar 
lordosis. Thorax is barrel shaped, compressed, reaching deep downward in front. Cir- 
cumference of the thorax at the level of the nipple is on deep inspiration 104 cm., on 
strong expiration 101 cm. The clavicles are markedly thickened. The ribs and the inter- 
costal spaces are striking broad. The upper and lower extremities have taken on in circum- 
ference in their distal parts. Abnormal breadth of the middle of the hand. Circumference 
Fig. 36. 
Fig. 37. 
Case of acromegaly (Observation XXIV) 
of the middle finger cm. Right hand displaces 625 cc. of water, left hand 640 cc. of 
water. X-ray examination shows chiefly hypertrophy of the soft parts. The metacarpi 
are biscuit-shaped on account of the pressure of the increased soft parts and decrease in 
size at their diaphysial portions. Also the middle portion of the foot is enormously 
broadened, showing a similar picture to the X-ray. Enormous thickening of the toes. 
Transverse diameter of the heart to the X-ray 13 cm. Otherwise cardiac findings normal. 
A slight decrease of tachycardia. Liver and spleen not palpable. On X-ray examina- 
tion the stomach is not enlarged. 
Examination of the eye. (Docent Ulbrich) O. D. %, O. S. Jf0- External halves of 
the papillae pale, with however a large physiological excavation so that the diagnosis paling 
is not possible. Visual fields for white and colors are normal. 
X-ray Examination of the Skull.—Enormous enlargement of the entire skull, especially 
the facial bones. Sella turcica enlarged to the size of a gulden. Clivus sharpened. 
Erythrocytes, about 4,500,000. 
Hemoglobin, 75 per cent. ACROMEGALY 
255 
Leucocytes, 6,240 of which: 
Polymorphonuclear neutrophiles, 57.6 per cent. 
Lymphocytes, 25.4 per cent. 
Large mononuclears, 15.7 per cent. 
Eosinophiles, 1.3 per cent. 
Examination as to alimentary glycosuria was unsuccessful, as the patient vomited 
No sugar in the urine on the administration of a diet rich in carbohydrates. 
Pulse between 90 and 100. 
Examination of the exchange of gases (Dr. Bernstein). 
co2 
0 
Respiratory 
C02 
o2 
quotient 
235-7 
288.8 
0.816j 
240.7 
296.3 
Q-793 
3-I56 
3-857 
243.2 
298.4 
0.781j 
The examination of the elimination of uric acid on a purin-free diet shows a marked 
increase of the endogenous factor. This lies higher than double the normal average (Novae- 
zinsky and Falta).1 
Examination of the ammonia amino-acids and polypeptid elimination shows normal 
relations as may be seen by few figures here adduced. 
N 
N(NH3) 
N. (amino acid) 
N. polyp. 
16.64 gm. 
0.7202 
0.2718 
0.0683 
18.65 gm. 
0.6902 
0.2842 
0.1561 
On Feb. 28, a portion of the hypophysis of the patient was removed by the endonasal 
route by Dr. Hirsch. 
Mar. 5, the patient was retransferred to the clinic. 
Mar. 15, patient has fallen off in weight and the acromegalic symptoms have not as 
yet retrogressed. Several times at the beginning the patient showed a rise in temperature, 
but at present the temperature is normal. Headaches at times. Examination of the 
purin metabolism shows just as decided an increase of the endogenous elimination of uric 
acid as before the operation. 
In many cases the muscle strength is not diminished in the. initial stages. 
Sometimes such individuals show even an extraordinary strength. There is, 
however, from the beginning a gradually increasing and rapid fatigability, and 
in the later stages such individuals cannot long follow their occupation on 
account of muscular weakness. Microscopically such muscles show increase 
of the connective tissue and degeneration and atrophy of the muscle fibers. 
Arnold describes vacuolization, multiplication of the nuclei, and atrophy of 
the muscle fibers, increase in the number of nuclei, and growth of interstitial 
connective tissue, also the occurrence of fat cells in the connective tissues. 
Also in the skin are found, especially in the acral parts, sclerotic processes 
affecting both the epidermis and cutis. The papillae are enlarged, and the- 
sclerosis extends to the nerves and vessels and to the connective tissue fasciculse 
surrounding the glands. Frequently abnormal pigmentations are found. In 
spite of sclerosing processes the skin may be readily raised up in folds, which 
fact is important in the differential diagnosis from myxedema. In the later 
stages true myxedematous alterations of the skin are found not rarely (see 
below). 
1 On the administration of sodium nucleinate there was a prompt and rather high increase of the 
uric-acid elimination 256 
THE DISEASES OF THE HYPOPHYSIS 
Fig. 38.—X-ray picture of hand in acromegaly (Observation XXV). ACROMEGALY 
257 
Pierre Marie found mollusca pendula in numerous cases. The secretion of 
the sebaceous glands is increased (see below for information concerning in- 
creased sweat secretion). 
The growth of hair on the head is often remarkably dense, and the individual 
hairs are thick. In the course of the 
disease abnormal hair growth occurs 
on the trunk and extremities, as may 
be seen in the following observation. 
Observation XXV.—T., thirty-one 
years old, cobbler, entered the clinic 
Dec., 1911. First admitted Nov. 16, 
1905. Since 1903 gradual enlargement 
of the hands. All military gloves were 
too small for him. Also face has become 
broader, nose and lips have become larger, 
weight somewhat less. Headache, pig- 
mentations of the skin, thyroid slightly 
enlarged. Eye-grounds normal. No 
hemianopsia. Sella turcica uniformly 
enlarged to the size of a cherry. The 
dorsum sellae thinned. The clinoid 
processes pushed backward. Skeleton of 
the hands and feet show appreciable 
thickening of the soft parts. 
Nov., 1907. Headache has become 
much more severe. The hairiness of the 
body has increased markedly. The hairs 
are brittle. Marked hairiness of the 
genitalia, abnormal hair ness of the abdomen 
and extremities. 
Arcus superciliares enormously devel- 
oped. Nose enlarged. Lower jaw slightly 
prognathous. Cushion-like ear lobules. 
Mustache bristly. Hairiness of the linea 
alba very strong. Very [deep wrinkle 
formation on forehead. Potency entirely 
normal. 
Sella turcica deepened three times 
more than is normal. Dorsum sellae 
much thinned and elongated. 
Alimentary glycosuria negative. 
Dec., 1911. During the last year the 
hairiness has become even denser. Libido 
ts unaltered, the potency has decreased 
slightly. Typical acromegalic alterations 
of the skeleton and the soft parts, no tachycardia. Slight enlargement of the thyroid gland. 
Investigations of the Exchange of Gases {Dr. Bernstein). 
Fig. 39.—Abnormally strong growth of hair in 
acromegaly (Observation XXV). 
co2 
02 
RQ 
Per kg. of body weight 
CO, 0, 
233 • 5 
288.7 
0.809 
275 • 5 
342.0 
o-753 
2-733 3-55 
266.7 
329.8 
O 
00 258 
THE DISEASES OF THE HYPOPHYSIS 
Fig. 40.—Widened sella turcica in acromegaly (Observation XXV). ACROMEGALY 
259 
Alimentary glycosuria strongly positive (0.78 gm. dextrose). 
Erythrocytes, 4,490,000 
Hemoglobin, 95 per cent. 
Leucocytes, 4900, of which: 
Polymorphonuclear neutrophiles, 56.7 per cent. 
Lymphocytes, 30.5 per cent. 
Large mononuclears, 12.6 per cent. 
Eosinophiles, 0.2 per cent. 
Investigation of the elimination of uric acid on purin-free diet shows values between 
0.72 and 0.97 gm.—therefore is very appreciably increased. 
Fig. 41.—Case of acromegaly (Observation XXV). 
The following is an additional example of abnormal hairiness in acromegaly. 
Observation XXVI.—I. Bo., thirty-one years, entered May, 1911. The sickness began 
in 1905. First enlargement of the fingers, then, about simultaneously, enlargement of the 
feet, the skull, the nose, the neck. In 1908 began enlargement of the lower jaw. Also 
the ears became somewhat thickened. Since 1909 the forearms and the metatarsus, too, 
have grown. Also the circumference of the chest has increased and the hairiness of the 
trunk has become essentially stronger. Number of collar formerly 4r, now 46. For two 
or three years on every psychical excitement, and less on every bodily movement instantaneous 
occurrence of outbreaks of sweats; potency not entirely normal since the age of twenty, since 
the beginning of the disease rapid diminution of libido, and now it is lost utterly. Appetite 
increases at times. In 1910 thyroidin administered at home; this led to palpitations of the 
heart, that have persisted to the present. Thyroidin also acted unfavorably on the sweats. A 
cousin of his father’s also suffered from acromegaly. For six or seven months headaches on 260 
THE DISEASES OF THE HYPOPHYSIS 
the vertex and occiput. Power of attention has considerably decreased. Often cramps of 
the musculature of the feet, and calves, and sticking pains in the bones of the hands and feet. 
Moderately compact body build. Head enormously big. Orbital margins protrude. 
Root of nose very much broadened. Nose very thick, lower jaw extraordinarily massive. 
Lower row of teeth about 2 cm. forward; the teeth of the lower jaw stand far apart from one 
another. The color of the face is pale. Hair of the head dense and turns gray easily. Cir- 
cumference of the skull 62.5 cm. Circumference of the neck 45 cm., larynx enlarged. 
Thyroid gland not enlarged. Enormous growth of hair on thorax. Circumference of the 
thorax 107 cm. on inspiration, 97 cm. on expiration. Large erectile nipples. 
Tulse 56. Extremities enormously thickened in the distal parts. 
Fig. 42.—Abnormally strong growth of hair in acromegaly. 
For example: Circumference of each thumb 8.5 cm., circumference of middle finger 
8.5 cm. 
Erythrocytes, 5,210,000. 
Hemoglobin, 85 per cent. 
Leucocytes, 8840, of which: 
Polymorphonuclear neutrophiles, 63.8 per cent. 
Lymphocytes, 29.7 per cent. 
Large mononuclears, 4.2 per cent. 
Eosinophiles, 2.3 per cent. 
Alimentary glycosuria (xoo gm. dextrose) negative. 
Pituitrinum infundibulare (2 cc.) on influence no diuresis, no glycosuria. 
X-ray examination (Docent Schuller) skull thick with enormous frontal sinuses. Sella 
markedly widened, dorsum sellae lengthened, coarse, reclining; anterior clinoid process 
broad, no sphenoidal sinuses. ACROMEGALY 
261 
Eye examination (Prof. Sachs). Vision and field of vision normal. 
Operation was undertaken by Dr. Hirsch on May 29, under local anesthesia, by the 
endonasal route. For the details I refer to O. Hirsch’s publications. The cavity made 
in the hypophysis by operation reached about 2% cm. in the sagittal and 1% cm. in the 
vertical diameter. The temperature rose to 38.0° transitorily, falling back to normal 
in a few days. On June 2, the patient already made the observation that the size of the 
end-phalanges of the fingers had decreased. There must also have occurred a diminution 
in the size of the feet, for the slippers, which were formerly too small, now fit him. On 
June 3, the patient observed that his hat, that also had been too small, now fell down on 
his forehead. On June 9, an improvement in the attention became apparent. The patient, 
who was a doctor of mathematics, could, before the onset of his illness, repeat all of 12 
two-digit figures that were told to him at intervals of five seconds. Before the operation 
he could remember only 7. Now he regularly repeated 11. June 11, the greatest circum- 
ference of the head which before the operation reached 62.5 cm., is now 61.4 cm. The 
greatest circumference of the neck, formerly 46 cm., now is 43 cm. The water displacement 
of the hands which formerly was 700 cc. is now 600 cc. The thickenings about the eyes 
have now retrogressed, and the soft parts of the cheeks and chin have also distinctly fallen 
off. On June 19, the patient left for his home. 
Histological examination of the material obtained on operation (D. Erdheim)showed 
an adenoma consisting in small round cells that look alike, with round vesicular nuclei 
and a well-developed protoplasm; at regular intervals the tissue is permeated with blood- 
vessels with capillary walls, giving to the tumor a trabecular, in some places on alveolar, 
appearance. At places proliferation and hyaline degeneration of the stroma, often with 
extensive hemorrhage. I mention briefly, from the patient’s report in July that the sweats 
have improved considerably, from his report in August that the circumference of the head 
has decreased still more, the thirst has subsided, but there has been no alteration in the 
vita sexualis. In January, 1912, he reported that retrogression of the acromegalic mani- 
estations had not gone further; that lately even an aggravation had set in, this consisting 
in the fact that the tongue had become thicker, the mental attitude was that of depression, 
the thirst had again become greater, but there was no more polyphagia. 
Often too the eyebrows became bushy. In women often hairs develop 
on the upper lip, and bristly hairs on the chin and on the lower lip, similar to 
the chin-beard in man, also hairs on the cheeks, and especially on the inner side 
of the thigh and even on the linea alba (also a case of Stumme’s). This 
occurrence of abnormal hairiness in women is illustrated by the following 
case: 
Observation XXVII.—E. T., thirty-three years, entered Nov., 1909. Menstruated 
first at the age of twelve years, followed regularly at intervals of four weeks, the flow lasting 
eight days, profuse. Lues at the age of nineteen years, primary sore on the left labium 
minor, twelve injections, after six weeks papules in the genitals, nineteen inunctions. The 
end of 1895, an abortion, and 1898 apparently a purulent parametritic exudate, 1907 another 
abortion. 
The present illness began in 1902 and within one-half year had attained almost its 
present intensity. First paresthesias in the upper extremities and shoulders, then thick- 
ening of the fingers, so that the patient had to discard her rings. A half year later en- 
largement of the feet, so that the shoes became very much too small. At the same time 
occurred enlargement of the lips and nose. The circumference of the neck had increased 
about 4 cm., the abdomen also became thicker, and hair began to gvow on the breast and 
calves. The breasts did not become especially larger, but milk began to be secreted by them. 
Periods extremely irregular, at one time remained away for seventeen months, libido at 
first increased, then diminished. The voice right at the onset became deeper. Lately 262 
THE DISEASES OF THE HYPOPHYSIS 
frequent outbreaks of sweat. Occasional voracious hunger and great thirst. Often frontal 
headache. 
Typical acromegalic appearance. Hands and feet enormously large. Skin very 
moist, marked hairiness of both arms, hairs between the breast and on the genitals, the hairs 
of the mons veneris reach as high as the navel. Hairiness therefore that of a man. Circumanal 
and perineal hairs abundant. Also the leg is markedly covered with hair. Nose and lips 
markedly thickened, lower jaw protrudes rather strongly. The incisor teeth of the lower 
jaw are far apart from each other. Tongue very much more enlarged. Thyroid enlarged. 
Colostrum can be expressed from the breasts on light pressure. Eye-grounds and field of vision 
normal. Lordosis of the lumbar spine. Enlargement of the nose and lower jaw, hands, and 
feet. X-ray: Sella turcica much widened, as big as a crown piece. The posterior clinoid 
process consumed. 
Dec. 3.—100 gm. dextrose—3.58 gm. dextrose in urine. On a purin-free diet the values 
of uric acid were 0.765, 0.720, 1.204, 1.296, 1.050, 1.097, 1.080, 0.762, 1.155, 1.011,0.855. 
Blood examination erythrocytes, 4,975,000. 
Hemoglobin, 12 gm. 
Leucocytes 5600, of which: 
Polymorphonuclear neutrophiles, 76 per cent. 
Lymphocytes, 22 per cent. 
Eosinophiles, 2 per cent. 
Fig. 43.—Case of acromegaly. 
Dec. 8—o.ooi gm. adrenalin subcutaneously. Pulse gradually rose from 72 to 102. 
Blood-pressure’from 95 to 115. After twenty minutes return to normal. Slight head- 
ache, tremors, slight arrhythmia, considerable increase in diuresis, no sugar. 
Abundant carbohydrate diet lead to glycosuria. 
Dec. 14—0.001 gm. adrenalin subcutaneously. Pulse from 72 to 96, blood-pressure 
from 115 to 125, slight headache, slight arrhythmia, no sugar, diuresis from 950 to 2000. 
Dec. 15—1 cc. pituitrinum infundibulare, marked diuresis, no sugar. 
Dec. 16—100 gm. dextrose, sugar strongly positive. 
Dec. 17—100 gm. dextrose, in urine 2.1 gm. dextrose. 
Dec. 21—0.01 gm. pilocarpine, moderate sweating, moderate flow of saliva. ACROMEGALY 
263 
Very noteworthy in acromegaly are alterations in the genitalia, that is, 
the manifestations that may be ascribed to functional alterations of the sexual 
glands. We shall see later that for the comprehension of especially the genital 
disturbances in acromegaly and for the pathogenesis and theory of acromegaly 
in general there seems necessary a sharp distinction between the function of 
the interstitial glands and the generative glands, at least so far as this is possible, 
according to our present-day knowledge. As will be seen from the description 
of the alteration in the hairiness, there is almost never found in acromegaly a 
retrenchment of the so-called secondary sexual characters and a retrogression 
of the external genitalia. An exception to this is perhaps certain cases of 
acromegaly in childhood, which I shall speak of in detail later. In acromegaly 
of adults, on the contrary, there is mostly sharp accentuation of the secondary 
sexual characters. As has been mentioned there is often seen a strikingly 
strong development of the hairs of the beard; the axillary hairs, the hairs on the 
genitalia and on the perineum grow more strongly, and often there develops 
a marked hairiness along the linea alba; the hairiness in women, as v. Noorden 
mentions, often assumes in this case a virile type. Moreover the external 
genitalia often show a distinct hyperplasia. The penis, the labia majora and 
the clitoris may appreciably increase in dimensions. 
These phenomena persist until the end of the disease. In certain cases we 
can at least say that a distinct retrogression does not occur. 
The function of the glands of generation behaves otherwise. Here we 
mostly find premature lessening or loss of function. There are, however, 
numerous exceptions, that I shall speak of first. At the beginning of the dis- 
ease there is found not at all rarely signs of the increased function. Thus 
there was for instance at the beginning, in the case of Buday and Janczo (acro- 
megalic gigantism) increased potency. 
In women, too, libido may be increased at the beginning; I here allude to 
Observation XXVII. In this case the illness had lasted seven years; in spite 
of this menstruation, although irregular, persisted; the libido at first increased, 
later decreased. Colostrum could be expressed from the breasts. Cases of 
persistent galactorrhea have been described by Gajkievicz and Fazio. In other 
cases the function of the glands of generation last until in the fully developed 
disease. I refer to Observation XXV. In this case the disease began in 1903, 
in the year 1907 the potency and libido were entirely normal, 1911 the libido 
was as yet entirely retained, but the potency had to a certain extent diminished. 
In such cases signs of increased activity of the sexual glands may be found 
at autopsy. Thus Schultze and Fischer state that in a man aged fifty-six 
(Case 2) in whom the acromegaly had lasted seven years, strikingly abundant 
spermatogenesis was to be found in the testicles, and the prostate was enlarged 
and in a condition of abundant secretion. 
The following case, although not so instructive, seems a further example of 
the preservation of the generative function: 
Observation XXVIIIF. Da., thirty-eight years old. Ambulant patient in 1911. 
lor nine years married, three children. Wife has had one abortion; for about one and 
one-half years the hands and feet have become thickened, etc. Collar number has risen 264 
THE DISEASES OF THE HYPOPHYSIS 
from 41 to 44, hat number from 55 to One year ago the incisor teeth spread apart 
from each other, and the lower jaw projected. Often polydipsia. Dyspnea on ascending 
stairs. More readily excited than formerly. Body weight has increased from 7 kg. to 
83 kg. Arching of the chest has increased. Potency not altered. Typical acromegaly. 
External genitalia strongly developed, large amount of hair on them. 
Erythrocytes, 5,300,000. 
Hemoglobin, 90 per cent. 
Leucocytes, 8100, of which: 
Neutrophiles, 74 per cent. 
Lymphocytes, 20 per cent. 
Eosinophiles, 6 per cent. 
Test as to alimentary glycosuria (100 gm. dextrose)—in urine 1.3 per cent. = 0.88 
gm. 
Eye findings normal, sella turcica almost the size of a gulden piece. 
Fig. 44.—Case of acromegaly (Observation XXIX) 
Menstruation may be present for a long time in acromegalic women. In 
Becker's case the menstruation ceased as late as eighteen years after the begin- 
ning of the affection; in a case of Dobbelin’s there was entirely normal genital 
function. A short time ago I even saw a case in which it was very likely that 
in a course of a very chronic acromegaly conception had occurred several times, 
and children had been carried to term. I here quote the case in extenso: 
Observation XXIX.—S. Ad., fifty-six years old. Entered the clinic Oct., 1912. The 
father of the patient seems to have been rather vigorous, and in his later years his condi- 
tion seems to have exhibited some resemblance to the patient. From the age of fifty- 
six years on his face became broader. He died of pneumonia in his seventieth year. Nc ACROMEGALY 
265 
ductless glandular diseases in the family. The patient has seven brothers and sisters, 
all well. She has five children, the first child born when she was in her twenty-eighth year, 
the last when she was in her fortieth year. All the births were normal, and all the children 
were well developed. Menstruated first at the age of twenty-two years, the menses were 
always rather profuse, lasting two to three days, and occurring regularly every four weeks, 
menopause at the forty-sixth year. For two years headaches, especially at the roof of the 
Fig. 45.—Widened sella turcica (Observation XXIX); neighborhood of sella retouched. 
skull of the right side, which headaches have increased in intensity. The pains now exist 
day and night and for the most part are so intense that the patient cannot sleep. During 
the last four to five months she has always remained in bed on account of these headaches, 
and on account of the fact that when she attempted to get up she would suffer with attacks 
of vertigo. The patient had also had headaches for some time before this but she did not 
give them much attention. She states definitely that the enlargement of the hands and 266 
THE DISEASES OE THE HYPOPHYSIS 
feet developed gradually between the twentieth and thirtieth year of life. At the time of the 
birth of her first child in her twenty-eighth year the hands and feet were much larger and 
thicker than at present, and have gradually decreased in circumference. Also the prognath- 
ism of the lower jaw has existed since that time. She never suffered from sweats or from 
pains in the extremities. 
The patient looks at least fifteen to twenty years older than she is. Height 145.5 
cm., span width 150.5 cm. Layer of fat well developed. Skin pale, smooth, and dry, 
musculature weak, build of bones medium, considerable kyphosis; the extremities are 
extraordinarily heavy, head large, fronto-occipital circumference 56 cm., nose large with 
broad insertion; distance from between the eyebrows to the tip of the nose 5.8 cm.; breadth 
of the nose 4.5 cm., distinct prognathism. From temporomaxillary joint to temporomaxillary 
joint, over chin, 26 cm. Lower lips thick, cushiony, and prominent. The teeth are in 
greater part absent, the two lower incisor teeth are present and are spread apart from each 
other. The clavicles are rather broad; the extremities extraordinarily awkward. The 
fingers are markedly thickened and the X-ray shows that the thickening affects the weak 
spots exclusively. The metacarpal bones are pushed apart from each other, only very 
slight bone formation at the seat of the muscular insertions. Also the feet are awkward. 
Axillary hair and pubic hair well developed. Isolated hairs on the upper lips. Slight 
arteriosclerosis. 
Alimentary glycosuria (100 gm. dextrose), 0.8 gm. 
Blood findings: Leucocytes, 9800, of which: 
Polymorphonuclear neutrophiles, 66 per cent. 
Lymphocytes, 30 per cent. 
Large mononuclears, 3 per cent. 
Eosinophiles, 1 per cent. 
One week later repetition of the test for alimentary glycosuria after two injections 
4 cm. pituitrinum glandulare intramuscularly (ioo gm. dextrose) 0.9 gm. 
X-ray examination of the skull (Dr. Schwarz): Widening of the sella turcica to the size 
of a 2-crown piece. Deepening of the floor of the sellae, processus clinoidei sharpened. 
Entrance to the sellae widened. 
Eye examination (Docent Ulbrich) papillae normal, the inner borders slightly effaced 
and slightly prominent. Nothing certainly pathological; on the contrary, vision O. D. 
6, O. S. but there is an old trachoma with corneal scars; visual field on each side, so 
far as can be tested, normal; also normal for colors. 
The examination of the uric-acid elimination on purin-free diet shows values between 
0.4-0.5 gm., therefore no increase. 
As far as I have been able to find, a similar case of conception in acromegaly 
has been reported only by Pirie. 
However, in the great majority of cases of acromegaly, as has already been 
mentioned, there occur sooner or later signs of extinction of the function of the 
generative glands. This may occur even early, constituting a differential 
diagnostic difficulty. In man there soon occurs lessening or complete loss of 
potency and libido, and in woman amenorrhea. As the latter is attended with 
a cessation of ovulation, it may very well be supposed that as yet no case of 
conception has been observed in an amenorrheic acromegalic woman. 
In such cases the sexual glands and the internal generative organs gradually 
atrophy. Tandler and Grosz found total retrogression of the primordial follicles 
and cessation of the formation of Graafian follicles, and in man alteration of 
the epithelium of the seminal tubules and, finally, also alteration of the inter- 
stitial cells. On gynecological examination the uterus is usually found to be ACROMEGALY 
267 
small. Not rarely cystic degeneration of the ovaries is also present. Atrophy 
of the internal genitalia was found in 36.4 per cent, of 118 cases, according to 
the statistics of Creutzfeldt. 
That even on long-continued amenorrhea the follicular apparatus may not 
degenerate entirely is shown by a case of Cagnetto; menstruation ceased at the 
age of nineteen years; at the age of forty-six years it reappeared and continued 
to the age of forty-eight years, when it disappeared for good; autopsy showed 
cystic degeneration of the tumor of the pituitary; in this case it is not unlikely 
that the hyperfunction was restricted by the cystic degeneration. 
We may therefore briefly sketch the relation between hypophysis and sexual 
glands, thus: Increased activity of the hypophysis stimulates the activity of 
the interstitial glands (apparently also the suprarenal cortex). The glands 
of generation are sometimes also stimulated to increased activity at first, but 
more often the activity is suspended. Conversely we find that on increased 
activity of the sexual glands there is also increased activity of the hypophysis. 
I believe, in opposition to the prevailing teaching, that there is in pregnancy, 
an increased activity of the sexual glands, as I regard the developing fetus as a 
prolonged ovulation (see chapter on the sexual glands)—there is found enlarge- 
ment of the hypophysis and signs of an increased function of that organ, 
coarsening of the facial features, etc. (Tandler and Grosz). Indeed a transitory 
acromegaly may even occur during this period. Such a case is reported by 
R. Marek. Pronounced acromegalic symptoms occurred during pregnancy 
in a twenty-seven-year-old primipara. Nose, tongue, and jaws became larger, 
the teeth spead apart, the hands and tongue increased in circumference, the 
tonsils swelled; glycosuria, lassitude, sleeplessness and insomnia, and also 
drawing pains in the muscles appeared. All signs disappeared during the 
puerperium. 
In such cases of formes frustes of acromegaly during pregnancy, we may 
think very plausibly of an existing predisposition; we might also be inclined 
to believe that repetition of the pregnancy would lead to permanent manifes- 
tation of the disease. 
Goiters and alterations in the junction of the thyroid occur in acromegaly with 
great frequence. The development of the goiter may occur about simulta- 
neously with that of acromegaly, and thus symptoms of hyperthyrosis or hypo- 
thyrosis may become manifest simultaneously with acromegalic symptoms. 
Manifestations of a slight hyperthyrosis in acromegaly are especially common. 
Magnus-Levy and Salomon have especially directed attention to this subject. 
Later, in the consideration of the manifestations on the part of the vegetative 
nervous system, we shall see that among the more frequent symptoms in 
acromegaly are sweats. We shall have to consider, however, whether we are 
justified in regarding them as a symptom of a simultaneous hyperfunction, and 
whether they do not signify rather than certain organs of supply of the vegeta- 
tive nervous system are not directly influenced by the irritation of these nerves, 
on account of the hyperfunction of the hypophysis. A tachycardia might be 
regarded as a surer symptom of hyperthyrosis especially when there exists 
thyroid swelling and increased fall in blood-pressure. 268 
THE DISEASES OF THE HYPOPHYSIS 
In case U (Observation XXIV) the thyroid was enlarged. There existed 
profuse sweats and a slight grade of tachycardia. Slight enlargement of the 
thyroid was present also in case T, Observation XXV, but in thiscase symptoms 
of hyperthyrosis was not distinct. 
Fig. 46.—X-ray picture of the hand in acromegaly (h> natural size). 
Of the remaining symptoms of Basedow’s the following have been stated to 
have occurred in the course of acromegaly: tremor, transitory rises of tempera- 
ture, cardiac palpitation, increased psychical irritability. 
The following is a very instructive example of the simultaneous develop- 
ment of acromegaly and a slight hyperthyrosis. ACROMEGALY 
269 
Observation XXX.—M. St., thirty-seven years old. First admission at hospital in Dec- 
ember, 1896. Menses appeared first at the eighteenth year, and were regular up to the 
twenty-fourth year of life. From then on they remained absent. At the thirty-first year 
tearing pains in all the members appeared, especially at night. The fingers were swollen, 
Fig. 47.—Dilated sella turcica in acromegaly (Observation XXX). 
and there were sometimes intense sensations of heat. Since that time there have existed 
severe headaches. Finally there developed about this time a goiter. In addition there 
appeared pains in the neighborhood of the thyroid gland, which recurred every month. Lately 
forgetfulness, lassitude, and weakness. The motor power has weakened. 
Typical acromegaly and thickening of the nose, hands, and feet. Circumference of the 
throat 44 cm. Slight degree of anemia. (Hemoglobin 65 per cent., erythrocytes 4,00c,- 270 
THE DISEASES OE THE HYPOPHYSIS 
ooo.) Enormous struma of the thyroid, both lobes diffusely enlarged, with circumscribed 
nodules, no hemianopsia, no disturbances of vision. Slight kyphosis. 
Second admission, March, 1892. Now marked kyphoscoliosis. The acromegaly has 
advanced. 
Third admission, August, 1899. 
Fourth admission, December, 1899. Fine tremor, exophthalmus, tachycardia, marked 
alimentary glycosuria 2.25 per cent, dextrose in urine when 100 gm. dextrose was administered. 
To 100 gm. levulose, Trommer at times distinctly positive. 
Fifth admission, May, 1907. For two years there has been a gradual diminution in the 
motor power. Goiter seems to be smaller. Appreciable enlargement of the sella turcica. 
The enlargement of the hands depends only on the enlargement of the soft parts. Frontal 
cavities enormously widened. Eye-findings normal. Alimentary glycosuria (50 gm.) 
now negative. Death from pneumonia. 
Autopsy.—Tumor( of the hypophysis of soft confluent consistence and grayish-red color. 
Besides, in various organs, numerous tuberculomata. 
Fig. 48a.—Before the disease 
Fig. 486.—At the height of the disease 
Case of acromegaly. 
In this case then in the thirty-first year of life the goiter appeared simulta- 
neously with acromegaly, the goiter subsequently developed enormously and 
led to pronounced symptoms of hyperthyrosis (tremor, exophthalmus, tachy- 
cardia, etc.). Also the alimentary glycosuria could have been a symptom of 
the hyperthyroidism, at least it disappeared later, when the goiter became re- 
duced. Such a retrogression of a preceding goiter occurs frequently in the 
later stages of acromegaly. With its disappearance may be associated not only 
a disappearance of the Basedow’s symptoms, but also, as in this case, the 
appearance of symptoms of true myxedema. 
Observation XXXI.—A. Str. First entered the clinic in February, 1896, then thirty- 
one years old. 
Chlorosis at the age of eighteen years. Menstruated first at the age of fifteen years; 
menstruation was regular until her marriage in her twenty-first year. Pregnancy and 
delivery normal, child well. Since that time has never menstruated, and has become pro- 
gressively weaker. Two years after the confinement (1898) the hands and feet began to 
become thicker and coarser, the wedding ring had to be filed off and enlarged, and it had 
to be made even larger in 1890 and 1893 respectively. Also the shoes had to be made 
larger. The rest of her body became always thicker and more awkward, the neck became ACROMEGALY 
271 
swollen, but the breasts became progressively smaller. The facial features altered more 
and more so that at times she was not recognized as herself by good friends. In spite 
of the increase in body she became progressively weaker. Burning pains in the fingers oc- 
curred early in the course of the disease, pains that were increased at night by the warmth 
of her bed. Later were added day-sweats and night-sweats, so that night-clothing and bed- 
linen had to be changed several times during the night. The eyes protruded distinctly. 
Occasionally she had headache and vertigo. Speech became rough and nasal, the tongue 
has become heavier, thicker, and longer, so that it was often caught by the teeth when 
she spoke. Formerly set of teeth was quite regular. At present the anterior incisor teeth 
of the lower jaw incline outward, are spread apart from each other, and do not fit those of the 
upper jaw. At first she suffered with constipation; often there was no evacuation for 
fourteen days, latterly she often has diarrheas. She is very nervous, and frequently has 
cardiac palpitations and difficulty in breathing. Slight tremor. The powers of memory 
have suffered, the (mental) attitude is depressed and she is easily excited. 
Fig. 49.—Acromegalic and normal hands 
Fig. 50.—Acromegalic feet. 
Circumference of skull, 57.7 cm. 
Length of nose, 5.5 cm. 
Distance apart of the alae of the nose, 4.2 cm. 
Circumference of the neck, 40.0 cm. 
Circumference of the waist, 86 cm. 
Height, 163 cm. 
Eye-grounds and perimetry normal. 
Second entrance, January, 1901. There now exist slight swellings of certain joints, 
especially of the knee and elbows, where crepitation is present on palpation. The cardiac 
oppression has become intense. The voice seems to have improved. The distance between 
the middle and upper incisors is now about 1 mm., that between the lower middle 
incisors 9 mm. The tongue is enormous; hands and feet have greatly broadened. The 
tubera parietalia project markedly, and does also the arcus superciliares; alae of the nose, 
the lips and lower jaw have enlarged enormously. The spinous processes are sensitive 
to pressure. Pain in the entire vertebral column is elicited by pressure on the head. Eye 
findings normal. The circumference of the throat has increased about 3 cm. 
Third entrance to clinic, January, 1903. Attacks of frontal headache with insomnia. 
Alimentary glycosuria, a trace of sugar on the ingestion of 100 gm. dextrose. 
Gynecological examination: Flat pelvis with very slight osteomalacic changes. Pain- 
fulness of the bones, Chvostek’s phenomenon positive.1 One time it was possible to elicit 
Trousseau’s sign. 
x0n account of these manifold symptoms, the case was exhibited by A. Muller before the 
Wiener Gesellschaft f. innere Medizin und Kinderheilkunde. 272 
THE DISEASES OF THE HYPOPHYSIS 
Flexion of the hip- and knee-joints much restricted. Spasms of the adductors. The 
knee-joints greatly distended, crepitation. Electrical irritability normal. Eye findings 
normal. 
Erythrocytes, 4,278,000. 
Hemoglobin, 10.2 gm. 
Leucocytes, 2900, of which: 
Polymorphonuclear neutrophiles, 6 per cent. 
X-ray: Skull capsule thickened. Sella turcica irregularly widened, clinoid processes 
hyperostotic. The thickening of the extremities affects the soft part exclusively. The 
bones are atrophic. 
Fig. 51 
Case of acromegaly (Observation XXXI) 
Fig. 52. 
Fourth entrance to the clinic, April, 1909. Copious night-sweats, cardiac palpitations 
Circumference of the throat 38 cm. Alimentary glycosuria negative. 
Pigmentation on the face, hands, and neck 0.001 gm. adrenalin subcutaneously, 
no sugar. 
Fifth entrance to the clinic, November, 1909. Circumference of the neck 35 cm. FTeart 
enlarged, extra systoles; Chvostek negative. 
Sixth entrance to the clinic, April, 1910. Alimentary glycosuria (100 gm.) negative. 
Adrenalin 0.001 gm., no sugar. 
Three thyroidin tablets administered thrice daily for three days, the pulse rate was 
somewhat increased. Cardiac palpitations slight, the neutrophilic leucocytes vary from 
71.5 per cent, to 84 per cent. Alimentary glycosuria after the beginning of thyroidin 
medication negative (confer Falta, Newburgh, and Nobel). 
X-ray: The sella turcica is destroyed to the extent that its site is no longer sharply 
delimited below and in front; it has given place to a cavity about the size of a chestnut. 
The anterior clinoid processes are replaced by washed-out bone masses; this is true also of 
the greater part of the floor, especially anteriorly. The somewhat enlarged clivus pro- 
jects forward as a characteristically nipple-shaped mass. 
Lately the patient has developed a pronounced cachexia. To this are added slight 
signs of a myxedema, especially a cushion-like thickening of the backs of the hands and of 
the skin of the supraclavicular fossae. The pulse rate in the fever-free intervals (the patient ACROMEGALY 
273 
now frequently suffers with bronchopneumonias) is about 70; the blood-pressure (Gartner) 
lies near the figure 70; the former rather frequent diarrheas now occur only in single isolated 
attacks. There is mostly constipation. The circumference of the throat, it is true, has 
indeed increased, but a myxedematous thickening of the soft parts may indeed play a part 
in it. 
The behavior of the thyroid gland in this case is instructive. We are 
dealing with typical case of acromegaly, which for a long time has shown signs 
of hyperthyroidism (sweats, tachycardia, tremor, slight exophthalmus, diarrhea, 
etc.). Later with the development of a cachexia, symptoms of hyperthyroidism 
retrogress more and more, to give place to a slight thyroid insufficiency. 
The regressive changes in the thyroid gland that so frequently become estab- 
lished in the later stages of acromegaly might well be regarded as a partial 
phenomenon of the degenerative alterations that in the later stages of acro- 
megaly involve not only these organs that are the seat of the tendency to 
growth fostered by the acromegaly, but also the entire body as well. Hence 
in the later stages of acromegaly we may often see myxedematous symptoms, 
even in the absence of previous manifestations of hyperthyrosis. Pineles 
reports two cases of acromegaly with myxedema of the skin, stupidity, and 
weakness of memory. Improvement of the myxedema symptoms followed the 
administration of thyroid gland, although they were not influenced by hypo- 
physis tablets. 
The pathologico-anatomical finding in the thyroid gland in acromegaly 
almost always shows something abnormal. When hyperthyrosis has existed, 
there is found the picture of a Basedow’s struma. Otherwise there is seen 
almost always connective tissue proliferation, such as is found also in other 
organs in acromegaly, or colloid degeneration in combination with, eventually, 
high-grade sclerosing and atrophy of the parenchyma. Gaussel found a thyroid 
gland that was normal. 
The vascular system in the later stages of acromegaly almost always shows 
changes. A slight grade of arteriosclerosis develops. Microscopical examina- 
tion shows that the three vascular coats are involved in these changes, and that 
the media becomes poor in muscle fibers. The heart not infrequently hyper- 
trophies, and the cardiac muscle soon degenerates. Especially those cases that 
are attended with other symptoms of Basedow’s disease often show in the initial 
stages a slight degree of tachycardia; in all cases manifestations of insufficiency 
of the heart-muscle develop in the later stages. Varices are strikingly frequent. 
In many cases the enlargement of the heart may very well be a partial mani- 
festation of the true splanchnomegaly. Humphrey describes a considerable 
cardiac hypertrophy without valvular changes in a man aged thirty-nine years. 
The case reported above (Observation XXIV) there was a broadening of the 
cardiac shadow, on X-ray examination, to 13 cm. The patient was thirty- 
two years old. Not rarely in addition to the enlargement of the heart there is 
found an enlargement of the liver, the spleen, the stomach, and the intestines. 
The enlargement of the liver is often only the sequel of an existing cardiac 
insufficiency, sometimes, however, the partial manifestation of a true splanch- 
nomegaly. The enlargement of the spleen is a partial manifestation of the 274 
THE DISEASES OF THE HYPOPHYSIS 
enlargement of the lymphatic apparatus to be described later. The dilatation 
of the stomach has been brought into association with the frequently observed 
polyphagia. Cunningham describes, in a case, a doubling of the length of the 
small intestines. Also the kidneys are often strikingly large, and in the urine 
a slight grade of albuminuria is not infrequently found. In two cases Fischer 
found enormous suprarenals, the enlargement affected especially the cortex; 
also Delille saw this several times. Lately Fischer and Schultze found enlarge- 
ment of the suprarenals in two cases of acromegaly, in one of which (a case of 
early acromegaly) the suprarenals were enlarged about five times at least. 
Histological examination showed that the suprarenals in toto were quite uni- 
formly enlarged. Also the kidneys were enlarged, showing on microscopical 
examination enormously large glomeruli. 
In many cases the pancreas was found to be sclerosed, in other cases the 
pancreas was found to have been entirely normal (see later the combination of 
acromegaly and diabetes). In many cases of acromegalic gigantism the pan- 
creas were of quite enormous size (up to 270 gm., Launois and Roy). A per- 
sistent thymus gland in acromegaly was already found by Klehs and Fritsche. 
Since their time this finding has been reported very frequently (Dalton, Arnold 
and others); detailed references as to the literature can be found in Borchardt 
(Deutsches Archiv fur klin. Med.) Pierre Marie regards the enlarge- 
ment of the thymus as a reviviscence. The enlarged thymus may produce a 
distinct dullness over the upper half of the sternum, although nothing should 
be concluded as to the enlargement of the thymus when this dullness is found, 
as in acromegalics the sternum is, often thickened enormously. 
The examination of the blood in acromegaly shows not rarely a reduction 
in the number of erythrocytes and in the hemoglobin contents. This was ob- 
served by Sabrazes and Bonnes. Messedaglia saw it in seven cases, Rotky in 
five cases. In the cases reported above, the case Str (Observation XXXI) 
had 4,700,000 red blood cells, 70 per cent, hemoglobin; the case Ta (Observa- 
tion XXVII) 4,900,000 red cells and 82 per cent, hemoglobin; the case Ti 
(Observation XXV), 4,490,000 red cells and 95 per cent, hemoglobin; the case 
Bo (Observation XXVI) 5,210,000 red cells and 85 per cent, hemoglobin. 
Hence it seems that in the latter stages the erythrocyte count and hemoglobin 
contents are reduced. 
The number of leucocytes is mostly normal (Rotky), although there is often 
found a somewhat reduced count. In my cases the case Ad (Observation 
XXVIII), showed 9800; case Bo (Observation XXVI) 8840; case Ta (Observa- 
tion XXVII) 5600; case Un (Observation XXIV) 6240, and finally case Str 
(Observation XXXI) only 2900. 
In the majority of cases the differential count shows a mononucleosis and 
not rarely an increase in the number of eosinophiles. Sabrazes and Bonnes 
found this in two cases, Messedaglia in seven cases (30-37.8 per cent, lympho- 
cytes), Rathy in five cases; Exner in one case found 39 per cent, mononuclear 
cells and 61 per cent, eosinophiles. Likewise Franchini and Giglioli found 
mononucleosis in four cases, and among these hypereosinophilia in two cases. 
Mendel in one case found even 18 per cent, eosinophilia. Also Messedaglia ACROMEGALY 
275 
and Rathy found for the most part an increase in the eosinophiles. In my own 
case Ta (Observation XXVII) showed 76 per cent, neutrophiles and 2 per cent, 
eosinophiles; case Da (Observation XXVIII) 74 per cent, neutrophiles and 6 
per cent, eosinophiles; case Bo (Observation XXVI) 63.8 per cent, neutrophiles 
and 2.3 per cent, eosinophiles; case Ad (Observation XXIX) 66 per cent, 
neutrophiles and 1 per cent, eosinophiles; case Str (Observation XXXI) 60 
per cent, neutrophiles; case Un (Observation XXIV) 57.6 per cent, neutrophiles 
and 1.3 per cent, eosinophiles, and in case Ti (Observation XXV) 56.7 per cent, 
neutrophiles and 0.2 per cent, eosinophiles. 
Lately a report on the blood-findings in three cases has been contributed by 
Borchardt. He found the erythrocytes approaching normal, the polymor- 
phonuclear neutrophiles but little reduced, the eosinophiles mostly increased. 
Hence the leucocyte count rather frequently shows, especially in the later 
stages, a relative and perhaps also an absolute reduction in the number of 
neutrophilic cells, and a relative increase in the large mononuclears; perhaps this 
is the expression of a more or less well pronounced status lymphaticus, as has 
been found in several autopsies. (Messedaglia, Schultze, Fischer, Rothy, Claude 
and Baudouin, et al.) 
The anomalies of metabolism in acromegaly need a very exact exposition. 
In many cases there exists obesity, as in the much-quoted case of Strumpell, 
although this was reported as simply “layer of fat abundant.” Lately Schultze 
and Fischer have reported a case of early acromegaly who was fat. Also the 
patient in Observation XXIX was fat. In a review of the literature I have 
never found pronounced obesity. Frequently there exists voracious hunger and 
polyphagia, relatively rarely lasting for long periods, and for the greater part 
intermittent. Whether this symptom should always be regarded as a sign of 
hyperthyrosis, or whether it belongs to acromegaly proper, I shall leave 
unanswered. 
Observations as to the exchange of gases in acromegaly have been carried 
out only by Zantz-Geppert’s apparatus (Mdgnus-Levy, H. Salomon, and the recent 
investigations of Bernstein and myself). I have summarized these investigations 
as follows: 
The investigations concerning the respiratory exchange of gases made up 
to the present do not appear to decide with complete certainty the question 
as to whether in acromegaly there occurs an increase in the caloric production 
that may be ascribed to the disease as such. In the case of Magnus-Levy the 
oxygen consumption and the production of carbonic acid doubtlessly are appre- 
ciably increased. But just here, according to the statement of the authorsr 
there were present svmptoms of hyperthyrosis that were not appreciable. 
In case 1 of Salomon the exchange of gases is not appreciably heightened, in 
proportion to the size and body weight of the individual. The slight glycosuria 
can certainly not be regarded as a sign of increase (confer later on, in the chapter 
on the pancreas, the statements as to the exchange of gases in diabetes mellitus). 
Whether the sweats that occur in this case and the voracious hunger that oc- 
curred from time to time are to be referred to a hyperthyrosis is not at all certain 
in itself. 276 
THE DISEASES OF THE HYPOPHYSIS 
Author 
Sex and 
age 
Height 
in cm. 
Weight 
O2 need in 
c.c. per kg. 
per min. 
C O2 produc- 
tion in c.c. 
per kg. per 
min. 
Remarks 
Magnus-Levy 
F 53 
147 
52.0 
5-19 
4-25 
No diabetes. 
Salomon case i 
M 49 
183 
112 . O 
4-9 
4-33 
Sick for about 19 years, copi- 
ous sweats, often voracious 
hunger and increased thirst. 
Potency not disturbed, built 
on herculean lines, diabetes 
(elimination of sugar reaches a 
few gm.). 
Salomon case 2 
F Si 
160 
79.6 
4-3 
3 °4 
The mother is also sick with 
acromegaly and diabetes. For 
7 years alterations in face, for 3 
years great thirst. Diabetes 
gravis, rather fat. 
Salomon case 3 
M 42 
158 
79-6 
396 
3-04 
Sick for about 20 years, no 
disturbance of potency. 
Salomon case 4 
F36 
143 
56.5 
4.00 
3-3 
Amenorrhea for 8 years, no 
diabetes. 
Bernstein and Falta 
M 31 
175 
00 
0 
0 
355 
2-73 
Strongly built, thyroid slightly 
enlarged, but no distinct signs 
of hyperthyrosis, alimentary gly- 
cosuria. 
Bernstein and Falta 
M 32 
168 
75° 
3-87 
3.r6 
Thyroid gland enlarged, slight 
signs of hyperthyrosis, no gly- 
cosuria on overloading. 
In case 2 the consumption of oxygen in proportion to the size of the patient 
is high. But there exists a severe diabetes. Also in case 3 the oxygen values 
lie somewhat above the upper limits of the normal. In case 4 the exchange 
seems to be normal. A heightening of the exchange of gases cannot be con- 
cluded from the cases reported by Bernstein and myself. On the whole the 
conclusion that Magnus-Levy and also Salomon have arrived at, namely, that 
in uncomplicated acromegaly the exchange of gases is not increased is correct. 
In the later stages of the cachexia and the decay, the exchange seems to be rather 
lower, especially when also the thyroid gland degenerates and myxedematous 
symptoms are added. 
Up to the present only very few investigations have been made with regard 
to the salt metabolism. Von Moraczewski found in a case of acromegaly pro- 
nounced retention of phosphorus, calcium, magnesium, and chlorine (and also 
nitrogen), and explains this by the increased growth of the tissue. 
Investigations as to purin metabolism have been instituted by Nowaczinsky 
and me in three cases. There were the cases already described as case T (Ob- 
servation XXV), U (Observation XXIV), and Ta (Observation XXVII). 
In case T (thirty-one years old) we found on purin-free diet a uric-acid elimi- 
nation between 0.72 gm. and 0.92 gm. in twenty-four hours. In case U 
(thirty-two years old) between 0.89 gm. and 1.16 gm.; fourteen days after 
the operation still higher values were found. As has already been men- 
tioned, in this case the operation had no influence on the acromegaly. After ACROMEGALY 
277 
the administration of sodium nucleinate there occurred a prompt increase 
of uric-acid elimination. In case Ta (thirty-three years) there were uric- 
acid values between 0.72 gm. and 1.29 gm. 
Hence in all three cases were found values for the elimination of endogen- 
ous uric acid that reached the double or more than the double of the endog- 
enous uric-acid factor observed in normal individuals. Any complications 
can hardly be regarded as the cause of this enormous increase. The patients 
were all free of fever; in case U there existed very slight symptoms of hyper- 
thyrosis, which was however absent in both other cases. Ta had had lues, 
but now no symptoms of lues were present. Hence we must assume that the 
increase of uric-acid elimination in acromegaly occurs as such, the more so 
because in some cases of hypophysial dystrophia adiposi-genitalis we find 
strikingly low endogenous uric-acid values. In one case of acromegaly there 
occurred after the administration of purin-free material a prompt increase in 
the elimination of uric acid, while in the cases of hypophysial dystrophy the 
elimination of uric acid was extraordinarily reduced. 
Such high values for the endogenous uric-acid elimination as we found in 
three cases of acromegaly have as yet been observed only in diseases in which 
much lymphatic tissue is destroyed, or in certain febrile processes attended 
with marked hyperleucocytosis (acute articular rheumatism). In the cases 
of acromegaly the leucocyte counts were rather lower than normal. There 
was no ground whatever for the assumption of an increased melting down 
of lymphatic tissue. Further investigations as to this question are very 
desirable (see Chapter I). 
Lately Dr. Vias has examined a quite chronically progressive case of acro- 
megaly, and has observed no increase in the endogenous uric-acid elimination. 
Quite especially frequent is acromegaly complicated with glycosuria or with 
diabetes mellitus. Already Pierre Marie had stated that in a third or a half of 
the cases of acromegaly glycosuria was found. Detailed references to the litera- 
ture are to be found in the articles of Launois, and Roy, and of Borchardt. 
Borchardt collects from the literature 176 cases of acromegaly in which 
there exist specific statements as to the examination of the urine. In sixty- 
three cases, that is 35.5 per cent., diabetes was found; in eight cases ali- 
mentary glycosuria. In many cases the diabetes shows the ordinary course 
and eventually leads to death in coma. In many cases, however, as v. Noorden 
first emphasized, the glycosuria shows a striking independence from the 
sugar-value of the diet. The cases reported by me behaved thus: 
Observation XXIV— U, on diet rich in carbohydrates ; neg. 
XXV.—T, alimentary glycosuria (ioo) pos. 
XXVI— Bo (distinct hyperthyrosis from thyroidin) neg. 
XXVII.—Ta, alimentary glycosuria also on diet remarkably rich in 
carbohydrates strongly pos. 
XXVIII.—Da, alimentary glycosuria pos. 
XXIX. —Ad, alimentary glycosuria pos. 
XXX. —St, alimentary glycosuria (also from levulose) pos. 
XXXI. —Str, at first alimentary glycosuria pos. 
then later, on many investigations neg. 278 
THE DISEASES OF THE HYPOPHYSIS 
Of eight cases, five were distinctly positive, and one for a time weakly 
positive. In one case (Ta) we may even speak of a very light diabetes. 
The behavior toward adrenalin was tested in two cases (Observation St 
and Observation Ta) with negative results. 
In many cases alimentary glycosuria or diabetes occurs only in the initial 
stages of acromegaly; later these cases show a marked tolerance. W. 
Schlesinger and Borchardt each report such a case. Lately also Cushing has 
reported about such cases. In the case of Borchardt the diabetes had existed 
five years; and later there occurred no glycosuria on the injection of 150 gm. of 
grape-sugar. It should be mentioned that not rarely such diabetic distur- 
bances of metabolism occur in Basedow’s disease (thyrogenic glycosuria). 
In the few cases in which I examined the excitability of the- vegetative 
nerves showed a very diverse behavior. In the case Ta there occurred, after 
the injection of adrenalin, marked rise of blood-pressure, tachycardia and 
arrhythmia. There also occurred marked diuresis, but not glycosuria. As 
in this case sugar appeared in the urine after overloading with carbohydrates, 
it stands as a fine example of the independence of the alimentary and the 
nervous factors (Falta, Newburgh, and Nobel, Case 43). Also the injec- 
tion of pituitrinum infundibulare acted as a marked diuretic. After the 
injection of pilocarpine there occurred only moderate sweats and a moderate 
flow of saliva; although the patient stated that she suffered with crises of 
copious sweats. In other cases the action of pilocarpine on the excitability 
of the sweat glands was more distinct. Hence there may occur temporary 
conditions of marked irritability of the sweat glands, without hyper- 
excitability of them during the interval. The outbreaks of sweat are known 
to be a very common symptom of acromegaly. Magnus-Levy and Salomon in 
their cases of acromegaly regard the sweats as the symptom of hyperthyrosis; 
however, it seems to me certain that the outbreaks depend on another cause 
lying in the nature of acromegaly itself, for we see them also in the cases in 
which other symptoms of Basedow’s disease—above all, the cardinal symptom 
of the hyperthyrosis, the tachycardia—are absent. This was the case, for 
instance, in case Ti (Observation XXV). 
The polyuria may also be looked upon as dependent on an abnormal 
condition of excitability of the vegetative nerves. This also usually occurs 
only temporarily, in crises. The specific gravity of the urine may sink in 
these attacks to very low values, reminding us of a true diabetes insipidus. 
As I have mentioned before, there may exist in many cases an especial 
sensitivity of the nerves of the kidney for adrenalin or for pituitrinum 
infundibulare. It is not clear how far such changes in the condition of 
excitability of certain vegetative nerves may be brought into relationship 
with functional alteration of the hypophysis. At most we may conjecture 
that the critic polyuria may be associated with te mporary irritation of the 
posterior lobe and with the increased production of hypophysial “diuretin.” 
The fact that complication with hyperthyrosis or hypothyrosis influences 
the condition of excitability of the vegetative nerves in many ways needs no 
further consideration in detail. ACROMEGALY 
279 
Very often the pathologico-anatomical examination in advanced cases, 
shows proliferation of the connective-tissue elements in the vegetative nerves 
and ganglia (Marie and Marinescu). 
The symptoms on the part of the somatic nervous system are very manifold. 
To the early symptoms often belong the very burdensome rheumatoid pains 
and eventually acroparesthesias {Sternberg). In many cases the pains 
occur during night, so that the patient must get up and walk around the 
room (Observation XXIV). Also sensation of heat in the fingers may occur. 
In one case there occurred transitory swelling of the finger-joints simul- 
taneously with the pains. Whether combinations with continued articular 
swellings and chronic deforming processes in the joints, as was present in 
Str, Observation XXXI, are common, I have not been able to glean from the 
literature. The behavior of the reflexes varies. Sometimes they are increased, 
sometimes reduced. 
Also alterations of the mind and intelligence occur in acromegaly. In 
many cases there exists a characteristic apathy, a want of initiative, and a 
slowing of the speech. In rare cases, conditions of exaltation are observed. 
The pathologico-anatomical examination of the nervous system shows no 
constant findings; except that in the later stages there occurs regularly an 
increase of the connective-tissue elements in the nerves. 
Among the symptoms of acromegaly there is still a group that has 
nothing to do with the disease process in itself but is produced mechanically 
by the enlargement of the hypophysis. To these belong first of all the changes 
in the sella turcica; Oppenheim was the first to recognize enlargement of 
the sella during life by means of the X-rays. Since that time X-ray technique 
has improved wonderfully and has become of important diagnostic aid. 
The changes in the sella may be very different; frequently when the tumor 
is situated purely intrasellarly there exists a widening out of the sella with 
deepening of the floor. This may bring the bony partition between sella and 
sphenoidal sinuses to paper-like thinness or to actual perforation; even 
when the tumors are large the clinoid processes may remain intact. In 
very large tumors too, however, there may be a widening of the entrance to the 
sella and final destruction of the clinoid processes. The tumor may also 
calcify. Calcifications of the dura are not rare. 
The following X-ray finding in a typical case of acromegaly serves as an 
example: 
Observation XXXII.—U, Dec. 9. The sella turcica is not only widened on the whole 
to twice its size (measured in the sagittal direction) but also is very roomy at its introitus. 
This also is at least double as wide as normal. The floor of the sella turcica has its homo- 
geneous rotundity infringed upon, and is polygonal with washed-out borders. Several 
crumbly calcareous masses in the interior of the sella may well be supposed to be calcified 
tumor-masses. The widening that is here present shows itself in a sharpening at its base. 
The lack of an enlargement of the sella does not militate against acro- 
megaly. On the one hand, as we shall see later, there may be present specific 
microscopical alterations also in hypophyses that are scarcely enlarged, 
especially in the initial stages of the disease; and on the other hand there 280 
THE DISEASES OF THE HYPOPHYSIS 
may be present a tumor of the hypophysis in the sphenoidal sinuses pro- 
ceeding from epithelial rests of the hypophysial duct, or such a tumor of 
the hypophysis of the pharyngeal vault. In the first case the floor of the 
sella may be even eroded from below, and thus the connection with the hypo- 
physis be established secondarily (Erdheim). 
Later, in the consideration of the tumors of hypophysis, we shall come 
back to the subject of the differential diagnostic significance of the alterations 
of the sella. 
To the symptoms called into existence by the pressure of the growing 
tumor belong also headache,1 and eventually dizziness and vomiting. But the 
last two symptoms as well as paresis of the cranial nerves are relatively rare 
in this disease. 
On the contrary there are found more frequently disturbances on the 
part of the optic nerves, disturbances not rarely in the form of bitemporal 
hemianopsia and hemianopic pupillary reaction; the latter according to re- 
searches of Wernicke and of Dejerine almost surely indicate a hypophysial 
tumor. 
In addition to the hemianopsia there is found, also commonly, simple 
amblyopia; these manifestations may occur unilaterally. They can lead to 
blindness of one or both eyes; examination of the eye-grounds shows for the 
most part alterations of the papillae in the sense of a neuritis (in 40 per cent.) 
or of an atrophy, rarely choked disc. I shall return to the manifestations of 
brain-pressure in the consideration of the subject of non-acromegalic hypo- 
physial tumors. 
Pathological Anatomy of the Hypophysis 
I now turn to the treatment of the nature of the hypophysial tumors in 
acromegaly. Although this subject is the most important, I have placed it at 
the end of the long series of symptoms, because it acts as transition to the 
subject of the pathogenesis of the disease. To-day we may state with great 
probability that in every typical case of acromegaly there exist in the ante- 
rior lobe of the hypophysis adenomata or adenocarcinomata, which in rare 
cases are dystopic, proceeding from cut-off hypophysial cells. The questions 
on this subject that have been energetically discussed recently are: Are there 
cases of acromegaly without hypophysial tumor, or without the adenomatous 
changes in the hypophysis retarded as specific; and, are there cases of such 
tumors that do not show any of the symptoms of acromegaly? These questions 
have recently been discussed with temperament in a monograph by B. Fischer; 
I shall refer the reader to the literature on the subject and shall attempt here 
only to bring to the front the principal opinions on this subject. 
Hanau first pointed out that in the overwhelming majority of cases of 
acromegaly, adenoma of the hypophysis was observed. Through the dis- 
covery of a specific coloration for the cell granules in the chromophilic cells 
by Benda the recognition of the adencmatous tumors has become essen- 
1 Headache is frequently an early symptom. See addendum.—Editor. PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
281 
tially easier. Benda himself found in three of four cases of acromegaly the 
cell granules in monstrous excess in the adenomatously degenerated anterior 
lobe of the hypophysis. For most part the forms of adenoma are benign. In 
the malignant form, which does occur, and in which growth is very rapid, the 
cells may remain very small. In such cases under circumstances the presence 
of these among the gland-cells can be determined only by the use of Benda’s 
stain. Such malignant adenomata were for the most part formerly regarded as 
carcinomata. Fischer says that the other kinds of tumors, such as carcinomata, 
sarcomata, endotheliomata, etc., never produce acromegaly; this statement 
seems to be correct except that the position of the cases of typical acro- 
Fig. 53.—Adenocarcinoma of the hypophysis made up, in great part, of eosinophilic cells. 
megaly in which the pathological finding points to adenocarcinoma. I refer 
to the case of Cagnetto. Cagnetto described a large adenocarcinoma with 
abundant secretion granules, proceeding from the glandular part of the 
hypophysis, which led to metastases in the spinal cord; in these metastases 
the chromophilic cells were demonstrable. Fig. 53, for which I am indebted 
to Prof. Stoerck, shows a similar case. The hypophysis is in this respect 
analogous to the thyroid gland, in which adenocarcinomata associated with 
metastases and manifestations of Basedow’s disease are described. If in 
cases with malignant degeneration of the adenomata of the hypophysis the 
chromophilic cells are sometimes very few, this would not militate against 
the applicability of the above-mentioned postulate,1 as in malignant tumor 
there frequently sets in an anaplasia of the cells, as Fhiscer correctly points 
out. Again cases of acromegaly have been described, in which the sec- 
1 i. e., that in every typical case of acromegaly the anterior lobe of the hypophysis shows adenoma 
or adenocarcinoma.—Editor. 282 
THE DISEASES OF THE HYPOPHYSIS 
tions indeed disclosed tumors proceeding from the glandular part of the 
hypophysis, which tumors, however, were cystically degenerated, and showed 
but very little glandular tissue. Here it is indeed remarkable how rapidly 
after extirpation of the part of the tumor, in the cases thus far operated 
on, the manifestations of acromegaly ameliorate. These cases, however, 
are fresh ones; in very old cases with acromegaly they perhaps would not 
ameliorate so rapidly. Finally the cases with colloid struma of the hypo- 
physis have been brought as evidence against the postulate, in that in acro- 
megaly such strumas may be found without proper adenomatous formation, 
and on the other hand there may be found typical strumas with small ade- 
nomata without acromegaly. As example of the first type I mention the 
case of Widal, Roy, and Froin. Here there existed typical acromegaly 
in a sixty-six-year-old man, and atrophy and sclerosis of the gland substance 
which was permeated with colloid cysts; in spite of the atrophy there could be 
found rather numerous chromophilic cells. As example of the second type 
I refer to the cases of Zack and of Cagnetto. The case of Cagnetto was that of a 
thirty-two-year-old woman without acromegaly; the hypophysis weighed 
1.55 gm., which is thrice the normal weight; microscopically was found a 
typical struma, in which small adenomatous portions alternated with stru- 
mous portions. The analogous relation with the thyroid furnishes a key 
in this case. There are also cases of Basedow’s disease in which only “Base- 
dow’s islands” are to be found in the thyroids. 
Pathogenesis.—Already Pierre Marie had recognized the connection of 
acromegaly with the hypophysis; at all events he supposed that the tumor 
destroyed the functionating pituitary tissue, v. Strumpell, Arnold and others 
advocated the opinion that the enlargement of the hypophysis is coordinated 
with that of the acral parts, in other words that it is only a partial phenomenon 
of a general disturbance of metabolism (endogenous theory). The theory of 
hyperfunction was first upheld by Tamburini, Benda, and Massalongo. Other 
authors have supposed a primary disturbance of function of the sexual glands 
{Freund, Verstraeten, Stumme, lately E. Mayer, especially). 
Finally the endogenous theory has been modified by other authors {Claude, 
Delille) in that they regard acromegaly as a pluriglandular affection. 
The assumption of a loss of function of the hypophysis in acromegaly can 
at the present day no longer be regarded as correct. We shall see later that 
processes that destroy the glandular hypophysis never lead to acromegalic 
symptoms, but to symptoms of an entirely different kind. The same thing 
occurs in animals after the hypophysis has been extirpated. The supposition 
of a primary functional disturbance of the sexual glands is no longer tenable, 
in that, as we shall see later, there are cases of acromegaly in which the sexual 
glands still functionate, even although the disease has been fully developed 
for several years. Against the endogenous theory, speaks, among other facts, 
the results of the partial extirpation of the tumor of the hypophysis, as will be 
dealt with more in detail later. This places the hypophysis as the central 
figure of the pathogenesis of acromegaly. That in acromegaly other ductless 
glands are involved very frequently was already mentioned by Pineles, which PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
283 
fact, as we have seen, makes the disease picture very manifold. The circum- 
stance that this involvement is a very diverse one, that, for example, at one 
time there occurs on the part of the thyroid symptoms of hyperfunction and 
at another time symptoms of those of insufficiency shows once more the pre- 
dominating position of the hypophysis. Hence only those manifestations may 
be regarded as cardinal symptoms of acromegaly, which are to be referred 
directly to the alteration of the hypophysis; there are in addition to these a 
herd of secondary symptoms. 
Besides the results of the surgical treatment it is especially the similarity 
of the pathologico-anatomical findings in the hypophysis in acromegaly with 
those of the thyroid in Basedow’s disease that indicate that acromegaly is brought 
about through an increase in the function of the glandular hypophysis. 
Against this assumption there has been objected that in many cases as 
above mentioned, there are found strumas of the glandular hypophysis in 
which degenerative manifestations predominate, and that on the other hand 
the strumas or small adenomata occur without acromegaly. I believe that the 
dictum of Kocher that there are strumas and strumas holds for the hypophysis 
as well as for the thyroid. To-day no one would be surprised that, especially 
in the old Basedow’s cases, parts of the thyroid are degenerated, and that on 
the other hand small adenomata of the thyroid gland are often unattended with 
any of the manifestations of Basedow’s disease. The morphological finding 
does not always indicate the functional condition. Finally should be mentioned 
that in rare cases of acromegaly entirely normal hypophyses are found. In 
many of these cases the diagnosis of acromegaly is doubtful (syringomyelia, 
congenital abnormal size of the acra, etc.1). In other cases we find dystopic 
adenomata of the hypophysis which proceed from cut-off cells [versprengte 
Keime] (Erdheim and Haberfeld). 
I have already referred several times to the manifold analogies that exist 
between the lesion of the thyroid gland and those of the hypophysis. As 
we shall see later the assumption that hypophysial dystrophia adiposo-genitalis 
depends on a lessened function of the hypophysis is based on experimental 
pathology in a fashion analogous to that in which the assumption of myxedema 
is a hypothyrosis has been demonstrated by experiment. On the contrary the 
conditions for acromegaly are to-day very much more unfavorable than those 
for Basedow’s disease. The most important support for the theory that it 
depends on a hyperfunction of the hypophysis lies, as I have mentioned pre- 
viously, in the results of the surgical treatment of acromegaly. Reduction in 
the size of the hypophysis through extirpation of portion of the gland leads in 
many cases to a retrogression of the acromegalic manifestations. That this is 
not true in all cases, for example, in the case of U (Observation XXIV), does not 
seem to me of great significance, as on account of the slight visibility of the field 
1 Also tall eunuchoids have been confused with acromegalics. Thus for instance we find described 
by Gallais a case of “gigantisme acromegalique sans elargissement de la selle turcique” with “inver- 
sion sexuelle and feminisme mental.” In this case quite sudden rapid growth started at fourteen and 
one-half years of age, that was also present to lesser degree in the twenty-fifth year. Hands and 
feet were very long and slender. In the illustration that accompanies the report of the case absolutely 
nothing of acromegaly is to be seen. It shows however typical eunuchoid obesity. 284 
THE DISEASES OF THE HYPOPHYSIS 
of operation, we do not know anything as to the size and value of the piece of 
tumor left behind. In analogy with experiences in Basedow’s disease it is 
very probable that a result could have been obtained by a further reduction of 
the tumor. 
On the contrary, the attempts to produce a hyperfunction of the hypophysis 
experiments have hitherto been attended with very slight results. The stimu- 
lating [fordernd] influence of the hypophysis on the growth as inferred from the 
clinical observations, has as yet not been demonstrated experimentally with 
certainty. The attempt to feed growing animals with hypophysis substance 
seems to me not to have furnished convincing results as yet. Worthy of note 
in this regard are the statements of Exner that implantation of several hypophy- 
ses hastened the growth of young rats. 
The investigations with injection of pituitary extracts have indeed led to 
recognition that the latter possess not inappreciable physiological actions, 
but, nevertheless, we have not been able to bring them into relation with 
the pathogenesis of acromegaly with such certainty as is the case in analog- 
ous experiments in Basedow’s disease. It is to be regarded as established, 
however, that the physiological actions of the extracts from the anterior lobe 
are quite other than those of extracts of the pars intermedia and posterior lobe. 
Let us first consider the action of the latter. 
The extract from the pars intermedia and posterior lobe, that has been made 
entirely free of albumin [proteid, Eiweiss] has in many respects actions similar 
to adrenalin, without however giving the color reactions of adrenalin. The 
extract from the entire hypophysis acts as a blood-pressure-raising agent and 
a pulse-slowing agent by contraction of the peripheral vessels (Oliver and 
Schafer). Howell later found that this action is due solely to the extract of 
the infundibular part. The initial lowering of blood-pressure that is sometimes 
observed, may be referred to the admixture with other substances, perhaps with 
those which are identical with what are found in large amounts in the glandular 
extract. These can be separated from the other by extraction with alcohol. 
The blood-raising action of pituitrinum infundibulare distinguishes from that 
of adrenalin in that it often remains absent on short spaced repetition of the 
injections. The vasoconstrictor action can, in man, be very readily shown. 
After subcutaneous injection of i to 2 cc. we mostly find a distinctly pronounced 
local ischemia that often lasts longer than an hour. Subcutaneous injection 
of so small an amount raises the blood-pressure, in man, for a long time after 
the injection. Also it produces mydriasis of the isolated ball of a frog’s eye. 
Further it acts as a strong diuretic (Magnus and Schdter) by a dilatation of 
the renal vessels (Halliburton); according to Pal only the peripheral section of 
the renal artery dilates, while the proximal part contracts. The different 
vascular distributions behave especially diversely to the action of the drug. 
The diuresis may be, in man, very considerable; in case Ta, Observation XXVII, 
we saw an increase in the amount of twenty-four-hour urine from 800 cc. to 
1200 cc. According to Kepinow pituitrinum infundibulare sensitizes the points 
of attack of adrenalin. The actions of pituitrinum infundibulare thus far de- 
tailed have, with the exception of the slowing of the pulse, all adjusted to the PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
285 
irritation of the sympathetic nerves. It also acts, however, on certain organs 
supplied by autonomous nerves in the sense of a stimulation through the autono- 
mous nerves. While according to Frankl-Hochwart and Frohlich the autono- 
ous vagal cardiac, the nerves of the pancreas, the chorda tympani, and the 
nervi erigentes are not influenced as to their excitability, the excitability of 
the nerves of the urinary bladder and the musculature of the uterus are mark- 
edly heightened, or the uterine musculature is brought to strong contraction. 
This action, according to the experiments of Fleming and myself may be set 
aside through the use of atropine. It is only constant in the gravid uterus, 
while in the virginal uterus there may even occur inhibition of the peristaltic 
waves. Also certain chemotactic actions (mononucleosis, hypereosinophilia) 
are perhaps to be referred to the irritation of autonomous nerves. According 
to Ott and Scott, and Schafer and Mackenzie, the extract of the posterior lobe 
contains galactogogue substances. 
Also the actions on the metabolism are very appreciable. Schijf on feed- 
ing a case of acromegaly with hypophysis tablets saw a 16 per cent, increase of 
elimination of phosphorus, whereas when he fed a case of paralysis agitans with 
them there was a 25 per cent, increase in the elimination of phosphorus. The 
increase principally affected the elimination through the feces. According to 
our investigations (Bolaffo and Tedesco) this action is to be referred to the 
pituitrinum infundibulare, as we saw appreciable increase in the elimination 
of phosphorus after its injection. That a large part of the phosphorus is elim- 
inated through the feces finds its explanation in the fact that also the calcium 
elimination through the feces is much increased, and the calcium travels with 
the phosphorus in the intestine. We also found an appreciable increase in 
elimination of nitrogen in fasting dogs and in those in whom the nitrogen metabo- 
lism was in equilibrium. In a case of acromegaly to whom he administered 
hypophysis tablets, v. Moraczewski found an increase in the elimination of 
nitrogen, but not in that of calcium. [McKinlay f using injections of the poste- 
rior lobe of the pituitary body in normal individuals elicited an increase of the 
basal metabolism. He speaks of the synergic action of pituitary extract and 
thyroxin, since he found that where he injected pituitary extract a week after 
thyroxin had been injected, there was an acceleration of basal metabolism.—- 
Editor.] 
Cushing recently states that, according to his investigations, extracts from 
the posterior lobe of the hypophysis or from the pars intermedia, also possess 
an action on carbohydrate metabolism. Intravenous injection of posterior 
lobe extracts into a rabbit always produces glycosuria. Furthermore, sub- 
cutaneous or intravenous injection of extract of posterior lobes reduce the 
tolerance limits for carbohydrates even in animals with heightened tolerance 
limits in which the hypophysis had been removed. Bernstein and I could not 
corroborate Cushing’s statement in experiments that we instituted, using the 
otherwise active pituitrin of Parke, Davis & Co. First, on the injection of large 
1 McKinlay (C. A.). The effect of the extract of the posterior lobe of the pituitary on basal 
metabolism in normal individuals and in those with endocrine disturbances. Archives of Int. Med., 
Vol. XXVIII, No. 6, Dec. 15, 1921, pp. 703-710. 286 
THE DISEASES OF THE HYPOPHYSIS 
quantities (up to 33 cc.) to rabbits and dogs, we never saw the appearance of 
glycosuria. Nor, according to earlier experiments of Priestley and myself is 
there an increase in the blood sugar-contents. Second, in experiments on man 
we have never been able to influence [by its use] the tolerance limits for carbo- 
hydrates. After the injection of pituitrinum infundibulare (up to 3 cc.) we 
never saw the occurrence of alimentary glycosuria on the administration of 
100 gm. of dextrose, and in individuals who already had alimentary glycosuria, 
this was never increased under the influence of pituitrinum infundibulare. Nor 
did we see an increase in the elimination of sugar in diabetics. Especially 
important seem to me the experiments on diabetics who at the time were sugar- 
free. Here if the tolerance limits for sugar were reduced as a result of the injec- 
tion, we would expect to see a recurrence of the sugar. Finally in respiratory 
experiments on men there occurred regularly after the injection of pituitrinum, 
an increase in the production of carbonic acid or of consumption of oxygen, but 
never a distinct rise of the respiratory quotient. 
As example I cite the following experiment: Case Ti (Acromegaly) 
Date 
CO2 
o2 
RQ 
February 14 
257.5 
342.0 
0-753 
February 16 
247.7 
329.8 
0.748 
40 min. after the injection of 2 cc. pit. inf 
393-9 
0-754 
Whether the investigation was made a short or a long time after the injec- 
tion, there could never be observed a distinct rise of the respiratory quotients. 
The increase in the respiratory metabolism that we found after the injection 
of pituitrinum infundibulare may very well be referred to an increased stimula- 
tion of smooth-muscled organs probably also to an increased activity of the 
liver. At least the hyperemia of the liver that E. Neubauer found in oncometric 
experiments seems to point that way. 
Miller and Dean Lewis state that intravenous or intraperitoneal injections 
of extracts of posterior (and anterior) lobes of the hypophysis in dogs indeed 
may sometimes induce transitory, very weak, glycosuria; it is here very ques- 
tionable, however, whether this has anything to do with the internal secretion 
of the hypophysis. 
The extract of the glandular portion of the hypophysis was formerly 
regarded as entirely without action. Ivkovic and / found, however, that one of 
the extracts furnished to us for trial by the firm of Parke, Davis & Co. possessed 
a pronounced depressor action; after the intravenous injection of 2 to 3 cc. 
of this extract there occurred a depression of the blood-pressure, which latterly 
again returned spontaneously to the normal; previous administration of atropine 
would not hasten this return to normal, but on the contrary would retard it. 
When large doses of the extracts were used, in two of our experiments the blood- 
pressure sank to zero, and there was cessation of respiratory and cardiac action, 
in one of these experiments the heart could be made to beat again by adminis- 
tration of pituitrinum infundibulare; the blood-pressure gradually rose to 
normal again, and the animal entirely recovered. Later Hamburger without 
knowing about our experiments, likewise reported concerning the depressor 287 
PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
action of the extract of the glandular hypophysis. In numerous experiments 
that Bernstein and I made on human beings since that time we could never 
demonstrate a distinct sinking of blood-pressure after the subcutaneous or 
intravenous injection of several cubic centimeters of this extract. Hence the 
dog seems very much more sensitive in this direction. We did observe in 
human beings, however, an extremely striking action. Shortly after the injec- 
tion of a slight amount of the extract—often 2 cc. intramuscularly was sufficient 
—the production of C02 and the consumption of oxygen were reduced. At the 
same time the respiratory quotient rose appreciably. This rise in the respiratory 
quotient lasts in man for thirty to forty-five minutes, then it gradually sinks to 
the normal, while ordinarily the lowering of the total respiratory exchange of 
gases lasts much longer. 
I cite the following experiment as an example: Case Ti (Acromegaly) 
Date 
C02 
02 
RQ 
February 23 
... 256.1 
327-9 
0.780 
One-half hour after intravascular injection of pit. gl 
... 230.77 
246.96 
o-935 
In experiments on a dog we found that on much longer doses (up to 30 
cc.) the lowering of the respiratory exchange of gases was much the less dis- 
tinctly pronounced, and that the rise in the respiratory quotient also was not 
so well expressed as in man. 
The extract used is albumin-free, [proteid-free, eiweissfrei], but often gives 
a biuret reaction. The slight amounts of albumoses present could not cause 
the depressor actions that we observed, as the action occurred just as promptly 
after the albumoses were removed. Also the chloretone employed with the 
extract furnished to us could not account for this action. Finally it could be 
shown that the active principle is not cholin, as the depressor action on the 
blood-pressure continued after the previous administration of atropine. 
The interpretation of these results is attended with great difficulties. 
The circumstance that we were not able to observe a depressor action in man 
does not signify very much. It is possible that also here a dilatation of the 
vessels occurs, but the action of this on the blood-pressure is neutralized by 
counter-regulations. The depressor action on the exchange of gases would let 
it be supposed that temporarily the tonus of organs with smooth musculature 
or that the activity of the great glands of the body is reduced.1 Still harder 
to explain is the action on the respiratory quotient. We originally thought 
that the extract called for mobilizing or increased combustion of the carbohy- 
drates, and that on account of this there occurred also a reduction in the total 
combustion. But in experiments on two severe diabetics it was shown that 
here also there occurred a lowering of the respiratory metabolism, but here the 
respiratory quotient remained quite unaffected. The experiments also speak 
against the objection that the rise in the respiratory quotients has its founda- 
tion in an alteration in mechanism of breathing. Further it has been shown in 
1 E. Neubauer was so kind as to make a oncometric experiment on the liver of rabbits. He 
found after injection of pituitrinum glandulare distinct reduction of the volume of the liver. 288 
THE DISEASES OF THE HYPOPHYSIS 
numerous experiments that were constantly modified, that this extract does 
not act as a glycosuretic, and does not essentially influence an existing alimen- 
tary glycosuria. Exceptions perhaps are certain experiments on diabetics on 
whom after institution on a very low elimination of sugar, there several times 
occurred a slight increase in the glycosuria after injection. Finally, however, 
it was shown that after the injection of this extract there was never observed 
either in experiments on man or on dogs, an increase of the blood sugar-con- 
tents, but on the contrary there was a decrease. Borchardt saw the occurrence 
of glycosuria after the injection of hypophysis extract in the rabbit. In dogs 
for the most part this was wanting. According to our experiment I would not 
estimate very highly the value of the evidence of the experiments on the rabbit. 
After all that I have said thus far as to the action of the extract of the glandular 
part of the hypophysis, it may well be assumed that the latter in some manner 
involves the carbohydrate metabolism, not, however, by mobilizing carbo- 
hydrates in the liver, but rather by an increase of the combustion of the 
sugar in the periphery. With this agrees very well the decrease in the blood 
sugar. I am fully aware, however, that this is nothing more than a 
hypothesis. 
If we consider once more the individual physiological actions that have thus 
far been demonstrated for the glandular or the infundibular extract of the 
hypothesis, we readily see that they furnish very little information for the 
pathogenesis of acromegaly. The function of the cardiovascular apparatus is 
ordinarily not altered in acromegaly in a striking manner, if manifestations of 
hyperthyrosis or hypothyrosis are not present at the same time. 
Closest lies the idea that the polyuria sometimes observed may be referred 
to a temporary irritation of the posterior lobe through the growing adenoma 
of the anterior lobe. This conception may explain the fact that such polyurias 
also frequently occur in tumors of the hypophysis of other sorts, that are asso- 
ciated not with phenomena of hyperfunction of the hypophysis but on the con- 
trary with those of insufficiency (see later). As far as the genital disturbances 
in acromegaly are concerned, the described action of the infundibular extract 
on the genital organs has not as yet helped to make the disturbances more 
intelligible. In acromegaly we find, as has been stated in detail before, rather 
an increased activity of the interstitial glands, and eventually, after transitory 
increase of function, setting aside of the functions of the sexual glands. In 
hypophysial dystrophy there exists a severe dystrophy of the genital organs that 
includes also the interstitial glands. It is therefore very much more likely that 
these alterations of the genital function rather stand in correlation with altera- 
tions in the function of the glandular hypophysis. Nothing at all is thus far 
known, however, as to the action of the glandular extract on the sexual glands. 
The respiratory exchange of gases does not tend to become altered in acromegaly, 
at least as far as there exist no complications with hyperthyrosis, and in dystro- 
phia adiposo-genitalis it is, as we shall see later, perhaps sometimes reduced. 
The depressor action of the glandular extract and the furthering action of the 
infundibular extract can hardly be called upon to explain this disease picture. 
Also the explanation of the disturbance of carbohydrate metabolism so com- PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
289 
monly observed in acromegaly seems to me to encounter unsurmountable 
obstacles. 
Rath and later Loeb supposed that in acromegaly the tumor of the hypophy- 
sis pressed on a neighboring sugar center; the diabetes in acromegaly would thus 
be placed in analogy to the glycosuria sometimes occurring in apoplexy. This 
view has also been adopted by Aschner. This author succeeded in demon- 
strating that a sympathetic center lies in the subthalamic region, the irritation 
of which causes glycosuria. The glycosuria does not occur after transection 
of the splanchnic nerves and therefore like that of Claude-Bernard’s piqure 
goes over the chromaffin tissue. In spite of the convincing experiment of 
Aschner, I cannot agree with his conclusion; it is not clear to me why just in 
acromegaly, a developing hypophysis tumor should press on this center, while 
the tumors of the hypophysis without acromegaly, that often lie in the hypo- 
physial duct or even extrasellary, and that give occasion to symptoms of great 
brain pressure, produce no diabetes; in these cases, on the contrary, as we shall 
see later, the tolerance limits for carbohydrates are practically always appre- 
ciably raised.. 
Pineles supposes a correlative affection of the pancreas. Actually Ilanse- 
mann and Dallemagne have found atrophy of the pancreas in acromegalic 
diabetes. It is indeed very probable that in the cases of acromegaly combined 
with severe diabetes the pancreatic genesis stands in the foreground. We 
see in acromegaly degenerative changes in almost all the organs occur simul- 
taneously with or in the course of the period of increased tendency for growth, 
and the insular apparatus may rapidly become involved in the process, just 
as are involved the sensitive glands of generation. 
Schlesinger assumes in acromegaly not only the occurrence of a true pan- 
creatic diabetes but also of a brain-tumor diabetes. Lorand is of the opinion 
that the glycosuria of acromegaly is thyrogenic as a result of the relationship 
of the hypophysis to the thyroid gland. The views may be very well true 
for a part of the cases, namely, that part in which distinct manifestations of 
the hyperthyrosis are present. How shall we explain, however, the inclination 
of alimentary glycosuria or even a spontaneous glycosuria in these cases in 
which, as in case Ti (Observation XXV) the hyperthyrosis is entirely absent, 
quite apart from the cases with severe diabetes or diabetes leading to coma? 
Naunyn and later Bor chardt regard the diabetes in acromegaly as directly hypo- 
physial, that is brought about through the production of an agent that induces 
glycosuria. The view seems to me to have a certain support in the repeatedly 
mentioned investigations of Bernstein and myself. I have previously stated in 
detail that the glandular extract somehow seems to enter in the regulation of 
the carbohydrate metabolism, but I am not in the ppsition to say anything 
exact about this action. We are thus evidently guided by opinions, and I would 
like to be understood as believing that in the majority of cases a premature 
degeneration of the insular apparatus seems the most likely explanation. 
Pathological physiology has as yet furnished with very little for the under- 
standing of the pathogenesis of acromegaly. As yet just the most important 
symptoms, the increased tendency for growth of a certain part of the organism, 290 
THE DISEASES OF THE HYPOPHYSIS 
especially the osseous system, have not been reproduced experimentally. In 
spite of this the supposition of a hyperfunction of the hypophysis in acromegaly 
is to-day the only satisfactory one. 
For this assumption speaks: 
1. The opposition of the clinical pictures of acromegaly and hypophysial 
dystrophy. 
2. The fact that the latter may be produced by extirpation of the hypophysis. 
3. The results of surgical interference. 
4. The analogy with affections of the thyroid gland. 
Early Acromegaly.—The statements thus far set forth as to the pathogenesis 
of acromegaly are concerned with the clinical picture that we meet with in 
adults. Acromegaly indeed develops almost exclusively after the twentieth 
year. We must now consider the important question as to whether there exists 
an acromegaly of child or adolescent life, and whether the picture of early 
acromegaly deviates from that of adults. Brissaud, and Launois and Roy adopt 
the view that hyperfunction of a hypophysis in early youth before the closure of 
the epiphysial juncture leads to gigantism and after the definite ending of 
growth to acromegaly. According to this view all pathological gigantism would 
then be acromegaly. This view was vigorously opposed by Pierre Marie. I 
shall deal with this question later in the chapter on gigantism, and only would 
remark here, that I also cannot subscribe to this view, as may be plainly seen 
on the perusal of the following details. I believe much more that there exists 
an early acromegaly with gigantism; only it seems that this condition is rela- 
tively very rare, and is much more manifold as to its symptomatology than is 
the typical acromegaly of adults. 
It here seems to me necessary to enter more in detail concerning the reports 
on this subject that occur in the literature. Most intelligible is a group of cases 
in which the clinical picture is very similar to the acromegaly of adults. To 
this group belongs the case described by Arnold as early as 1891. According 
to the definite statement of the author the acromegalic manifestations in this 
patient began to develop distinctly in the eighteenth year of life. In a brother 
of the patient, who also suffered from acromegaly, the beginning of the affection 
came on at a still earlier period of life. There is no doubt at all that this case 
was one of acromegaly; this was shown by the typical thickening of the bones 
that increased in intensity toward the periphery. Also the exact microscopical 
examination of the bones showed architecture typical for acromegaly. In 
the muscles, in the peripheral nerves, the vessels, and the weak parts, there could 
everywhere be found hyperplasia of the connective tissue. It is worthy of note 
in this case that the sella turcica was not essentially widened, and that further 
there was a markedly developed hairiness, especially of the extremities. Hence 
although in this case the beginning of the affection occurred at the time at which 
normally the epiphyses are not as yet closed, increase in height was not persent 
in this case. In this respect it seems to me significant that there were not 
eunuchoid manifestations in this case; on the contrary, as was evinced by the 
hairiness, rather was there an accentuation of the function of the interstitial 
glands. PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
291 
A case of Claude's shows that in acromegaly the closure of the epiphysial 
junctures may occur prematurely. It was that of a girl nineteen years old in 
whom the acromegalic manifestations had gradually developed since the 
fifteenth year. The epiphysial junctures were completely closed, and there 
was no tendency to abnormal height. 
Very important is the case recently reported by Sckultze and Fischer. 
Here the disease began at the eleventh year of life. Since that time had existed, 
headache, vomitings, and temporary salivations. The patient had never 
menstruated. In the course of three days she became blind and almost deaf 
(probably on account of narrowing of the inner ear on account of osseous 
thickening). 
The girl was 167 cm. tall, weighed 81.5 kg. At various places there were 
pronounced pigmentations, the skin of the entire body was rather dark, from 
the navel there was marked development of the hair in the middle line, also hair 
on the upper lip. At various places dark nevi. Inclination for sweats. Head 
very long, horizontal circumference 59 cm. Upper lip markedly cushioned, 
nose thick. Tongue enormously thickened, alimentary glycosuria negative. 
Bilateral choked disc and atrophy. Death manifestly due to cerebral pres- 
sure. Pronounced obesity. Thymus hyperplastic. General splanchnomegaly. 
Also the liver, kidneys, and especially the suprarenal glands greatly enlarged 
(the last to five times their size). Uterus small, infantile, cysts of the ovaries, 
no formation of follicles. The tumor of the hypophysis was of abnormal size 
(6.5 to 4.5 cm.). Microscopically typical adenoma rich in cells. 
Schultze and Fischer regard this case as a mixed form between an ordinary 
typical acromegaly and dystrophia adiposo-genitalis. 
Another type is found in the case described by Pel, a type that I herewith 
describe in detail. The case was that of a sixteen-year-old youth. Since birth 
the size of the hands and feet had been strikingly large and they gradually 
increased in growth; especially of late, after a febrile affection, they have become 
of enormous dimensions. In this increase in size the increase in the dimensions 
of the individual bones of the extremities at the distal parts was quite extra- 
ordinary. Thus the forearms were 29 cm. long, the circumferences of the elbows 
about 27 cm., the middle finger about n cm. long, the thumbs cm., the 
circumference of the knee 40-41 cm., the length of the feet about 31 cm., the 
left leg weighed 4.85 kg., the right 5.1 kg. With all this the total height of 
the body was not very great (172 cm.). The body weight was 50 kg. The 
head was small, only the nose and the tabular part of the occipital bone were 
somewhat larger; the teeth, especially the upper incisors, were strikingly large. 
The dimensions were eunuchoid (lower length 112 cm.), the genital organs were 
entirely infantile (penis 5 cm.), the secondary sexual characters were not 
developed. X-ray examination showed that the sella turcica was widened, and 
that only the body parts of the extremities were so considerably enlarged. 
From youth on there had existed pains of a lancinating character; lately there 
were very profuse sweats, great muscular weakness, and sensitiveness of the 
periosteum of the long bones to pressure. It is further noteworthy that veins 
of the enlarged parts were markedly dilated. A nearly analogous case was 292 
THE DISEASES OF THE HYPOPHYSIS 
recently observed in the Hochenegg clinic and was exhibited by Demmer before 
the Gesellschaft der Arzte in Vienna [Vienna Medical Society]. Pel termed 
this case “acromegalie partielle avec infantilisme.” 
Another type is described by Babonneix. The case was that of a seventeen- 
year-old epileptic, 174 cm. tall, two years ago gradual beginning of abnormal 
growth of the extremities. The hands became strikingly long, the feet “ laugh- 
ably” voluminous, this together with alteration of the disposition, polyphagia, 
and polydipsia; pubic hairs sufficiently developed, genitalia strikingly well 
developed, especially the penis and testicles, the frontal sinuses remarkably 
large, eye-grounds normal, sella turcica not enlarged. Babonneix speaks of an 
acromegaliform syndrome. A similar case was exhibited by Mosse before the 
Societe de neurologie of Paris in May, 1911. 
Still another type is described by Renon and Delille. A sixteen-and-one- 
half-year-old girl, who was normal up to the sixteenth year of life, became 
affected with eye-disturbances, headaches, and backaches with vomiting, 
increased growth. Now 168 cm. tall (lower length 103 cm., span width 180 
cm.) outbreaks of sweat, obesity especially in the loins and on the abdomen, 
breasts poorly developed (fat is painful). Slight hairiness of the pubic region 
and axillae. Has not as yet menstruated, sella turcica much enlarged, optic 
atrophy. The authors regard this case as a polyglandular disturbance. 
Finally these are reports as to the occurrence of acromegaly in early child- 
hood. Salle reports the following: The nose of a new-born infant was strik- 
ingly large, the chin prominent, the auricles large, flap-like, the tongue large. 
The relation of the extremities and of the head to the total length was that of a 
two-year-old child. Hands and feet especially large, fingers and toes strikingly 
large. Ossification corresponds to that of a three- to four-year-old child. The 
child died at the age of two and one-half months. The sella turcica was very 
large, the hypophysis was deformed in the shape of a bean through the projec- 
tion of an exostosis into the sella turcica; it was as large as that of an adult, the 
enlargement affected especially the glandular part. Microscopically was found 
a very considerable richness in eosinophilic cells, such as is found in adults but 
not in children.1 
Finally Hutinel describes a case with enlargement of the acra in a thirteen- 
and-one-half-year-old boy. 
The cases set forth suffice to indicate the great multiplicity of the forms of 
early acromegaly. In one is found a large tumor of the hypophysis, in the 
others the sella turcica is not at all abnormally large; but despite this latter 
fact I would not doubt that in these cases {Arnold, Pel, Demmer, etc.) the diagno- 
sis acromegaly is certain or at least hardly doubtful. Further, the deformation 
of the bones is also very varied. A manifestation that apparently may occur 
in early acromegaly in an especially well-marked manner, is the entirely irrela- 
tive increase in size of the bones of the extremities in a distal direction. Very 
diverse, too, is the proportioning, in that in many cases the eunuchoid propor- 
1 Also Benda (Med. Klin., 1912, 284) regards the histological alterations as typical, but does not 
regard the fact ruled out that the alterations of the jaws, tongue, and hands, may simply have been 
inherited. PATHOLOGICAL ANATOMY OF THE HYPOPHYSIS 
293 
tion is very prominently in the foreground; then again the condition of the 
genitalia is very different; in some cases there is hyperplasia, in others hypo- 
plasia and faulty development of the secondary sexual characters, even asso- 
ciation with eunuchoid obesity; then, as in the case of Schultze and Fischer, 
hypoplasia of the genitalia and obesity, but marked hairiness (hyperplasia of 
the suprarenals). 
The cause of this great multiplicity of type can perhaps be seen in the fact 
that the child organism or the ductless glandular apparatus of children reacts 
to a hyperfunction of the hypophysis in a very much more diverse manner than 
that of adults. Especially the developing genital glands that are involved 
can behave differently, in that here the interstitial glands may be damaged and 
thus may bring to the total picture admixture with features of eunuchoidism. 
Then again, dependent to a large extent on the behavior of the genital glands 
is the premature, normal, or delayed closure of the epiphysial junctures. Also 
the dimensioning of the body may be influenced on account of this. I would, 
however, treat of one point with emphasis. In some cases the diagnosis may 
very well be doubted, in fact in some cases it is even made by the respective 
authors with reserve. In other cases, however, there is no room for doubt; 
and we must reckon with the fact that acromegalic alterations in the extremities 
may occur also in youth, and that therefore the hyperfunction of the hypophysis 
in early youth does not necessarily lead to gigantism. 
Differential Diagnosis.—The point of difficulty in the diagnosis of acrome- 
galy lies in the disproportionate growth of the peripheral parts, not in the 
enlargement itself, as this may be congenital. There is found for instance 
a cranium progeneum in many other conditions that have nothing to do with 
acromegaly {Sternberg). Confusion with osteitis deformans of Paget is hardly 
likely on careful examination. In osteitis deformans the cranium is enlarged 
chiefly in circumference, the long bones soon show curvatures, the alterations 
in the skeleton are very asymmetrical. In osteoarthropathie hypertrophiante 
pneumonique the skull remains unaltered, only the nose may be larger. In 
this condition we have a dorsolumbal kyphosis, in acromegaly a cervicodorsal 
kyphosis; the end phalanges show the well-known drumstick form, the nails 
show curving and longitudinal ridges; while chiefly the region of the knuckles 
is very much swollen up, the metacarpal and metatarsal region, as Souza 
Leithe points out, show but slight increase in volume. Under circumstances 
there may occur in the osteoarthropathy club-like swellings of the hands and 
feet, that may have given occasion to confusion with acromegaly (confer the 
case of Schultz and Fischer). Combination with symptoms of Basedow’s disease 
or myxedema may in the beginning occasion an overlooking of the acromegaly. 
Early genital disturbances or rheumatoid pains may lead to a faulty diagnosis. 
Syringomyelia may also lead to an increase in volume of the extremities, but 
in this condition there are usually found in addition deformities and the well- 
known dissociation of the sensation-qualities. In ordinary macrosomia only 
single members are affected, never both upper extremities and both lower ex- 
tremities simultaneously. Cases in which hands and feet were enormously 
enlarged I have already discussed in the consideration of early acromegaly 294 
THE DISEASES OF THE HYPOPHYSIS 
{Pel, Demmer). We must not forget that the acra of the face may begin to 
become enlarged very much later. Erb saw such a case; the enlargement of 
the extremities had existed for about twenty years before the tongue and nose 
began to enlarge. 
Finally we must refer to the significance of the demonstration of the 
enlargement of the sella turcica by Rontgen transillumination, as first demon- 
strated by Oppenheim. 
In acromegaly there is usually found deepening of the floor of the sella 
without material widening of the introitus, while in the tumors of the hypophy- 
sis without acromegaly dilatation of the introitus and destruction of the 
clinoid process is commoner, although there are exceptions. 
Important for a differential-diagnostic standpoint is, finally, the cir- 
cumstance that genital disturbances may occur. Salbey reports a case in 
which oophorectomy was undertaken because of amenorrhea and pains in 
the back and abdomen. Several months later there developed a picture of 
acromegaly. 
Until lately the treatment was utterly ineffective. Striking results were 
first brought about by the resection of the hypophysis tumor first inaugu- 
rated by Horsley, by Schlojfer, and by v. Eiselsberg, and first happily carried out 
by Hochenegg. I refer to the consideration of hypophysial dystrophy for 
a discussion of the method of operation. In the first two cases of Hochenegg 
(reported by Stumme and Exner) there occurred not only a disappearance of 
the symptoms of cerebral pressure but also a retrogression of the acromegaly 
manifestations as well. The teeth of the upper jaw again approached each 
other, the acra became smaller, the skin softer and wrinkly, the menses returned, 
and the abnormal hairiness again retrogressed; the retrogression of the acro- 
megalic skeletal alteration could also be demonstrated by the X-ray (Hochenegg). 
In two cases, Exner saw an enlargement of the thyroid after the operation. 
Since this time a number of other operated cases have been reported, in part 
with good results (fl. Eiselsberg, Kocher, Moskovitz, Lecene, Cushing, 0. Hirsch, 
and others). Especially striking was the result in the case of O. Hirsch, in 
which rheumatoid pains disappeared, the acra decreased in size, and the 
menses recurred and since that time remained regular. Hochenegg, on the 
basis of a third case that pursued an unfavorable course, points out that in 
cases in which the tumor is chiefly extrasellar the chances of operation are 
always very much less. Considerable destruction of the clinoid processes 
and slight deepening of the floor of the sella must, like myodegeneratio cordis 
and status lymphaticus, be taken in consideration when the question of opera- 
tion arises. 
I refer again to the cases already described in detail that were operated 
on by O. Hirsch. In one there came about an essential subjective and objec- 
tive improvement. In the other case, which I saw again after a half year 
there had been no improvement at all. 
If in cases of acromegaly with high-grade brain-pressure affections a 
radical operation is not possible, a palliative trepanation or an Anton’s “ Balken- 
stich” [puncture of the corpus callosum] is to be thought of. HYPOPHYSIAL DYSTROPHY 
295 
The X-ray treatment of acromegaly was first suggested by Gramegna 
and first practiced by Beclere. It is stated that retrogression of the symptoms 
of cerebral pressure and improvement in the visual disturbances have been 
obtained (see also treatment of hypophysial dystrophia adiposo-genitalis). 
A result can be expected from thyroid-gland therapy only in cases complicated 
with myxedema. Concerning the treatment of the more prominent symp- 
toms of complicating Basedow’s, I refer to the chapter on Basedow’s dis- 
ease. Otherwise in acromegaly the therapy can at most assuage pain by 
means of antineuralgics and eventually combat cardiac insufficiency and the 
decay of strength by means of general roborant measures. 
[Charles Frazier1 also has operated on pituitary gland cases. He has ap- 
proached the gland in some cases by the transfrontal route, in other cases by 
the transphenoidal route. The X-ray was used to determine as far as possible 
the localization of the tumor. The surgeon must choose, states Frazier, between 
the following procedures: sella decompression, sella decompression with excava- 
tion of lesion, sella decompression followed by radium and X-ray therapy, and 
suprasella subtotal extirpation. If an operation is indicated in the management 
of an individual case, a simple subsella decompression is done, with incision 
of capsule, but without extirpation of the growth. Should there be a recurrence 
of visual disturbance, X-ray and radium are employed by an experienced 
roentgenologist. If, despite these, the condition is not under control, the 
lesion is exposed by a transfrontal craniotomy and removed in whole or in 
part—to prevent impending blindness. At least in the cases Frazier reported 
in this article, he found X-ray and radium therapy of value after operation. 
In the cases where subsella decompression is indicated this should precede the 
use of X-ray and radium, first, because substantial and immediate relief 
usually follows a sella decompression, and, second, the effect of radium on the 
pituitary is increased by the removal of the bony partition between the sellar 
floor and the roof of the sphenoid sinus. At least this was Frazier’s experience 
when the article was written.—Editor.] 
b. Hypophysial Dystrophy 
Hypopituitarismus, type Frohlich; dystrophia or degeneratio adiposo-genitalis. 
Historical.—The occurrence of cerebral adiposity or of dysgenitalism 
in tumors of the hypophysis was mentioned already by Babinski, Anderson, 
Shuster, Uhthoff, and others. 
In the year 1901, A. Frohlich on the exhibition of a case that came from 
v. Frankl-Hochwart's dispensary first coined the diagnostic dictum that rapidly 
developing obesity, infantilism of the genitalia, and myxedematous alterations 
of the skin suggest tumor of the hypophysis. 
The case reported by Frohlich was that of a fourteen-year-old boy in whom 
the disease began two years before the presentation, with headaches, vomit- 
1 Frazier (C. II.). The control of pituitary lesions, as affecting vision, by the combined surgical- 
X-ray-radium treatment. Archives of Ophth., Vol. i, T921, pp. 217-226. 296 
THE DISEASES OF THE HYPOPHYSIS 
ing, and rapid increase in weight. He had a characteristic distribution of 
fat, such as will be described later, the genitalia remained entirely infantile, 
there was no hairiness of the genitalia, the axillary region, and the trunk, 
and the skin showed slight signs of myxedema. Since that time numerous 
cases such as this have been reported by v. Frankl-HochwarF s assistants, 
A. Berger, by Erdheim, Zak, A. Fuchs, Bartels, Madelung, Launois and Cleret, 
Babonneix and Peisseau, Creutzjeld, Neurath, Bychowski, Marinesco and Gold- 
stein, Jutaka Kon, and others, and finally several cases by v. Frankl-Hochwart. 
A series of cases is presented by the author in course of the following exposition. 
Definition.—By hypophysial dystrophy we understand a clinical picture 
characterized by accumulations of fat in definite places or eventually by 
pronounced obesity of definite localization, such as is found in eunuchs and 
eunuchoids; further by inhibition of development or by subsequent atrophy of the 
interstitial glands and the glands of generation, and corresponding inhibition of 
development; or by more or less distinct retrogression of the secondary sexual 
characters and of the genitalia; further, when the disease occurs in youthful years, by 
inhibition of growth and inhibition of ossification. Finally, on account of a slug- 
gishness of the entire metabolism, there is often added as a symptom of irrita- 
tion a polyuria; there are also added symptoms of pressure on the optic nerves. 
A lessening or a loss of the function of the glandular hypophysis called forth by 
processes in the hypophysis itself or in the vicinity of the hypophysis may be looked 
upon as a cause of this condition. 
Symptomatology.—One of the most important symptoms is the obesity, 
with a quite definite type of fat-distribution, such as is found also in primary 
inhibition of development of the genitalia. The agreement in the distribu- 
tion of fat in the two types (the primary genital and the hypophysial 
dystrophia adiposo-genitalis) was first mentioned by v. Noorden. The accumula- 
tion of fat is chiefly localized to the hips, the buttocks, the mons Veneris, 
and the mammae. 
In the higher degrees of the fattening the abdominal wall is affected 
especially in its lower part, where there may develop thick fatty layers. These 
were seen in several cases; when they were removed the patients felt con- 
siderably relieved. The supraclavicular and infraclavicular fossae may become 
quite covered over by pads of fat. There is found, moreover, a collar-like 
collection of fat on the neck, and as Launois and Cleret call them, fatty cuffs 
on the malleoli. The obesity may attain an excessive grade, but it attracts 
attention also when it is developed only relatively slightly on account of 
its characteristic distribution. Moreover, the literature frequently empha- 
sizes that in spite of the slight ingestion of food, even in spite of the develop- 
ment of a certain cachexia, antemortem, the retrogression of fat was only 
very slight. I shall later report a case (case Sch, Observation XXXVII) 
in which a marked adiposity developed in a short time. Then attacks of 
cerebral vomiting occurred several months, on account of which the inges- 
tion of food was prevented sometimes for days. The boy now lost in weight, 
it is true, but on account of the residual cushion of fat on the mons Veneris 
and the delicate texture of the skin the type remained still unmistakable. HYPOPHYSIAL DYSTROPHY 
297 
(There also exist cases of hypophysial dystrophia without obesity. Rennie 
reports such a case and remarks that he was unable to find a similar case in 
the literature. Probably in such cases the abnormal distribution of fat would, 
however, be recognizable. Such a case is reported by Kummel. I also shall, 
later report such a case (Observation Gr, XLV). Moreover, I shall report 
a case of dystrophia adiposo-genitalia, probably of hypophysial origin (Observa- 
tion Fr, XLIV), who on his entrance into the clinic was very much emaciated 
on account of a nutritional disturbance. In him also the fat collection on the 
mons Veneris was unmistakable in spite of the emaciation. When he came 
under better condition for nourishment in the clinic, the obesity with the 
typical fat distribution developed rapidly. 
The excessive degree of obesity is regarded as endogenous. This con- 
ception is based, as we shall see later, on the investigations of the respiratory 
exchange of gases, which in some cases of hypophysial dystrophy shows pro- 
nounped lowering of the basal metabolism, while in other cases the lowering is 
not at all considerable. [According to an as yet unpublished address, by Frazier, 
the lowering of the basal metabolism in pituitary lesions is not without 
significance—Editor] 
It is to be expected that in hypophysial dystrophy just as in primary 
genital adiposity the muscles are permeated with fat, as they are, as is known, 
in castrated animals. Up to the present this condition has had very little 
attention paid to it except that Marinesco and Goldstein report a case of typical 
dystrophy with microscopically recognizable damaging of the hypophysis 
through a hydrocephalus, in which the fat-permeation of the muscles was 
apparently found. At all events Marinesco and Goldstein assume a specific 
nutritional disturbance of the muscles. 
In dystrophia adiposo-genitalis the skin shows a quite characteristic 
texture. It is often described as alabaster-like, is remarkably delicate and 
white, mostly is cool to the touch, and sometimes is dry and exfoliates readily. 
In some, apparently rare, cases myxedematous-like swellings of the skin are 
distinctly present. Some cases are reported to have falling-out of the hair 
(see Observation XXXIV). On the contrary, the trophic alterations of 
the nails seem to be rare. 
The following case shows typical distribution of fat: 
Observation XXXIII.—J. L., ten and one-half years old. Entered the clinic June, 
::909. Has a poor heredity. Father and two sisters are insane. An eight-year-old brother 
is hard of hearing. Three years ago began violent headaches, that gradually increased, and 
recently there occur, now and then, slight attacks of vertigo. Sometimes the lad sees 
indistinctly and with blurring. Sometimes there occur parching sensations of thirst, polydipsia, 
and polyuria. Obesity has developed only recently. For two years growth has been at a 
standstill. 
The boy is rather small for his age. 
Height, 131 cm. 
Circumference of skull, 56 cm. 
Jugulum-symphysis, 45XA cm. 
Chest circumference, 80 cm. 
Distance between the spines, 30 cm. 298 
THE DISEASES OF THE HYPOPHYSIS 
Upper extremities, 62 cm. 
Upper arm, cm. 
Anterior superior spine to lower border of patella, 38 cm. 
From there to internal malleolus, 31 cm. 
The boy is very fat, especially in the pelvic region, on the outer side of the thigh, and 
on the mons Veneris. The penis is abnormally small, the testicles also small, the mammae 
are very rich in fat, genua valga. 
The intelligence is normal, the status of the nervous system shows normal conditions, 
with the exception of nystagmoid twitching in all end-positions. Fundus and perimetry 
are normal, the development of the hand-skeleton about corresponds to the patient’s age, 
no alimentary glycosuria (100 gm. dextrose). 
The X-ray examination of the skull shows: 
Sella turcica not deepened, but the entrance to the sella is remarkably broad. This 
makes the clivus somewhat more sharpened. 
Adrenalin 0.001 gm. subcutaneously, no glycosuria. 
Diagnosis: Dystrophia adiposo-genitalis, probably hypophysial. 
I cite the following as a typical case of hypophysial dystrophia 
adiposo-genitalis. 
Observation XXXIV.1—L. S. B. [female! from Russia. Sixteen years old. Entered 
the clinic Nov. 1, 1911. Family history shows nothing bearing on the case. Nine years 
ago the patient sustained a febrile disorder which she states was typhoid fever. After the 
recovery the body weight began gradually to increase. She eats a fair amount of food since 
that time, but especially has she noticed an increase of thirst, so that she often has to get up 
at night to drink. She also urinates very frequently. The patient believes herself to 
have been well otherwise until about three years ago. At that time she began gradu- 
ally to complain of severe headaches, especially at night. She complained of formications in 
the hands, and remarked that there was a decrease in the power of vision. Already at that 
time an eye doctor had forbidden her to read. Lately the headaches have gradually become 
worse, especially at nights, the patient readily becomes fatigued, and four months ago she 
remarked one day that she could not see at all with the left eye. At the end of May, 1910, an 
eye doctor diagnosed bitemporal hemianopsia, optic nerve atrophy, vision 0. D. 10/40, 
O. S. 10/70. At the end of August, 1911, there was a supplementary report, O. D. 10/50, 
O. S.: Counts fingers just in front of the eye. 
At present there are headaches almost daily; for six months there has existed falling 
out of the hair, the nails have not become brittle; however, the patient is almost always 
listless and indifferent to all things that occur around her, she yawns very much, but sleeps 
very little at night. According to her statement she sweats hardly at all. There is no 
vomiting. As yet she has not menstruated. 
The patient is small, about 145 cm. The build of the bones is slender, the musculature 
poorly developed, the layer of fat very abundant. Especially fat are the mammae, in 
which no trace of glandular substance is palpable. The nipples are small and retracted. 
Especial accumulations of fat are found on the hips, on the outer sides of the thighs, and on 
the mons Veneris. The axillce as well as the mons Veneris possess only a very few hairs. The 
genitalia are rudimentary. The labia minora are scarcely developed. The clitoris is very 
short, hymen intact. The uterus very small, the ovaries are not felt. 
The patient shows great difficulty in thinking. She speaks German well enough it is 
true, but responds to only very simple questions. In Russian she converses rather fluently. 
She lies in bed very much, and is indifferent to her surroundings. During the examination 
she yawned very much. 
The left eye is amaurotic, the pupils do not react although the consensual reaction is 
present. On the right side is temporal hemianopsia and temporal hemianopic pupillary 
reaction. Vision of O. D. 1/10. Both papillae are sharply demarcated and atrophic. The 
reflexes are normal. The neck is short, thick, the thyroid not palpable. The supraclavicular 
1 The case has been also published in detail by 0. Hirsch. HYPOPHYSIAL DYSTROPHY 
299 
and infraclavicular fosses as well as the intercostal spaces are entirely obliterated by the 
pads of fat. The abdominal walls are extremely fat. The fatty tissue of the skin is every- 
where markedly sensitive to pressure. The amount of urine is 4000 cc., specific gravity, 
1008. 
Hemoglobin, according to Sahli, 75 per cent. 
Leucocytes, 8400 of which: 
Neutrophiles, 56.1 per cent. 
Lymphocytes, 35.8 per cent. 
Eosinophiles, 3.2 per cent. 
Large mononuclears, 4.9 per cent. 
Body weight, 62 kg. 
Temperature varies between 36° and 36.6°. 
Alimentary glycosuria (200 gm. dextrose) negative. 
The blood sugar is 0.0826 per cent. (Dr. Bernstein). 
Fig. 54.— Case of dystrophia adiposo-genitalis. 
Fig. 55.—Hypophysial dystrophy, 
X-ray.—Cranial vault of normal size and form. Internal surface smooth, sutures are 
present, sella moderately widened and deepened. Its floor shows an anterior arching 
forward and a thinning. The dorsum sellae is thinned, the anterior clinoid processes are 
retained. Sphenoidal sinuses capacious. The ossification of the hand skeleton about 
fits in with the age. 
The patient was operated on Nov. 29, 1911, by Dr. O. Hirsch at the Urb ants chits ch 
clinic, under local anesthesia. The septum was subjected to a submucous resection, both 
sphenoidal sinuses were opened, the floor of the sella was chiseled off, and the tumor partially 300 
THE DISEASES OE THE HYPOPHYSIS 
curetted out, and partially removed through suction through a glass tube. The total mass 
together with the blood, measured about 45-50 cc. There was no fever for the first two days 
after the operation, then on the third day the temperature suddenly rose to 39.50. Vomiting 
Fig. 56. Widened and deepened sella in hypophysial dystrophy (Observation XXXIV). 
that lasted for five days. There was probably a hematoma in the dural sac of the hypophysis, 
that went over into suppuration, was in part absorbed, and in part flowred off (Hirsch); for 
several days the fever was very high, 39-40.50. The third and fourth weeks it gradually 
declined. At the end of the fourth week the patient was retransferred to the first medical clinic. HYPOPHYSIAL DYSTROPHY 
301 
The patient now makes an entirely different impression, she is incomparably more lively, is 
interested in the surroundings and promptly answers all questions. The falling out of hair 
has lessened. The thirst still exists. She yawns much less, the hairiness of the axillae and of the 
mons Veneris has increased, the visual power of O. D. has risen from 1/10 to 1.67/10. The 
headache disappeared entirely after the operation, but reappeared again four weeks afterward. 
Very noteworthy are the blood-findings. The differential count now shows: 
Fig. 57.—X-ray picture in Observation XXXIV. 
Neutrophiles, 71 per cent. 
Lymphocytes, 25 per cent. 
Eosinophiles, 1 per cent. 
Mononuclears, 2 per cent. 
Transitional forms, 1 per cent. 
There is now distinct reduction on the ingestion of 100 gm. of dextrose. 
The patient has lost about 6 kg. 
In typical dystrophia adiposo-genitalis is found, in addition to the fat- 
tening, an inhibition of the development of the genitalia and of the secondary 302 
THE DISEASES OF THE HYPOPHYSIS 
sexual characters; in male individuals the penis remains quite small and may 
even be entirely buried in the fat cushions (see Observation Sch, XXXVII), 
the scrotum also remains small, the testicles remain quite diminutive and 
are usually entirely undescended or partially descended on one or on both 
sides. Also the prostate remains abnormally small. In female individ 
uals the external and internal genitalia remain quite infantile; the labia 
minora are developed but very poorly, the clitoris is short, the uterus infan- 
tile, the ovaries may be not palpable, the breasts as a rule are indeed very 
rich in fat, but are poor in glandular substance (see Observation XXXIV). 
The nipples are small and retracted. Moreover there is either no hairiness 
of the axillas, the pubic region, and the perineum, or in the pubic region there 
are only a few bristly hairs. Men remain beardless. The voice does not 
change or changes very incompletely. The vita sexualis does not develop, 
and menstruation and ovulation do not occur. In certain cases in which 
the disease has developed after puberty, there have been reports as to sub- 
sequent falling out of the beard hair and the pubic hair, in men impotence 
sets in, and there is a cessation of erection and ejaculation; in women there 
is a cessation of menstruation. Libido disappears in both the sexes. There 
may also occur a partial retrogression of an accessory genital apparatus that 
once was fully developed (see Observation G, XLV). 
The Metabolism.—Very few investigations as to the metabolism of 
hypophysial insufficiency have as yet been made. Already clinical observa- 
tions would indicate that in hypophysial dystrophy there are considerable 
alterations in metabolism. We not rarely find the statement that on the 
one hand, at the beginning of the disease there occur a transitory polyphagia 
and increased appetite. I refer to S, Observation XXXIV and Sch, Observa- 
tion XXXVII, to be reported later. On the other hand, obesity that develops 
gradually and which in certain cases may attain an excessive degree suggests 
a reduction in the metabolism. 
Also the observation that after operation there is often an appreciable 
reduction of body weight speaks to the same effect. Statements as to 
this question are made by v. Frankl-Hochwart, concerning the first case that 
v. Eiselsherg operated on with good results. Also in the case of Hirsch, pre- 
viously mentioned (Observation S, XXXIV), a reduction of 6 kg. in weight 
followed during a short time after the operation. 
The investigations as to the basal metabolism or the resting exchange 
in dogs in which the hypophysis had been removed show unequivocally an 
appreciable reduction of the respiratory gaseous exchange (Benedict and 
Homans, Porges and Aschner). 
The first experiments, in two cases of hypophysial dystrophy are reported 
in the second edition of v. Noorden’s book on “Obesity.” These experiments 
which were carried out by Porges gave rather normal values. The cases were 
undoubted cases of hypophysial dystrophy and had been described by v. 
Frankl-Hochwart. Later Bernstein found an appreciable reduction in one 
case. Finally Bernstein and I have recently investigated a case. I here 
tabulate some cases. HYPOPHYSIAL DYSTROPHY 
303 
Investigator 
Case 
Age 
Height 
Weight 
CO2 
02 
Porges, cited by v. Noorden 
25 
166 
70 
Bernstein 
G. Wi 
28 
149 
65-62 
2.29 
O * Oj 
2.94 
Bernstein and Falta 
Fr. 
IS 
I 21 
33 
5-i4 
6.11 
(25, formerly) 
The few cases do not furnish any certain conclusion. Only in Bern- 
stein’s case is the respiratory metabolism certainly reduced. This observation 
hence coincides with the experiences met with in animal experimenta- 
tion. In case Fr, Observation XXXIV, values of comparison with values 
furnished by a normal individual equally heavy and tall are lacking. [See 
Frazier’s view, page 297.'—Editor.] 
The observation as to the carbohydrate metabolism in hypophysial dys- 
trophy show a noteworthy opposite behavior to that in acromegaly. While 
in acromegaly, in the great majority of cases, we find the tolerance for carbo- 
hydrates more or less reduced, this has not as yet been found in hypophysial 
dystrophy. On the contrary it seems, so far as investigations up to the present 
have shown, that the limits of assimilation are raised {Bondi, cited by v'.Frankl- 
Hochwart; v. Noorden, and others). I here publish all of my own observations 
of dystrophy, equally whether the diagnosis hypophysial disturbance has 
made certain, or whether it is merely tentative. 
Observation L, XXXIII, alimentary glycosuria (xoo gm.) negative. 
Observation Si, XXXIV, alimentary glycosuria (200 gm.) negative. 
Observation Si, XXXIV, after operation, alimentary glycosuria (100 gm.) distinct reduction. 
Observation Sch, XXXVII, alimentary glycosuria (100 gm. D) negative. 
Observation K, XXXVIII, alimentary glycosuria (100 gm. D) negative. 
Observation W, XXXIX, alimentary glycosuria (100 gm. D) negative. 
Observation P, XLIII, alimentary glycosuria (200 gm. D) negative. 
Observation F, XLIV, alimentary glycosuria (200 gm. D) negative. 
Observation G, XLV, alimentary glycosuria (200 gm. D) negative. 
Observation G. Wi, XXXVI, alimentary glycosuria (100 gm. D) negative, alimentary gly- 
cosuria (200 gm. D) trace. 
Observation E. M., XXXV (200 gm. D) negative. 
From the observation on pertinent cases in the literature as well as the 
cases here reported is elicited the fact that in hypophysial dystrophy this ere 
no inclination to glycosuria, but on the contrary an abnormal high tolerance for 
carbohydrates. A single exception exists in the case of Link, a case of hypophy- 
sial tumor without acromegaly and with diabetes. We shall simply state this 
fact here and return to it in the discussion of the theory. 
Investigations as to the contents of sugar in the blood are up to the present 
scarce. Cushing states that in certain cases he found an abnormally low 
amount of sugar in the blood. Bernstein estimated the sugar in the blood 
in two of the cases here reported. Both were certain cases in one of which 
(Observation S, XXXIV) the diagnosis was verified on operation, in the other 
(Observation G, XLV) at autopsy. The values were 0.082 per cent, in case 
S, 0.081 per cent, in case Gr, therefore normal. 304 
THE DISEASES OF THE HYPOPHYSIS 
Investigations as to purin metabolism have as yet been carried out only 
by Nowacznski and myself. 
In the one case the following was noted: 
Observation XXXV.—E. M., forty-four years old. Entered clinic March 29, 1912. 
Six years ago sustained a sprain of the lumbar spine by a blow from a stay. Present disease 
began about six weeks ago with vomiting. Severe headache, twelve days ago diplopia. 
Flickering before the eyes, weakness of vision. Patient is a heavy drinker; no venereal 
diseases; for several months increase of weight, reduction of libido and potency. 
Vigorous man, sensorium unimpaired, distinct abducens palsy of left eye. Left palpe- 
bral fissure narrower than right. Left pupil wider than right. Pupillary reaction on 
right prompt, on the left delayed. Diplopia on looking toward the left. Nystagmus of 
left eye on looking toward left. Facialis normal. Tremor of the hands, otherwise no motor 
or sensory disturbance. 
No ataxia. Reflexes normal. X-ray: Sella turcica itself is normal, but the clivus is 
atrophic, as corresponds to the generally increased cerebral pressure. 
Alimentary glycosuria (200 gm.) negative. 
Diagnosis: Dystrophia adiposo-genitalis due to tumor in the region of the hypophysis. 
The investigation of elimination of uric acid on a purin-free diet gave the following 
values: 
0.398-0.406—(20 gm. sodium nucleinate by mouth'' 0.434-0.593. The endogenous 
uric acid value hence lies rather low, at all events the elimination of uric acid after the 
administration of purin is very low. 
The second case was the following: 
Observation XXXVI.—G. Wi., twenty-eight years old [female]. Entered the clinic 
May 1, 1912. For one year headache without definite localization. Vertigo, vomiting, 
ear noises at intervals of months, which for the last three months have occurred almost 
weekly. Since childhood, slight weakness of vision on the left. For the last six months, 
decrease of vision on both sides, amaurosis on the left, still some vision remains on the 
right, for the last months increase of weight. Absent menstruation for the last nine months. 
Lues denied. 
Findings as concerning the lungs, heart, etc., normal; rather fat, especially on the 
abdomen. Pupils unequal, left larger than the right. The left has lost its round contour, 
does not react to light, the right reacts slowly. Accommodation on both sides good, globe 
free, no nystagmus, corneal and conjunctival reflexes present. Fundus normal, right 
temporal hemianopsia, basal limitation of the visual field, left amaurosis; facial nerve nor- 
mal. Face hyperalgetic; trigeminus sensibility, temperature-sense, pain-sense, motility 
and motor power normal. Patellar reflexes lively. Suspicious Babinski reflex on the left. 
Abdominal reflexes present. No vertigo, no diplopia. 
X-ray: Sella turcica dilated quite lightly, especially in the infundibular part. This 
finding does not speak unconditionally for hypophysial tumor, but may be present in other 
brain tumors. 
Alimentary glycosuria: (100 gm. D) negative; (200 gm. D) trace. 
The investigations of the uric-acid elimination on a purin-free diet show the following 
values: 
0.287-0.334—(20 gm. sodium nucleinate by mouth) 0.513-0.206-0.298-0.214. 
Hence the endogenous factor lies even lower than in the preceding case. Administra- 
tion of purin increases the elimination of uric acid but very little. 
Quantities of urine up to 2400 cc. with specific gravities between 1005 and 1010. 
Investigations as to the gaseous exchange (Bernstein)•—average of seven investigations. 
CO2 elimination, 2.29 
O2 consumption, 2.94 
Blood-count: Erythrocytes, 4,600,000 
Hemoglobin, 84 per cent. HYPOPHYSIAL DYSTROPHY 
305 
Leucocytes, 7800 of which: 
Polymorphonuclear leucocytes, 74.1 per cent. 
Lymphocytes, 19.5 per cent. 
Eosinophiles, 0.7 per cent. 
Large mononuclears, 5.7 per cent. 
At the beginning of the stay at the clinic the patient was very sleepy, and uninterested. 
Later there developed a clinical picture similar to Korsakoff’s psychosis, and the patient 
was transferred to v. Wagner’s clinic. Increasing weakness, lately Babinski reflex positive 
on each side. Facial palsy on the left and pareses of the lower extremities. Pneumonia. 
Death. 
August 6, 1912. Necropsy (assistant Erdheim) showed: Cystic hypophysial tumor 
of the size of an apple, at the base of the brain, at the site of the infundibulum, with pro- 
trusion of the tumor into the third ventricle and giving off of the peduncle of the hypo- 
physis from its lower surface. The tumor extends to the circle of Willis and hollows out 
considerably both the temporal lobes; at the anterior pole of the tumor lie the flattened 
optic nerves, which are wedged in between the tumor and the anterior cerebral arteries 
and which show a squeezing together at this place; more on the left than on the right; the 
lower pole of the tumor lies at the entrance to the sella turcica and dilates it. The dorsum 
sellae is moderately eroded, the floor of the sella distinctly eroded, but moderately deep- 
ened. In the sella is the hypophysis, which is of normal size with a slight concavity of its 
upper surface. The tumor is a unilocular thin-walled cyst, in the clear yellowish contents 
of which float consistent opaque flakes. General adiposity. 
A third case, which since this time has been investigated by Dr. Vias and 
myself, is later set forth in detail. (Observation F, XLIV). It was that of 
a juvenile dystrophy, the hypophysial origin of which is only conjectural. 
Therefore, in all three cases the endogenous uric-acid value is at the lower 
limit of the normal, and the elimination of any purin that is administered is 
protracted. Of course there exists the possibility that in such cases the absorp- 
tion of sodium nucleinate is incomplete. After all, even in this respect, there is 
a noticeable difference from the state of affairs in the cases of acromegaly 
investigated. 
Investigations as to the behavior of the vegetative nervous system in hypo- 
physial dystrophy are up to the present very scarce. As far as the excitability 
of the vegetative nerves through pharmacological means is concerned, I can 
mention only the following: The glycosuric action of adrenalin (1 mg.) has failed 
in the cases I have thus far examined (Observations XXXIII and XLIII, see 
later). 
After the injection of 0.01 gm. of pilocarpine in case Si (XXXIV), there was 
only a very slight sweat. After the injection of pituitrinum infundibulare 
(2-3 cc. Parke, Davis & Co.’s preparation) there could be obtained a marked 
diuretic action. Hence the excitability of the vegetative nerves seems to be, 
as in myxedema, generally reduced. Perhaps the nervous mechanism regulat- 
ing temperature forms an exception to this (see part dealing with the 
temperature). 
Many circumstances speak for the fact that there is a reduction in the 
tonus of certain vegetative nerves. In all cases we find, for example, statements 
as to the dryness of the skin and the lessened tendency to sweats. 
Here I might mention the statements of v. Frankl-Hochwart, and Frdhlich, 
that in hypophysial dystrophy there not infrequently occur vesical disturbances. 306 
THE DISEASES OE THE HYPOPHYSIS 
For the most part they have been referred to the compression of the pespedun- 
culi by the growing hypophysial tumor; both authors express the opinion that 
perhaps a reduction of the function of the posterior lobe and lack of pituitrinum 
infundibulare is responsible. It would indeed be important to pay attention 
to the behavior of the vesical disturbances in those cases in which transitory 
polyuria points to an irritation of the posterior lobe. I shall consider this 
symptom somewhat in detail. 
We find that polyuria or polydipsia has been mentioned in the history rather 
frequently. In v. Frankl-Hochwart’s statistics the picture of diabetes insipidus 
occurred seven times. When I turn to the newer 
literature I find that polyuria or at least transitory 
attacks of thirst are very frequent. I cite the follow- 
ing cases: 
Case i of Zack.-—Transitory polyuria, with urine 
of 1000 specific gravity. 
Case Fuchs.—At times attacks of thirst. 
Case Rosenhaupt.—An average of 5 liters of 
urine. Autopsy showed a sarcoma of the anterior 
lobe of the pituitary. 
Case 1 of Bartels.—Twenty-one-year-old man. 
Polydipsia very pronounced. 
Case 1 of Cagnetto.—Nine-year-old girl, poly- 
dipsia. 
Case Gotzl-Erdheim.—Diabetes insipidus. 
Own Observation (L, XXXIII).—Sometimes in- 
tense feeling of thirst and polyuria. 
Own Observation (Si,XXXIV).—Polydipsiaand 
polyuria, must get up serveral times at night. 
Own Observation (Wi, XXXVI).—At times 
polyuria, with urine of low specific gravity. 
Own Observation (F, XLIV).—Amounts of urine 
up to 4000 cc., specific gravity 1005-1010. 
Also a case of Frank's perhaps belongs here: a 
thirty-nine-year-old corpulent man several years ago 
attempted suicide by firing two bullets into the right 
temple. Six to seven liters of urine daily, of specific gravity 1005. Libido 
lost; X-ray shows one of the bullets in the median line, projecting into the sella 
turcica from above. 
Hence there are found in a great number of cases of hypophysial dystrophy, 
transitory or more permanent polyuria, indeed in many cases the condition 
may assume the picture of a severe diabetes insipidus. 
The combination with polyuria occurs not only in diseases of the hypo- 
physis but also in diseases that affect the neighborhood of the hypophysis (vicinity 
of the chiasma, subthalamic region, etc.). As we shall consider these cases later 
in the discussion of the pathogenesis I shall bring to the front the most essential 
facts in the existing clinical material. Oppenheim first pointed out that polyuria 
Fig. 58.—Tumor of the sub- 
thalamic region with diabetes 
insipidus. HYPOPHYSIAL DYSTROPHY 
307 
frequently occurs in gummatous diseases of the chiasm. Of thirty-six cases 
of basal luetic meningitis from the literature, twelve had polyuria. Oppenheim 
himself reports two cases with autopsies. Spctnbeck and Steinhaus found dia- 
betes insipidus eleven times among fifty cases with bitemporal hemianopsia. 
They themselves report a case of typical hemianopsia, who eliminated 6-7 
liters of urine with a specific gravity of 1002. Mercury and iodine treatment 
brought about a complete cure. 
I here report a case I saw a long time ago that in many respects is very 
interesting. 
Observation XXXVII.—A. Sch., fifteen years old. Entered the clinic Sept , 1909. 
Father and mother well; no nervous affection in the family. The mother had had four 
deliveries and three abortions. The first child is entirely well, the second is the patient. 
The third and fourth children have had transitory illnesses that were without relevance 
to the patient’s condition. 
The patient has had a remarkably large head ever since birth. The first tooth appeared 
in the sixth month, and he began to walk at the age of two years. At this time he was 
remarkably tall—a giant child. At three years of age there developed gradually convergent 
strabismus that has existed up to the present time. The boy learned well at school, and 
was even very intelligent and lively. From the age of twelve years there developed a 
gradual lessening of visual power; vertigo often occurred, the boy had very great thirst, had to 
drink very much and urinated very much. Also the statement is made by the mother that at 
this time the boy had a remarkably large appetite. He also had to expectorate very much. 
Gradual increase of body weight became apparent. 
In 1908 the patient had been at v. Neusser’s clinic. There it was noted that there was 
marked panniculus adiposis. Body weight 46.8 kg. Slight concomitant convergent 
strabismus. The movements of the eye-balls toward all directions are very good, how- 
ever. The penis is small, no pubic hair, patellar reflexes lively, temporal paleness of bolh 
papillce. Field of vision normal. Amounts of urine between 2500 and 4500. Specific 
gravity about 1008. 
According to mother’s statement the emaciation began during the mentioned stay at 
the clinic. Since that stay there have also existed severe headaches that occur about twice 
weekly and are especially localized in the frontal region. During severe attacks there 
exist marked sensation of heat and reddening of the skin of the face with outbreak of sweat, 
vertigo and flickering before the eyes, and mostly severe vomiting. Between these attacks 
there exists great tendency to sleep, the boy sleeping twelve hours uninterruptedly. Accord- 
ing to the mother, there is a common inclination for yawning. The boy states that now 
and then erections occur. The polyuria is now very considerable. It now is as much as 
seventy-one times daily, and he must get up often at nights to urinate. According to the 
definite statement of the mother, the boy has not grown for a year. 
The boy is tall, the body shows the following measurements: 
Jugulum to ant. sup. spine, 38.5 cm. 
Jugulum to symphysis, 46 cm. 
Vertebra prominens to coccyx, 47 cm. 
Circumference of chest, 72 cm. 
Circumference of pelvis, 71 cm. 
Upper extremities, 68 cm. 
Lower extremities, 72 cm. 
The face has a more childish expression than corresponds to the age. The intelligence 
is entirely normal, rather more mature than corresponds to the age. Hair is absent in the 
axillae and on the pubes, also on the perineum. The boy is extremely emaciated, especially 
on the extremities; the most fat is found on the outer surface of the thighs. Themons Veneris 308 
THE DISEASES OF THE HYPOPHYSIS 
is very rich in fat. The penis is small, and on both sides the very small testicles remain in the 
inguinal canal. 
The strabismus remains unaltered. The examination of the fundus shows on both sides 
temporal paling of the papillae. Perimeter normal. 
X-ray examination that had been made even before the patient’s entrance into the 
clinic shows entirely normal relations of the sella turcica. Examination of the hand-skeleton 
shows that the epiphysial junctures and the rudiments of the hand-skeleton correspond 
fully to the age. The patellar reflexes are lively, but with the exception of the nervous 
status there is nothing else especial. 
Alimentary glycosuria (ioo gm. D) negative. 
The amounts of urine vary between 4000 cm. and 6700 cm. The specific gravity is 
1002-1003. 
During the stay at the clinic an attack of headache and vomiting occurred such as 
is already described. This lasted for two and one-half days, the vomiting was uncontrol- 
lable. Ingestion of food during this time nil. 
Ingestion of fluid very slight, only 1600 cm., or 
500 cm., or 1050 cm. The specific gravity {of the 
urine) rose to 1013. The boy during this time 
lost 3 kg., falling from 37K kg. to 34 kg. 
The patient died a half-year after his entrance 
into the clinic. 
Summary.—When the patient came into the 
clinic, he showed the entire picture of dystrophia 
adiposo-genitalis. As X-ray examination shows 
the sella turcica to be normal, it may well be 
assumed that a tumor pressed on the hypophy- 
sial peduncle from above. Also the diabetes 
insipidus fits into the picture, also the undoubted 
temporal paling of the papillae, which had not as 
yet led to a demonstrable hemianopsia. It is 
further noteworthy that the concentrating power 
of the kidneys was still present under certain 
circumstances. 
Very noticeable is also the statement of Strauss as to cases of diabetes 
insipidus combined with corpulency of the hypophysial type, with lack of 
pubic and axillary hair and with hypoplasia of the genitals. In many such 
cases we are perhaps dealing with developing tumors of the vicinity of the 
hypophysis, even though there are as yet no other signs of brain tumor. 
As an example of this type, I cite the following case: 
Observation XXXVIII.—S. K., twenty-one years old. Entered the clinic July 12, 
1912. Mother of the patient was corpulent, and died of brain tumor. The patient’s 
corpulency began in the thirteenth year of life, together with increased sensation of thirst, 
the patient sometimes drinking 5 liters of water a day. Corresponding polyuria. This 
has continued since that time, and only during the last three years has it become somewhat 
slighter. For years violent headaches, which of late have been increasing in intensity and 
frequency. The patient has not as yet had sexual intercourse, although according to his 
statement there exists a certain amount of libido and vita sexualis, and he believes that 
he could have potentia cceundi. He states, however, that nightly pollutions almost never 
occur. 
About 170 cm. tall, the skin quite soft, mustache and beard are almost completely ab- 
sent, axilla; show but very sparse hairiness on the mons Veneris hairiness rather good, 
Fig. 59.—Genitalia of Observation 
XXXVII. HYPOPHYSIAL DYSTROPHY 
309 
closing off above in a horizontal line, otherwise hairiness of the trunk and extremities is 
entirely absent. 
Typical eunuchoid fat deposits. Mammae extremely rich in fat, as are also the vicin- 
ity of the hip, and the mons Veneris. The small penis is embedded in a cushion of fat. 
Testicles of rather normal size and consistency. Genu valgum on each side. 
Alimentary glycosuria (100 gm. dextrose), negative. 
Blood count: Erythrocytes 4,240,000. 
Hemoglobin (Sahli), 65 per cent. 
Leucocytes, 6500, of which: 
Neutrophiles, 65 per cent. 
Mononuclears, 28 per cent. 
Eosinophiles, 7 per cent. 
X-ray examination of the skull shows normal relations. 
On freely chosen administration of liquid, an average of 7400 cc. of urine per day. 
The investigation as to the specific gravity of the urine at different times of the day shows 
6-II A M. 1550 CC. 1008 
11-4 P.M. 1300 CC. 1008 
4~9 P.M. 19OO CC. IOO4 
9-6 A.M. 1600 CC. 1002 
After addition of 15 gm. of common salt to the breakfast. 
6-11 a.m. 1200 cc. 1007 
11-4 P.M. 1850 CC. 1007 
4-9 p.m. 1950 cc. 1007 
9-6 A.M. 2600 CC. 1004 
Summary.—Combination of eunuchoid obesity and deficient development of the 
secondary sexual characters with diabetes insipidus. Growth-disturbance is absent, as is 
also any disturbance worth while in the ossification. Probably disease of the brain-stem 
of unknown nature. 
v. Frankl-Hochwart emphasizes that in tumors of the hypophysis without 
acromegaly, often the temperature is established at subnormal values; he 
himself observed this in three of ten cases. In the case of Gotzl-Erdheim the 
temperature varied between 350 and 36°, only exceptionally rising as high as 
36.3°. Among my cases this was very evident in case Si, Observation XXXIV, 
here the temperature varied for a time between 36° and 36.6°; and in case F, 
Observation XLIV (see later), the temperature varied for a while between 36° 
and 36.4°; and later even between 35.8° and 36.2°. We could bring this reduc- 
tion of body temperature into relation with the reduction of the metabolism, 
as is the case in myxedema. Everything speaks for the point of view that also 
in hypophysial dystrophy the vegetative functions proceed slower than in 
normal individuals. 
It seems, however, almost as though in hypophysial dystrophy the regu- 
lating of temperature may under circumstances show an especial lability. 
v. Frankl-Hochwart has already pointed out the fact that in tumors of the 
hypophysis without acromegaly sometimes hyperthermia occurs. Cushing 
further reports that the injection of glandular extract into hypophysioprivic 
animals leads to an increase of temperature, while in normal animals this 310 
THE DISEASES OF THE HYPOPHYSIS 
increase after the injection never occurs. Cushing has used this “ thermoreac- 
tion ” as a diagnostic aid, and assumes a state of hypophysial insufficiency in 
all cases of pituitary disease in which the increase of temperature occurs after 
the injection of 2 cc. of a 5 per cent, extract of the anterior lobe of the ox 
hypophysis. 
Kahn and myself in studies on tetany have several times seen in the acute 
stages, after the injection of 2-4 cc. of pituitrinum glandulare of Parke, Davis 
Co. that, as was shown especially actively in investigations on respiratory 
metabolism, there occurred an increase of temperature to over 38°. Lately 
Bernstein and myself instituted experiments on twenty individuals, some of 
whom were normal and some affected with various diseases, injecting them 
subcutaneously with 2 cc. and eventually 10 cc. of the glandular extract. Never 
did there occur an increase of temperature. In one case of very chronic acro- 
megaly, the experiment was negative (case Ad, Observation XXIX). We 
saw, on the contrary, in case F, Observation XLIV, which will later be reported 
in detail, no distinct action after the injection of 4 cc., but later on repetition 
with 5 cc. twice an increase of temperature of more than 20. 
I would not attempt an explanation of this remarkable phenomenon. 
More extensive observations are necessary to establish the diagnostic signifi- 
cance of the reaction. 
Almost regularly in hypophysial dystrophy are found alterations of the blood 
picture. 
I have carried out investigations as to this point for years, at first in colla- 
boration with Dr. Bertelli, in a series of cases at the clinic. 
Through the kindness of Prof. v. Frankl-Hochwart, we were permitted to 
examine some of the cases reported by him. I cite the following observations: 
Observation XXXIX.—W., twenty-six years old, typical case of hypophysial dystro- 
phy. Examination of the blood in July, 1907. At that time diplopia, reduction of the 
visual power, bitemporal hemianopsia; since the nineteenth year of life no erections, and no 
libido, genitalia infantile, pubic hair and axillary hair almost entirely absent. X-ray 
shows widening of the sella turcica. 
Alimentary glycosuria (100 gm. dextrose), negative. 
Erythrocytes, 4,800,000. 
Leucocytes, 5600 
Hemoglobin, 7.5 gm. 
Dec., 1907, operation by Prof. v. Eiselsberg, after which improvement of the power of 
vision and of headache. 
March, 1908: erythrocytes, 5,260,000 
Leucocytes, 7500 
Hemoglobin, 8.2 gm. 
Observation XL.—D., twenty-one-year-old man, November 1909, for ten years grad- 
ually occurring headaches and vomiting. For eight years, diminution of the visual acuity. 
At that time temporal hemianopsia. Pronounced obesity, genitalia infantile, pubic and 
axillary hairs absent. Destruction of the body of the sphenoid bone and of the dorsum 
sellae. June, 1907, operation by Prof. v. Eiselsberg. Cyst of the hypophysis, histologically 
carcinoma. Improvement of the power of vision. May, 1908, occurrence of erections. 
August, 1908, voice deeper. October, 1909, sparse hairiness in the axillae and on the pubes. 
Eye-findings as formerly. No erections. Body weight now kg. (formerly 65.2 kg.). HYPOPHYSIAL DYSTROPHY 
311 
Blood count: Erythrocytes, 4,200,000 
Hemoglobin, 9.4 gm. 
Leucocytes, 8200 
Polymorphonuclear leucocytes, 52 per cent. 
Large mononuclears, 7 per cent. 
Lymphocytes, 37 per cent. 
Eosinophiles, 4 per cent. 
Observation XLI.—O. M., girl, twenty-three years old, Dec. 3, 1909. No hereditary 
taint, always well, except that from childhood she has been strikingly pale. One menstrua- 
tion at the age of twelve years, she menstruated regularly between the ages of fourteen 
and nineteen years, then sudden cessation, with normal genitalia. Now and then mod- 
erate pressure in the head. March, 1909, influenza, after which dietary treatment with- 
out rest in bed. Increased in weight 8.5 kg. (from 53.5 to 62 kg.). At the beginning of 
October, 1909, blurring before the left eye, since which time things have remained station- 
ary. No headaches, no vertigo, no vomiting, no fainting-spells, no insomnia, no yawning, 
no disturbance of movements, no rhinorrhea. 
Eyes.—O. D. normal, O. S. 6/12, fundus normal, L. P., temp, scotoma for white. Bi- 
temporal color hemianopsia. The nerve findings negative. Internal findings and urinary 
findings negative. Moderate struma, patient is of medium height, strikingly pale, does 
not make an impression of corpulency, except that a rather large collection of fat is present 
on the abdomen. Hair of the head abundant, axillary and genital hairiness normal. The 
fingers seem somewhat puffed up and thickened. Slight development of hair on the upper 
lip and chin. 
X-ray (Docent Dr. Keinbock): Sella turcica appreciably enlarged, especially below and 
behind. The dorsum sellse is visible only as a small bolt-shadow strip. 
Weight 61 kg. Temperature on Dec. 6 and Dec. 7 varied between 36.2° and 36.7°. 
Blood count: Erythrocytes, 4,464,000 
Hemoglobin (according to Sahli), 70 per cent. 
Leucocytes, 5900 
Polymorphonuclear leucocytes, 60.8 per cent. 
Lymphocytes, 30.8 per cent. 
Large mononuclear, 4 per cent. 
Eosinophiles, 4 per cent. 
Mast-cells, 0.4 per cent. 
Observation XLII.—K. L., seventeen years old. December, 1909. Up to this time has 
not yet menstruated, since the autumn of 1906 headaches, decrease of visual power, and 
rapid increase of body weight. Bitemporal hemianopsia. Genitals infantile. Axil- 
lary hair poorly developed. X-ray shows dilatation of the sella. 
Operation by Prof. v. Eiselsberg. 
Blood count, December, 1909: Erythrocytes, 4,680,000 
Hemoglobin, 9.34 gm. 
Leucocytes, 9400 of which: 
Polymorphonuclear neutrophiles, 56.3 per cent. 
Lymphocytes, 31.3 per cent. 
Large mononuclears, 7.9 per cent. 
Eosinophiles, 3.3 per cent. 
Mast-cells, 1.2 per cent. 
I tabulate these observations together with those of the other observations 
reported in detail in this book, in the following list: THE DISEASES OF THE HYPOPHYSIS 
312 
Observation 
Erythrocytes 
Hb 
Leuco- 
cytes 
Neutro- 
philes 
Eosino- 
philes 
Observation XXXIX, W, be- 
4,600,000 
7 • 5 gm. 
5,600 
fore operation. 
four months after operation. 
5,260,000 
8.2 gm. 
7,500 
Observation XL, D, two and 
4,200,000 
9-4 gm. 
8,200 
52.O 
4 0 
one-fourth years after opera- 
tion. 
Observation XLI, Ogla M.... 
4,460,000 
70 per cent. 
5,900 
60.8 
4.0 
Observation XLII, K. L, after 
4,680,000 
9-34 gm. 
9,400 
56.5 
3-3 
operation. 
75 per cent. 
8,400 
56.1 
3 •2 
about 5 wks. after operation 
71.0 
1.0 
10,000 
50. I 
5 • 5 
4,680,000 
S>9°° 
64.0 
5 • 5 
6,500 
65 O 
7 -° 
Observation XLV, Gr 
4,800,000 
57 per cent. 
15,000 
62.0 
90 
later. 
3,300,000 
45 per cent. 
13,900 
58.0 
25.0 
Observation XXXVI, G. W.. 
4,600,000 
84 per cent. 
7,800 
74.I 
0.7 
Lately there are observations of Borchardt in four cases, in which he found 
the red blood cells to be somewhat reduced, the leucocytes at the lower limits 
of normal, the neutrophiles mostly markedly reduced, the eosinophiles some- 
what high, in one case up to 11.5 per cent. 
If we summarize all these cases, we find that there is mostly only a slight 
reduction of erythrocyte count or none at all (or even after operation an 
increase in the number of erythrocytes), while in all cases there was a not 
inappreciable reduction of hemoglobin; the leucocyte count is often diminished, 
and in one case increased. Most important is the result of the differential 
count of the leucocytes. Almost in all cases the number of neutrophilic 
cells is, relatively, markedly reduced, while that of the mononuclears, and 
especially the lymphocytes, relatively and also absolutely raised. The eosino- 
philes show in many cases an appreciable increase. After operation the 
leucocyte picture may revert to normal (Observation Si, XXXIV). In 
two cases (Observation D and K. L.) there were, however, marked mono- 
nucleosis after the operation. In these cases the hemoglobin remained mark- 
edly reduced after the operation. Perhaps the mononucleosis is the expres- 
sion of a slight grade of status lymphaticus. The blood-count in general, 
as far as mononucleosis and poverty in hemoglobin are concerned, is similar 
to that of myxedema. 
I enter more in detail into the consideration of a symptom which up to 
the present has not been sufficiently regarded in the differential diagnosis. 
I refer to the inhibition of growth. Already v. Frankl-Hochwart emphasized 
that the cases of tumor of the hypophysis without acromegaly in youth almost 
always affect small individuals. Almost in all cases in which the disease 
began in the years between childhood and adolescent life is remaining behind 
in growth reported. I here quote what I have been able to find on this 
subject: HYPOPHYSIAL DYSTROPHY 
313 
Case of Berger.—Began at twelve years. 
Case i of Bychowski.—K. L., seventeen-year-old girl, very small, 132 
cm. tall (operated on by v. Eiselsberg), cyst of the hypophysis. 
Case 2 of Bychowski.—Reported very briefly. Growth ceased at the 
age of thirteen years, 132 cm. tall. 
Case 2 of Nazari.— Normal development up to between the sixth and 
seventh years, then remaining behind in growth; at twenty years of age, 
125 cm. tall. 
Case 1 of Babonneix and Paisseau.—From eleven and one-half years 
on, height remained stationary. 
Case 1 of Erdheim- Twenty-year-old woman, “body very small.” 
Case of Zollner.—One hundred forty-five centimeter tall individual. 
Case of Uhthojf.—Dwarfism with bitemporal hemianopsia. 
Case 1 of Ettore Levi.—Twenty-and-one-half-year-old woman, from ten 
years old on cessation of growth, 130 cm. tall, lower length 71 cm., genitalia 
infantile, sella turcica considerably widened. 
Case 1 of Bartels.—Twenty-one-year-old man, cessation of growth at 
the fourteenth year. 
Case 2 of Bregman and Steinhaus.—Seven-year-old girl, “relatively small.” 
Case of Mixter and Quackenbos.—Twenty-seven-year-old man who 
looks as if he were eighteen years old, enlargement of the sella, operation. 
Epithel. congen. of the hypophysis with cystic degeneration. 
Case of Kilmmel.—Twenty-three-year-old man, looks as if he were fourteen 
years old, no obesity. 
Case of Leman and Van Wart.—Twenty-four-year-old woman, infantile. 
Case of Bournier.—Twenty-six-year-old man, 125 cm. tall, eye distur- 
bances since his eighth year, disturbance of growth since his tenth year. 
Case of Rennie.—Cessation of growth at the same time as the appearance 
of manifestations of hypophysial tumor. 
Own Observation XXXIII (L).—One hundred thirty-one centimeters 
tall since ten years old. Has not grown for two years. 
Own Observation XXXIV (Si).—Sixteen-year-old girl, 145 cm. tall. 
Own Observation XXXVII (Sch).—At the beginning very marked growth, 
cessation of growth at thirteen years of age. 
Also the cases of dystrophia adiposo-genitalis with brain processes in 
which a limitation of the function of the hypophysis may be suspected, show 
the inhibition of growth. 
Case of E. Muller. 
Case 1 of Goldstein.-—Cessation of growth at the fifth year. 
Also Case 3 of Goldstein is called “small.” Both were diagnosed serous 
meningitis. 
Case 2 of Neurath.—Scarlet fever at seven years of age, shortly afterward 
cessation of growth; at ten years of age 109 cm. (instead of 130 cm.), prob- 
ably hydrocephalus due to meningitis (see later, case Fr, Observation XLIV). 
The following case may be regarded as a case sui generis of hypophysial 
dwarfism: 314 
THE DISEASES OF THE HYPOPHYSIS 
Case of Jutaka Kon.—A thirty-seven-year-old “dwarfishy built man” 
(147 cm. tall), could not visit the school on account of weakness of the eyes. 
Now and then epileptic attacks, coarse, glittering face, skin dry, lately increas- 
ing mental slowness, no hairiness on the mons Veneris, on the scrotum, or 
near the lips. Genitalia entirely infantile. Autopsy showed a slight hypopla- 
sia of the thyroid gland and an enormous calcified tumor of the infundibu- 
lum, that histologically was a teratoma. The tera- 
toma had existed since earliest youth, it was “evi- 
dently congenital.” 
The case of Benda was that of a thirty-eight-year- 
old dwarf. There was found a hazelnut-sized 
teratoma of the hypophysis. The remnant of the 
gland was atrophic, the genitalia were infantile. 
Here likewise there was a teratoma, so that it is prob- 
able that it had existed since youth and was respon- 
sible for the dwarfism and the genital dystrophy. 
The case of Woods Hutchinson is correctly re- 
garded by Breus and Kolisko as chondrodystrophy. 
In the case of Hagenbach (sarcoma of the hypop- 
hysis in an individual 103 cm. tall) the connection 
between the growth disturbance and the tumor of 
the hypophysis is, as the author points out, hard to 
show, as it is not known when the tumor began to 
form. 
Aschner describes a case of dwarfism which he 
regards as hypophysial—entirely incorrectly. In this 
case there does not exist a single symptom that points 
to this hypothesis. I regard this case as a true 
infantilism. 
The case of Hueter, quoted by Aschner, is quite 
uncertain. Hueter himself is of the opinion that the 
tuberculous disease of the hypophysis, in the forty-two-year-old woman, is 
of recent date, and therefore has nothing to do with the drawfism. In this case 
the sexual organs were well developed. This speaks against the existence of 
the hypophysial affection since youth. 
In May, 1911, I observed a case that perhaps belongs to this category. 
Observation XLIII.—M. S. P., forty-one years old, from Palestine. Entered the 
clinic May, 1911. Family history good. The patient states that his genitals have been 
of the present size since childhood. In spite of the fact that the penis is diminutively 
small, it is subject to erections. First coitus at the age of twenty-two years. Coitus was 
then practised several times a month up to the twenty-sixth year. The pleasurable sensation 
was very great, but there had never occurred an ejaculation. Also now the penis sometimes 
becomes erect, the erection lasting for six to eight hours; they are associated with intense 
voluptuous sensations. We ourselves saw such an erection, the penis measuring 3 cm. 
For three years the patient has suffered with violent right-sided headaches. There 
exists a slight right-sided ptosis and paresis of the superior oblique and inferior oblique 
muscles with diplopia. 
Fig. 60.—Teratoma of the 
hypophysis. HYPOPHYSIAL DYSTROPHY 
315 
The patient is 154 cm. tall; span width 172 cm., lower length 97 cm.; he is somewhat 
fat, and there are abundant accumulations of fat on the hips and on the mons Veneris. 
Hairs of the beard are entirely absent, and there is very sparse hairiness of the mons Veneris, 
and the axillae. The penis is diminutive, and there is a slight hypospadias. The scrotum 
is very small. There is bilateral cryptorchidism. 
X-ray. Both clivi sharpened, entrance to sella widened. Floor of sella not essentially 
deepened 
Examination of the eye-grounds; both papillae present a washed-out appearance, old 
neuritis. 
Blood count: Erythrocytes, 5,000,000 
Hemoglobin, 65 per cent., according to Sahli 
Leucocytes, 10,000, of which: 
Polymorphonuclear neutrophiles, 50.1 per cent. 
Large mononuclears, 15.0 per cent. 
Lymphocytes, 24.4 per cent. 
Eosinophiles, 0.5 per cent. 
x\drenalin subcutaneously (o.coi gm.), no glycosuria. 
Fig. 6i.—Genitalia of Observation XLIII. 
At first I regarded this case as a eunuchoid, in which a certain function 
of the genitalia was retained. Also the proportioning of the body seems to 
me to speak to the same effect. Against pure dysgenitalism speaks however: 
1. The disturbance in growth (both patient’s parents are large individuals). 
2. The disturbance of eye muscles, the symptoms of brain pressure, and 
the X-ray findings. 
As the genital disturbance had acted already in earliest youth, the eye- 
muscle disturbance first becoming apparent only about four years ago, we 
must think of a gradually developing hypophysial tumor. This may be a 
teratoma. 
Lately Sprinzels has shown a case before the Wiener Gesellschaft der 
Arzte [Vienna Association of Physicians] that, on account of the interest it 316 
THE DISEASES OF THE HYPOPHYSIS 
affords, I shall describe in detail. It was that of a young man seventeen 
years old. In the third year of his life after a knock he sustained spasms, 
probably of a toxic character. Since that time, great thirst and polyuria. 
Since the fifth year of life cessation in growth, sometimes headache, intelli- 
gence well developed, gay temperament. Height 106 cm., circumference of 
head 52.5 cm., physiognomy that of a mature individual, skin soft, smooth, 
rough and scaly only at certain places, dry, no secretion of sweat. Abun- 
dant deposition of fat on chest and abdomen (mons Veneris?), no hairiness 
on the trunk. Voice childish, several of the teeth 
belonging to the milk set, genitals correspond to those 
of a six-year-old boy (erections were observed, how- 
ever). Amount of urine 3500-4000 cm., specific 
gravity 1002-1003. Ossification relations correspond 
to those of a four-and-one-half to five-year old child. 
Sella turcica shows no tendency to bone destruction. 
“A shadow focus coming into the sella from above, 
and filling out the sella like a bolt, leaving a light 
zone free,” no disturbance of vision. Diagnosis 
being tumor of the hypophysis or in the vicinity 
of the hypophysis, probably teratoma. 
I quote the following as a further case of marked 
disturbance in growth, apparently due to a destruc- 
tion of function of the hypophysis. We shall find 
that it will interest us later, in the consideration of 
the proportioning of the body and the behavior of 
ossification. 
Observation XLIV.—Case F., fifteen years old. Entered 
the clinic September, 1912. The mother of the patient 
states that the birth was normal, but that she cannot say 
with certainty when the growth disturbance first began; but 
that there was rachitis at the eighth year. The child walked 
late. The abdomen at that time was distended. At all 
events it is to be supposed that the growth disturbance goes 
back very far. When the mother was asked concerning fat 
stools, she answered that these had existed as long as she can 
remember. Measles at six years of age. In early child- 
hood, patient had frequent sweats. Of late years, he has 
become thin, and has felt very weak; he became silent and melancholy. He complains of 
violent vertigo and of headache. For three weeks diarrheal evacuations, that have seemed 
fatty. The development of the intelligence was apparently normal. 
The boy measures 121 cm., the span width is 121 cm., lower length (from ant. sup. 
spine to internal malleolus), 63 cm. The skull has the form of a tower [dome-head];1 the 
greatest circumference measures 61 cm. The tubera frontalia project to a degree, no 
saddle-nose, the teeth are very bad, the incisor teeth are much ridged, certain teeth belonging 
to the milk set. Genua valga. The color of the face is pale, the skin of the entire body is 
white, remarkably delicate, quite feminine. The patient is thin, but nevertheless there are 
deposits of fat on the hips and nates, in the hypogastric region-, and somewhat more dis- 
Fig. 62. 
1 German term, “Turmschadel.”—Editor. HYPOPHYSIAL DYSTROPHY 
317 
tinctly on the mons Veneris. No rosary formation; no bending of the extremities. No glands 
palpable. Lung-findings normal. The heart sounds are clear, after several sittings extra- 
systoles. Examination with the electrocardiogram shows complete dissociation. 
The development of the genitalia has remained behind to a marked degree. The 
penis is small, prepuce well developed. The inguinal canals are pervious for two fingers, 
the testicles lie in the inguinal canal and come down a little only on marked coughing. They 
are about the size of beans and very soft; the paradidymis is hardly delimitable. The hairi- 
ness on the trunk and genitalia is entirely absent. 
Wassermann reaction negative. Alimentary glycosuria (200 gm. dextrose) negative 
Blood count: Erythrocytes, 4,800,000 
Hemoglobin, 45 per cent. 
Leucocytes, 5900 of which: 
Polymorphonuclear leucocytes, 64 per cent. 
Lymphocytes, 25 per cent. 
Large mononuclears, 4L2 per cent. 
Eosinophiles, 5% per cent. 
Mast-cells, 1 per cent. 
The eye examination shows prominent eye-balls, oblique palpebral fissures, dilated 
pupils, nerves pale, well delimited; the vessels, especially the veins-and the peripheral and 
muscular branches are appreciably convoluted without dilation, old neuritis (?) (Docent 
Ulbrich). 
X-ray. Skull strikingly large and high; hydrocephalus, sella of normal dimensions, 
dilated only at its entrance, its contour retained. The dilatation of the entrance to the 
sella is perhaps only a partial manifestation of the hydrocephalic extension of the skull 
(Docent Schuller). 
The examination of the respiratory gas exchange {Dr. Bernstein) shows: 
C02 elimination 5.14 1 . .. „ . 
„ . > Average of three well-concurring observations. 
02 consumption 0.11 J 
The temperature is instituted at a low level, ordinarily between 36° and 36.4°. 
Injection of 4 cc. pituitrinum glandulare intramuscularly shows slight increase of temper- 
ature, up to 370. 
Nov. 6. Injection of 5 cc. pituitrinum glandulare intramuscularly at 9 a.m. causes an 
afternoon rise of temperature to 38.5° (4 o’clock). At 8 o’clock still 38°. On the next 
morning temperature again 36.2°, no subjective manifestations. 
The investigation of the gaseous exchange after the injection shows a very marked 
decrease of the carbonic acid production and the oxygen consumption. There was appre- 
ciable increase of respiratory quotient. 
Repetition of the exper ment on Nov. 13 with 5 cc. of pituitrinum glandulare (intra- 
muscularly) brought about an increase of temperature to over 38° C. 
The amount of urine varied between 2000 and 4000 cc. Correspondingly the specific 
gravities varied between 1010 and 1006, exceeding 1010 very rarely. 
At the beginning several bowel movements daily, later only one or two. The stools are 
mostly more or less brothy, whitish, glistening like fat, containing as is shown on micro- 
scopical examination, many needles of soap fatty acids and of neutral fat. 
Appetite and general condition improve rapidly, also a rapid increase of body weight 
from 24 kg. to kg. in the course of five weeks, with distinct prominence of the abnor- 
mal distribution of fat on the buttocks, mons Veneris, etc. 
The intelligence of the boy is in general well developed, temperament is gay. The 
complaints as to headache are less. 
X-ray examination of the hand shows marked developmental disturbance of ossifica- 
tion. The development of the bone-nuclei about corresponds with that of an eight- to 
nine-year-old boy. 318 
THE DISEASES OF THE HYPOPHYSIS 
Fig. 63.—Sella turcica of Observation XLIV. HYPOPHYSIAL DYSTROPHY 
319 
Fig. 64.—X-ray picture of hand of Observation XLIV. 320 
THE DISEASES OF THE HYPOPHYSIS 
Fic. 65. X-ray picture of the hand of a normal individual of the same age as Observation XT.TV HYPOPHYSIAL DYSTROPHY 
321 
In this case we are dealing with a chronic hydrocephalus that apparently 
has led since earliest youth to disturbance of the function of the hypophysis 
through pressure on the entrance to the sella. For the disturbance of hypo- 
physial function speak: (i) The growth disturbance and the disturbance in 
ossification and dentition. (2) The genital dystrophy with the typical obesity. 
(3) Perhaps the “thermoreaction.” Whether there exists here a disturbance 
in metabolism we cannot decide, as there are no values of comparison with 
normal individuals of the corresponding size and weight. Fitting in with 
the diagnosis are also the behavior of the carbohydrate metabolism, the blood- 
count. the hypothermia, and the slight degree of polyuria. 
There are as yet no statements in the literature as to the pro portioning of 
the skeleton and the ossification conditions. In the study of my cases I made 
certain observations that seem to me important for the differential diagnosis 
of the hypophysial dystrophy from the primary genital dystrophy. 
The proportioning is sometimes more of an infantile, sometimes more of a 
eunuchoid type, that is, in the latter case the lower length considerably ex- 
ceeds the upper length. In a case of Ettore-Levi the total length was 130 cm., 
the lower length 71 cm. In my case L, Observation XXXIII, the total length 
was 131 cm., the distance from the anterior superior spine to the interior malleo- 
lus 69 cm.; also in case Si, Observation XXXIV, the lower length is not 
essentially greater than the upper length. Quite infantile are the dimensions 
in case Fr, Observation XLIV. On the contrary in case Sch, Observation 
XXXVII, the lower length again distinctly exceeds the upper length, as it does 
also in case P, Observation XLIII. It seems to me that here two factors are 
working in opposite directions. The one is a genital disturbance, which 
brings about tallness and excess of the lower length over the upper length, 
the other is a growth disturbance conditioned by the falling out of hypophysial 
function. According as the one or the other predominates do the proportions 
approach the eunuchoid or the infantile type. In the severest cases it is indeed 
mostly infantile.1 
A distinct difference exists in the ossification conditions of hypophysial 
dystrophy and eunuchoidism. As we shall see later, in the latter only the 
epiphysial closure is disturbed; the development of the bone nuclei, however, 
according to what has been observed up to the present, is not essentially de- 
layed. But the delay in the epiphysial closure is, however, of a high grade and 
lasts until late life. 
How are the conditions in hypophysial dystrophy? Case W. (Observation 
XXXIX) reported by v. Frankl-Hochwart and v. Eiselsberg, was, when I ex- 
amined him, twenty-seven and one-half years old. The first symptoms had 
set in at nineteen years of age; the condition of ossification was entirely normal. 
In an eunuchoidism that had set in so late certain epiphysial junctures would 
have remained open, and there would have been an additional growth of some 
centimeters. In case L. (Observation XXXIII) and in case Si (Observation 
XXXIV) the behavior of ossification approached the normal. 
11 refer to Chapters X and XII. 
21 322 
THE DISEASES OF THE HYPOPHYSIS 
Quite otherwise are the relations in the cases in which the severe disturb- 
ance of growth sets in early. In Case F. (Observation XLII) the development 
of the bone nuclei corresponded to that of an eight- to nine-year-old boy rather 
than to that of a fifteen-year-old boy. I refer to the X-ray picture of this case 
as compared with that of a normal fifteen-year-old boy (Figs. 64 and 65). 
Hence in these cases the growth disturbance is similar to that in hypo- 
thyroidism. From the literature I can quote only the case of Bournier, which 
shows that in the high degrees of growth disturbance also the closure of certain 
epiphyses is markedly delayed. In the twenty-six-year-old patient the proxi- 
mal epiphyses of the phalanges and of the first metacarpal bones, and the distal 
epiphyses of the ulna and radius, are still open. Finally there is the case 
reported by Sprinzel in which ossification has remained behind much farther 
than in my case F. 
From all this seems to be inferred, that the disturbance of ossification in 
light grades of hypophysial dystrophy is not very pronounced, in severer grades 
it affects in the same manner the occurrence of the bone-nuclei and of the epiphysial 
closure, while in pure eunuchoidism the epiphysial closure is indeed involved, 
but this disturbance lasts until late in life. 
To the above-described manifestations is added, according to the process 
that damages the hypophysis, a series of manifold symptoms. Most common 
are tumor symptoms, such as tend to appear in tumors of the middle fossa of 
the skull. Most frequent are headaches, that for the most part are not local- 
ized; also disturbances of vision (bilateral hemianopsia or simple amblyopia 
and amaurosis, genuine atrophy, and not rarely choked disc). First there 
appears bilateral hemianopsia for colors, and only later for white; in quite rare 
cases there may occur a homonymous hemianopsia owing to destruction of the 
tract by a tumor (a case of O. Hirsch’s); in addition vertigo, insomnia, frequent 
yawning (little sleep at night however), apathy, finally psychic disturbances, 
sometimes also nasal discharge of cerebrospinal fluid. With these symptoms 
are associated pareses of the eye-muscles, disturbances of smell, taste, and 
hearing, vomiting, manifestations of a hydrocephalus, bilateral clonic twitching, 
eventually paresis of the extremities. Exophthalmus may also occur, owing 
to penetration of the tumor into the orbit (case of Pechkranz). 
According to the nature of the picture, the X-ray examinations show widen- 
ing of the introitus to the sella with destruction of the clinoid processes and 
eventually with deepening of the sellar floor (especially in tumor of the hypo- 
physis), but in extrasellar processes sharpening of the clinoid processes, and 
only later destruction of these (.Erdheim and Schuller), deepening of the impres- 
siones digitatae in youthful individuals, eventual enlargement of the skull and 
essential thinning of its bony walls. 
Noticeable, finally, are certain alterations of the psyche, v. Frankl- 
Hochwart emphasizes that in these patients there is a remarkable restlessness 
and resignation, and that in spite of the existing headache they often show a 
gay temperament. In youthful individuals, at all events, this gay tempera- 
ment (case F., Observation XLIV, and the case of Sprinzel) contrasts markedly 
with the stupidity and moroseness of hypothyroidism in childhood. In many HYPOPHYSIAL DYSTROPHY 
323 
cases of hypophysial dystrophy there may, of course, also occur a fairly appre- 
ciable degree of uninterestedness, which, however, may be much benefited by 
operation (confer case Si., Observation XXXIV). Now and then there develop 
also more or less pronounced psychoses. Finally it should be mentioned that 
also hypophysoprivic dogs show characteristic psychic alterations. 
The pathologico-anatomical findings that are found in this syndrome are 
extremely manifold. First of all, there are tumors of the hypophysis itself; 
a detailed summary of the tumors of the hypophysis without acromegaly is 
found in the publications of v. Kollarits and of v. Frankl-Hochwart. 
v. Frankl-Hochwart has collected ninety-seven cases of tumors of the 
hypophysis (without acromegaly). Among these are twelve carcinomata, 
thirteen adenomata,1 nine strumas, and twenty-seven sarcomata. Among 
the carcinomata are especially worthy of mention the hypophysial duct flat- 
celled epithelial carcinomata, described by Erdheim. These proceed from the 
accumulations of pavement epithelium, which lie in the process of the glandular 
anterior lobe that extends into the hypophysial peduncle, and which constitute 
remnants of the hypophysial duct cut off from the oral ectoderm. (See Figs. 
30 and 32.) Histologically they consist in epithelial nests and concentric 
layers lying very close to each other. Erdheim compares them with adaman- 
tinomata, which also originate from cut-off parts of the oral epithelium, as 
the remnants of the rudiments of the teeth. It may be readily understood that 
tumors of the hypophysial duct mostly lead first to a dilatation of the sellar 
introitus. Then the glandular hypophysis microscopically may appear normal, 
as in case of Bregmann and Steinhaus. 
Further, there were to be observed, according to v. Frankl-Hochwart, fifteen 
cysts, among them the interesting case K. L., that was operated on by v. Eisels- 
berg, and that was more accurately described by Bychowski. Finally a vascular 
tumor of indefinite texture, three gliomata, two teratomata, seven tubercles, 
three gummas, and one case each of steatoma, chondroma and fibroma. 
A case that is very important for the pathogenesis of hypophysial dys- 
trophy was that of a cyst of the hypophysis recently reported by Marahon. It 
occurred in a man about forty years old with typical dystrophy. Micro- 
scopically the hypophysis was apparently normal, and on microscopical exami- 
nation more than three-fourths of the glandular part was found to be destroyed 
by an old focus of hemorrhage. 
I report another case that I observed a short time ago: 
Observation XLV.—G. J., fifty-five years old, tailor. Entered the clinic May 30, 1912. 
Part of the history was furnished by the wife. Until ten years ago entirely normal. Then 
marked pains in the frontal region, attacks of vertigo and vomiting. These pulled him down 
very much, and the attacks were attended with high fever. He was confined to his bed 
for six months, then he could again take up his occupation, but since that time his libido 
has been markedly weakened, and finally disappeared altogether. Also complete impotence 
came on. The axillary hairs gradually fell out. Since that time attacks of vertigo have 
been less frequent. In the course of the year 1910 there gradually developed a swelling of 
the thyroid and slight hoarseness. Otherwise there were no other complaints. Dec., 
*1 have already mentioned that not every adenoma must have an increased function and 
lead to acromegaly. 324 
THE DISEASES OF THE HYPOPHYSIS 
igu, influenza. Remained in bed for six to seven weeks, after which there were lightning- 
like pains and formications in the [lower] legs. Also the bones were tender. Five weeks 
ago, according to statement, suddenly a toxic spasm in the right hand and then also in the 
left hand. 
Markedly emaciated cachectic individual. Skin pale, dry, scaly, the visible mucous 
membranes pale. Patient often cannot recollect well, right pupil wider than the left. 
Reaction somewhat sluggish. Eye-grounds normal. The middle lobe of the thyroid 
gland is of the size of an apple, rather hard, and extends under the sternum, as is seen on 
examination of the X-ray plate. Circumference of the neck 44cm. Voice slightly 
roughened. Chvostek I positive. Electric excitability normal. 
Blood-pressure (according to Gartner) 90 
Blood count: Erythrocytes, 4,800,000 
Hemoglobin (Sahli), 57 per cent. 
Leucocytes, 15,000, of which: 
Polymorphonuclear neutrophiles, 62 per cent. 
Lymphocytes, 19 per cent. 
Large mononuclears, 10 per cent. 
Eosinophiles, 9 per cent. 
Pirquet’s reaction negative. Patellar reflexes weak. Hyperesthesia of both lower 
extremities. Nerve trunks slightly tender. Especial hyperesthesia of the soles of the 
feet. No hairs in the axillae. No mustache hairs. Beard hairs almost entirely absent. 
Hair on the body absent with the exception of the pubic hair that is still present somewhat 
copiously. There are no hairs at all on the perineum. The entire body is extremely thin, 
and there is a cushion of fat still indicated only on the mons Veneris. The penis is strikingly 
small, prostate hardly palpable. Nipples quite stunted. 
X-ray examination of the skull showed considerable enlargement of the sella turcica to 
the size of a two-crown piece. Sellar introitus apparently intact. 
Alimentary glycosuria (200 gm. dextrose), negative. 
Sugar in blood, 0.081 per cent. 
Rapidly increasing cachexia, development of a pneumonia that led to an increase of 
temperature. Kernig’s symptom is positive, lumbar puncture negative. On July 5, the 
blood count was: 
Erythrocytes, 3,300,000 
Hemoglobin (according to Sahli), 45 per cent. 
Leucocytes, 13,900, of which: 
Neutrophiles, 58 per cent, 
Lymphocytes and large mononuclears, 17 per cent. 
Eosinophiles, 25 per cent. 
On both sides the struma decreases very much in size, so that on July 1 the circumference 
of the throat was only 39 cm. 
Death on July 23. 
Autopsy (Assistant Erdheim): Hazelnut-sized cyst of the hypophysis with marked pres- 
sure atrophy of the pituitary parenchyma and dilatation of the sella turcica. The peduncle 
of the hypophysis and the base of the skull unaltered. The operculum sellse deeply 
retracted. Cerebral hernias with erosion of the vitreous table in the domains of the posterior 
and middle cerebral fossae. But the convolutions are not flattened. Growing struma 
(.Langhans) proceeding from the middle lobe of the thyroid gland with extensive pressure 
atrophy of the thyroid parenchyma proper. The thymus small, rich in fat, the suprarenal 
markedly atrophic, the atrophy affecting exclusively the cortex, the medulla remaining 
abundantly developed. Atrophy of the testicles, marked general marasmus, marked senile 
atrophy of the upper and lower jaws without almost complete absence of teeth. Lobular 
pneumonia, etc. 
The microscopical examination of the hypophysis in the sagittal direction, for which I 
am indebted to Dr. Erdheim, shows the following: The hypophysis is taken up centrally HYPOPHYSIAL DYSTROPHY 
325 
by a single-chambered, smooth-walled cyst, which is partly filled with a homogeneous 
portion and partly with a shreddy portion. The cyst for the most part is not lined with 
epithelium, there being present a single layer of epithelial cells for a short distance only. 
The tissue surrounding the cyst is H mm. thick and constitutes the markedly pressure 
atrophied, strongly fibrous, glandular tissue of the hypophysis. This is bounded externall} 
by the fibrous capsule of the hypophysis. 
The microscopical examination of a piece of the thyroid gland showed a well-limited 
benign epithelial tumor with numerous cavities filled with colloid, that are separated from 
each other by septa that are purely epithelial. 
In this case there is surely a marked retrenchment of function of the 
hypophysis of ten years’ standing with a gradual increasing cachexia. The 
disease was ushered in with an unknown infectious process. Perhaps this 
also affected the hypophysis and gave occasion for the cyst formation. At all 
events we find since that time a disturbance of the generative function, a 
gradual partial retrogression of the secondary sexual characters, slight atrophy 
of the accessory genital apparatus, especially the prostate. Perhaps the marked 
atrophy of the suprarenal cortex plays a part in the retrogression of the genitals 
and of the secondary sexual characters. 
Worthy of mention in this case is also the uncommonly rapid diminution 
of the struma. At the beginning this was so hard that originally we thought 
of a malignant process. 
Much cited is the case of Madelung. This concerned a nine-year-old girl. 
At the age of six years, a shot injury from a Flobert gun. The girl has re- 
mained behind in mental development, is very quiet. Considerable adiposity 
which first developed after the injury (at the time the patient remained 
in bed for five months). The shot had penetrated the sella turcica via 
the left eye; there was a slight dragging of the left leg and weakness of the 
left arm. 
Besides these tumors originating from the hypophysis there are numerous 
processes in the neighborhood of the hypophysis in which such cases of dystro- 
phia adiposo-genitalis are found. To these belong tumors that proceed from 
the brain membranes or the bones, or brain tumors. All possible brain processes 
can lead to genital disturbances and adiposity, in so far as they apparently call 
forth an increase of pressure in the third ventricle. Already in 1855, Fr. Konig 
reported a case that seems to me to belong in this category. It was that of an 
eighteen-year-old girl with undeveloped genitalia; she had never menstruated. 
The visual power was disturbed. The head was very large. Here was found a 
hydrops of all ventricles and atrophy of the optic nerves; in the cerebellum, on 
the left, an echinococcus. This case, on account of the deficient ossification 
of the pelvis was considered by A. Paltauf one of the true dwarfism. For the 
first exact description of such cases we have to thank E. Muller; but Axenfeld, 
already in 1903, had pointed out that tumors at the base of the brain may pro- 
duce permanent amenorrhea even at the beginning of the disease. In many of 
Muller’s cases there developed a pronounced obesity. There was observed in 
the two autopsied cases a tumor of the cerebellum, and a tumor of the occipital 
lobe respectively. In the cases that he observed only clinically there was prob- 
ably secondary ventricular hydrops after brain tumors. 326 
THE DISEASES OF THE HYPOPHYSIS 
Marinesco and Goldstein described two cases of hydrocephalus with genital 
hypoplasia and obesity (no autopsy). Like the case of E. Muller, the patients 
were small of stature. Neurath further reports cases of hydrocephalus with 
obesity in children. The genital disturbance was not always distinct. We 
have to consider however that in children the genital disturbance would not be 
so prominent as in adolescents. In a review of the pertinent literature I have 
received the impression that in the slight grades of hypophysial insufficiency the 
first sign is the development of an obesity. 
Also case 2 and case 3 of Babonneix and Paisseau belong to the group just 
mentioned. In case 2 as in case 1 of Neurath the hydrocephalus developed 
after scarlet fever. 
Pathogenesis.—The views as to the pathogenesis of the clinical picture 
described, or as to the role that the hypophysis plays in it, deviate from one 
another markedly. Even although at the present we are not in the position 
to clarify satisfactorily all the manifestations belonging to this picture, I still 
believe that the later results of pathological physiology and the evident analogies 
with those diseases of the thyroid that are well-known have furnished us with 
a valuable criterion. Let us first consider the results of the pathological physiol- 
ogy. The difficult accessibility of the organ and its immediate vicinity to 
centers important for life have made extraordinarily difficult the experimental 
studies of the symptoms dependent on loss of the hypophysial apparatus. Only 
recent years have brought comparative clearness to the solution of the problem. 
In stating the experiments and their results I shall confine myself to the most 
important. Paulesco was the first to succeed in the complete extirpation of the 
whole hypophysial apparatus. He and Cushing used the method of trepanation 
and pushing aside the cerebral hemispheres. Both authors came to the result 
that the complete extirpation of the entire hypophysial apparatus in dogs leads 
to death under fall of temperature and blood-pressure, slowing of the pulse, 
increasing apathy, and deep coma, and they inferred that the hypophysis is an 
organ important for life, of which the anterior lobe is the part important for life; 
this because complete extirpation of the anterior lobe alone led to all the mani- 
festations described. According to Cushing total extirpation of the posterior 
lobe in several cases called forth convulsions and sexual overexcitement, but 
mostly was without especial action. On the contrary B. Aschner on the basis 
of his very beautiful experiments upheld the opinion that the lethal result 
described depends on an injury to the tuber cinereum. Aschner used the buccal 
method and found lethal coma on injury to the tuber cinereum and opening of 
the third ventricle. Less severe injuries or wound infection brings about the 
appearance of the so-called hypophysoprivic cachexia (marked fall of tempera- 
ture, apathy, anorexia, polyuria, eventually glycosuria, also adynamia, crying- 
out of the animals under experimentation, tonic and clonic convulsions and 
death). On the contrary when the hypophysis is removed without injury to 
the hypophysial peduncle, the manifestations detailed remain absent, the 
animals are again lively a few hours after the operation, and remain alive. 
There develops, especially in youthful animals a condition that in the most 
important features simulates hypophysial dystrophia adiposo-genitalis. The HYPOPHYSIAL DYSTROPHY 
327 
animals become fat, they remain appreciably behind in development, the denti- 
tion and the ossification are markedly delayed, the epiphysial junctures can 
remain open for a long while, the childish proportions are retained, and the 
epidermoidal structures, such as the hairs and claws, show developmental dis- 
turbances. The genitalia remain markedly infantile, spermatogenesis is 
extremely sparse, the sexual instinct is markedly reduced, in female animals 
rut is weakened and never is there pregnancy. Investigations as to the meta- 
bolism of such animals shows that there is great similarity with alterations that 
Eppinger, Rudinger, and / found in animals without thyroids. The fasting 
protein metabolism is markedly reduced. The glycosuric action of adrenalin 
is reduced, and is associated with a slowing of the pulse and of breathing, reduc- 
tion of the body temperature, and an appreciable reduction of caloric produc- 
tion. Benedict and Homans have demonstrated the reduction in the carbonic 
acid production, Aschner and Porges the reduction of oxygen consumption, in such 
animals. The alterations described must be referred to the extirpation of 
the glandular hypophysis, as extirpation of the posterior lobe alone calls forth 
no essential alteration. The traces of the epithelial seam of the intermedia 
that must remain behind in the hypophysial peduncle do not, as Aschner 
supposes, come into consideration. 
It is perhaps hardly necessary to describe in detail the great similarity 
of this symptom-complex produced by extirpation of the hypophysial apparatus 
with that of hypophysial dystrophy. In spite of this I must enter into a dis- 
cussion of the individual symptoms and their relation to the hypophysis, as 
just on this point the opinions differ from each other considerably. In this 
discussion we shall have to keep our attention directed to the fact that, as in 
acromegaly, the cardinal symptoms due to the deficiency of function of the 
hypophysis (in acromegaly, the excess of hypophysis function) must be kept 
separated from the symptoms that are due to the pressure of the growing tumor 
on the neighboring organs or due to the associated disease of other ductless 
glands. 
To-day the view of most authors is that hypophysial dystrophy with 
both of these cardinal symptoms—the genital disturbances and the obesity 
—depends on a loss or diminution of function of the hypophysis (a. Noorden, 
Fettsucht [Obesity] 2nd edition). The relation of both these symptoms to the 
hypophysis has, however, been called into question. Erdheim assumed 
that the tumor on growing out from the sella actuated an as yet unknown 
center at the base of the brain, occasioning obesity. Erdheim was forced to 
this conception by the observations that also tumors situated extrasellarly 
can lead to obesity. Among those authors who refer the obesity directly to 
the loss of function the hypophysis, there are some who refer the tumor to the 
loss of function of the nervous lobe, others to that of the glandular. Espe- 
cially B. Fischer is an adherent of the doctrine that it is due to the nervous 
lobe. He states as a chief argument the fact that the genital disturbance 
belongs to the early symptoms of acromegaly too. Here it is produced by 
pressure on the nervous lobe. Also Cushing, who formerly in common with 
Crowe and Homans, brought the obesity into relation with the glandular 328 
THE DISEASES OF THE HYPOPHYSIS 
hypophysis, now agrees with Goetsch and Jacobson as to the significance of 
the posterior lobe. Finally, another much discussed question is as to whether 
the obesity is produced directly by the alteration of function of the hypo- 
physis or secondarily by the functional disturbance of the sexual glands. 
Lately B. Aschner has again taken up Erdheim’s hypothesis and has cham- 
pioned a trophic center at the base of the brain, the function of which is dis- 
turbed by the pressure of the growing tumor. He bases his opinion on the 
fact that in growing animals total extirpation of the hypophysis never leads 
to a marked grade of obesity, nor to such distinctly pronounced genital 
disturbances as in youthful human beings. The result of the operation 
on tumors of the hypophysis in human beings, so far as concerns the lessening 
of the obesity and the improvement of the genital function, depends on a release 
of pressure from the hypothalamic region. Aschner sees an especially strong 
support for his opinion in the experiments, the results of which were recently 
published, by which it was possible to produce marked trophic disturbance 
of the sexual glands through injury to the hypothalamic region. To this 
view, E. Muller has already opposed the fact that trophic disturbances in 
processes at the base of the skull must be ascribed to the compression of the 
hypophysis, as dystrophy and sexual glandular disturbances are absent in 
brain tumors unattended with hydrocephalus that have not involved the 
hypophysis. Also Marinesco and Goldstein incline to this opinion, v. Noorden 
regards the obesity as thyrogenic (through secondary influencing of the function 
of the thyroid gland). Finally, here, as in acromegaly, the attempt has been 
made to place in the foreground a primary disturbance of the sexual glands 
(.Schuller, Tandler and Grosz). Novak, on the other hand, influenced by the fact 
that operation may bring about an improvement of the genital function without 
essential effect on the obesity, is of the opinion that the obesity is independent 
of the genital disturbance. We see almost “quot capita, tot sententise.” 
I shall first describe the genital disturbance, as I am of the opinion that the 
obesity is given its characteristic expression through the genital disturb- 
ance. It must here again be mentioned that the genital disturbance in hypo- 
physial dystrophy is throughout not identical with that of acromegaly, which 
was formerly assumed to be the case, and which has recently again been upheld 
by B. Fischer, Cushing, and very recently also by Biedl. We find on the con- 
trary that in the beginning of acromegaly the genital disturbance is exactly 
the opposite from what it is in hypophysial dystrophy, and also varies from it 
later on in the disease. In acromegaly is found at first even increase of the 
generative function, at all events always a marked accentuation of the function 
of the interstitial glands or at least no signs of a disturbance. Apart from rare 
exceptions, that are becoming even fewer, the condition lasts until well in the 
course of the disease. On the contrary we find in hypophysial dystrophy from 
the beginning, in addition to the disturbance in the function of the generative 
glands, disturbances of the interstitial glands. This is the more pronounced 
the younger the individual affected. Moreover, the cases in which the disease 
begins in later life are very rare. In them the disturbance of the generative 
function is more distinct than that of the interstitial glands, indeed it appears HYPOPHYSIAL DYSTROPHY 
329 
as though the retrogression of the once fully developed secondary sexual 
characters only becomes more distinct when atrophic processes in the other 
ductless glands, especially the suprarenal cortex, are added, as happened in the 
case I reported (Observation XLV). Here indeed may occur all transitions to 
multiple ductless glandular sclerosis with its pronounced late eunuchoidism. 
Aschner mentions that the disturbances of the function of the sexual glands in 
animals experimented on are found wholly pronounced only when the extirpa- 
tion of the hypophysis has been undertaken in an animal that is still developing. 
It seems to me that this does not constitute a contradiction to, but rather an 
agreement with, the experiences met with in human pathology. 
Clinical experience further teaches us that in hypophysial dystrophy the 
genital disturbances may develop fully even if the pathological process is 
limited to the hypophysis and entirely intrasellar. I refer to the case of 
Marahdn or to Observation XLV. If for the existence of the genital disturb- 
ance there was necessary a pressure on a center lying in the hypothalamic 
region, hence a forward growth of the tumor, in these cases the occurrence 
of the genital disturbance would be as inexplicable as in animal experimenta- 
tion after extirpation of the hypophysis. Also in many cases of acromegaly 
in which the sellar introitus is dilated, in which growing out of the tumor leads 
to visual disturbances, perhaps early, and in which there are manifestations of 
an increased brain pressure, we would then find genital disturbances of the type 
of hypophysial dystrophy. From all this seems to me to be elicited the fact 
that loss of function of the hypophysial function alone can lead to genital 
disturbances of the type of hypophysial dystrophy, just as conditions of 
hyperfunction of the hypophysis may lead to those of the acromegalic type. 
The results of the operative treatment of hypophysial dystrophy throughout— 
as I already mentioned in 1908—do not speak against this supposition. The 
most essential result consists in the relief of the headaches and an improvement 
in the visual power and manifestations that are intelligible as the result of the 
release of pressure. In some cases are also observed the occurrence of slight 
menstrual hemorrhages or of erections. As far as I know, this improvement in 
the activity of the sexual glands is only slight, and may also be explained by the 
release of the pressure from the part of the hypophysis that is still capable of 
functionating. 
I must naturally leave open the question of the possibility that through 
damaging of centers in the hypothalamic region similar disturbances may be 
brought about in genital function, and that in the cases of diseases of the 
mid-brain which lead to hypophysial dystrophy, without any essential patho- 
logico-anatomical alterations of the hypophysis, the disturbance may perhaps 
find its explanation in the fact—and indeed even in such cases does the position 
seem to me just as capable of being maintained in discussion as in the cases 
mentioned above—that through such processes the function of the hypophysis 
is disturbed on account of the characteristic topographic relations, the more so 
because in such cases we tend to find also other symptoms of hypophysial 
dystrophy, symptoms such as disturbance in growth, raising of the limit of 
assimilation of carbohydrates, alterations of the blood picture, etc. 330 
THE DISEASES OF THE HYPOPHYSIS 
Let us now consider the obesity. The obesity to be observed in cases of 
hypophysial tumors without acromegaly shows in respect to the distribution 
of fat full analogies with that which is seen in eunuchs and eunuchoids, (y. 
Noorden). Especially important seems to me the circumstance that even 
where there is no obesity proper the abnormal distribution of fat is always 
indicated. This holds true almost always, even in markedly cachectic emaci- 
ated individuals. Moreover, we hardly find this distribution of fat expressed 
in typical manner unless there is present at least some degree of insufficiency. 
Finally I would again point out that in the predominating majority of the 
observations reported up to the present the beginning of the disease occurred 
in youth. Among the cases that have developed the disease later are 
apparently those in which the abnormal distribution of fat is indeed indi- 
cated, but in whom there is otherwise no obesity, but marked emaciation 
rather. 
The loss of the function of the hypophysis hence seems to lead to obesity 
only under certain conditions. Marked cachexia may prevent the occurrence 
of the obesity, apart from the suggestion of the abnormal distribution of fat. 
As example, I quote the above accurately reported Observation XLV, or the 
case of Sokolojf in which a large gumma was found in the hypophysis. For 
the most part this seems to be the case in sclerotic processes that involve not 
only the hypophysis, but also other ductless glands. In multiple ductless 
glandular sclerosis, we come to recognize the rapidly developing cachexia as an 
important symptom; here is found at most a suggestion of the abnormal 
distribution of fat, or no obesity, even when the hypophysis is seriously involved 
(see Chapter XI). 
If we assume, as does Aschner, in agreement with Erdheim’s hypothesis, 
that the higher grades of obesity only come about through the pressure of the 
superiorly growing tumor on a center lying in the hypothalamic region, the 
occurrence of these in cases in which the process is limited to the sella would 
be unintelligible. We would therefore find obesity likewise in those cases of 
acromegaly in which the tumor grows out of the sella and leads to marked 
eye disturbance. In these diseases, however, obesity belongs to the rarities, 
and is even then apparently not of a high grade. Finally, as is even of more 
weight, we never find in typical acromegaly an indication of eunuchoid fat 
distribution, such as we always find in the dystrophy. Hence it seems to me, 
that the obesity depends entirely on the genital disturbance and to be a residual 
manifestation of the same. Under circumstances we also find in pure eunuch- 
oidism an obesity of quite the same type as in hypophysial dystrophy; the same 
distribution of fat and in addition the same softness and delicacy of the 
skin; here, however, there can be no question that there is no process in the 
hypothalamic region. 
Also the remaining cardinal symptoms speak for the supposition that the 
clinical picture depends on a loss or decrease of function of the hypophysial 
apparatus. The reduction in the exchange of gases fits in well with the results 
of experimental physiology, as does also the reduction of the excitability of the 
vegetative nerves observed in my cases, and also the sluggishness of carbohydrate HYPOPHYSIAL DYSTROPHY 
331 
metabolism. The supposition of Aschner as to the genesis of glycosuria in 
acromegaly is made quite unlikely by the fact that then we would have to expect 
glycosuria very much more frequently in intrasellar or extrasellar tumors 
without acromegaly than in acromegaly, while as already mentioned the carbo- 
hydrate metabolism shows in all cases the abnormal sluggishness. The case of 
Link, with tumor of the hypophysis (without acromegaly) and diabetes, 
does not mean anything. An occasional individual may have degeneration 
of the insular apparatus and diabetes and also a tumor of the hypophysis. 
Finally the growth disturbance! On a careful review of the literature, I 
have been able to ascertain that all cases that begin in youth are associated with 
disturbance of growth, so that in this respect there is an entire agreement with 
experimental pathology. I cannot agree with the conjecture of Aschner that 
true dwarfism depends on a lessening of the function of the hypophysial appa- 
ratus (see Chapter XII). 
On taking into consideration all the facts and convictions set forth above 
it is my opinion that to-day we are justified in the assertion that the disease 
picture of hypophysial dystrophy depends on a loss or lessening of the function of 
the hypophysial apparatus. 
Finally the question comes up for discussion as to which part of the 
hypophysial dystrophy is to be ascribed to the involvement of the glandular 
lobe of the hypophysis and which part to that of the nervous lobe. B. Fischer 
has upheld the opinion that the obesity and the genital disturbances are due to 
the involvement of the nervous lobe; Cushing has agreed with him and would 
ascribe to the glandular lobe only the growth disturbance. Fischer regards 
as the principal support of his argument the similarity of the kind of genital 
disturbance in acromegaly and hypophysial dystrophy. I need hardly again 
mention that this is not correct. A further support for the view is found in the 
known tonic actions of the extracts of the posterior lobe on the genitalia, and 
further the circumstance that in certain typical cases of hypophysial dystrophy, 
especially in squamous epithelial carcinoma, the sellar introitus is very much 
distended and the nervous lobe is found to be destroyed, while the glandular 
part is well retained (for example, case 2 of Bregman and Steinhaus), although 
we find a very much larger number of cases in which the glandular hypophysis 
has been destroyed by cyst formation, gummas, etc., while the nervous lobe 
was found to be intact. The known tonic action of the extracts of the posterior 
lobe applies only, as before mentioned, to the nerves of the uterus, and on the 
contrary an activating influence on the sexual glands is not at all known. 
Against a direct connection of a disturbance of the function of the posterior 
lobe with the genital disturbance speaks, however, the following: It is very 
probable that the polyurias of longer or shorter duration that occur so frequently 
depend on an irritation of the posterior lobe. Now such polyurias of long 
duration are found also in cases with pronounced genital disturbance. If, 
therefore, we refer the polyuria to a hyperfunction and the genital disturbance 
to a falling away of the function of the posterior lobe, we would not expect to 
find them both occurring together. In addition polyuria is found eventually in 
acromegaly, also in cases with increased function of the genitalia, or at least 332 
THE DISEASES OF THE HYPOPHYSIS 
with failure of a functional disturbance of the interstitial glands, hence it is 
quite independent of the nature of the genital disturbance. 
I must consider the question of polyuria somewhat more intimately. 
Let us remember that transitory or more permanent polyurias, that eventually 
may show the entire disease picture of diabetes insipidus, are found very fre- 
quently in the most diverse hypophysial diseases without acromegaly, and 
indeed sometimes in acromegaly, and that the same thing is observed also in 
tumors and other diseases of the brain-stem. Very important facts for the 
origin of these polyurias are furnished by experimental pathology. As has 
been previously presented, there may be obtained from the nervous lobe of the 
hypophysis a protein-free heat-stabile extract that possesses in addition to 
its known action on the blood-pressure, exquisite diuretic characteristics. 
Schafer states further that the polyuria occurs in the different classes of animals 
also after feeding with the posterior lobe. Furthermore, implantation of the 
hypophysis causes an increase of the amount of urine (Crowe, Cushing and 
Homans) that again disappears after extirpation of the transplant. Under 
circumstances the polyuria lasts for several days. 
[Bab1 supported by Englebach2 suggests that hypofunction of the pars inter- 
media is responsible for hypophysial polyuria. The sugar metabolism may then, 
according to Englebach be influenced by the activity of the posterior lobe. But 
see the work of Bailey and Bremer, below.—Editor] 
Furthermore, polyuria that may last for many days is very frequent in 
operations on the hypophysis, as all later authors agree (Schafer, Cushing and 
others). Schafer found a similar polyuria in non-bloody mechanical or chemical 
irritation of the hypophysis. All these experiments seem to indicate that 
increased production of this secretion through chronic conditions of irritation 
(pressure, inflammation, etc.) can occasion a polyuria. 
On the other hand it is known that in the medulla oblongata and also 
further up in the brain-stem, there are found loci, the irritation of which may 
cause marked polyuria lasting for days. As is known, Bernard’s piqure is 
associated with polyuria. If, however, the puncture is done further up, 
exclusively, polyuria results. 
Hence the conditions are such as the conditions with regard to the genital 
disturbance. Extirpation of the hypophysis or destruction of a place in the 
subthalamic region lying above the hypophysis leads to genital atrophy; irritation 
of the posterior lobe or irritation of a definite place in the brain-stem leads to 
polyuria. 
Hence one can readily conceive that in tumors or inflammatory processes 
in the brain-stem or at the base [of the brain], a continuing condition of irrita- 
tion may be set up in these centers, and on account of it a transitory or 
permanent polyuria. 
The following possibilities should be considered: These polyurias may be 
1Bab (H.). Die Hypophyse als Regulator der Diurese und des spezifischen Gewichts des 
Harnes Munch. med. Wchnschr. Vol. LXII1, 1916, 1685. 1721, 1758. (Cited by Englebach.) 
2 Englebach (W.). Classification of disorders of the hypophysis. Endocrinology, Vol. IV, 
July, Sept., 1920, pp. 347-365- HYPOPHYSIAL DYSTROPHY 
333 
always the result of a condition of irritation or of hyperfunction of the pars 
intermedia or the posterior lobe, assuming that tumors proceeding from the 
glandular hypophysis or from the peduncle, and other lesions, irritate the 
posterior lobe for a longer or shorter time, and that disease processes localized 
to the brain-stem also influence the hypophysis in like manner; or all these 
polyurias may originate through irritation of the nervous centers lying in the 
brain-stem; or, finally, it is possible that there is a nervous connection between 
those centers and the nervous posterior lobe, and that irritation of the former 
spurs on the latter to increased secretion. The decision of this question is not 
as yet possible. However, it seems to me very improbable that the exquisite 
diuretic action of infundibular extracts should stand in direct relation with the 
polyurias of the tumors of the hypophysis. Also it seems very probable that 
in processes in the immediate neighorhood of the hypophysial peduncle, the 
same series of actions is in play; naturally we must acknowledge the possibility 
that such polyurias may come about through stimulation of centers in the brain- 
stem, without mediation of the hypophysis. 
[Bailey and Bremer have recently studied polyuria in dogs following punc- 
ture of the parainfundibular region and the hypothalamic region. These poly- 
urias vary in duration from transient to apparently permanent (depending on 
the extent of the lesion). In the latter case the polyuria was associated with 
cachexia hypophyseopriva, genital atrophy, and adiposity. The permanent 
polyurias had all the characteristics of diabetes insipidus of man. They did not 
depend on supposed vascular and nervous influences on the kidneys (denerva- 
tion experiments). A lesion of the tuber cinereum produced in two dogs a 
cachexia hypophyseopriva with acute genital atrophy. In two other dogs in 
which the pituitary body remained intact an adiposogenital syndrome developed 
insidiously. An extensive lesion of the tuber cinereum was incompatible with 
life. Glycosuria was an inconstant result of the lesion. It seemed to depend 
on the nutrition of the animal. Even deep lesions of the base of the brain 
outside the parainfundibular region produced glycosuria, but never polyuria. 
The relation of the mamillary bodies to polyuria remained undetermined. 
There was no evidence that these results were due to injury of the hypophysis. 
These experiments are important in that they tend to show that other 
structures—perhaps not the pituitary bodies at all—are mainly at fault in the 
production of some at least of the symptoms of the supposed hypophysial 
dystrophy.—Editor.] 
Finally we must consider the questions as to whether there are any grounds 
for the fact that also idiopathic diabetes insipidus may be referred to an increase 
of function of the pars intermedia. The question has been recently discussed 
by Frank, among others. As up to the present there are no pathologico-anatom- 
ical findings corresponding to diabetes insipidus—and we must also not 
neglect to mention that not enough attention has been directed to the hypo- 
physis in this respect—it seems to be worth while to approach the question by 
asking whether there exist any essential differences between the polyurias of 
idiopathic and of symptomatic diabetes insipidus. Forschbach and Weber 
assume that in idiopathic diabetes insipidus the kidneys are especially sensitive 
and irritable, so that they react to a diet rich in gram molecules [molenreich] 334 
THE DISEASES OF THE HYPOPHYSIS 
with more marked diuresis. Talquist and E. Meyer formulate their opinion by 
the assumption that the kidneys are incapable of concentrating the urine. 
Breuning believes, from a collection of the pertinent cases from the literature, 
that he is able to conclude that (also in symptomatic diabetes insipidus) the 
kidneys have lost the capacity of concentration. Also Frank found it absent in 
his case. I must point out in opposition to this that this dictum in a general 
sense does not hold for symptomatic diabetes insipidus. I refer to Observation 
XXXVII, in which the specific gravity of the urine, after several days of vomit- 
ing, rapidly rose to 1013. Also the test in case K, Observation XXXVIII, 
showed, after increase of salt to the diet, an increase in the elimination of salt, 
but during this day the total amount of urine did not increase. I would here 
mention some experiments that we carried out on rabbits. In these, injection 
of pituitrinum infundibulare produces marked diuresis. When sodium chloride 
is administered at the same time there occurred, in spite of diuresis, an appreci- 
able increase of the concentration of the urine. Hence it appears to me that we 
must leave the question of the genesis of idiopathic diabetes insipidus open. 
For the comprehension of the diseases of the hypophysis, a careful con- 
sideration of the relations between the hypophysis and the thyroid gland seems 
indispensable, so that I shall here enter into a more intimate discussion of these 
relations. First some experimental facts. After extirpation of the' thyroid 
gland in young animals there has been observed an enlargement of the hypo- 
physis (Gley and others). The enlargement affects the glandular part. Vacu- 
oles are found in the cells. Conversely, an enlargement of the thyroid gland 
occurs after extirpation of a part of the adenoma in acromegaly. In myxedema 
the hypophysis has been found to be enlarged; sometimes, not always. In 
such cases the enlargement may well depend on strumous degeneration. On 
the other hand, Benda has stated that in Basedow’s disease the glandularhypo- 
physis is small. The statements as to the physiological correlations be ween 
the two ductless glands evidently do not agree. Of greater clinical intterest 
seem to me the pathological correlations between hypophysis and thyroid. 
I already have often referred to this question. Thus in endemic cretinism 
we have seen that not the thyroid alone, but mostly also the hypophysis is 
strumously degenerated. Josef son reports associated hyperplasia of the hypo- 
physis in a case of congenital struma of the thyroid gland. Also quite other 
kinds of processes seem to occur spontaneously in the two ductless glands. 
Thus Rosenhaupt reports a case of sarcoma of the anterior lobe of the hypophy- 
sis, in which there was also a similar tumor of the thyroid gland. We have also 
seen that in acromegaly, often manifestations of hyperthyrosis occur, or, especi- 
ally in the later stages, hyperthyrosis with corresponding pathologico-anatom- 
ical alterations of the thyroid gland. Moreover, we shall see later that in mul- 
tiple ductless glandular sclerosis, the sclerotic process affects almost regularly 
thyroid gland and hypophysis. A slight degree of the thyroid gland insuffici- 
ency does not seem to be rare also in hypophysial dystrophy—at least, a 
myxedemoid puffmess of the face may be observed, especially in the later 
stages. Finally, the hypophysis may degenerate also in the later stages of 
Basedow’s disease. I would surmise this, because in such cases are found HYPOPHYSIAL DYSTROPHY 
335 
characteristic fat-deposits and swellings of the skin that remind one of myxe- 
dema, while the hyperthyrosis still continues and shows a great sensitiveness 
against thyroidin. 
All this points to the fact of an uncommonly intimate pathological corre- 
lation between hypophysis and thyroid gland, that is well adapted for the 
complication of clinical pictures. 
Differential Diagnosis.—The first question to be decided in the matter of 
differential diagnosis is as to whether an existing adiposo-genital dystrophy is 
of hypophysial origin, or whether the individual is a eunuchoid; if the latter is 
the case, of course all symptoms of brain pressure are absent, and the X-ray 
plate shows a sella of normal size. But it should not be forgotten that also 
in hypophysial dystrophy, the sellar alterations and the pressure symptoms 
may be absent, if gummata, tubercles, or sclerotic processes cause a distur- 
bance of function of the hypophysis. Perhaps also in many cases the examina- 
tion of the respiratory metabolism might be used for purposes of differential 
diagnosis. Marked reduction of it would probably only occur when the case 
is one of hypophysial dystrophy. Of course, many more investigations in this 
direction are necessary. Probably the ossification conditions are important 
from the standpoint of differential diagnosis. In primary genital dystrophy 
certain epiphysial junctures remain open until high age, and there occurs tallness 
and growth beyond the [age] growth limits of normal. In severe cases of 
hypophysial dystrophy there occurs, on the contrary, an inhibition of develop- 
ment in the occurrence of the bone-nuclei and also dwarfism, and the epiphysial 
junctures apparently remain open less long. 
The differential diagnosis from tumors of the pineal gland may be attended 
with difficulty. In the cases of pineal gland tumor that begin in early life the 
diagnosis is easy, as here is also found a premature development of the genitalia. 
But even in youthful cases, the tumor of the pineal gland may under circum- 
stances restrict the function of the hypophysis, so that the picture may become 
admixed with features of the hypophysial insufficiency (see the case of Raymond 
and Claude, in the chapter on the epiphysis). 
Also the distinguishing of hypophysial dystrophy from multiple ductless 
glandular sclerosis may present difficulties, as there exist cases that are 
associated with marked cachexia. This we saw, for instance, in case G 
(Observation XLV). Very marked retrogression of the genitalia and of the 
secondary sexual characters leads one to think of associated involvement of 
the suprarenal cortex. Attention should also be especially directed to myx- 
edematous skin alterations and to pigmentations, hypotonia, and reduction in 
the amount of sugar in the blood. When these symptoms are present, we 
should consider the associated involvement of the thyroid gland or of the 
chromaffin tissue. In an adiposo-genital dystrophy of hypophysial origin, 
the exact differentiation of the processes that lead to an impairment of the 
hypophysis is often very difficult or impossible; and yet this would be of great 
practical importance for the indications for operation. Here the X-ray 
examination furnishes important information. 336 
THE DISEASES OF THE HYPOPHYSIS 
Tumors that proceed from the hypophysial apparatus itself, deepen, when 
they lie intrasellarly, the floor of the sella. If they proceed from the hypo- 
physial duct they dilate chiefly the sellar introitus, but can also, if they are 
large, deepen the floor of the sella. An intracranial process chiefly sharpens 
the clinoid processes to a point (.Erdheim, Schuller). Later it may erode them. 
Then the X-ray would readily lead to faulty conclusions; in such cases ero- 
sions are mostly found, however, in other places. Exceptionally a similar 
destruction—here I follow the dissertation of Schuller—may be produced by 
an aneurysm of the carotid artery, by an endothelioma of the dura mater, or 
by basal tumors of the middle fossa of the skull. In tuberculous caries or in 
primary tumors of the body of the sphenoid bone, the infiltration of the sphe- 
noid bone is shown in the X-ray plate, thus enabling differentiation. Fin- 
ally the clinoid processes may be eroded and sharpened from behind by 
tumors of the cerebello-pontile angle. The finer details of the bone erosions 
are alone of value for the X-ray diagnosis, for as Schuller mentions, the tumors 
themselves are only visible in the X-ray picture when they calcify or when 
they penetrate in one of the pneumatic cavities of the skull. Apart from 
the X-ray examination, the presence of early pressure symptoms on the part 
of the more distant cranial nerves or symptoms of a hydrocephalus speak 
against the primary involvement of the hypophysial apparatus. 
Treatment.—To-day operation stands in the mid-point of therapy. 
Schlojfer and v. Eiselsberg in the cases of v. Frankl-Hochwart, O. Hirsch, and 
Cushing first carried out operation in hypophysial adiposo-genitalis, with 
partial good results. The methods now used are all intracranial. Schlojjer 
and v. Eiselsberg made a path to the hypophysis by making a flap of the nose, 
O. Hirsch by operating endonasally. The result consisted at all events chiefly 
only in the combating of the symptoms of brain pressure; the tormenting 
headaches disappeared, and the visual power improved, but only in few cases 
did there result in addition a recession of the dystrophic manifestations, and 
did the patients lose some kilograms of their fat; in certain cases hair even dis- 
appeared on the pubis and in the axillae; in one case erections occurred; in 
another a slight menstrual hemorrhage was observed some months after the 
operation. The improvement in the blood picture after operation is noticeable 
in Observation XXXIV. Also the mental condition changed, and the patient 
was much more impressionable. Even the combating of the pressure symp- 
toms alone and the saving from complete blindness might in themselves 
be regarded as a striking result; extreme care must always be taken in con- 
sidering the indications for or against operation. Apart from the danger 
of the operation we should consider that the surgeon should not remove just 
that part of the hypophysis that functionates, thereby increasing the dys- 
trophic manifestation and eventually bringing on a cachexia. The operation 
is therefore only indicated in tormenting symptoms of brain pressure or in 
rapid increase of the visual disturbance. The tumor tissue cannot be radically 
removed by any of the methods named. Therefore no case without relapse. 
The conception of dystrophia adiposo-genitalis as hypopituitarism leads 
us to expect results from a therapy by administration of hypophysial sub- ADDENDUM 
337 
stance. Levy and Rothschild, Axenfeldt and Delille, as well as Cushing, claim 
to have seen good results. In one case I also saw a striking improvement. 
Leman and van Wart after the administration of hypophysis tablets saw a 
growth of hair on the torso. The tumor symptoms (hemianopsia, etc.) are 
naturally not improved by this treatment. Thyroidin may be used with 
effect against the obesity. In cases with marked tormenting symptoms of 
cerebral pressure in which a radical operation is not possible or does not seem 
advisable, palliative trephining or Anton’s “Balkanstich” [puncture of the 
corpus callosum] brings relief. Finally it should be mentioned that Beelere 
saw improvement of the visual disturbance after X-ray irradiation. [See re- 
marks on surgical treatment of acromegaly—Editor.] 
Therapeutic Use of Hypophysis Extracts.—While in the treatment of hypo- 
physial diseases the use of preparations from the hypophysis of animals 
has not as yet won general recognition, yet the extracts from the pars 
intermedia or the posterior lobe of the hypophysis, pituitrinum (pituitrinum 
infundibulare is a preferable designation) have rapidly acquired a place in 
gynecology and obstetrics. The investigations of v. Frankl-Hochwart and 
Frohlich have justified our using them in postpartum bleedings. Foges and Hof- 
stdtter in Vienna and simultaneously Bell in England first reported the favorable 
influence on hemorrhages after labor, in which the tendency of the uterus 
to contraction was heightened by the preparation. The agent may be used 
intramuscularly as well as intravenously (1-2 cc. in 20 cc. physiological salt 
solution) (Flofhauer). In the numerous experiments of Foges and others, 
it was found to be entirely harmless. The agent is especially valuable in 
Cesarean section. Lately its use has been commended for hemorrhage from 
the non-gravid uterus (Bab). It is also recommended in postoperative paresis 
of the bladder (Hofstdtter). The voluminous literature pertaining to the 
subject is found in the works of J. Novak and of C. Heeke. Finally there 
are statements as to the treatment of osteomalacia with pituitrinum infun- 
dibulare (Bondi, Pal, Bab, Neu). Its use as a cardiac and vascular tonic has 
not as yet been tested. When it is injected subcutaneously in man it can 
increase blood-pressure not inappreciably and for a long time, so that tests in 
this direction seem to me very desirable, the more so as disagreeable by-actions 
are very much rarer than when adrenalin is used. As pituitrinum infundibulare 
increases the respiratory metabolism, Bernstein and / have tried it in one case 
of adiposity, without result. 
Pituitrinum glandulare has been tested but little. Very interesting is 
the statement of Pal that two cases of osteomalacia that were treated with 
extract of anterior lobe (Parke, Davis & Co.) improved essentially. 
Addendum 
The subject of acromegaly, always an interesting one, has been well 
dealt with by the author, and much has been written about it in this country, 
especially by Cushing. The anatomy and histology of the pituitary body, 
Atwell's resume of which has been presented in the text, has been dwelt within 
a painstaking way by Tilney. In England, Blair Bell especially has concerned 338 
THE DISEASES OF THE HYPOPHYSIS 
himself with the structural features of the pituitary gland, and has attempted to 
elucidate its symptomatology. Eminent surgeons especially interested in it 
are Elsberg and Frazier, to mention two only. Yet in spite of the interest the 
pituitary body has awakened, the functions of its various parts and just what 
diseases are due to the excessive, deficient, or perverted activities of these parts 
have not at all been settled. The two syndromes that have been thought to be 
due to disease of the pituitary body are acromegaly and hypophysial dystrophy, 
although the work of Bailey and Bremer referred to in the text (p. 333), throws 
doubt on whether the latter is really a pituitary syndrome. Krumbaar has 
shown that the pituitary body may be the seat of tumor for months, even 
to the extent of destruction of both lobes without obvious signs of pituitary 
disease, although this may be brought out by careful functional tests. Bell 
includes among the syndromes due to hypofunction the Lorain type of infan- 
tilism, a type which we shall consider under infantilism—and also overgrowth 
with some adiposity and genital inactivity. It is a pity that the term “ dyspitui- 
tarism” is still used in the literature, as Krumbaar appropriately remarks, 
to designate any and all conditions in which the pituitary body is at fault. 
The author is perhaps a trifle misleading in a portion of his manuscript on 
hypophysial dystrophy, perhaps conveying the impression that all cases of pitui- 
tary tumor that cause the affection are associated with the characteristic fat 
distribution. This is not so a priori, although authors who have reported 
cases do not always take pains to deny that such a distribution is present. 
v. Frankl-Iiochwart himself did not find it in the case reports that he reviewed, 
and in some of these reports an emaciation was spoken of. In eleven of his 
own cases it was present pronouncedly in eight, and was only suggested or 
indicated in three, v. Frankl-Hochwart points out that the cases more nearly 
approach the classic types the earlier in life the disease sets in. 
Wolf stein in reporting a case of hypophysial tumor calls attention to the 
importance of bitemporal hemichromatopsia in the early diagnosis. In this 
author’s case the pubic and axillary hair did not fall out, although there was 
a sudden cessation of menstruation. 
Sweet and Allen have done apparent total hypophysectomy in dogs, with 
characteristic changes in the animals, but not death. They believe that in 
the dog the entire gland can be removed without danger to life. 
Goetsch has ascertained, as the result of numerous experiments, that 
extract of anterior lobe of pituitary body (representing pituitrinum glan- 
dulare), when fed to young rats, has a stimulating effect upon the growth 
of the animal and upon its sexual development and activity. Posterior lobe 
extract (representing pituitrinum infundibulare), when given in the same 
manner, has a retarding influence. 
Uhlenhuth found that feeding anterior lobe of pituitary gland to sala- 
manders produced gigantism, although it did not affect the growth of larvae. 
Feeding of the posterior lobe did not stimulate growth; it rather retarded growth. 
Hoskins and Hoskins had done similar experiments in which metamor- 
phosis of tadpoles were hastened by the administration of hypophysis extract. 
Smith and Cheney found that the anterior lobe tablets used in the experi- ADDENDUM 
339 
ments of Hoskins and Hoskins contained iodine; fresh anterior lobe substances 
and dried anterior lobe substance failed to alter decisively the development 
of the normal tadpole or to induce metamorphosis in thyroidless specimens. 
Smith has shown that early and complete removal of the epithelial hypo- 
physis from the amphibian tadpole as perfected independently by Smith and 
B. M. Allen in 1916, causes a characteristic silvery or “albinous” appearance 
in the tadpole. In this change the deep melanophores are contracted, at 
least in the younger animals, and the silvery pigment cells or xantholeucophores 
are expanded. Immersion of the albinos in a pars intermedia solution produced 
temporary darkening. Feeding with posterior pituitary body produced 
a permanent darkening. The endocrine equilibrium was upset. Atwell 
has likewise worked on these tadpoles. 
In obstetrics, the efficiency of pituitrin when properly used remains 
unquestioned. 
Kraus has shown that in diabetes mellitus the pituitary body is poor 
in eosinophile cells, and those which are present show changes. The editor 
believes that these changes are probably secondary, although Kraus ascribes 
to the eosinophiles a sugar-regulating function. 
Oppenheim calls attention to the fact that both tabes and general paralysis 
may be closely simulated by pathological processes affecting the hypophysis. 
Among the effects of such processes may be a simple optic atrophy and evidences 
of true posterior column degeneration. These symptoms have nothing to 
do with the presence of the tumor per se, that is, they are not due to pressure, 
for instance, nor are they due to a true tabetic or paretic process, but are due 
to the alteration (quantitative or qualitative) of function of the ductless glands. 
Says De Schweinitz: “ Ophthalmoscopic examination of the eyegrounds of 
patients with hypophyseal disorders should be thorough, including, after 
dilatation of the pupil, the periphery of the fundus. Discovery of patches of 
retino-choroiditis, centrally placed are not readily overlooked but otherwise 
lesions especially in the far periphery may be overlooked; this is particularly 
true of congenital lues, where other stigmata of this disease may not be 
conspicuous.” 
Headache is one of the early signs of hypophysial disease. Especially has 
migrane and migranoid headache been ascribed to pituitary trouble. At all 
events in cases of migraine the pituitary body should be investigated. Zentmyer 
states the following: 
“Fisher believes that so-called hereditary optic atrophy is primarily due 
to an inherited temporary disorder of the pituitary body. He bases his 
assumption on the neuropathic type of the affected individual, the similar 
symmetrical field defects noted in some cases, the occurrence of subjective 
phenomena of light and colors, the epochal relation between the onset and the 
period of puberty and the climacteric, and that in both conditions, frequently 
in the early stage of the disease, a very mild papillitis may be detected. In 
one instance a honeycombed shadow in the depression of the sella turcica was 
found. About two years ago I reported the roentgen ray findings in two 
families in which certain members were affected with Leber's disease. Dr. 340 
THE DISEASES OF THE HYPOPHYSIS 
Pancoast, who made the roentgengraphs, concluded that as each of the four 
cases showed a pituitary fossa which was either at the border line of being 
abnormal in size or was slightly past this point, it would seem as though a 
pituitary enlargement might be regarded as the possible cause of the condition. 
Since this study was made, other cases have been reported, some of which 
supported, while others failed to support these findings.” 
Cushing (H.). Pituitary body and its disorders. Phila and London, J. B. Lippincott Co. 
19x2. 
Cushing (H.). Concerning the symptomatic differentiation between disorders of the two 
lobes of the pituitary body; with notes on a syndrome accredited to hyperplasia of the anterior and 
secretory stasis or insufficiency of the posterior lobe. Am. J. M. Sc., March, 1913, pp. 313, 328. 
v. Frankl- Hochwart (L.). Die Diagnostik der Hypophysistumoren ohne Akromegalie. Wien, 
med. Wcnsch., 1909, 37, p. 2127, 38, p. 2297, 39, p. 2326, 1909, 37, p. 2127, 38, p. 2257. 
Wolfstein (D. J.). Tumor and clinical pathology of the hypophysis. Lancet-Clinic, Vol. 
CVIII, Oct. s, 1912, pp. 365-373- 
De Schweinitz (G. E.). Concerning the ocular symptoms in the subjects of hypophyseal disease 
with acquired syphilis; with illustrative cases. Archives of Ophthal, Vol. L, No. 3,1912, pp. 203-216. 
Sweet (J. E.) and Allen (A. R.). The effect of removal of the hypophysis in the dog. Annals of 
Surgery, 58, 1913, p. 485. 
Goetscli (E.). The influence of pituitary feeding upon growth and sexual development. An 
experimental study. Bulletin of the Johns Hopkins Hospital, Vol. XXVII, No. 300, Feb., 1916, 
p. 29-50. 
Atwell (IF. J.). Anatomical consideration of hypophysis cerebri. N. Y. M. J., Vol. CXIII, 
March 2, 1921, pp. 366-370. [Bibliography.] 
Tilney (F.). Contributions to the study of the hypophysis cerebri with especial reference to its 
comparative histology. In Univ. of Penna., Wistar Inst. Memoirs, 1911, Vol. II. 
Bell (B.). The pituitary. New York, Wood, 1919. 
Marinus (C. /.). The effect of feeding pars tuberalis and pars anterior proprior of bovine 
pituitary glands upon the early development of the white rat. Amer. J. Physiol., Vol. XLIX 
July 1, 1919, pp. 238-247. 
Kraus (E. J.). Hypophyse and Diabetes mellitus. Virchow’s Arch Vol. CCVIII, 1920, pp. 
68-134. 
Krumbaar (E. B.). Pituitary disorders in their relation to acromegaly (hyper-prepituitarism) 
with suggestions for the use of a more precise terminology. M. Clinics of N. America, Nov., 1921, 
pp. 927-956. 
Uhlenhuth (£.). Experimental production of gigantism by feeding anterior lobe hypophysis. 
General Physiol., Vol. Ill, Jan., 1921, pp. 317, seq. 
Smith (P. E.) and Cheney (G.). Does the administration of the anterior lobe of the hypophysis 
to the tadpole produce an effect similar to that obtained from thyroid feeding? Endocrinology. 
Vol. V, No. 4, July, 1921, pp. 448-459. 
Hoskins (E. R.) and Hoskins (M. M.). The inter-relation of the thyroid and hypophysis in the 
growth and development of frog larvae. Endocrinology, Vol. IV, No. 1, Jan.-March, 1920, pp. 1-32. 
Smith (P. E.). The pigmentary, growth and endocrine disturbances induced in the anuran 
tadpole by the early ablation of the pars buccalis of the hypophysis. American Anatomical Memoires 
No. 11, 1920. Reviewed in Endocrinology, Vol. V, No. 2, March, 1921, pp. 231-236. 
Atwell (IF. /.). Further observations on the pigment changes following removal of the epithelial 
hypophysis and the pineal gland in the frog tadpole. Endocrinology, Vol. V, No. 2, March, 1921, pp. 
221-232. 
Oppenheim (II.). tiber Vortaiischung von Tabes und Paralyse durch Hypophysistumoren 
(Pseudotabes pituitaria, ect.). Ztschr. f. d. ges. neurol. u. psychiat., i, 1914, xxv, pp. 527-535. 
Zentmyer (IF.). The etiological relation of the eye to the endocrine organs. Pa. M. J., Vol. 
XXV, No. 8, May, 1922, pp. 527-529. CHAPTER VII 
THE DISEASES OF THE EPIPHYSIS (Glandula Pinealis, “Zirbel- 
druse”) [Conarium] 
Anatomy and Embryology.—The epiphysis originates from an extrusion 
from the roof of the third ventricle. About the fifth month of fetal life there 
develops between the posterior commissure and the habenular commissure 
a thin epithelial extrusion that later thickens and penetrates the mesodermal 
tissue. The epiphysis in many of the animal classes, for instance the reptiles, 
is very well developed, and in the developed human being it constitutes a 
Fig. 66.—Epiphysis of man. 
flat body that arches forward, about i cm. long and 0.5 cm. broad, which by the 
dorsal lip comes into connection with the habenular commissure and by 
the ventral with the posterior commissure. Between the two lips the recessus 
pinealis extends from the third ventricle into the gland. In the new-born it 
is more spherical, and contains regular follicles with polygonal cells, and, toward 
the recess, glial tissue. Commencing with the seventeenth year there begin 
signs of involution, increase of the connective tissue and glia; the follicles some- 
times form cysts or contain concrements, the so-called brain sand. 
Pathological Anatomy.—The diseases of the epiphysis known up to the 
present time consist chiefly in cyst formations, gummata, and tumors. Neu- 
341 342 
THE DISEASES OE THE EPIPHYSIS 
mann has collected twenty tumors from the literature and adds two of his 
own; they were sarcomata, carcinomata, teratomata, gliomata, psammomata, 
and cysts. The individuals affected were chiefly youthful so that, as Neumann 
supposes, the underlying factors might well be chiefly developmental anomalies; 
these are very much more frequent in the male sex. The teratomata contain 
hair follicles, sebaceous glands, cartilage, fat, smooth muscle fibers, etc. (Weigert 
and others). 
Symptomatology.—The symptoms that are produced by these lesions of 
the epiphysis are on the one hand local symptoms, on the other hand character- 
istic trophic disturbances. The first are caused by the pressure of the enlarged 
organ on the neighboring brain structures (thalamic and subthalamic regions, 
pulvinar, pons, cerebellum, corpus callosum, etc.), and through congestion in 
the brain ventricle. If the tumor grows backward, congestion in the fourth 
ventricle occurs on account of closure of the aqueduct of Sylvius; if it grows 
forward, there occurs hydrocephalus of the third and lateral ventricles. The 
pressure symptoms consist in motor symptoms of irritation or paralysis, 
ophthalmoplegias, conjugate deviation, alteration of pupillary reactions, 
nystagmus, ataxia, epileptiform convulsions (mostly bilateral), pareses, rigidity 
of the neck, choked disc, or more rarely genuine atrophy, difficulty in hearing, 
vertigo, headaches, vomiting and eventually slowing of the pulse, lethargy, 
symptoms that are common also to all the tumors of the quadrigemina. 
In addition to these symptoms there occur, if the tumor develops in early 
childhood, characteristic trophic disturbances that consist in an abnormally 
rapid bodily development and in a premature development of the genitalia, 
and are uncommonly similar to those which we shall consider under adenomata 
of the suprarenal cortex. To this group belong the cases of Ostreich-Slavyk, 
Ogle, Marburg, v. Frankl-Hochwart, and Raymond and Claude. Throughout 
the cases were those of children under ten years of age. 
In the case of Ogle, the premature development of the genitalia was very 
considerable. It was the case of a six-year-old boy who died with the mani- 
festations of a brain tumor. Lately the boy had masturbated. The penis 
was developed like that of a seventeen-year-old youth. There was an abun- 
dance of hair on the mons veneris. The testicles were apparently not enlarged. 
Autopsy showed an alveolar sarcoma of the pineal body. The case of Ostreich- 
Slavyk was that of a four-year-old boy who from the third year of life had shown 
a striking body development; the penis was 9 cm. long, the genitals were 
covered with hair 1 cm. long. The boy was 108 cm. tall and weighed 20 kg.; 
these measurements correspond with those of a seven- to eight-year-old boy. 
The mammae were hypertrophic and contained colostrum. At the beginning 
also voracious hunger existed, but later this disappeared. The case was 
also described by Heubner. The case of v. Frankl-Hochwart was that of a 
five-and-one-half-year-old child, whose body length corresponded to that of a 
nine-year-old boy; the development of the penis and of the entire genitalia and 
the secondary sexual characters corresponded with those of a fifteen-year-old 
boy; frequently erections occurred. The voice was deep, and in addition there 
was a premature mental development (thoughts about the immortality of the SYMPTOMATOLOGY 
343 
soul); also Ostreich-Slavyk designated the four-year-old boy described by him as 
“old-wise” [altklug]. 
In most cases the conditions of nutrition were stated to be very good. In 
other cases—apparently in those which develop later—there occurred an 
excessive adiposity. So for example is the case of O. Marburg; here we are 
dealing with a nine-year-old girl, in whom right at the beginning of the disease 
(eight months ago) obesity developed, that finally became excessive, especially 
on the breast and abdomen. Autopsy showed a complex tumor of the epiphy- 
sis consisting of tissue of the pineal gland, the ependyma, the choroid plexus, 
and glia. In addition to this was found a slight colloid thyroid gland struma, 
and a slight status lymphaticus; the genital glands and the hypophysis were 
normal. Also in the case recently described by Bailey and Jellijje, that of a 
twelve-year-old boy, there was obesity; the 
genitalia were normal. Autopsy showed a tera- 
toma of the pineal gland. 
In the epiphysial tumors that up to the 
present have been observed in adults and adole- 
scents there occurred either no especial trophic 
manifestations (for example in the case of Neu- 
mann, twenty-seven-year-old man, or in the 
case of Askanazy, nineteen-year-old man) or the 
trophic manifestions were varied of quite a 
different kind. Here there occurred either adi- 
posity, which, as in Muller’s case may attain 
an excessive degree (increase of 55 to 79.5 kg. in 
weight); other cases of adiposity in pineal gland 
tumor or of tumors that destroyed the pineal 
gland havebeen described by Coats, Daly,Falck- 
son, Kny, Konig, Nothnagel, and others; in other cases there develops a striking 
cachexia in which the skin may show a pasty consistency. In certain cases 
polyuria has been observed, in others persistence of the thymus gland, in the 
case of Neumann formation of a goiter. There may also occur atrophy of the 
genitalia and of the mammae. 
The significance of all these trophic manifestations is not yet clear. As far as the pre- 
mature development that occurs in childhood is concerned, the great morphological differ- 
ence in the tumors may be explained by the fact that they represent the failure or insufficiency 
[of function] of the epiphysis. We should therefore understand that normally in child- 
hood inhibitory influences on development proceed from the pineal gland, which gradually 
fall away or become slighter with the partial involution. 
This view has been especially developed by Marburg. Marburg believed that 
hypopinealism leads to premature development of the genitalia, hyperpineal- 
ism to universal obesity and apinealism to cachexia. The interpretation of 
adiposity as hyperpinealism is no longer held to be correct, even by Marburg. 
It may very well come about through disturbance of the hypophysial func- 
tion; one may see very well that the pineal gland tumors may behave in this 
respect just like other processes that increase cerebral pressure, the more so 
Fig. 67.—Hypertrophy of the ex- 
ternal genitalia of a four-and-one-half- 
year-old boy, 123 cm. tall (penis 6 
cm. long, hair on the mons Veneris), 
according to v. Frankl-Hochwart, 
Ztsch. f. Nervenh., 1900. THE DISEASES OF THE EPIPHYSIS 
344 
because on account of their position they lead to stagnation in and dilatation 
of the third ventricle. The interpretation of the premature development as 
hypopinealism has recently been supported by animal experimentation. Exner 
cind Boese could not indeed observe a premature development after extirpation 
of the epiphysis in young animals. C. Fod, however, saw after extirpation of 
the epiphysis in young fowls a premature and extraordinary development of 
the testicles and some of the secondary sexual characters. Extirpation of the 
sexual glands in youth produces in male and female animals atrophy of the 
epiphysis (Biach and Hulles). Askanazy believes that every embryonal tera- 
toma is to be regarded as a sort of pseudopregnancy that should lead to a 
premature maturation and a premature development of the genital sphere, a 
view that Hart accepts, and Pappenheimer opposes. I do not regard it as 
impossible that the trophic influences of the pineal glandular tumors in early 
life go over the suprarenal cortical system, [hyperplastic development of] which 
also leads to premature maturation and premature development of the genitals 
(see the following chapter). 
At least it should be noticed that in one case Raymond and Claude found 
hyperplasia of the suprarenal cortex. I will quote this interesting case in 
greater detail. It was that of a ten-year-old boy. The disease began in the 
seventh year of life with gradual blindness and increasing adiposity. The boy 
at the age of ten years was 138 cm. tall (about corresponding to a thirteen- 
year-old boy) and weighed 39 kg. Much fat had accumulated, especially on 
the abdomen and on the hips. The pubic hairs were well developed and there 
was a foreshadowing of a beard on the upper lip. Penis and testicles were 
small. Histologically the testicles showed no spermatogenesis, but the inter- 
stitial glands were very well developed. The less strong predominance of the 
premature genital development could in this case have been brought about 
through a restriction in the function of the hypophysis; for the epiphysial tumor, 
which was the size of an apple, had led to a marked dilatation of the lateral and 
the third ventricles and to a marked flattening of the hypophysis. 
The diagnosis of epiphysial tumors in adults is hardly possible, as the 
symptoms produced are hardly to be distinguished from the tumors in the 
neighborhood of the corpora quadrigemina. 
According to Marburg the possibility of an epiphysial tumor should be 
thought of when there occurs associated symptoms of initial headaches— 
especially of the occipital region—early choked disc, vertigo, sleeplessness, 
convulsions, later, somnolence, paralysis of the eye muscles associated with 
ataxia (Nothnagel), and disturbances in hearing. What makes the diagnosis 
the more difficult is that epiphysial tumors, as above mentioned, also lead to 
dystrophia adiposo-genitalis, probably through limitation of the function of 
the hypophysis. On the contrary, the diagnosis in childhood is possible, 
through the combination of general brain tumor symptoms and those of quad- 
rigeminal lesion with those of premature development of the body, the psyche, 
and the genital sphere, and was first made in vivo by v. Frankl-Hochwart. 
The treatment by operation has not as yet been tried. ADDENDUM 
345 
Addendum 
Jordan finds that there is no clear histological evidence indicative of a 
glandular function of the pineal body, and that if the pineal body in the sheep 
subserves an important physiological function, this is probably active only 
during the first eight months of postnatal life. Pineal bodies of sheep older 
than one year present much variation and degeneration. 
An editorial in the Journal of the American Medical Society, Vol. LXVI, 
No. 5, Jan. 29, 1916, p. 361, calls attention to the stimulating effects of pineal 
gland extracts when administered to young animals, and to negative results 
following extirpation of the pineal gland. The literature dealing with the 
material of this apparent incongruence will be found in conjunction with 
Walter E. Dandy's article: Extirpation of the pineal gland, Journal of Experimen- 
tal Medicine, Vol. XXII, No. 2, Aug. 1, 1915, p. 237-247. 
Tilney and Warren have shown that the pineal body cannot be a vestige, 
that it may subserve a visual function in cyclostomes, amphibia, and in primi- 
tive reptiles. They believe that in the higher mammals it is an endocrine 
organ. The pineal body in mammals cannot be regarded as the vestigial or 
metamorphosed atrophic residuum of the parietal eye in vertebrates. 
Jellife has summarized the literature on pineal gland. He states that there 
are at least a hundred cases of tumor formation of this gland in the literature. 
Simple atrophy, hypertrophy, cysts, hemorrhage, syphilis and abscess are among 
the non-tumor involvements, while among the tumor formations have been 
described teratomata, gliomata, chorio-epitheliomata, carcinomata, adenomata, 
lipomata, with various types of sarcomata, as the most numerous. Mesence- 
phalic, pontine, cerebellar and thalamic syndromes are described in his article. 
Askanazy and Brack have recently reported a case of sexual prematurity in 
a female idiot in which the hypophysis, suprarenals, and pancreas were nor- 
mal; there was a small pineal gland, in which glandular structure was present. 
The thyroid gland was also not entirely normal. The authors regard this as 
the only case of its kind in the female sex that has been reported. 
Berblinger has recently mentioned this article in a review of the subject of 
pineal function. He does not agree with Askanazy that the “pubertas 
praecox” is a result of tumor formation in the pineal gland, but regards it 
rather as an accompaniment of hypopincalism. He implies however that the 
subject is still very obscure. 
Baar however, has reported cases in female children five years and three and 
three-quarter years respectively in which signs of over-development in some part 
of the sexual organs were associated with intracranial disease. Sections were 
lacking however. 
To the mind of the editor the function of the pineal gland and the relation 
of the gland to sexual prematurity still remain obscure. 
Jordan (//. £.). The histogenesis of the pineal body of the sheep. Am. J. Anat., Vol. XII, 
1911-12, pp. 249-270. 
Tilney (F.) and Warren (L. F.). Morphology and evolutional significance of the pineal body. 
American Anat. memoirs, 1919, Vol. IX. 
Jellife {S. E.). Pineal body; its structure, function and diseases. N. Y. M. J.,Vol. CXI, Feb. 
7, 1920, p. 235 et seq. 346 
THE DISEASES OF THE EPIPHYSIS 
Askanazy (M.) and Brack (W.). Sexuelle Friihreife bei einer Idiotin mit Hypoplasie der 
Zirbel. Virchow’s Archiv. fur path. Anat. und Physiol, und fur klin. Med., Vol. CCXXXIV, Heft 2, 
Sept., 1921, pp. i-ii. 
Baar (H.). Makrogenitosomia praecox Zirbeltumor. Zeitschr. fur Kinderheilk. Orig., XXVII, 
1921, pp. 143-151* 
Berlinger. Zur Frage der Zirbelfunktion. Virchow’s Archiv fur path. Anat und Physiol, und 
ftir klin. Med., Vol. CCXXXV1I, 1922, pp. 144-153- CHAPTER VIII 
THE DISEASES OF THE SUPRARENAL APPARATUS 
Anatomy and Embryology.—The suprarenals are paired organs, that rest 
hook-like on the upper pole of the kidneys. Their breadth according to v. 
Neusser and Weis el, is about 40-50 mm., their height 30-35 mm., their thickness 
2-8 mm., their weight averages 10.6 gm. in women and 11.6 gm. in men. They 
are made up of two embryologically independent parts, the cortex and the 
Fig. 68.—Suprarenal gland of man. C-capsule, Cor-cortex, Af-medulla, Z.gl.-zona glomerulosa, 
Z.f.-zona fasciculata, Z.r.-zona reticularis. 
medulla. The so-called intermediary zone belongs to the cortex. The cortex 
is made of columns of cells, which cells are filled with glistening granules, most 
doubly refractile, of a lipoid character. The medulla contains numerous 
nerves and multipolar ganglion cells, and in addition nests of cells, which take 
a brown color when they are stained with chromic acid, and a green stain with 
iron chloride. They are termed chromaffin cells. 
347 348 
THE DISEASES OF THE SUPRARENAL APPARATUS 
From the arteries of the diaphragm, from the aorta, and also from the renal artery, re- 
spectively, are given off a branch to the suprarenal glands. These form subcapsularly an 
anastomosis, from which the cell columns of the cortex are surrounded by a fine capillary 
network, and which also continues into the medulla; moreover there are the so-called arterise 
perforantes, which run through the cortex and first form a capillary network in the medulla. 
The suprarenal veins empty into the vena cava. 
True accessory suprarenals that are made up of cortex and medulla are 
rare. On the contrary accumulations of chromaffin tissue may exist outside 
the suprarenals. The larger have been termed “paraganglia” by Kohn. 
Such cell accumulations are found on the carotid artery, in the ganglia of the 
sympathetic trunks and in the solar plexus, in the left stellate ganglion, on 
the site of the giving off of the left coronary artery and of the superior mesenteric 
artery, at the hilus of the kidney, and along the course of the sympathetic 
nerves (Zuckerkandl, Kohn). In the adult the total amount of the extramedul- 
lary chromaffin tissue is not smaller than the medullary part; in the new-born 
it is greater. Accumulations of cortical substance can be found at the hilus 
of the kidney, in the renal substance itself, along the suprarenal veins, and in the 
internal genitalia. Schmorl found them in 92 per cent, of cases, Weisel in the 
genitalia of new-born boys in 76.5 per cent. Aichel found them never absent in 
the broad ligament of new-born girls. Some of these, also, later retrogress. 
Embryological and phylogenetic studies agree with the anatomical that 
the suprarenal apparatus consists of two independent systems which in the 
lower classes of animals are arranged segmentally and remain separated per- 
manently. The chromaffin or adrenal system is of ectodermal origin and is 
part of the sympathetic. 
Already at a very early period the primitive cells separate into two differ- 
ent forms, into the primitive form of the sympathetic nerve cells and into the 
so-called phaeochromoblasts, from which the chromaffin cells originate. The 
cortical tissue—the so-called interrenal system—develops from the ventral 
part of the mesoderm and indeed quite in the neighborhood of that place of 
the celomic epithelium from which the sexual glands originate; suprarenal 
cortex and sexual glands are laid out in the Wolffian duct, which explains the 
topography of accessory suprarenals consisting in cortex alone along the 
entire way that the sexual glands travel, indeed even in the seural glands and 
kidneys themselves (Soulie). During fetal life the suprarenal is at first larger 
than the kidney, and at birth is about the same size. Already at an early 
period some of the chromaffin cells have broken through the complex of cortical 
cells to form the medulla. Through the descent of the genital organs small parts 
of both systems are displaced. This shows that the former complete physio- 
logical independence of both systems later gives place to a common function, at 
least in part (Biedl), which fact is also indicated by the previously mentioned 
relations of the blood-vessels. It is indispensable for the comprehension of 
diseases of the suprarenals to consider that the two systems for a great part are 
functionally independent. The higher we go in the classes of animals, the 
greater become the complexes of the two systems that finally unite to form a 
single organ, the suprarenal. addison’s disease 
349 
a. Conditions of Hypofunction of the Suprarenal Apparatus 
1. Addison’s Disease 
Definition.—In the year 1855 Thomas Addison described the disease that 
bears his name. The disease mostly develops in the third or fourth decades 01 
life, usually quite insidiously, with adynamia and apathy. To these are added 
disturbances of the digestive tract (constipation, often alternating with diarrheas) 
and pigmenting of the skin and the mucous membranes; the patients succumb 
under a gradually increasing cachexia, not rarely with stormy terminal mani- 
festations; autopsy almost always shows disease of both suprarenals, mostly 
tuberculous caseation. Addison’s description embraces all the essential features. 
Symptomatology.—The disease affects mostly individuals, often heredi- 
tarily inclined to tuberculosis, who have been weakly from youth. Mostly 
it is individuals of middle age who are affected, rarely are children or old 
people affected. Almost always the disease manifests itself in ready fatiga- 
bility, disinclination for work, and apathy; to these symptoms are sometimes 
added headaches, poor sleep, sometimes obstinate insomnia, psychical ill- 
humor and depression, often too, abnormal irritability; further, diminution 
in memory, noises in the ears, vertigo, and commonly fainting attacks, singultus, 
and rheumatoid pains in the back and in the extremities, sometimes also 
epileptiform convulsions. Extremely stormy manifestations on the part of 
the nervous system may, especially in the later stages, make their appearance— 
violent delirium, acute confusion, convulsions, deep stupor, and coma. The 
symptoms on the part of the digestive tract are very various. The patients 
complain about pressure in the stomach, eructation, nausea, pyrosis, sometimes 
vomiting and epigastric pains. In the later stages there are mostly lessening 
or absence of the hydrochloric acid and ferment production. Often diarrheas 
alternate with constipation. The diarrheas may occur in crises with great 
violence, may be associated with spasms of the calves and may simulate the 
picture in cholera nostras. In the terminal stages there is often immitigable 
vomiting. To this may be added abdominal pains and constipation; the 
abdomen is retracted, the abdominal walls are tense, the pulse becomes small, 
in short, there exists the picture of peritonitis {Ebstein). 
In the later stages the adynamia becomes prominent. Early the pulse is 
strikingly small and soft, the blood-pressure reduced, the force of the pulse 
lowered (Munzer). Dyspnea ensues on slight physical exertion. Edema is 
almost never observed, even later. Arteriosclerosis is extremely rare; when 
it is present, the rise in blood-pressure does not occur. 
The blood picture always shows changes. The count of erythrocytes and 
the hemoglobin contents are almost always reduced, the leucocyte count 
is mostly normal. Lymphocytosis was first observed by v. Neusser. In 
the cases from the literature in which the leucocytic formula is given, especially 
in the cases of Bittorf and Munzer and in those described by myself, lymphocyto- 
sis was always present. Hypereosinophilia is not constant. Moreover the 
number of large mononuclear cells is often increased, and the number of neu- 
trophilic cells relatively and absolutely much diminished, sometimes to 40 350 
THE DISEASES OF THE SUPRARENAL APPARATUS 
per cent. Commonly there are found in addition signs of a status lymphaticus; 
swelling of the glands, the tonsils, the papillae at the base of the tongue, etc. 
Also hyperplasia of the thymus was observed in some cases {Weisel, Kahn, 
Hedinger). [A recent article by Cowie1 agrees that the changes in the blood 
picture after intramuscular injections of adrenalin are purely mechanical — 
Editor.] 
Of alterations of the metabolism should be mentioned especially the falling 
off in weight. In very rare cases only is observed corpulency lasting until 
death (Bittorf). Investigations as to the basal metabolism are not known to 
me. The gastrointestinal disturbances may very well cause the emaciation. 
The few investigations as to the protein metabolism are too short as to time. 
Wolf and Thacker found the endogeneous uric-acid elimination very low. In 
three cases of Addison’s disease, Eppinger, Rudinger, and I found very high 
tolerance for grape-sugar and absence of glycosuria after injection of adrenalin. 
Also in a case of Pollack’s there was no sugar after 2 mg. adrenalin. Later 0. 
Porges found pronounced hypoglycemia (up to 0.033 Per cent.) while in other 
cachexias the blood-sugar picture lay normally high. The finding of Porges 
that was corroborated by Bernstein in several cases, has therefore come to have 
a diagnostic value attached to it. The body temperature is often reduced, 
but when the manifestations become violent there may be found sudden 
increases in temperature, even to hyperpyretic values. 
The making use of the diet is, so far as there are no diarrheas, normal; 
frequently there is indicanuria. In the later stages are found very frequently 
disturbances of the genital function, deficiency or absence of menstruation, in 
men diminution or loss of sexual power. 
The pigmentations that are so important from a diagnostic point of view 
mostly begin on the uncovered parts of the body, or on parts where the clothing 
presses, or on parts on which certain irritants, for instance plaster, have exerted 
their action. Sites of especial predilection are the borders of the lids, the 
areolae of the nipples, the linea alba, the genitalia, the anal folds, the folds of the 
palm; otherwise the palms, the soles, and the nail beds usually remain free. In 
many cases too the hairs become darker. The pigmented places are light 
brown to dark brown, and in many cases the entire body may assume a bronze 
tint. Pigment displacements are less frequent. The pigmentations of the 
mucous membranes are almost always spot-like and blackish-blue. They are 
found on the borders of the lips, on the mucous membranes of the cheeks, on the 
soft palate, and on the border of the tongue. Pigmentations of the vaginal and 
rectal mucous membranes are also observed. The skin pigment lies in the 
deeper layers of the rete Malpighii and is iron-free. In rare cases there is 
observed also a combination of Addison’s disease with hemochromatosis (Fod, 
Bittorf, and others). The pigmentation is extraordinarily frequent. In the 
statistics of Lewin, based on five hundred sixty-one autopsied cases, it was 
found in 72 per cent., and Bittorf believes that these figures are too low. 
1 Cowie (D. M.). The action of adrenalin on the leucocytes and erythrocytes, etc. Contri- 
butions to Medical and Biological Research. Dedicated to Sir Wm. Osier, New York. Hoeber, 
1919, pp. 829-844. addison’s disease 
351 
The course of Addison’s disease is very manifold. There are peracute 
cases in which destruction of suprarenal is brought about by hemorrhages, 
thrombosis, etc.; in these cases death may occur in a few days with stormy 
cerebral and intestinal manifestations. Pigmentation is absent. 
A short time ago Brodnitz reported an interesting case which I shall repeat 
in detail. It was that of a thirty-six-year-old, strongly built, markedly fat 
man, previously healthy. Two and four years ago there suddenly occurred 
violent intestinal colics, which ceased after a few hours, and were followed 
only by a marked loss of strength. Also at present such a colic has come on 
quite suddenly. The facial expression is anxious, the pulse hard and full, 
50-60 beats per minute, the temperature normal or slightly subnormal. No 
improvement on injection of morphine. This condition lasted two days and 
was then followed by an operation. On the jejunum and ileum were found 
columnar contractions of 10-20 cm. of the intestine at three places. Otherwise 
conditions were normal. In the course of the fourth day manifestations of 
peritonitis made their appearance. Tympanites appeared, the pulse was soft, 
thread-like, very rapid. Vomiting, temperature increased to 39°C. Death 
on the fifth day. At autopsy was found marked inflation of the stomach and 
duodenum, the small intestines, and the colon. No peritonitis. Complete 
destruction of the right suprarenal, partial destruction of the left. On micro- 
scopical examination the left suprarenal at one place showed marked develop- 
ment of the connective tissue, with hemorrhagic pigment, in brief signs of a 
previous hemorrhage. 
As a further example I cite the case of Karakascheff. A young man of 
eighteen years of age became sick suddenly with pains in the head and abdomen 
and felt very ill, but nevertheless went about. The manifestations became 
stronger only after three days, when vomiting ensued, and finally loss of con- 
sciousness. Autopsy showed old total destruction of the right suprarenal, 
apparently through thrombosis, and a quite fresh infarction of the left 
suprarenal. Death had occurred five days after the beginning of the illness. 
In other cases the affection lasts for weeks. Here the adynamia comes 
more in the foreground. In the case of Straub there developed within two 
weeks asthenia, adynamia, pigmentations that were iron-free, and only a slight 
depression of the blood-pressure. Also psychic disturbances (at first more 
excitement, then apathy) made their appearance. Autopsy showed a scirrhous 
carcinoma of the pylorus with metastases into the retroperitoneal tissue, 
especially at the hilus of the left kidney, into the lungs and pleura, and 
bilateral thrombosis of the suprarenal. The older of these metastases could 
very well have occurred simultaneous with the beginning of the Addison’s 
disease. 
Moreover, sometimes in the subacute cases there is observed graded 
[schubweises] occurrence of the stormy manifestations. Chronic Addison’s 
disease mostly shows remissions, in which also the pigmentation may retrogress. 
Cases that have lasted ten years are on record. As the remissions may have 
lasted for years, we must be cautious as to our assertions that an individual case 
has been cured. 352 
THE DISEASES OF THE SUPRARENAL APPARATUS 
Such individuals with chronic Addison’s disease are for the most part very 
labile; physical exertion, excitements or slight complicating affections may lead 
to a fatal collapse. 
As an example of the chronic course, I cite the following case: 
Observation XLVI.—H. K., forty-two years. Entered the clinic November, 1911. No 
tuberculous taint; the family, however, shows the presence of gout. The illness began 
ten years ago, when a gradually increasing brown coloration of the skin became apparent; 
during the first years the coloration was extraordinarily intense, the greater part of the 
skin, but especially that of the face, the neck, hands and forearms being deep brown—a 
bronze color. Since that time the brown coloration has persisted in varying intensity. 
At that time the patient spent a year at Davos, as the lungs had become affected. Ten 
years ago an attack of articular rheumatism that affected especially the joints of the feet 
and toes. Since that time several attacks, two or three times a year, in which the most 
different joints are involved. At present such an attack is in progress after an interval 
of some years. Loss of 12 kg. weight during the last half year. 
On examination, it was found that the skin of the whole body shows a brown colora- 
tion, which is especially intense on the extensor surface of the forearm, on the backs of the 
hands, on the face and neck, and on the genitalia and inguinal region. The brown coloration 
is partly diffuse, partly more circumscribed in spots, the individual spots attaining the size 
of a lentil. Mucous membranes of the lips, mouth, and throat show numerous mustard- 
seed-sized, irregularly limited brownish-black spots, which are especially distinct on the 
mucous membrane of the cheeks. The mucous membranes are pale, the skin is dry, the 
percussion sound over the left pulmonary apex is shortened, the vesicular murmur weakened; 
no rales. The cardiac dullness is rather small, the heart-sounds are clear, the blood-pressure, 
according to Gartner, 60, liver and spleen not enlarged. 
Several joints are reddened, swollen and painful, especially both knee-joints, right 
great toe-joint, left ankle-joint, left shoulder-joint, right elbow-joint and left hand-joint. 
No uric acid demonstrable in blood. 
Traces only of albumin in the urine. 
Temperature up to over 38°. 
Estimation of sugar in the blood (Bernstein) 0.067 Per cent. 
Leucocyte count normal (8 per cent, eosinophiles). We are here dealing with the 
chronic Addison’s disease, that has existed for ten years and that shows long remissions. 
During the last years the condition is apparently rather stationary, lately a new exacer- 
bation (reduction in weight). With this there exists complications with frequently recurring 
articular rheumatism. 
Pathological Anatomy.—Congenital errors of development of the supra- 
renal are often found combined with other malformations. Zander quotes 
forty-two cases of hemicephaly in which the suprarenals were always small. 
This finding is also constant with other malformations, if there is an absence of 
the anterior cerebral hemispheres. There apparently exists in such cases 
aplasia of the cortical system. At least Elliott and Armour in a case of anen- 
cephalus found the suprarenal medulla and the paraganglia normal; while the 
cortex was entirely absent. Czerny found the medullary substance entirely 
absent in five cases of congenital hydrocephalus. Ulrich observed in an adult 
complete aplasia of the suprarenal medulla; here the paraganglia must have 
been especially well developed. 
Important practically is the hypoplasia of the chromaffin tissue described 
by Wiesel, Hedinger, Goldzieher, and others, which is mostly associated with addison’s disease 
353 
status lymphaticus and sometimes with great parenchymal value of the thymus 
gland. According to Wiesel such individuals are especially predisposed to 
Addison's disease. Acute destruction of the suprarenals may occur as a result 
of hemorrhage of thrombosis of the suprarenal veins (Virchow, Carrington, 
Karakaschejf, Goldzieher, [Lavenson, Hektoen, Ellis]) and others or through suppu- 
ration (Janowsky). Much more frequent are simple atrophy or sclerosis 
(Rolojf, Simmonds, Bittorf, Goldzieher). 
Bittorf collected forty-seven cases of true atrophy or cirrhosis of the supra- 
renal glands, adding to these three cases of his own. In such cases the supra- 
renals are much decreased in size or entirely shrunken and often grown together 
with the surrounding tissue. Microscopical examination usually shows a 
very considerable reduction of the parenchyma, fattening and eventually 
necrosis of the cells. With the cirrhosis, one finds thickening or obliteration 
of the vessels, and growing together with the surroundings. Sometimes the 
sclerosis exists on a luetic basis (Schwyzer, Esser). Esser found gummata in 
connection with symptoms resembling Addison’s disease in a new-born. Ac- 
cording to Lichtwitz, pigmentations occur in all these cases. This author found 
the condition complicated with scleroderma in four cases in the literature, 
adding a fifth case. Most commonly, however, tuberculosis of the suprarenals is 
found bilateral, not rarely isolated. Often, however, other tuberculous foci 
in the body are found. Among five hundred forty-nine cases from the litera- 
ture, Elsasser found isolated tuberculosis of the suprarenals in 17 percent., in 
48 per cent, combination with pulmonary tuberculosis, and in the rest of the 
cases tuberculous foci in other parts of the body. 
In four hundred seventy-two cases the lesion of the suprarenal was bi- 
lateral. The suprarenals may be destroyed also by tumors. Bittorf reports 
two cases of hypernephromata with symptoms of Addison’s disease. 
There are also cases of Addison’s disease in which the suprarenals are 
found to be healthy. Nieszkowski, and Virchow, first reported such cases. 
Lewin found them in 12 per cent, of five hundred sixty-one cases. There 
are, further, cases in which clinically no signs of Addison’s disease are present, 
but which at autopsy show destruction of both suprarenals. v. Neusser hence 
expressed the thought that a lesion in the splanchnic itself or at some other 
point of the sympathetic system could lead to Addison’s disease. There are 
but few cases, however (Jurgens, Bramwell), that are adapted for such an 
explanation; otherwise changes in the sympathetic are rare and mostly slight 
(v. Kahlden, Martineau). An explanation of the above-mentioned exceptions 
would be possible only on the recognition that the suprarenals represent only 
a part of the chromaffin or interrenal system, and on the consideration of the 
presence of accessory suprarenals. 
Whether the complete or partial destruction of the suprarenals will in a 
given case lead to Addison’s disease, depends upon the fact whether the por- 
tion of the suprarenal apparatus lying outside the glands proper is sufficiently 
well developed to assume the function of the destroyed tissue, apparently 
also on whether the destruction has progressed slowly enough to give time 
for vicarious hypertrophy. 354 
THE DISEASES OF THE SUPRARENAL APPARATUS 
There has taken place a lively discussion as to whether Addison’s disease 
should be referred to a lesion of the chromaffin tissue or of the interrenal system. 
Wiesel in five cases of Addison’s disease observed that the entire chromaffin 
tissue was destroyed, while the cortex seemed to be less affected. He thought 
that the destructive process began primarily in the chromaffin tissue, and 
involved the cortex only secondarily. On the other hand, Karakaschejf 
reported cases in which chiefly the cortex was affected, and in which he regarded 
the cortical lesion as the sole course of the symptom-complex. The ques- 
tion is not as yet fully cleared up, although the pathologico-anatomical 
investigations of latter times and the physiological researches tend to show 
that in Addison’s disease a disturbance of function of both suprarenal systems 
is present, a standpoint that is upheld in the new monographs (Bittorf, v. 
Neusser and Wiesel, Biedl). Of other pathologico-anatomical findings I 
mention only the known atrophy of the heart, and the atrophy of the sexual 
glands that is almost regularly present. Kyrle has made exact investiga- 
tions as to the testicles. He found a deficient spermatogenesis and also changes 
in the interstitial glands. 
It is very noteworthy that the suprarenal often becomes affected espe- 
cially in severely infectious diseases and intoxications. Diphtheria toxin has 
an especial affinity for the suprarenals. In animals after the injection of 
diphtheria toxin, the suprarenals are always found to be markedly hyperemic 
and suffused with hemorrhages (Roux and Yersiri). Necroses, hemorrhages, 
and edema of the suprarenals are found in the various infectious diseases 
{Oppenheim and Loeper). In many cases, an acute insufficiency of the supra- 
renal apparatus and especially the chromaffin tissue is well an important cause 
of the cardiac insufficiency. In such cases the suprarenals show an essential 
reduction in their adrenalin content (Comessati, Schmorl, Goldzieher). 
Finally we must mention a rare finding of v. Recklinghausen's. In an 
eighteen-year-old dwarf who died in convulsions, he found what was apparently 
a very chronic tuberculous change of both suprarenals. I shall have occasion 
to refer to this case later. 
Pathological Physiology of the Suprarenals.—The thesis established by 
Brown-Sequard that the extirpation of both suprarenals led to the death of 
the animal experimented on has met with much contradiction. The sure 
knowledge that the cortical system and chromaffin tissue are in like manner 
important for life was first mentoned by later investigators (I mention only 
Biedl, Hultgren, and Anderson) who took into consideration the presence of 
accessory suprarenals. 
Biedl could at the same time furnish an important demonstration that the 
death of the animal was not to be blamed on the operative shock due to injury 
of the sympathetic nerve plexus, as the operation also ended fatally 
after transplantation of the suprarenals under the skin. After extirpation 
of both suprarenals, the animals, after a latent period, showed increasing 
apathy, adynamia, paresis, and emaciation. Blood-pressure and bodily 
temperature gradually sank, so did also the amount of blood sugar (Porges, 
Bierri, and Malloisel). Injection of phloridzin would now produce no gly- addison’s disease 
355 
cosuria or only minimal glycosuria (Eppinger, Falta, and Rudinger); the 
glycogen rapidly disappeared from the liver and muscles (Porges), there existed 
a higher sensitivity for poisons (O. Schwarz), the blood seemed to act toxic, 
death occurring in convulsions. The symptom picture shows great simi- 
larity with the peracute cases of Addison’s disease. We have not as yet 
a sufficient explanation as to the question as to which symptoms of Addison’s 
disease are to be referred to the absence of the medullary system and which 
to that of the cortical system. Before I enter into this question, I will briefly 
mention the most important facts we know as to the physiological significance 
of these systems. 
The active constituent of the chromaffin tissue is adrenalin. After the 
important preliminary researches of v. Fiirth, it was first isolated in a crystal- 
line form by Takamine and Aldrich. 
Later investigations of Aldrich, v. Furth, Pauli, et al., then led to the estab- 
lishment of its chemical formula. It is a methylaminoethanol pyrocatechin, 
with the formula C9H13NO3. 
Stolz first succeeded in making optically inactive adrenalin synthetically, 
and Fldcher then obtained the separation into the dextro- and sinistro-adrena- 
lins. The sinistro-adrenalin is far the more active and is identical with 
that produced in the body {Ahderhalden). Probably the organism forms 
adrenalin from the aromatic split products of albumin, tyrosin, and phenyl- 
alanin or oxyphenylserin {Halle, Frdnkel, Friedmann). 
Of the chemical methods for demonstrating adrenalin we will mention 
only the iron chloride test (Vulpian), the sublimate test {Comesatti), the 
iodine reaction {Vulpian, Schur, Frdnkel, and Alters), the potassium perman- 
ganate lactic acid test {Zanfrognini). 
I shall limit myself to sketching briefly the most important of adrenalin’s 
physiological actions. It acts as a powerful increaser of the blood-pressure 
through narrowing of the peripheral vessels, it mostly acts first by slowing 
the pulse, then accelerating the pulse; it slows the pulse by reflex excitation 
of the vagus center, this action belonging to the so-called by-activities 
[Nebeneinwirkungen] of adrenalin {Biedl). Other by-activities are the shal- 
lowing of respiration, and, according to {Biedl) perhaps also the increase of 
the excitability of the striated muscles. It acts in a relaxing manner on the 
stomach and intestines, as a contracting agent on the three sphincters (the 
pyloric, and ileo-colic, and the internal sphincter of the anus). The uterine 
muscle is contracted or relaxed by adrenalin, according to whether the pressor 
[forderndenj or the inhibitory fibers predominate or are excitable {Falta and 
Fleming). Probably the bladder behaves in the same manner. Under cir- 
cumstances mydriasis occurs. The vessels of the kidneys react to minimal 
doses by dilatation and diuresis {Jonescu). Under circumstances adrena- 
lin may produce salivation and secretion of tears, indeed in large doses (in 
guinea-pigs), also secretion of sweat {Falta and Ivcovic). Adrenalin produces 
hyperglycemia and glycosuria {F. Blum, Metzger, and Ziiltzer). The hyper- 
glycemia comes about by mobilization of the glycogen and probably also by 
secondarily increased carbohydrate formation in the liver {Eppinger, Falta, 356 
THE DISEASES OF THE SUPRARENAL APPARATUS 
and Rudinger, L. Poliak). It increases the protein decomposition during 
hunger. At the same time the respiratory quotient is temporarily increased 
(.Bernstein and Falta). In large doses it produces in dogs increased elimina- 
tion of uric acid and allantoin. Often it leads to increase of temperature. 
Further it brings about a neutrophilic hyperleucocytosis, during which the 
eosinophiles vanish from the circulating blood. The simultaneous increase 
of the mononuclear cells is a by-action, as this remains absent after the admin- 
istration of atropine. Finally adrenalin produces hyperglobulia (Bertelli, 
Falta, and Schweeger), chiefly through transudation of plasma. 
Apart from the accessory actions mentioned, adrenalin acts only on the 
purely sympathetic nerve-endings, and indeed on the so-called musculoneural 
junction {Langley, Elliott). It is therefore a purely sympathetic hormone. 
The giving-off of adrenalin to the blood of the vena cava is continuous. 
The blood of the suprarenal vein should contain about one-half part 
per million of adrenalin per cc. {Ehrmann). Biedl estimates that in twenty- 
four hours about 4.3 mg. are given off to the blood. This amount of adrenalin 
may be increased by stimulation of the suprarenal nerves {Biedl, Asher). 
The assumption that the activity of the chromaffin tissue and the excita- 
bility by the myoneural junction {Bayliss and Starling) is regulated by cen- 
ters lying in the medulla oblongata is essentially based on the knowledge 
that “puncture glycosuria” is brought about by dissemination of adrenalin 
by means of the chromaffin tissue. Already Blum had supposed this. Ep- 
pinger, Falta, and Rudinger further pointed out concerning this that in the dog 
without a thyroid, “piqure” may remain as ineffective as injection of adrena- 
lin. After A. Mayer had established the fact that “piqure” remains ineffec- 
tive in rabbits after bilateral removal of the suprarenals, Waterman and Smith 
tried to demonstrate an adrenalinemia by means of the insufficient Ehrmann's 
reaction. The question was first entirely cleared up by investigations of 
R. Kahn. This author could show that after the sugar-puncture, the tingibility 
of the suprarenals to chrome stains in great part disappears and the contents 
of adrenalin markedly diminish. Cutting of the splanchnic nerves not only 
prevents the occurrence of “piqure” glycosuria, as Claude Bernard had shown, 
but also the coming about of any change in the suprarenal medulla. It should 
be noted that in rabbits the right suprarenal is supplied by the right and left 
splanchnic, the left by the right splanchnic only. 
We will now consider the path that adrenalin takes in the body. The 
blood in the cava, containing the adrenalin, first reaches the right heart and 
then the lungs. The pulmonary vessels act refractory to it; hardly any 
adrenalin is consumed here {Brodie and Dixon). From the lungs it reaches 
the left heart and from this the greater circulation. The coronary vessels 
of both sides of the heart are dilated by it, hence the heart is better permeated 
with blood {Langendorf). That part of the adrenalin-containing blood which 
flows through the brain, also hardly loses in its adrenalin contents; the cere- 
bral vessels are dilated {Gerhardt). On the contrary there occurs a marked 
consumption of adrenalin in the other peripheral capillary territories of the 
body, especially the muscles and the intestines {Elliott, Carnot and Josserand, addison’s disease 
357 
Falta and Priestly). It therefore is to be assumed that the blood proceeding 
from these organs (veins of the extremities, portal veins) is adrenalin-free 
or at least poor in adrenalin. Therefore it is very striking that the test of the 
arterial and venous blood as to its adrenalin contents by means of the known 
biological methods (frog eyes, strips of vessel, uterus method) in the experi- 
ment of Falta and Fleming showed just as strong an action, if indeed not 
stronger, of the venous blood (extremity). On the contrary, after the subcut- 
aneous injection of adrenalin, the arterial blood showed stronger action. We 
must therefore be very cautious in the interpretation of the biological 
methods mentioned, as the pressor action of the blood serum must depend 
on other, as yet unknown, factors, a view that is also upheld by O’Connor. 
I shall have something to say later as to the value of the biological methods 
that we use for demonstrating adrenalin in the blood serum. However this 
may be, a stronger unloading of the chromaffin tissue must lead to a quite 
definite distribution of blood. We find slight hyperemia of the lungs, the 
heart, the brain, the kidneys, marked hyperemia of the peripheral venous 
system and above all that of the liver and the roots of the portal vein, while 
the other capillary systems are poor in blood. The purpose of this arrange- 
ment is evident. It means the forcing of a greater amount of blood into 
those organs which are the seat of life-maintaining centers and of the regula- 
tion of metabolism, thus heightening the activity of these organs. The liver 
occupies an especial position: It receives adrenalin-poor or adrenalin-free 
blood through the portal vein and thus becomes markedly hyperemic, and 
blood containing adrenalin through the hepatic arteries; by this means especially 
favorable conditions are, it seems, provided for the action of adrenalin on the 
metabolism {Falta and Priestley). Also E. Neubauer found by oncometric 
methods a hyperemia of the liver after the injection of adrenalin. 
The physiological significance of the chromaffin tissue may be adduced 
from what has just been said with regard to adrenalin’s intensive and mani- 
fold actions. We may assume that it maintains the normal excitability 
of the sympathetic nerves and that by means of graduation of the secretion 
it is concerned in the regulation of the blood-pressure, the distribution of 
blood, and the tonus of all other organs innervated by the sympathetic; fur- 
ther that it maintains constant the amount of sugar in the blood and enters in 
a regulatory manner into other factors of the metabolism; further that it 
influences muscular power (whether directly or through carbohydrate 
metabolism is questionable); and finally it exercises an influence on the pro- 
duction of neutrophilic leucocytes and on the plasma contents of the circulat- 
ing blood. 
As to the function of the cortical system, we as yet know very little. Ac- 
cording to Jacoby, it contains an oxydase. Lohmann obtained cholin from 
the cortex. Cholin acts as a toning agent on the autonomous nerves. It 
is also found, however, in many other organs, and we do not know whether 
it is given off from the cortical system into the blood paths. The assumption 
of a “systeme cholinogene” (Gautrelet) as an antagonistic regulator against 
the chromaffin system has not as yet received sufficient support. Also the 358 
THE DISEASES OF THE SUPRARENAL APPARATUS 
experiments of Goldzieher do not seem to me conclusive enough with respect 
to the significance of this question. 
It is assumed rather generally that the cortical system possesses a detoxi- 
cating function (Brown-Sequard). The blood of animals without their supra- 
renals seems to be poisonous. As has been mentioned previously these animals 
show a greater susceptibility for certain poisons; this does not, however, 
furnish absolute evidence for the detoxicating activity of the suprarenals, 
for we may assume with Theiroloix that the withdrawal of the regulatory 
function lessens the general resistance. It is supposed by many authors 
that the symptoms on the part of the intestinal tract and the central nervous 
system, which are severe and remind one of an acute poisoning, depend on the 
falling out of the function of the cortex. It should further be mentioned 
that in the growing organism enormous influences on the sexual glands and on 
the general hairiness proceed from the cortical system. I shall return to these 
in detail later. 
Pathogenesis of Addison’s Disease.—Also the results of the pathologico- 
physiological investigations just cited justify the dictum that Addison’s disease 
depends on an acute or chronic, more or less complete, loss of the function of the 
suprarenal apparatus. 
Probably from youth up there exists in individuals who acquire an Addi- 
son’s disease a certain weakness of the suprarenal function {Wiesel). Almost 
always we find pathological processes which have affected the suprarenal 
apparatus itself, but we cannot on this account rule out the assumption that 
an affection of the nervous apparatus which regulates the activity of the supra- 
renal apparatus cannot lead to a (after a fashion) purely functional Addison’s 
disease. 
Very difficult is the comprehension of the rare cases of Addison’s disease 
with unilateral affection of the suprarenal apparatus that become healed 
after extirpation of the affected suprarenal, v. Neusser has supposed a reflex 
influencing of the healthy suprarenal after the manner of reflex anuria, and 
Bittorf a damaging of the same through abnormal metabolic products of 
the diseased gland. 
Among the symptoms of Addison’s disease depending on the lessening 
of function of the chromaffin tissue probably are the low blood-pressure, the 
low sugar contents of the blood, the abnormally high tolerance for grape- 
sugar, the adynamia, and the mononucleosis or the status lymphaticus, although 
in the explanation of the alterations in the hematopoietic apparatus we must 
not forget what is frequently present—tuberculosis. To the deficiency of 
the cortical system are referred by most authors the manifestations on the 
part of the gastrointestinal tract, vomiting, diarrheas, etc., and the psychical 
alterations, the convulsions, delirium, coma, etc. No certain justification 
for these views have as yet been adduced (see later). 
Very difficult is the interpretation of the coming into existence of the 
pigmentations in Addison’s disease. The pigment is always iron-free. On 
reduction with hydriodic acid it yields no hemopyrrol and on oxidation no 
hematinic acid. We have, therefore, discarded any relationship with blood addison’s disease 
359 
pigment, and have found the mother substances in the aromatic split prod- 
ucts of proteids (tryptophan, tyrosin, and also adrenalin) (5. Frdnkel). 
Further, Zuzer and Lichtwitz saw the occurrence of pigmentation of the skin 
and mucous membranes after the injection of adrenalin in rabbits. As accord- 
ing to Eppinger the melanogen in melanocarcinoma is an N-methypyrrolid- 
inoxycarbonic acid and its elimination is increased through the administration 
of tryptophan, so it would not be unlikely that an increased production of 
tryptophan has been brought about in the body by the administration of 
adrenalin. Further it should be mentioned that Neuberg demonstrated in 
the tumors of the cases of melanoma of the suprarenal cortex a ferment which 
let a pigment formation be recognized after the addition of adrenalin or oxy- 
phenylethylamin. Further Jaeger has obtained from a melanoma an enzyme 
that decomposes adrenalin with pigment formation. Jaeger supposes that 
adrenalin is the mother substance of the iron-free pigment of the organism. 
Finally, according to Meirowsky, freshly excised pieces of skin show in the 
incubator an increase of pigmentation, and according to Konigstein this increase 
of pigment is greater in the skin of dogs without their suprarenals. Therefore 
it would not be unlikely that the cortex as well as the chromaffin takes part 
in the pigment formation, the first furnishing the mother substance of the 
melanogen (tryptophan), the latter the further decomposition. Increased 
formation of pigment may occur under the most diverse circumstances, as 
in Basedow’s disease, when the production of adrenalin is increased, or in 
Addison’s disease when the production of adrenalin is absolutely lessened, 
or perhaps less disturbed than the function of the cortical system. Thus 
may also be seen why pigment formation often remains away entirely 
in' acute destruction of the entire suprarenal apparatus. This should, 
however, be regarded merely as a hypothesis that still requires experimental 
support. 
Differential Diagnosis.—For differential diagnosis, of great importance 
are the pigmentations. The number of cases of Addison’s disease without 
melanoderma is, as Bittorf has emphasized, less than the older statistics would 
lead one to expect. Similar pigmentations are found, however, in normal 
individuals. Also they are found in itching skin affections and [those due] to 
vermin, during the use of arsenic, in pregnancy, in chronic heart affections and 
in phthisis pulmonalis; in slight grades of the latter the thought of Addison’s 
disease may be erroneously awakened on account of the emaciation and the 
slighter hypotonia; it is hence important to remember that in all conditions 
enumerated the mucous membranes remain free. In persons cachectically 
tuberculous the pigmentations may become quite similar to those of Addison’s 
disease. Here indeed it is questionable whether the pigmentations might 
not be referred directly to a damaging of the suprarenal function, an opinion 
that is upheld by Lavignel-Lavastine. 
In cirrhose bronzee the coloration of the skin is more blue-gray; here also, 
the mucous membranes are affected only rarely and more in a diffuse form 
{Heller). Here we should consider the liver lesion and the eventual compli- 
cation with pancreatic disease (diabetes). Naturally it should be taken into 360 
THE DISEASES OF THE SUPRARENAL APPARATUS 
consideration that combinations of cirrhose bronzee and Addison’s disease 
may occur, if the sclerosing process in cirrhose bronzee also involves in strong 
degree the suprarenal apparatus (Fod, Bittorf). As is known, pigmentations 
are also frequent in scleroderma. From this we must not conclude that a 
complication of scleroderma with Addison’s disease is present in the individual 
cases as pigmentations belong to scleroderma as such. Also similar pigmenta- 
tions are observed in pellagra (v. Neusser). Statements as to the characteristic 
erythema in the warm seasons of the year clinch the diagnosis in this case. 
Arsenic melanosis and argyrosis show another tint. Pigmentations are also 
observed in leucemia. V. Neusser thought that there were leucemic infiltrations 
of the suprarenals, which opinion a case of Zeigler’s later corroborated. Pig- 
mentations in Basedow’s disease are very common. The complication with 
Addison’s disease is very rare. However, such cases in which the diagnosis 
was confirmed by autopsy have been reported by Fletcher, and by 
Greenhow. Such a diagnosis should be made in vivo with great caution, as 
markedly pigmented cases of Basedow’s disease with cachectic symptoms— 
such as occur in the latter stages—nan easily give rise to the impression of a 
concomitant Addison’s disease. 
Very difficult is the delimitation from cachectic conditions associated 
with occult carcinomas and diseases of the liver, in which diseases melano- 
plakia of the oral mucous membrane may occur also (Schultze). In these cases 
and in the case of Addisonoid anemias described by Grawitz, the demonstration 
of a hypoglycemia and of a mononucleosis with hypereosinophilia is very 
important. 
The diagnosis of acute Addison’s disease may be very difficult. Brodnitz 
points out the importance of the following syndrome: Extraordinary slowing 
of the fully tense pulse, together with normal temperature; violent intestinal 
colics occurring in attacks; failure of the peristalsis and isolated intestinal disten- 
tion. Brodnitz believes that thrombosis of the suprarenal vein occurs in many 
cases of postoperative spastic occlusion of the intestine. 
The prognosis of Addison’s disease is always very dubious. The few 
certain cases of cure concern mostly luetic disease of the suprarenal, some with 
and some without specific treatment (Merckel and Birch-Hirschfeld)', in a case 
of Oesterreich’s the extirpation of the one tuberculous suprarenal led to cure. 
Cure has also been observed in cases of hypernephroma with Addisonian 
manifestations {Bittorf). 
Treatment.—It remains to be said that treatment is very ineffective. 
The statements as to improvement after subcutaneous or peroral administration 
of suprarenal substance are more sparse than those concerning results that are 
negative. The administration of small doses of adrenalin per os is ineffective, 
as might be gathered from our researches, which show that even more than 20 
mg. per day do not call forth any especial manifestations. Only when the 
doses are very much larger did we see in animals after administration for days 
the occurrence of hyperglycemia (Falta and Turin). I quote one of our 
experiments: addison’s disease 
361 
8.3 kg. dog, Mar. 5, sugar in blood 0.1008 per cent. 
On March 8, the dog received daily 25 cc. of a 1 per cent, solution of adrenalin through 
the stomach tube. 
From March 9 to 16, inclusive, 25 c.c adrenalin twice. 
Mar. 16, sugar in blood, 0.1552 per cent. 
From Mar. 19 to 30, inclusive, 25 cc. adrenalin twice. 
From Mar. 13 to 17, a trace of sugar was demonstrable in urine, later the urine was 
always sugar-free, but contained traces of protein. 
Subcutaneous injection of adrenalin is not advisable for any length of 
time. Boinet saw manifestations of collapse. Also after the injection of the 
glycerine extract of the whole suprarenal there occurred in Boinet’s case, after 
a time, conditions of excitement, tremor, and insomnia. Perhaps, however, a 
slight result is to be obtained by the peroral administration of tablets made 
from the whole gland. According to Magnus-Levy, the pigmentations have 
become lighter in color after the administration of these tablets, under certain 
circumstances. 
The beautiful investigations of v. Haberer and Stoerck as to the healing-in 
of pedunculated suprarenal glands [transplanted] into the kidney scarcely give 
hopes for a practical application, as apart from the necessary pedunculation, 
probably only autotransplantations of the suprarenals are possible.1 
Only the symptomatological treatment remains. Grawitz recommends 
washing out the stomach with sodium chloride solution, predominance 
of vegetable diet, avoidance of alcohol, and hydrochloric acid medication. 
Grawitz saw a case that presented all the symptoms of Addison’s disease which 
benefited under this treatment. Also the pigmentations of the skin 
disappeared. The case was observed for a period of three years after this 
successful result. Very important in Addison’s disease is the avoidance of 
every severe exertion. Boinet reports seven cases of sudden death in Addison’s 
disease, immediately after a marked fatigue. 
Proceeding from the observation that dogs after the extirpation of their 
suprarenals, lose all their glycogen except traces, O. Borges combated the 
adynamia in several cases of Addison’s disease by the administration of large 
amounts of carbohydrates (especially of levulose) with good results. Also 
Gautrelet reports favorable results. 
Here might also be mentioned the favorable results of adrenalin in other 
diseases. Very widespread is the employment of adrenalin in the stilling of 
hemorrhage. Proceeding from the observation that animals bear enormous 
amounts of adrenalin, Turin and I in ulcus ventriculi increased administration 
of adrenalin per os up to 7 mg., thrice daily, and up to the present have seen 
good results. Many authors report the excellent action of adrenalin in condi- 
tion of collapse {John and others), especially in the infectious diseases (for 
example, Heubner, in diphtheria). According to our observations adrenalin 
given subcutaneously in man increases the blood-pressure, often for a long 
time. According to our experiment the subcutaneous injection is to be pre- 
ferred in not too urgent cases. 
1 Tanner has recently transplanted, under the direction of Hurst, the suprarsenal of a foetus 
into the testicle of a patient with Addison’s disease with some degree of success. Hurst (A. F.). 
Addison’s disease treated by suprarsenal grafting. Brit. M. J., Feb. 18, 1922, pp.268-269.— 
Editor. 362 
THE DISEASES OF THE SUPRARENAL APPARATUS 
Several times we saw, too, an astonishing result from subcutaneous admin- 
istration (thrice 5 mg., each in one-fourth glass of water) in obstructing car- 
cinoma of the esophagus, in which the passage was reestablished probably by 
subsidence of the tumefaction of the inflamed mucous membrane, but such 
results only last for a few days. Further, adrenalin was introduced by Neu 
into obstetrical practice. After the injection of adrenalin the uterus was 
brought to a condition of tetanoid contraction. The drug has been especially 
serviceable in Cesarean section. It may be injected either subcutaneously or 
directly into the uterus. Probably pituitrin will supplant adrenalin in this 
respect, as it has the same action and is less deleterious. [As a stimulant to the 
uterus during delivery pituitrin has found a well-recognized place in practice. 
It is especially useful in inertia uteri and in premature separation of the placenta 
after the delivery of the child. See Hirst's1 Manual or other recent books on 
obstetrics.—Editor.] 
The employment of adrenalin is also useful in phosphorus poisoning. E. 
Neubauer and Porges observed that in animals poisoned with phosphorus, the 
ability of chromic acid to stain the chromaffin tissue disappeared; both these 
authors attribute the vanishing of carbohydrates from the liver, the subsequent 
fattening of the liver and the hypoglycemia (E. Neubauer, and Frank and Isaac) 
to the falling out of the chromaffin tissue and in most cases could actually 
prevent these symptoms by the administration of adrenalin. 
As to the treatment of osteomalacia with adrenalin, see chapter on sexual 
glands (appendix). 
2. Isolated Symptoms Due to Failure of Function of the Suprarenal Cortex 
In the consideration of the pathogenesis of Addison’s disease, it has been 
pointed out that we as yet know nothing certain concerning that group of cases 
which has as the basis of the symptom-complex the destruction of the suprarenal 
cortex. It is true that many authors regard the manifestations of intoxication 
that tend to enter into acute cases and in the terminal stages of Addison’s 
disease as due to deficiency or absence of the suprarenal cortex. But as yet 
experimental pathology has furnished no certain foundation for this assump- 
tion. Nor does clinical observation, as will be seen from the following, seem to 
me to substantiate this assumption. 
First let us consider the malformations. In anencephalus is found, as 
has already been mentioned, in addition to anomalies in the genital organs, also 
aplasia of the suprarenals. Apert points out that in aplasia of the suprarenals 
the cortical defect seems to play the most important role. I mention again 
the case of anencephalus reported by Elliott and Armour, in which the suprarenal 
medulla and the paraganglia were intact. Again, in cases in which the 
suprarenals are entirely absent the paraganglia may be normal, as in the case 
of Apert. The aplasia of the cortex in the new-born is the more remarkable 
because here the suprarenals, as is known, are especially well developed. 
An indication as to the direction in which are to be found manifestations 
of deficiency of the suprarenal cortex is found, under certain circumstances, 
in adenomata of the suprarenal cortex. We shall see later that in such hyper- 
1 Hirst (J. C.). A Manual of Obstetrics, Philadelphia, Saunders, 1919. ISOLATED SYMPTOMS DUE TO SUPRARENAL CORTICAL FAILURE 
363 
plasia of the cortex there occurs in youth abnormally rapid growth of the 
organism and premature development of the secondary sexual characters and 
the genitalia, and in adults a tendency to abnormal hairiness. Hence arises 
the thought that when manifestations of the opposite kind are present there 
may exist a cortical insufficiency. 
Moreover, in the chapter on the hypophysis I have reported a case of 
hypophysial dystrophy in which the disease first developed in later life and led 
to a marked retrogression of the hairiness on the trunk and on the face. In 
this case both suprarenals were found to be highly sclerosed and we shall see 
later in the consideration of the multiple ductless glandular sclerosis that in 
man a retrogression of the secondary sexual characters may indeed set in as the 
result of the failure of the function of the sexual glands, but that in woman 
the mere loss of the function of the sexual glands is not usually followed by 
distinct retrogression. First in cases in which the sclerosing process involves 
numerous ductless glands does there seem to be in women a distinct, and in 
men a marked retrogression of the hairiness and the genital organs. 
In the cases of multiple ductless glandular sclerosis in which there have 
been autopsies there is always to be found a marked sclerosis of the suprarenal 
cortex. Further there should be observed in eunuchoidism whether in rare 
cases there does not exist, in addition to the hypoplasia of the sexual glands, 
a hypoplasia of the suprarenal cortex. 
Finally Variot and Pironneau have described a case which was character- 
ized by marked disturbance in growth, absence of any hairiness at all (eye- 
brows, lashes, and almost complete baldness of the head). They have desig- 
nated this case “nanisme type senile” and refer to two entirely analogous 
observations by Gilford Hastings and Sir [Jonathan] Hutchinson. In the 
last case the suprarenals were found to be sclerosed. Variot therefore con- 
cludes that these vegetative disturbances depend on a loss of the function 
of the suprarenal cortex. It seems to me, however, that in the case of Hutch- 
inson there was an insufficient examination of the other ductless glands. Also 
Gilford Hastings points this out, and I hold that it is not impossible that this 
case constitutes multiple ductless glandular sclerosis in childhood, although 
I am not in a position to prove this. Perhaps some objections may be made 
against this view. At least I shall speak again of these cases under the consid- 
eration of multiple ductless glandular sclerosis. 
It is also doubtful whether the dwarf described by v. Recklinghausen 
should be grouped under cortical insufficiency. In a dwarf eighteen years 
old who had died in convulsions, v. Recklinghausen found an apparently chronic 
tuberculous caseation of both suprarenals. The individual was 95 cm. tall 
and weighed kilograms. The measurements correspond to about those 
of a three- or four-year-old child. The body dimensions were well proportioned. 
The epiphysial junctures were retained, the penis and the testicles were rather 
small. If we were already disposed to regard a loss of the suprarenal function 
as the cause of the disturbance in growth, we would have to hold responsible 
the suprarenal cortex, as hypoplasia of the chromaffin tissue rather produces 
a tall, weak, individual. I regard as more likely that here we are dealing with 
a true dwarfism and that the suprarenal caseation constitutes an accidental 
complication. 364 
THE DISEASES OF THE SUPRARENAL APPARATUS 
On reviewing the preceding material, we find that it is a question if the 
observations are to be referred to an isolated withdrawal of the cortical func- 
tion. The observations seem rather to suggest that from the cortex there 
proceeds a furthering influence on the genital sphere and especially on the hairi- 
ness, an assumption, as we shall see later receives essential support through 
corresponding manifestations in hyperplastic conditions of the cortex. These 
observations furnish no support for the assumption that loss of the function 
of the suprarenal cortex leads to manifestations of intoxication. 
b. Conditions of Hyperfunction of the Suprarenal Apparatus 
Here we are interested especially in tumors of the suprarenal apparatus, 
which usually, but not always, are associated with conditions of hyperfunction, 
I. Tumors That Proceed from the Chromaffin Tissue 
These seem to be very rare. Kuster describes two cases of glioma of the 
suprarenals, one affecting a fourteen-month child whose entire right suprarenal 
had been converted into a tumor, while in the left suprarenal was found a tumor 
occupying the site of the medulla. Numerous metastases were present. 
In the second case the findings were accidental. Kuster regarded these 
tumors as a glioma, Wiesel as a growth made up of formative cells of the sym- 
pathetic, although Schilder has lately described a certain glioma of the sym- 
pathetic and regards Kuster's case as glioma. More recently there have been 
described chromaffin tumors, in part proceeding from the paraganglia, by 
Weichselbaum, Manasse, Stangl, Monckeberg, and Kolisko. Kolisko’s case 
(reported by v. Neusser and Wiesel) was that of a vigorous, otherwise healthy, 
man who suddenly died during cocaine anesthetization on account of the extrac- 
tion of a tooth. Here was found a bilateral suprarenal tumor made up of 
chromaffin tissue, and very rich in adrenalin, v. Neusser and Wiesel regard this 
case as adrenalin intoxication. Very interesting is the case of Wiesel, a tumor 
of the sympathetic in a two-year-old child with arteriosclerosis which resembled 
histologically the sclerosis produced experimentally in animals by adrenalin. 
Hence it seems that these tumors can be associated with hyperfunction of the 
chromaffin tissue. For this also speaks the associated cardiac hypertrophy that 
is so frequently found. 
Moreover, there should be mentioned here the case of Kawashima. In 
this case were found multiple skin fibromata proceeding from the connective- 
tissue sheath of the nerves, and also tumors of the suprarenal medulla. 
Kawashima discusses the association of neurofibromata with diseases of the 
nervous system. He points out that neurofibromata are very frequently 
associated with general symptoms (disturbances of nutrition, intellectual dis- 
turbances, gastrointestinal affections, certain visual disturbances, headaches, 
spasms, depressed states, and alterations in the sexual sphere) and believes 
that these as well as the general symptoms are the expression of an affection of 
the nervous system. There should also be mentioned two cases of paragangli- 
oma reported by M. Herde. Both cases were those of chromaffin tumors. 
In one case there existed arteriosclerosis, in the other genuine “Schrumpfniere.” CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 
365 
Finally I mention a case of Sazuki’s (chromaffin tumor of the suprarenal 
medulla) and of E. Hedinger’s (struma medullaris cystica suprarenalis). 
The question as to whether there exist conditions of hyperfunction of the 
chromaffin otherwise than when due to tumor has been recently discussed. 
It is noteworthy that numerous authors take the negative attitude concerning 
this question, at least as far as chromaffin tissue is concerned. In tumors of 
the chromaffin tissue we have learned to recognize a group of clinical conditions, 
which we may regard as due, with great probability, to an increased function 
of the chromaffin tissue. 
Are we then justified in regarding similar clinical conditions as the expres- 
sion of a hyperfunction of the chromaffin tissue, even where a pathologico- 
anatomical substratum has not as yet been found for them? 
Originally French authors (Pilliet, Vagues, Aubertin and Ambard) en- 
deavored to explain the increase of blood-pressure in interstitial nephritis 
by an increase in the function of the suprarenal cortex, as they often met with 
strikingly large suprarenals in cases with hypertonia. Josue has assumed such 
in the atheromatosis associated with hypertonia. After, however, we had 
recognized the significance of the chromaffin tissue for the regulation of blood- 
pressure, Beaujard regarded it as regulative against increased circulation of 
toxic products in the organism, which would be conditioned on the lessened 
eliminatory capabilities of the kidney. Apparently the chromaffin tissue alone 
seems to be significant for the pathogenesis of this condition, in so far as we 
might wish to bring it into correlation with the suprarenal apparatus. The 
question should, however, be formulated as to whether secondary hyper- 
functional conditions of the chromaffin tissue occur as the reaction to other 
processes in the body, processes that are released eventually by a permanent 
reflex condition of over-excitement of the centers of this system lying in the 
medulla oblongata or in the brain stem; also we should consider the possibility 
as we have discussed in Basedow’s disease, that these centers are primarily 
in a state of hyperirritability on grounds that are not at all clear. If this were 
so, we could speak of a true neurosis. 
Wiesel was the first who referred the disease process associated with 
hypertonia to a condition of hyperfunction of the chromaffin system. He 
found hyperplasia of the chromaffin tissue in twenty-two chronic and some 
acute cases of nephritis, and in a case of aortic insufficiency—all cases showed 
cardiac hypertrophy—the hyperplasia affecting the suprarenal medulla as well 
as the paraganglia. Later Schur and Wiesel tried to demonstrate in such cases 
the increased amount of adrenalin in the blood, by means of the Ehrmann- 
Meltzer reaction. The hyperplasia of the chromaffin tissue was corroborated 
by numerous authors, of whom are named Schmorl, Goldzieher and Molnar, 
and Comisatti. Both Schmorl and Goldzieher also found an increase in the 
adrenalin content of the suprarenals. Other authors, as Bittorf, found no 
such hyperplasia. Certain negative cases do not seem to me to mean very 
much, as not every case of hyperplasia need be distinct. The statements as 
to the increased adrenalin content of the serum have met with more contradic- 
tion. It is certain—with the following my own experiences agree—that in 366 
THE DISEASES OF THE SUPRARENAL APPARATUS 
numerous cases with hypertonia the frog’s-eye method fails. But also other 
fine biological methods give negative results, for Schlayen, using Meiers 
vessel-strip method, and A. Frank el, using the myographic method, found the 
serum of nephritics even less active than normal serum. These behaviors 
were complicated by the foreign serum, as Schlayer ascertained, in a manner 
that could not be overlooked. The myographic method is, however, from its 
very nature hard to interpret, for Fleming and /, also on the use of an adrenalin 
Ringer-solution, saw inhibition of the movements and the tonus of a rabbit’s 
uterus. O’Connor, using the Laewin-Trendelenburg frog muscle method came 
to like results. He found that the activity of the serum was conditioned not 
only by its adrenalin content but also by other substances, that first get into 
the serum on coagulation. We therefore can say only that up to the present 
the biological methods do not furnish a certain evidence for the increased adre- 
nalin content of the serum. On the strength of this, however, I do not feel 
justified in denying the teaching of Schur and Wiesel. In favor of it speaks in 
addition to the hyperplasia of the chromaffin tissue the increased diuresis, 
which agrees with the increased amount of sugar in the blood as shown by 
E. Neubauer and also, as I believe, with alterations in the distribution of the 
blood as seen in experimental hyperadrenalinemia. Very frequently we see 
congestive conditions in the lungs, in the brain (retinal hemorrhages, apoplexies), 
and in the liver. In beginning decompensation very often the swelling of the 
liver is the first to appear. Again, in such conditions, very often at the begin- 
ning, we see a slight grade of hyperglobulia; later the count of red blood cells is 
very often reduced (destructive effect of chronic adrenalinizing on the erythro- 
poiesis). Finally we find the count of neutrophilic cells mostly at the upper 
limits of the normal or even slightly exceeding these. 
As to the question why interstitial nephritis is associated with an increase 
of function of the chromaffin tissue I shall not enter into here more intimately. 
In many cases, for instance in the nephritis of scarlet fever, the disease of the 
kidney is primary, in other cases the contracted kidney can only be a partial 
manifestation of the general arteriosclerosis of the small blood-vessels. Such a 
general arteriosclerosis must lead reflexly to a hypertonia through lowering of 
the resistance, if the accessory amount of blood should be driven through the 
capillary system of the muscles, etc. Finally it is conceivable that the increase 
of function of chromaffin tissue (as for instance in tumors of the sympathetic, 
perhaps also in premature arteriosclerosis of diabetics, or in transition of diabetes 
into contracted kidney) is the primary factor {Frank’s hypertonic diathesis). 
Still less clear is the significance of the chromaffin tissue for the coming 
into existence of the atheromatosis. As is known, chronic adrenalizing of 
rabbits can produce sclerosis of the great vessels (Josue, Erb, and others). 
This is an affection of the media. The vascular lesions in tumors of the 
sympathetic are also affections of the media. Braun, however, by the intravenous 
injection of minimal doses of adrenalin could produce atheromatosis of the 
small vessels. The ordinary arteriosclerosis of the large vessels, that occurs 
without increase of blood-pressure, has nothing at all to do with the chromaffin 
tissue; it depends on a primary degeneration of the elastic elements. CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 
367 
Finally, some observations as to the influence of hyperfunction of the chrom- 
affin tissue on the carbohydrate metabolism. In hypertonics we find, as already 
mentioned, hyperglycemia. The kidneys adapt themselves to a very gradual 
increasing amount of sugar in the blood, without glycosuria (v. Noorden). 
In many cases of diabetes mellitus, and especially in advanced cases, much 
speaks for the view that here also there is a slight overproduction of adrenalin 
(Falta, Newburgh, and Nobel). That the administration of this escapes detec- 
tion by the known biological methods is not to be wondered at, when on the 
one hand we take into consideration the unreliability of the biological methods 
(see above) and on the other, when we consider what monstrous dilution i gm. of 
adrenalin, which under circumstances may produce much sugar in the urine, 
must experience when injected subcutaneously in man. Such a slight increase 
in adrenalin production may very well be overshadowed by the counter-regula- 
tions without leading to increase in blood-pressure. On the contrary the toxic 
components seem to dissociate, as is shown by the premature arteriosclerosis 
so frequently observed in diabetes. An exact histological study of the same 
has not as yet been made. Finally we should point out the frequent transition 
of diabetes into contracted kidney. On the grounds detailed the negative 
standpoint that G. Bayer, and Broking and Trendelenburg have taken against 
the assumption of a functional increase of the chromaffin tissue in certain forms 
of diabetes mellitus, does not seem to me to be justified a priori. 
2. Tumors That Proceed from the Cortex 
These appear to possess greater clinical interest than the tumors of the 
chromaffin tissue. The knowledge that they may be associated with hyper- 
function of the cortical system is one of the achievements of recent years. In 
a clinical respect we can distinguish two groups of cortical tumors. In one of the 
groups chiefly the sarcomata, lymphosarcomata, carcinomata, alveolar 
sarcomata, endotheliomata, the melanotic carcinomata, and the cysts (litera- 
ture in Bullock and Sequeira, Frew, Glynn, Tilestone, Winkler, Hanschen, and 
Arnaud). These seem to bring forth only the usual symptoms of a benign or 
malignant tumor. We shall not discuss this group any further. The other 
group embraces the numerous cases of adenomata of the cortical substance. 
These show great diversity in their point of departure. They may pro- 
ceed from the cortex itself, or may originate in the separated germs of the 
cortical system in the kidney, or in the genitalia, etc. The process concerned 
in such adenomata may be that of a simple hyperplasia, that may either run 
its course without symptoms or give rise simply to the local manifestations of 
tumor, or may assume malignant character, and then show great inclination 
for the formation of metastases. Finally these tumors may, without the men- 
tioned tumor symptoms, lead to profound alterations of the organism, that 
with a certain probability may be regarded as the expression of a hyperfunc- 
tion of the cortex. Before I enter into the consideration of the clinical mani- 
festations, I should like to refer to the demonstration of Bourneville that in 
idiots with “sclerose tubereause du cerveau” there are regularly found in the 368 
THE DISEASES OF THE SUPRARENAL APPARATUS 
cortex of the suprarenals lumps that Pellizzi regards as adenomata of the 
suprarenals. 
The hypernephromata consist in round, oval, or polygonal cells, of an 
epithelial character. The cells are often of many shapes. As the suprarenals 
are of mesodermal origin, it is readily intelligible that the cells often assume a 
mesodermal character, and in their histological structure approach primitive 
sarcomata {Glynn). They are different, however, from the suprarenal sar- 
comata proper; true lumina are never observed in them {Woolley). 
The simplest form clinically is represented by so-called Grawitz tumors. 
These may originate in the kidneys {Grawitz) or the ovaries {Vonwiller) or in 
the tail of the pancreas {R. Mohr). Lately their origin from separated germs 
of the suprarenals has been combated by Stoerck and Zehbe, while R. Mohr 
has again arrayed himself for this genesis. In the clinical respect it is signifi- 
cant that they are never associated with alterations in the genital sphere. 
This without doubt speaks for the view of Stoerck and Zehbe. At most we 
must assume that the Grawitz’s tumors are strumas of the suprarenals that 
analogously to strumas of the thyroid do not tend to be associated with 
manifestations of hyperfunction. 
When the Grawitz’s tumors are of large growth they may lead to local 
oppressions (pains in the lumbar region, intercostal or femoral neuralgias, 
and when there is pressure on the kidneys to hematuria, albuminuria, cysturia, 
etc.), or they may degenerate malignantly and lead to metastases and cachexia. 
Westphal has gathered twenty-four cases from the literature, and has added 
seven cases from his own statistics. 
In Grawitz’s tumor there is frequently a tendency to formation of cysts 
due to softening, with characteristic chocolate-colored content, which is 
eventually demonstrable on puncture. 
It is true that Westphal adduces symptoms that indicate a hyperfunction 
of the chromaffin tissue. In two of seven cases he found temporary, glyco- 
suria, in three cases a relative increase in the neutrophilic cells and4 a distinct 
increase in blood-pressure in the early stages. I believe that these symptoms 
are only of a secondary nature, called forth by an initial irritation of the medul- 
lary substances by the growing tumor. It is worth mentioning that Bittorf 
in two cases of unilateral hypernephroma also found symptoms of an Addison’s 
disease, emaciation, lassitude, pigmentations, and low blood-pressure. These 
cases also showed a lymphocytosis. It seems to me that this furnishes a cor- 
roboration of my view that the manifestations on the part of the chromaffin 
tissue (irritation or deficiency) are only of a secondary nature. Bittorf also 
observed slight psychical symptoms in his case and believes that they are of 
diagnostic importance and they do not occur in tumors of the kidneys {v. 
Strumpell). Both Bittorf s cases were cured on operation, only the pigmenta- 
tions remaining unaltered. 
Perhaps the following two cases also belong to this group, v. Neusser 
mentioned a twenty-five-year-old man with very tense pulse, multiple hemor- 
rhages in the brain. The section showed a carcinoma of one suprarenal. 
Vascular system and kidneys were normal. CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 
369 
In addition v. Neusser cites a case of FrdnkeVs, an eighteen-year-old girl 
with headaches, vomiting, and high pulse tension. Section showed a vascular 
neoplasm of the left suprarenal; the kidneys were normal. Here, too, can the 
hyperfunction of the chromaffin tissue be regarded as an irritative symptom. 
Conversely in rapidly growing cortical tumors symptoms of deficiency of the 
chromaffin tissue may occur. 
Of very great interest for the knowledge of the internal secretions are 
those adenomata of the 'suprarenal cortex that are associated with hyper- 
function of the cortex. In the clinical picture of these cases there seems to be 
an appreciable difference according to whether they develop in the entirely 
childish, or in the juvenile, or in the adult organism. 
I. With the development of such hyperfunctionating cortical tumors in 
the childish organism there occurs an enormously accelerated development of 
the body, a premature development of the genitalia. Such cases are described 
by Cooke, a seven-year-old female; Tilesius, a four-year-old female; Ogle, a 
three-year-old female; Calcott-Fox, a five-year-old female; Orth, two and one- 
half-year-old female; Dobbertin, four-month-old female; Ritsche, four-year-old 
female; Bullock and Sequeira, eleven-year-old female; Linser, five-and-one- 
half-year-old male; Adams, fourteen-and-three-fourth-year-old male. In the 
case of Adams, puberty set in at the age of ten years. The boy was large and 
strong muscularly. Autopsy showed tumor of the left suprarenal proceeding 
from the cortex. A careful compilation of the literature has been made by Neur- 
ath, and more recently by Glynn. Further caes are reported by Guthrie and W. 
d'Este Emery (four-and-one-half-year-old boy, fat, large tumor of the suprarenal 
cortex), by Richards (seven-year-old girl), by Glynn and by French (reported by 
Glynn); and perhaps also the case of Guinon Bijou belongs here (no autopsy). 
Some cases I shall quote more exactly. The case of Linser was that of a 
five-and-one-half-year-old boy, who looked like a youth and therefore was 
admitted into the men’s department of the hospital. He was 138 cm. tall, 
the penis was 8-9 cm. long, the testicles as large as pigeon’s eggs, the prostate 
like that of a fifteen-year-old boy, the musculature was well-developed. The 
size of the body, the ossification, the almost complete set of permanent teeth, 
corresponded fully to those of a fifteen-year-old boy. The upper length was 
larger than lower length, hence childish dimensions were present in a potentized 
form. The hypophysis was normal and there was adiposity. 
The case of Bullock and Sequeira was of an eleven-year-old female who 
looked like a forty-year-old woman. Menstruation had set in at the age of 
nine and three-fourth years and from this time on there developed an in- 
creasing adiposity. The girl was 4 ft. 6 in. high and weighed 6 stones, 3 lb. 
[87 lb.]. The breasts were fully developed. Long hairs were present on the 
genitalia. Autopsy showed a large tumor of the left suprarenal consisting in 
cells of zona fasciculata, with numerous metastases, hyperplasia of the thyroid 
and the parathyroids, fully developed uterus and large ovaries with corpora 
lutea of recent date. 
The case of Richards was that of a seven-year-old girl. At the age of five 
she developed pubic hair and hair on the face. At seven years old she looked 370 
THE DISEASES OF THE SUPRARENAL APPARATUS 
like a woman twenty years old, the hairs on the genitalia were fully developed, 
and hairs were present on the side of the face and on the site of the mustache. 
The case of Glynn was that of a girl five years old. In the third year of 
life she began with pains in the abdomen and the head, later apathy. She 
was as large as a girl fourteen years old, and fat. Hairs were present on the 
upper lip, on the pubis, and on the back. The sexual organs were especially 
well developed. There was found a large tumor of the suprarenal cortex, 
ovaries and hypophysis were normal. In the case of French (seven-year-old 
girl) the abnormal hairiness began to develop as early as the eighteenth month; 
the genital organs were very large; here also was found a suprarenal tumor. 
[The case of Jump, Beales, and Babcock,1 was that of a seven-year-old girl in 
whom there was precocious development of the external genitalia (precocious 
growth of pubic hair, enlarged clitoris), but no true sexual maturity. She 
died during the operation for the removal of the hypernephroma.—-Editor] 
It will be seen that the condition nearly always affects girls. Of seventeen 
cases offered by Glynn, fourteen were of the female sex. What is common to 
all in the clinical picture of these cases is, as Neurath emphasizes, the premature 
excessive development of the secondary sexual characters and of the external 
genitalia. Neurath mentions that in this category of premature sexual develop- 
ment, the function of the generative portion is, on the contrary, not prematurely 
developed. This does not always point to an especially intimate relation 
between the suprarenal cortex and the interstitial glands. Moreover, common 
to almost all cases adiposity, the accelerated growth, probably with retention 
of the infantile dimensions, and the accelerated ossification and dentition. 
The development of the psyche in such children as a rule does not keep pace 
with the bodily development. Also the development of the sexual instinct is 
usually retarded. 
II. The manifestations that occur on the development of hypernephro- 
mata in the juvenile or mature organism are likewise characterized by an enor- 
mous influencing of the sexual sphere. Here also I would enter more fully in the 
case reports. The case of Bortz and Thumim was that of a sixteen-and-three- 
fourth-year-old girl. At first she had developed quite normally, then the 
menses ceased, and there developed a luxuriant deep black beard and a sparse 
mustache. Hairs developed on the chest and on the linea alba, the voice be- 
came deeper and universal obesity developed. Death occurred as the result of 
an intercurrent illness. Section revealed atrophy of the ovaries, enormous 
enlargement of the thyroid gland, normal hypophysis; on both sides there 
existed a suprarenal tumor rich in blood-vessels that had apparently developed 
only from the cortex. 
Case of Winkler.—Sixteen-year-old girl. Abundant black hair on the 
upper lip. Uterus small. Tumor of the right suprarenal with metastases. 
Case of Bovin.—Twenty-eight-year-old woman. Two labors, then cessa- 
tion of menses at the age of twenty-one. Development of the beard. There 
1 Jump (H. Z>.). Beates, Jr. (//.), and Babcock (W. W.). Precocious development of the external 
genitals due to hypernephroma of the adrenal cortex. Am. J. Med. Science, Vol. CXVII, 1914, pp. 
568-574. CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 
371 
is also an abundant growth of hair on the abdomen. Simultaneously, the 
development of an abdominal tumor. Operation showed a large ovarian tumor 
proceeding from separated suprarenal germs. The patient recovered from 
the operation, the uterus became larger again, menstruation reappeared, and 
the abnormal hairiness disappeared. However, the observation after operation 
was for a short period of time only. 
The case of Hegar perhaps belongs to this group (abnormal hairiness, 
uterus duplex, cystic tumor of the ovary). Moreover, perhaps also the case 
of Alberti. In this case menstruation was normal up to the nineteenth year. 
Development otherwise normal. Then set in hypertrichosis, development of 
a beard, mustache, and hair on the trunk. At the same time a tumor developed 
in the abdomen. Death occurred. Autopsy showed a cystoma pseudomu- 
cinosum proceeding from the right ovary. The clitoris was appreciably 
enlarged (autopsy only partial, no statement as to the suprarenals). 
Case of Goldschwend.—Thirty-nine-year-old woman, had five children. 
Cessation of menses three years ago. For four months pains in abdomen, 
development of an abdominal tumor, development of a mustache and beard, 
and hair on the abdomen, malignant adenoma of the left suprarenal, uterus 
and ovaries small, epiphysis and hypophysis normal. 
Case of Launois, Pinard, and Gallais.—Nineteen-year-old girl. Menstru- 
ated first at the age of thirteen years. At seventeen violent vomiting, gradu- 
ally colossal obesity, mental changes. Cessation of menstruation, emaciation, 
then diffuse depilation, and only then hypertrichosis and myasthenia. The girl 
appeared to be much older than she was, black beard and mustache. Tumor 
of the right suprarenal. 
Possibly also the following case of Dalche belongs here; twenty-eight-year- 
old woman, body quite feminine, for five years development of a mustache 
and beard and (after miscarriage) cessation of menstruation. Breasts well 
developed, voice feminine, uterus small, atrophy of the inner genitalia,- hyper- 
trichosis on abdomen, slight manifestations of hyperthyrosis, there were no 
other symptoms of a suprarenal tumor. 
Also a case has been reported that began at the menopause. 
Case of Santi.—Fifty-three-year-old woman, two normal pregnancies, 
menstruation always regular until six years ago. Then the periods became 
more frequent, until the woman lost blood almost constantly. Enlargement 
of the abdomen, enormous obesity. Autopsy showed a tumor of the kidney 
proceeding from separated suprarenal germs, and a similar tumor of the ovary. 
No statement as to hairiness. 
Under this category may well belong the case of Vollbracht, mentioned 
by v. Neusser and Wiesel. The case was designated by the last named authors 
as Addison’s disease with contrasexual sexual characters. 
Let us look over the cases I have mentioned. In women simultaneously 
with the development of a hypernephroma there occur cessation of the menses, 
hypertrichosis of a definite localization (linea alba, growth of bread) and 
obesity. The development of hypernephroma at the menopause apparently 
gives rise only to obesity. 372 
THE DISEASES OF THE SUPRARENAL APPARATUS 
III. Cases of Pseudohermaphroditism.—Marchand first reported the 
autopsy findings in a fifty-year-old individual who in life was always regarded 
as a man. 
The individual showed masculine body conformation and masculine hairi- 
ness of the face; autopsy showed a hermaphroditismus spurius femininus, a 
very large penis-like clitoris, a distinct scrotum, and a rather large prostate; 
there was also a vagina with the traces of a hymen, a uterus, and atrophic 
ovaries. Finally colossal hypertrophy of the suprarenal cortex and a large acces- 
sory suprarenal. A similar case had previously been reported by Crecchio. 
Three cases of pseudohermaphroditismus femininus by Fiebiger: Habitus 
and hairiness quite masculine, larynx masculine, penis and prostate present, 
no vasa deferentia, vagina, uterus, and ovaries. The last showed the follicle 
formation. No menstruation; capable of cohabitation. Masculine sexual 
sense. Very large suprarenals, apparently hyperplasia of the cortex. Fiebiger 
regards these cases as an especial teratological type. 
Case of Engelhardt.—Fifty-nine years. Married a woman at the age of 
twenty-seven years. Erections were present, but only weak and very rare. 
Questionable whether ejaculations were present. Beard and mustache. 
Facial features masculine. Breasts feminine, hands and feet slender. Penis 
embedded in a cushion of fat. Hypospadia, corpora cavernosa present. 
Scrotum only indicated by tissue rich in fat, testicles, buttocks, hips and 
thighs are feminine. Prostate feebly developed. Autopsy showed an aber- 
rant suprarenal struma at the lower pole of the right kidney. The ovaries were 
small and dense, with sparse, poorly developed, follicles. 
Here also belongs the case of Hepner and Ogston and furthermore the very 
interesting case of Meixner (case III). This was the case of a new-born child 
with pseudohermaphorditismus masculinus, bilateral cryptorchidism, with 
separated and enlarged suprarenal glandular tissue in the neighborhood of 
the testicles. 
v. Neugebauer mentions in his large work thirteen cases of pseudoher- 
maphroditism with suprarenal tumors. 
Summarizing the cases cited: Only one case was that of pseudohermaph- 
roditismus masculinus. The other cases were pseudohermaphroditismus 
femininus. All cases showed a bilateral swelling of the suprarenal cortex. 
IV. Finally it should be remembered that also in acromegaly there occur 
certain cases in which hyperplasia of the suprarenals is observed (Delille, 
Fischer, and Fischer and Schultze). Fischer and Schultze find the entire supra- 
renals, cortex as well as medulla, hyperplastic, while Delille observed only a 
hyperplasia of the cortex. It is very probable that in the future when we pay 
more exact attention to these relations we will find hyperplasia of the supra- 
renals, and especially of the cortex, in many cases of acromegaly. I would also 
call attention to the fact that in many cases of acromegaly, there occurs both 
in men and women abnormally abundant hairiness. In women the hairiness 
may assume quite the masculine type. 
Surveying the entire field of facts, one is surprised by the wealth of clinical 
observations that properly classified demonstrate that from the suprarenal CONDITIONS OF HYPERFUNCTION OF THE SUPRARENAL APPARATUS 
373 
cortex there proceeds an enormous influence on the growth of the body, and 
the genital sphere, and on the hairiness, therefore on an important secondary 
sexual character. Until a short time ago these connections were scarcely 
suspected. In the books of Neusser and Wiesel on the diseases of the suprarenal 
glands they are hardly taken up. As to what concerns the alterations in the 
organisms that occur in hyperplasia of the suprarenals, that is in conditions 
of hyperfunction, it is worthy of note that they are different according to the 
age at which such hyperplasia develops. Their action occurs earliest in pseudo- 
hermaphroditism. Here their development occurs in fetal life. That the 
development of such cortical hyperplasias stands in a causal relationship with 
the development of pseudohermaphroditism is hardly at all probable; when one 
considers that up to the present insufficient attention has been paid to such 
relationship, it would not do to assume that the hyperplasias occur constantly 
in pseudohermaphroditism. It is much more likely that they are only a partial 
manifestation of the malformation, which would lend to them at all events a 
definite expression. It has already been mentioned, they occur almost exclu- 
sively in pseudohermaphroditismus femininus. 
In the age of childhood we see with development of the tumors of the 
suprarenal cortex a premature development of the entire organism, a sort of 
transient gigantism associated with potentized childish dimensions and pre- 
mature development of the genital organs, a clinical picture that in almost 
all respects is similar to that observed in the development of tumors of the pineal 
gland in childhood. Whether hyperplasia of the suprarenal cortex is frequently 
present with tumors of the pineal in childhood is as yet not certain. Up to 
the present it has been observed in one case only. As we shall see later in the 
development of tumors of the sexual glands in childhood there occur the same 
clinical pictures, even, if possible, better pronounced. Here also future studies 
must decide as to the behavior of the suprarenal cortex. Apparently there 
exists an intimate connection between these three forms of premature develop- 
ment and it would not be unlikely that the bond of union is the suprarenal cortex. 
At any rate, a certain influence of the suprarenal cortex on the growth is evi- 
dent; with this agrees also the occurrence of cortical hyperplasia in acromegaly. 
Just as evident is a certain stimulating influence on the development of the 
sexual glands. Apparently there exists here a reciprocal correlation, as hyper- 
plastic changes in the suprarenal cortex occur during rut in animals and in 
pregnancy (Guiyesse, Stoerck, and v. Haberer). In this also can be seen a certain 
relation of the suprarenal cortex to growth. As is known, women who are 
pregnant and whose epiphysial junctures are still open often take on a renewed 
growth during the pregnancy. And finally there can be seen on it a relation to 
the growth of the fetus, if it be not forgotten that the hyperplastic alterations 
in the anterior lobe of the hypophysis may also produce and maintain the 
tendency to increased growth. 
When the cortical tumors develop in the fully developed organs the mani- 
festations are quite different. Thus far the cases have been favorable. Here 
there comes about a pronounced disturbance of the functions of the sexual 
glands with involution of the uterus and in addition a tendency to obesity and 374 
THE DISEASES OF THE SUPRARENAL APPARATUS 
to the development of hairiness, both of which with respect to abundance and 
localization are entirely masculine. The influence of the suprarenal cortex 
on the hairiness is especially unmistakable in all the conditions mentioned. 
We find abnormal hairiness in pseudohermaphroditismus femininus, in the 
premature development in childhood, in the cortical tumors that develop in 
the adult organism, perhaps just in the cases of acromegaly with hyperplasia 
of the cortex, and finally, as is known, in pregnancy, in which hair begins to grow 
in places that otherwise represent the virile type. Therefore it seems necessary 
that in future, when the question is asked as to which influences the secondary 
sexual characters have to thank for their origin, attention should also be paid 
to the suprarenal cortex. The near relationship that the suprarenal cortex 
and the substances of the sexual glands show embryologically and morpholog- 
ically seems also to exist in the function of these parts. 
Treatment.—Up to the present, only the operative treatment of hyper- 
nephromata has been tried. In every case an early diagnosis is important, as 
the tumors are often malignant. That result may be expected from operation 
is shown by the previously mentioned case of Bovin. Perhaps in certain cases 
a result may be expected from the use of the X-rays. 
3. Tumors of the Suprarenals That Apparently Consist in Cortex and Medulla 
Davidsohn has reported a case of melanoma of the suprarenals with numer- 
ous melanotic metastases. Histologically he found cells of the zona fasciculata 
and glomerulosa, and also cells of the medulla. The metastases, on chemical 
examination and on blood-pressure tests, were found to contain adrenalin. 
Moreover, perhaps here belongs the case of Neuberg, in which indeed no adre- 
nalin could be demonstrated, but in which an enzyme was found which could 
change adrenalin into a black pigment. Neuberg believed that the adrenalin 
further produced in the metastases was the mother substance of the melanin 
found there. These cases were not accompanied with disturbances of the sexual 
sphere. 
Addendum 
The principal exponent of so-called functional insufficiencies of the supra- 
renal gland is probably Sergent, who has described a white line on the skin of 
patients as the result of stroking when suprarenal secretion is insufficient. 
As Sergent has written extensively on this subject, a reference to his book is 
included below. Kay and Brock on the basis of clinical observations on 255 
cases doubt that the line is pathognomic of adrenal insufficiency. 
Glynn, from a review of the literature, arrives at about the same opinions 
as the author with reference to the relation of the suprarenal cortex to the other 
ductless glands and to sex. He adduces as a further argument for the view that 
renal hypernephromata arise from suprarenal rests the fact that such rests are 
rare in the kidney, while hypernephromata are common kidney tumors; and 
that suprarenal rests in other localities, though comparatively common, 
especially in early life, rarely produce tumors at all. ADDENDUM 
375 
We quote Krabbe to the following effect: ‘‘The development of pubic hair 
and beards in little girls with adrenal cortex tumors cannot be regarded as a 
special sign of precocious puberty but must be considered as a natural link in 
hypertrichosis. This hypertrichosis and the development of a large clitoris and 
transformation of the voice in little girls are only to be considered as a virilism, 
analogous to the virilism in adult women suffering from adrenal cortex tumors 
and to the so-called fetal virilism (female pseudohermaphroditism) in females 
with adrenal hyperplasia. Only in boys and in a single case of adrenal tumor 
in a girl aged ten years has there been found true pubertas precox. This 
theory has already been expressed partially by Glynn and Leiner.” 
Krabbe continues: “Many authors conclude from these facts, that a 
special connection exists between the normal function of the adrenal cortex 
and the sexual organs, that a hormone from the adrenal cortex has a special 
influence in producing secondary sexual characteristics. This theory does not 
seem to have sufficient basis; the presence of virilism in girls and women with 
adrenal cortex tumors, especially, cannot be explained by the suggestion that 
the adrenal cortex should have any influence on the normal sexual development 
in females.” 
Several investigators show that the ovary in the early stages is hermaphro- 
ditic, and that the adrenal gland includes in its substance some of the testicular 
cells which in embryonal life are in its immediate vicinity. 
Cannon, Shohl, and Wright subjected cats to fright, and uniformly obtained 
glycosuria. This glycosuria was not present after adrenalectomy. Their work 
is well known. As has been stated in the first chapter, Cannon and Rappert have 
recently located an adrenalin center in the medulla. 
Gley doubts the role of adrenalin in maintaining blood pressure, and 
presents evidence that it has not the role in emotional activity and in the regula- 
tion of the circulation of the blood that was formerly ascribed to it. Cannon 
also states that there is no good evidence that it has any tonic effect in main- 
taining blood pressure. 
The trend of recent opinion seems to be that the adrenal cortex is of at least 
as great importance to the maintenance of life as the adrenal medulla. 
Stewart may be quoted as stating that there is no foundation for the state- 
ment that emotional disturbances, as fright or anger, cause a depletion of 
the adrenalin store of the suprarenal bodies. 
Mauerhofer has found that fatigue is produced in adrenalectomized rats 
and guinea pigs much more readily than in normal rats and guinea pigs. He 
regards the suprarenals as glands that counteract the products of metabolism 
that are created by intensive muscular activity. 
Marine and Baumann have subjected the suprarenal glands of rabbits 
to freezing. They find that there is an increased heat production and C02 
output after this procedure. A picture develops which resembles exophthalmic 
goiter in man. They regard the cortex as the part of the suprarenal gland which 
is essential to life. 
This view is shared by Stewart who does not regard the medulla as a very 
important part of the gland, and who emphasizes the fact that the therapeutic 376 
THE DISEASES OF THE SUPRARENAL APPARATUS 
effects of adrenalin must not be regarded as a sign of diminished production 
of the substance. Even Sergent has recently published his views that the signs 
of diminished adrenal gland function are not due to disturbance of the supra- 
renal medulla alone. Stewart does not fail to criticise the Viennese school for 
their theories of sympatheticotonia and vagotonia. It should be mentioned, 
however, that in the sin of ascribing various clinical conditions to the hypo- 
function or hyperfunction of organs, Falta seems to be far behind the usual 
run of clinical endocrinologists. 
Rich has shown lately that shock exists in adrenalectomized animals 
precisely as it does in control animals. 
Squier and Grabfield fed rabbits capsules containing thyroid extract by a 
tube method and believe that they have shown an increase in the size of the 
adrenal glands in these rabbits (mainly the cortex), but as the supposed changes 
occurred just as well in rabbits who were fed empty capsules by the same method 
the work need corroboration. 
Glynn (E . E.). The adrenal cortex, its rests and tumors; its relation to other ductless glands and 
especially to sex. The Quarterly Journal of Medicine, Vol. V, 1911-1912, p. 157. 
Cannon (IE.), Shohl (A. T.), and Wright (W. S.). Emotional glycosuria. Am. J. Physiol., 
1911-1912, pp. 280-287. 
Sergenl (E.). Etudes cliniques sur 1’insuffisance surrenale, 1898-1920. Paris, A. Malone, 1920. 
Kay (W. E.) and Brock (S.). The white adrenal line {Sergenl)-, its clinical significance. Amer. 
J. Med. Sc., Vol. CLXI, No. 4, April, 1921, pp. 553-561. 
Krabbe (K. II.). The relation between the adrenal cortex and sexual development. N. Y. 
Med. Jr., Vol. CXTV, No. 1, July 6, 1921, pp. 4-8. 
Leiner {J. IE). Pubertas precox with especial attention to mentality. Endocrinology, Vol. 
IV, Aug. 7, 1920, pp. 369, et seq. 
Cannon [W. B.) and Rapport {D.). Studies on conditions of activity in endocrine glands; 
reflex center for adrenal secretion and its response to excitatory and inhibitory influences. Am. J. 
Physiol., LVIII, Dec., 1921, pp. 353 seq. 
Gley (E.). The problem of the adrenals. N. Y. Med. J., July 6, 1921, pp. 9-11. 
Cannon {W. B.). Some correlations controlling internal secretions. J. A. M. A., Vol. EXXIX, 
No. 2, July 8, 1922, pp. 92-95. 
Stewart (G. N.). Manual of Physiology. Eondon, 1918. 
Mauerhofer (E.). Untersuchungen fiber die Eunktion der Nebennieren mit Hilfe der funktion- 
ellen Ueberlastungsmethode, und fiber die Erzeugung eines Kardinalsymptoms des Morbus Addi- 
sionii. (Beitrage zur Physiologie der Driisen von Leon Asher. Zeitschrift f. Biol., Vol. EXXIV, 
No. 3 and 4, pp. 147-172. 
Marine (D.) and Baumann (E. J.). Influence of glands with internal secretion on the respiratory 
exchange. Ill effects of suprarenal insufficiency (by removal or by freezing) in rabbits. Am. J. 
Physiol., Vol. LVII, No. 1, Aug. 1, 1921, pp. 135-152. 
Stewart (G. N.). Adrenal insufficiency. Endocrinology, Vol. V, No. 3, May, 1921, pp. 283-306 
Sergent (£.). L’insuffisance surrenale devant les recentes critique des physiologistes. La 
Presse medicale No. 82, Oct. 12, 1921, pp. 813-816. 
Rich (A. R.). A study of relation of adrenal glands to eaperimentally produced hypotension 
(shock); with a note on the protective effect of preliminary anesthesia. Bull. Johns Hopkins Hosp., 
Vol. XXXIII, March, 1922, pp. 79-93. 
Squier and Grabfiela. Adrenal enlargement in rabbits. Endocrinology, Vol. VI, No. 1, Jan., 
1922, pp. 85-101. CHAPTER IX 
STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS 
A. Status Lymphaticus 
Here at the conclusion of the discussion of the suprarenal apparatus we 
might add some remarks on the so-called status lymphaticus, because recent 
investigations have shown that it possesses a close relation to conditions of 
hypofunction of the chromaffin tissue. As I already mentioned in the chap- 
ter on the thymus gland, the tendency among many authors is for the separa- 
tion of status thymicus from status lymphaticus. The frequent coincidence 
of a large thymus gland and status lymphaticus can perhaps be explained by 
the increase in the lymphoid elements in the thymus gland. The great interest 
that clinicians and pathological anatomists have turned on status lymphaticus 
depends on the fact that it is associated with cases of sudden, quite inexplicable, 
death. It is the great service of A. Paltauf to have recognized that here 
there is an underlying profound constitutional alteration, which is always 
associated with lymphatism. 
How, now, is status lymphaticus characterized? Here it seems that I 
must give vent to a conception that has forced itself upon me especially in the 
study of the diseases of the ductless glands. I am forced to distinguish a 
primary and a secondary lymphatism. The first develops in earliest youth, 
and has on this account a profound influence on the development of the whole 
organism. It is characterized by the following earmarks (in this I follow the 
description of A. Paltauf and especially the new excellent description by 
Kolisko). Under normal circumstances we find that in childhood the lym- 
phatic apparatus is essentially more strongly developed than in adults. Hence 
it comes about that the leucocytic formula of the child shows a greater content 
of lymphocytes. The years of childhood are those in which lymphatism 
is especially prone to develop. The involution of the lymphatic appara- 
tus follows, chiefly at puberty. In true status lymphaticus the involution of 
an already abnormally developed lymphatic apparatus remains absent. We 
find enlarged follicles at the base of the tongue, hyperplasia of the entire 
pharyngeal lymphatic ring, lymphoid growth in the nose, enlargement of the 
lymphatic glands in the neck, in the axillary and inguinal regions, hyperplasia 
of Peyer’s patches and red bone marrow , large spleen, and more or less large 
thymus gland. Very frequently we found hypoplasia and narrowness of the 
aorta and the whole arterial vascular tract. The heart likewise is often 
abnormally small, although it can also be hypertrophic. Commonly there is 
dilatation of the left ventricle with diffuse clouding of the endocardium, and 
not rarely remaining behind in the development of the genitals, slight develop- 
ment of the secondary sexual characters, retarded onset of menstruation, 
and retarded, lessened, sexual instinct. 
377 378 
STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS 
According to the new researches of Wiesel and Iledinger there is regularly 
associated with these characteristics an abnormally slight development of the 
chromaffin tissue. The medullary substance of the suprarenals is essentially 
lessened, and the paraganglia are illy developed. According to v. Sury this 
underdevelopment of the chromaffin tissue mostly sets in after birth. 
In status lymphaticus there occurs in the blood picture a relative or 
absolute reduction of the neutrophilic leucocytes and a corresponding increase 
in the mononuclear cells, eventually also a hypereosinophilia (v. Neusser). 
This fact is readily intelligible when the experiments of Bertelli, Schweeger, 
and myself are considered. On the one hand it is possible that the giving off 
of mononuclear cells of the blood is increased in hyperplasia of the lymphatic 
apparatus, and on the other hand we must assume that an enormous trophic 
influence is exerted on the production of the neutrophilic elements of the bone 
marrow, this influence proceeding from the chromaffin tissue by mediation of 
the sympathetic; here the production of neutrophilic elements by the bone 
marrow is probably diminished. 
It is very possible that this anomaly of constitution is the cause of the 
sudden death. If the chromaffin tissue is underdeveloped and not attained 
to a great functional breadth, it may, if especial demands are made on it 
especially by a cold bath or by the effects of narcosis of the sympathetic nerv- 
ous system, suddenly give out. This form of status lymphaticus may well 
be designated an “entite morbide.” The opinion has been expressed that 
substances are given off from the lymph-glandular system to the blood path, 
substances that in their action are in a certain way antagonists of adrenalin 
(v. Neusser). Also in this sense can we consider this form of status lymphati- 
cus under the diseases of internal secretion. Such individuals, as Eppinger and 
Hess point out, not rarely show symptoms of the relatively increased vagal 
tonus (inclination to sweats, certain anomalies of the pulse and respiration, 
etc.). The slight functional breadth of the chromaffin tissue is, however, 
especially important for the fate of such individuals. Often the blood-pres- 
sure lies near the lower limits of normal, as Miinzer emphasizes, the pulse 
shows a slight force [Wurfkraft]. According to Wiesel such individuals are 
especially predisposed to Addison’s disease, in that tuberculosis and other 
processes become established in the hypoplastic suprarenal medulla, and by 
spreading to the cortex call forth the typical picture of Addison’s disease. 
The secondary form of status lymphaticus is characterized by the fact 
that the signs of lymphatism predominate only later, the development origi- 
nally being normal. According to the age of the individual, according to 
whether the lymphatism is only transitory or remains permanent, does the 
development become more or less inhibited. In childhood, as already II. 
Kundrat mentioned, rachitis leads to lymphatism not infrequently, as do also 
tetany, the exudative diathesis, especially scrofulosis, and a series of other 
infectious processes. In adolescent and adult individuals occasion is given 
for a temporary or a permanent lymphatism by the vagal neurosis, bronchial 
asthma, chronic infectious diseases, especially lues and tuberculosis, osteo- 
malacia, and especially the affections of the ductless glands. In a great num- ADDENDUM 
379 
ber of cases perhaps there occurs at first, through chemotactic influences, only 
a slight mononucleosis of the blood, and only later a slight hyperplasia of the 
lymphatic apparatus, therefore a forme fruste; in other cases, especially in 
many formations of ductless glandular affections, the hyperplasia of the lym- 
phatic apparatus may be fully developed. Of the ductless glandular diseases 
should be mentioned especially Addison’s disease, myxedema, Basedow’s dis- 
ease, acromegaly, tetany, and dystrophia adiposo-genitalis. Also in some 
cases that we must regard as true eunuchoids we found appreciable mononu- 
cleosis of the blood. It is self-evident that mononucleosis is a symptom with 
many meanings, and in itself speaks nothing for the diagnosis of status lym- 
phaticus. Thus we found it strikingly present also in many severe forms of 
diabetes mellitus in which autopsy showed no status lymphaticus. It is very 
probable that under secondary lymphatism are concealed numerous and diverse 
conditions, in part chronic inflammatory in nature, the differentiation of 
which perhaps can first be made by a careful microscopical examination of 
the lymphatic apparatus. 
The great difficulty in the diagnosis of status lymphaticus in vivo is made 
prominent in the comprehensive exposition of this subject brought out a short 
time ago by v. Neusser. v. Neusser relates how important it is to have in mind, 
in consideration of the minute factors, the possibilities of an existing status 
lymphaticus, because the infectious diseases and especially the most diverse 
noxious agents frequently take on a characteristic expression on the ground 
of this constitutional anomaly and often pursue their course unfavorably. 
B. Status Hypoplasticus 
In several works, Bartel has indicated a form of developmental disturbances 
that he designates hypoplastic constitution. It is frequently, but not always, 
associated with status lymphaticus. The body size of such individuals is on 
the average normal. Often the fatty tissue is very well developed. There is 
found hypoplasia and narrowness of the vascular system and poverty of the 
smooth musculature of the aorta (Wiesner), and in addition faulty develop- 
ment of the sexual glands and secondary sexual characters. The sexual 
glands are indeed of normal size, the ovaries often even enlarged; microscop- 
ically there is found, however, proliferation of the connective tissue (.Herrmann 
and Kyrle). When status lymphaticus is present an atrophic stage can follow 
the stage of hyperplasia. Bartel assumes as the cause of this condition con- 
genital predisposition on the one hand, and on the other hand damaging of 
the sensitive childish organism, especially by infectious diseases. The length 
of life of such individuals is mostly shortened, and 56% of the cases 
investigated by Bartel died between the fourteenth and twenty-fifth years 
of life. The status hypoplasticus is thus not entirely identical with status 
lymphaticus, but also not with true infantilism, which will be described in 
another chapter. 
Addendum 
The subject of status lymphaticus and status hypoplasticus has become 
intimately associated with status thymicus. In addition infantilism sometimes 380 
STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS 
presents features that readily may associate it with a so-called status thymo- 
lymphaticus. Cases of variations in the size of the constituents of the supra- 
renal gland have been described both in status lymphaticus and in status 
thymicus. Also the lymphatic apparatus is supposed to be involved in certain 
pluriglandular syndromes. This subject is further dealt with in the addenda 
to the chapters on the thymus gland and on infantilism. As has been suggested 
under status thymicus Brugsch considers status lymphaticus, “true lympha- 
tism”—an expression of a narrow vascular system with respect to hemato- 
poiesis. Recent observation and research leads us to believe that lymphatism 
is much oftener a normal phenomenon than we were wont to believe. This is 
especially shown in the work of Heilman. He shows that the lymphoid tissue 
is better developed in cases who have died suddenly from accident than we 
were wont to think, and that one is not justified in making the diagnosis 
“status lymphaticus” when one finds vigorously developed lymphoid tissue 
in the intestinal canal. The diagnosis “status lymphaticus” he says, is made 
much too frequently. Some at least of the hyperplasias may be due to acci- 
dental non-constitutional factors. Perhaps too, he thinks, the lymphatic 
tissue is less well developed in many corpses because of the diseases that 
killed their living occupants. See addenda to chapters on the thymus gland 
and on vegetative disturbances. 
Brugsch (T.). Allgemeine Prognostik oder die Lehre von der artzlichen Beurteilung des 
gesunden und kranken Menschen. Berlin, Urban, 1918. 
Heilman (T. J: son). Studien liber das lymphoide Gewebe, IV Zur Frage des Status lymphaticus. 
Zetschr. f. Konstitutionslehre, VIII Band, Heft 3, Nov. 30, 1921, pp. 191-219. CHAPTER X 
THE DISEASES OF THE SEXUAL GLANDS 
The knowledge of the internal secretion took its origin from the sexual 
glands. Brown-Sequard injected himself with testicular extract and believed 
that thereby he could obtain a sort of rejuvenation of the organism. 
The experiments on the sexual glands also first brought the knowledge that 
the function of the ductless glands is in a high degree independent of the nerv- 
ous system. Goltz transected the spinal cords of animals and observed that 
these animals conceived, carried their young normally, gave birth, and suckled, 
in spite of the fact that the ovaries were cut off from the higher nervous cen- 
ters. The later researches on transplantation of the sexual glands showed 
this independence in still higher degree. Ribbert, and later Knauer, trans- 
planted the ovaries under the skin in animals and observed that in such ani- 
mals there occurred no involution of the uterus such as would otherwise 
tend to occur after castration. Halban showed that also in the youthful 
incomplete organism transplanted ovaries could exercise their protective 
influence on the development of the genital apparatus. The ovaries were 
transplanted under the skin of new-born guinea-pigs. After one year Graa- 
fian follicles and ova were present in the transplants. Uterus and breasts 
developed normally, while in the castrated control animals breasts and geni- 
talia remained quite rudimentary. Foges and later Steinach then showed 
that after transplantation of the testicles the secondary sexual characters 
develop (although not always completely), while in the castrated control 
animals the development of these characters suffer marked damage. 
While not until lately has experimental pathology furnished an insight 
into the function of the sexual glands, clinical observation from the very 
beginning has stirred the interest of physicians and the laity, because 
the instinct of procreation affects everything that lives. The influence that the 
loss of the sexual glands exercises on the configuration of the body and the 
development of the secondary sexual characters has been known since antiq- 
uity. Just those malformations that stand in especial relations with the 
sexual glands, such as hermaphroditism, or the development of the so-called 
contrasexual character, belong to these curiosities that since that time have 
been exhibited in show-booths [museums]. Also the problem of heredity is 
intimately associated with the function of the sexual glands. 
Finally this problem has always had a great significance for breeders 
of animals. 
Embryological, Anatomical, and Physiological Preliminary Remarks. 
For the comprehension of the physiology and pathology of the sexual glands 
it is necessary to distinguish sharply between these proper and the accessory 
genital apparatus. The rudiments of the accessory apparatus (primordial 
381 382 
THE DISEASES OF THE SEXUAL GLANDS 
kidneys with Wolffian and Mullerian ducts) are common to both sexes. Accord- 
ing as to whether sexual glands develop into testicles or ovaries the indifferent 
rudiments develop into epididymis, paradidymis, vasa deferentia, and prostate, 
or into epoophoron, paroophoron, Gartner's ducts, tubes, uterus, and vagina. 
Two parts of the sexual glands are to be distinguished: The interstitial 
glands1 (consisting in the so-called Leydig’s interstitial tissue), and the specific 
glands of generation (in man, seminiferous tubules, Sertoli’s cells [?] in women, 
the follicular apparatus). 
[The question mark after Sertoli’s cells occurs in the German edition. 
The subject still remains questionable in spite of the experiments of Steinach 
(see Addendum) and the voluminous work of some of his followers such as 
Lipschiitz.2 It is fairly well established that the atretic follicles in the human 
female correspond to the Leydig cells in the male, although objections to this 
point of view have been raised.—Editor.) 
A. The Interstitial Glands 
The Leydig’s interstitial cells are epithelioid cell accumulations imbedded 
in the sexual glands of the male. They are filled with acidophilic and baso- 
philic granules, show great similarity to the cells of the suprarenal cortex, 
and like these are of mesodermal origin {Simon, 1892, Wallart, Seitz). These 
cell formations develop enormously at the time of puberty. In women we 
understand by “interstitial glands” a cell complex that develops from the 
atretic follicles of the theca interna. In women these cells develop very 
markedly at the time of puberty, and temporarily during pregnancy (Wallart). 
I must not omit to state that the view is held by many that in the highest 
female mammals, in the human species and in monkeys, the interstitial glands 
are inconstant (Bucura). This has been denied on other sides, and I would 
only state here that the function of the interstitial glands in man is to-day 
already so sharply delimited and that it is concerned with functions so important, 
functions that influence the conformation of the body in such an extensive 
manner, that it is hard to believe that so important an organ is absent in women. 
According to the view of some of the authors the interstitial glands govern 
in man in this special field the development of the primary and secondary 
sexual characters, and are hence of great importance for the formation of 
the body. 
The distinction between interstitial glands and generative apparatus is 
based on a series of clinical observations and experimental facts. The clinical 
observations, which I shall describe first, are concerned with cryptochiidism. 
1 The distinction between “internal secretory and germinative” that up to the present has 
been the practice in the literature, and that was also retained by me in my article on the diseases 
of ductless glands in Mehr-Staehelen’s handbook, must be rejected by me, as it seems to me to lead 
to the crudest misunderstandings. Steinach designates the “innersekretorische” glands as “Puber- 
tatsdriise.” It seems to be Undoubted however that the “internal secretory” activity of the gener- 
ative apparatus is very considerable. Indeed the entire teaching of hormones has been developed 
from the influencing of the growth of mammary glands through the hormone of the fetus or of the 
chorionic epithelium, that is properly speaking, the ovum. 
2 Lipschiitz (A.). Die Pubertatsdriise, etc. Bern, Bircher, 1919 [Bibliography). THE INTERSTITIAL GLANDS 
383 
Variot first pointed out the great difference between kryptorchdes ab- 
dominaux and kryptorchides inguinalis. The first is associated with obesity 
and broadening of the pelvis; the larynx remains small, the voice remains 
high and shrill, the beard and the pubic hairs do not grow; microscopical 
examination shows marked connective tissue proliferation in the extremely 
small testicles. I shall speak of this form later in the consideration of 
eunuchoidism. 
In the adult kryptorchides inguinales, in which the testicles remain behind 
in the inguinal canal, the sexual potency may be present. Such individuals 
may have ejaculations without the expulsion of spermatozoa. They are 
therefore potent, but sterile. These individuals have an entirely masculine 
habitus, the voice changes, there occur growth of beard and normal hairiness 
of the trunk, the musculature is vigorous, the dimensions of the sleketons are 
normal, etc. Here the function of the interstitial glands is retained, while 
that of the generative glands is not developed. In twenty cases of cryptorchic 
testicles, Tandler did not find spermatogenesis in a single case, but did find 
normal interstitial substance. Therefore, in cryptorchidism the disturbance 
in the development of the glands of generation is the rule, while the disturbance 
of that of the interstitial glands is found only in severe cases. 
The first experimental observations were made by Ancel and Bouin. 
They ligated the vasa deferentia and found that after a time spermatogenesis 
had entirely disappeared, while interstitial glands were retained. These 
animals showed complete normal development of the masculine habitus. 
Tandler and Grosz further showed that after intensive Rontgen irradiation of 
the testicles of young Cerviden [roebucks] the spermatogones, on account of 
their greater sensitiveness become destroyed, while the interstitial glands were 
retained. In these animals the masculine sexual characters developed in 
entirely normal manner. Latterly Simmonds has shown that after Rontgen 
irradiation there are always found individual undamaged seminal tubules, 
that can again regenerate; but the significance of this finding must not be 
estimated too high. Lately Steinach has reported concerning transplantation 
experiments that place the matter in a secure position. If in young sucklings 
the testicles are transplanted, the secondary sexual characters proceed to 
develop entirely normally. The histological examination shows that the 
spermatozoa are entirely absent. Clinical observation was thus entirely 
corroborated by experiment. 
As in such animals also the external genitalia develop entirely normally, 
it is to be assumed that the interstitial glands exercise an important influence: 
1. On the development of the generative glands. An isolated develop- 
ment of these without the interstitial glands is not known in the male 
sex. 
2. On the accessory genital apparatus. 
3. On the so-called secondary sexual characters. 
Hence the question is explained in the male sex. As has been mentioned 
it is hard to assume that in women such an important organ should be absent. 
[They probably are not absent, although it is problematic as to what significance 384 
THE DISEASES OF THE SEXUAL GLANDS 
should be attached to them. Lipschiitz1 and others, including Aschner,2 
consider that they are represented by the remains of the atretic follicles. 
—Editor.] 
Although it is now established that the interstitial glands perhaps exercise 
an entirely essential influence on the development of the secondary sexual 
characters, we must still regard the question of the genesis of the secondary 
sexual characters and their relations to the sexual glands as one that is much 
argued. There is no uniformity in the definition, even of the secondary 
characters. Darwin understands by them any sexual characters that are 
sexual characteristic for the sex in question, but which have nothing directly to 
do with reproduction. 
R. Miiller divides the secondary sexual characters into physical and 
mental, and further divides them into: 
1. Such as have entered into an intimate relationship with the propaga- 
tion and nurture of the young animals: For example, female pelvis, 
mammary glands, temperament, sexual instinct, maternal love. 
2. Such in which are shown an immediate dependence on sexual glands: 
Skeleton, muscular system, skin-appendages (antlers, horns, combs, 
etc.), formation of the larynx, swelling of the thyroid gland, etc. 
3. Such that are only mediately dependent on the sexual glands: Internal 
organs, different psychical activity, etc. 
I wish from the beginning to limit myself to these two definitions. My 
attitude toward them will be stated later. 
First I shall describe more in detail the distinguishing features between 
the [human] male and female bodies, following the exposition of Novak. 
The female and male bodies are far more like each other up to the time of 
puberty than later. Before puberty both show the infantile type, although 
extensive differences exist even in the earliest period of embryonal life. For 
instance the pelvis may be recognized as feminine as early as the fifth month 
of embryonal existence (Fehling). At the time of puberty the growth in both 
sexes is essentially increased. In the male the larynx now enlarges, the voice 
changes, the growth of the beard begins to be more evident; in the female, the 
breasts develop, the characteristic form of pelvis becomes more prominent, the 
figure becomes rounded and an abundant deposit of fat is found especially on 
the hips. In both sexes there now occurs a growth of pubic and axillary 
hairs, the former in women remaining bounded above by a horizontal line, 
while in man it closes above in the form of a triangle. In man the body size 
is on the average greater, the horizontal circumference of the head is less in 
relation to the body height, in woman the capacity of the head is less, as is also 
the extension of the facial part. In man the extremities are longer in relation 
to the length of torso, in woman this is reversed. In women the shoulder-girdle 
is relatively small, the hips broader, hairs on the head in woman are much 
longer, the hairiness of the body is absent. Michaeli’s quadrangle is broader 
1 Lipschiitz (-4.)- Die Pubertatsdriise. Bern, Bircher, 1919 [Bibliography]. 
2 Aschner (B.). Die Blutdrlisenerkrankungen des Weibes und ihre Beziehungen zur Gynakologie 
und Geburtshilfe. Wiesbaden, Bergmann, 19x8. THE INTERSTITIAL GLANDS 
385 
in woman, the sacrum is less curved and is shorter, the symphysis is broader 
and lower, the pubic angle is greater, the iliac fossae are broader, the transverse 
extension of the pelvis is greater, the pelvic entrance and exit are greater and 
wider. The glandular substance in the breast is always developed even in the 
virgin, the nipples are more prominent, and more easily erectile. In addition 
there is in woman a less number of erythrocytes per cubic millimeter of blood. 
Then there are differences in the psyche, that become more prominent from 
the time of puberty. 
I would now briefly sketch those problems that seem to me most 
important for the evaluation of the secondary sexual characters and for 
their genesis. 
Almost all of the distinguishing signs that have been mentioned may be 
included under Darwin’s definition. The mammary glands seem to me to form 
an exception. Much seems to speak for the fact that the female mammary 
glands are a primary sexual character, or rather that they should be directly 
ascribed to the generative apparatus. We cannot say of them that they have 
nothing to do directly with propagation, for in mammals the brood would be 
annihilated if the mammary glands were to cease to functionate. We can, 
however, go farther and suppose that the growth impulse that the mammary 
glands experience in women emanates not from the interstitial glands, but from 
the generative apparatus, that there exists no development of the glandular 
substances (certainly not of the fat substances) without development of the 
follicular apparatus, and that the most extensive growth impulse, namely that 
during pregnancy, proceeds from the generative apparatus, equally if we regard 
as the source of the mammary hormone the growing fetus or the chorionic 
epithelium. We shall enter more fully into this question later. 
A further moot point is whether the secondary sexual characters are 
preformed from the ovum—as to the question whether before or after con- 
ception, I shall not enter into here at all—or whether they develop in the 
masculine or feminine direction under the influence of the sexual glands. 
Lenhossek and Halban hold the opinion that the total sexual characters are 
somewhat preexistent and that the sexual glands exercise only a protective 
action on their development.1 Another view that stands rather bluntly 
opposed to that just described is that the sexual glands furnish a direct 
formative stimulus on the sexual characters. Recently Steinach on the ground 
of transplantation experiments inclines to this view. Finally Biedl supposes 
a hermaphroditic rudiment of the sexual glands. The secondary sexual charac- 
ters develop either in a masculine or a feminine direction according as to whether 
the development of the masculine or feminine internal secretory sexual glands 
predominate. The occurrence of heterologous sexual characters is explained 
by Biedl by the supposition that the internal secretory portion of the sexual 
glands that belongs to the other sex obtains the upper hand. 
1 Also Tandler upholds the opinion that the sexual sphere of action of the secondary sexual 
characters as well as those of the germinal glands are preexistent. Tandler and Grosz mention 
in this connection that the so-called secondary sexual characters are only characters of species and 
enter into relation to the genital sphere only secondarily. 386 
THE DISEASES OF THE SEXUAL GLANDS 
A further problem lies in the fact whether the sexual characters in their 
development especially depend exclusively on the sexual glands, or whether 
they do not rather receive decisive influences from the other ductless glands. 
The discussion of all these questions makes necessary not only the resort 
to experimental pathology and physiology, but to an abundance of clinical 
observations as well. It seems to me therefore suitable to describe first the 
generative apparatus, then to set forth the most important clinical observations, 
and only later to enter into the discussion of these questions. I need hardly 
emphasize that judging from the contradictory nature of the opinions, the 
discussion must be strongly tinged subjectively. 
B. The Generative Apparatus 
As previously mentioned, the interstitial glands are of mesodermal origin. 
This has also been assumed for the generative apparatus, although to me the 
view seems very noteworthy that the generative apparatus (spermatogonia 
in man, follicular apparatus in women) develop out of the primordial cells. 
Then the interstitial glands and generative apparatus are differentiated em- 
bryologically. Primordial follicles and Sertoli’s cells are demonstrable already 
at an early embryological stage. 
We shall first take note of the development of the generative glands and 
their influence on the total organism, in woman. The development of the 
follicular apparatus is quite gradual. First at the time of puberty, together 
with the beginning of maturation of the interstitial glands does it come to 
full development; at the same time too with an enormous growth impulse for 
the breasts and the beginning of menstruation. While in man after complete 
maturity there enters the condition of rather continuous function of the sexual 
glands and especially the generative apparatus, in woman the activity of the 
sexual glands and especially of the generative apparatus is subjected to periodic 
variation. With the periodically recurring ovulation and menstruation, there 
enters into the vital processes a noticeable wave movement that has been 
deeply studied by Goodman, Jacobi, Rabutau, Reinl, Ott, and others. We must 
distinguish a premenstrual period, a period of menstruation, and a postmen- 
strual interval. During the premenstrual period there are found signs of a 
gradually increasing vitality of the internal organism, which rapidly reduces 
during the bleeding. In the seven or nine days immediately before menstrua- 
tion the blood-pressure increases, it falls rapidly with the beginning of the flow, 
and reaches its lowest value at the close of the period. With this variation in 
blood-pressure are associated variations in the erythrocyte count. In the 
premenstrual period the erythrocyte count may lie i to ijqj millions higher 
than toward the end of menstruation. It is very possible indeed that just as 
in tetany, these variations in the erythrocyte count are to a great degree the 
expression of an increased or diminished tonus of the vessels; for which view 
speaks also the careful blood-pressure measurements. In connection with it 
may stand too the strong permeation of many organs with blood. Moreover 
in the premenstrual period there is found a higher level of bodily temperature THE GENERATIVE APPARATUS 
387 
that becomes prominent especially in latent diseases (Reinl). On the day 
preceding and the day following menstruation the temperature is the lowest. 
In many individuals there may also be demonstrable, in the premenstrual 
period, a slight neutrophilic hyperleucocytosis and a slight heightening of the 
coagulability of the blood. Also the respiratory volume is often raised in the 
premenstrual period, while it is slightly decreased during menstruation 
{L. Zuntz). Many of the manifestations set forth seem to me to point to an 
increased function of the chromaffin tissue. With this may be connected the 
observation that in the premenstrual period the glycosuric action of adrenalin 
is heightened. Moreover there is found an increase in reflex excitability 
and often a higher mental alertness and capacity, while during menstruation 
there often occurs a certain mental obtuseness. Known for a very long time 
is the swelling of the thyroid gland in the premenstrual period (struma-ante- 
menstrualis, Ileidenhain). It is further stated that before rut and in the pre- 
menstrual period the suprarenal cortex increases in size. Also the interstitial 
glands show the same behavior during this period, apparently also does this 
hold true for the glandular hypophysis. At least such a conclusion seems 
suggested by the similar alterations of these ductless glands during pregnancy;, 
perhaps there is also found in the premenstrual period an increased growth of 
any beard that may be present (Halban). Finally it is known that the mam- 
mary glands often swell slightly, and in rare cases even in the virgin may secrete 
a slight amount of colostrum. Further the nipples often show an increased 
erectibility and are painful. 
What now is the cause of this rhythmically occurring menstrual wave? 
Pjluger developed a theory that monthly ovulation leads by reflex paths to a 
hyperemia of the pelvic organs, thereby causing menstruation. PJluger’s 
law has been made untenable by the knowledge that the influence of the 
ovaries in the organism is independent of the nervous system and depends on 
the giving off of substances to the blood-path. Hence it must be modified 
to state that the influence of the internal secretion of the generative apparatus 
on the organism is, through the maturation of the ovum, increased in a rhyth- 
mic manner. It is now urged against the dependence of menstruation on 
ovulation that not rarely menstruation and ovulation do not occur at the same 
time, but that under circumstances ovulation can take place after menstruation 
(.Leopold and Mironow, Ravano). Frankel has therefore upheld the view that 
the retrogression of the corpus luteum gives rise to menstruation. According 
to the view of most authors there can, however, be attributed to the corpus 
luteum at most a postponing but not a releasing [auslosende] action {Halban). 
Halban would principally ascribe to the ovulation, that is to the sexual glands, 
only a protective but not a formative influence on menstruation or on rut and 
on the cyclical menstrual phenomena, pointing out the known fact that after 
even a long time after bilateral ovarectomy the menstrual wave may reappear. 
Numerous extensive statistics exist as to this question; I mention only the 
statement of Pfister that in on an average of 12 per cent, of castrated women 
menstruation reappeared and that among 116 castrations vicarious menstrua- 
tion from the bowel or the nose occurred for a time in cases. Finally it must 388 
THE DISEASES OF THE SEXUAL GLANDS 
be pointed out that in a great percentage of cases after castration there exist 
cyclical menstrual molimina (backache, nausea, colics, etc.). Of course these 
molimina occur when the uterus is removed and the ovaries remain behind in 
the body. Halban is therefore of the opinion that the menstrual wave is 
released not from the ovary itself, but by an as yet unknown agent and that 
much the more the ovary itself reacts to this agent in an especially sensitive 
way, and this reaction of the ovary first brings the menstrual wave to its 
complete fulfillment. 
I would not subscribe unreservedly to the view of Ilalban. The depend- 
ence of menstruation on ovulation is in any case very considerable. Halban 
himself has shown that in baboons, which have a menstruation similar to that 
of human beings, menstruation is retained after transplantation of the ovaries. 
On the other hand after ovarectomy, rut remains away with almost every case. 
Lately Adler has shown that subcutaneous injection of watery extract of ovaries 
calls forth in virginal animals alterations in the internal genitalia, especially 
the uterus, that remind one of the changes that take place during rut. In two 
amenorrheic women in whom pieces of mucous membrane were obtained from 
the uterus by curettement before and after injection of this extract, microscopi- 
cal examinations of these pieces showed that there were menstrual alterations 
of the mucous membrane. Since after castration the menstrual wave is 
recovered after a time in an attenuated form, this does not seem to me quite 
inexplicable. We can imagine that the menstrual wave that has existed for 
several years may under circumstances continue for a while after castration, 
if the sexual life has once been fully developed. The difficult point according 
to my view would lie in the question whether, in youthful persons in whom 
menstruation is mostly absent, the development of the wave would be entirely 
prevented by castration. I believe that this would be the case, just as the 
sexual life fails to develop in those castrated in early youth. The circum- 
stance that ovulation and menstruation do not always occur at the same time 
does not seem to me very essential. It is conceivable that the acme of the in- 
ternal secretory function of the maturing follicle and the reaction of the organ- 
ism due to this in many cases occur before the extrusion of the egg, in fashion 
similar to that which Halban assumes for the function of the chorionic epithe- 
lium in pregnancy. While therefore ovulation is independent of menstruation, 
ovulation may continue to exist when menstruation is absent. This is satis- 
factorily demonstrated by the fact that women a long time amenorrheic may 
conceive. Indeed ovulation may take place in women who have never men- 
struated; then are found eventually only cyclical swelling of the uterine mucous 
membranes, or cyclical leucorrhea (Ogorek). 
Pregnancy.—Even after fructification the ovulation shows certain starts 
[Ansatze] (Ravano-Fellner), then it ceases entirely, and menstruation ceases 
with it. The corpus luteum persists. Probably the cessation of ovulation is 
to be referred to persistence of the corpus luteum, or both manifestations are 
to be referred to the developing fetus or much more to the development of 
the chorionic epithelium. I cite the following from known facts that are 
important for the understanding of these relationships. In the cow there not THE GENERATIVE APPARATUS 
389 
rarely occurs persistence and hypertrophy of the corpus luteum. Then rut 
ceases. If the corpus luteum be removed, rut recurs. Moreover, Kleinhans 
and Schenk showed that extirpation of the corpus luteum alone does not lead 
to interruption of pregnancy therefore that the development of the fertilized 
egg is not dependent on corpus luteum. 
Pregnancy leads to profound changes in the maternal organism. Accord- 
ing to Neumann and Hermann lipoidemia can always be demonstrated. They 
found the lipoidemia also after castration and in the climacteric period. I 
would refer it especially to the cessation of the activities of the follicular appara- 
tus. Further, during pregnancy, are found signs of a heightened excitability 
of the vegetative nervous system. L. Poliak could show during pregnancy 
heightened glycosuric action of adrenalin. The statement as to an increased 
adrenolinemia in pregnant women (Neu) could not be corroborated by 
Neubauer and Novak. 
Very commonly in the latter stages of pregnancy is found a neutrophilic 
hyperleucocytosis. Further the temperature is placed at a higher level, and 
also the blood-pressure and the pulse rate are higher. 
Also investigations on the metabolism1 have shown that there are profound 
alterations. Falk and Hesky, and Zangemeister found relative increase in the 
ammoniacal nitrogen, Leersum, Rebaudi, and Falk and Hesky found increase 
in the amino acids, the authors last-named also an increase in the polypeptid 
nitrogen, and Salomon and Saxl an increase in the elimination of oxyproteinic 
acid. The tendency of pregnant women to alimentary glycosuria and alimen- 
tary levulosuria is well known. Novak and Porges have discovered a tendency 
toward ketonuria. The cause of these metabolic alterations is seen by most of 
the authors cited in a disturbance of the function of the liver, from which they 
have inferred degenerative processes in that organ. It would, however, be 
remarkable if a physiological process such as pregnancy should regularly lead 
to such severe disturbances; I would regard as the cause of these metabolic 
disturbances only an increase in the irritability of the liver, which is a partial 
phenomenon of the increased vitality of the whole organism. 
It is very noteworthy that numerous symptoms point to an increased 
function of almost the whole ductless glandular system. Certain of the pre- 
viously mentioned symptoms may be referred with some probability to an 
energetic activity of the chromaffin tissue; the regular occurrence of iron-free 
pigment perhaps points also to an increased adrenalin consumption.2 As is 
known such pigmentations develop along the linea alba, at the navel, on the 
perineum, on the labia majora, on the areolse of the nipples, and on the face 
(chloasma uterinum). Very noteworthy is the occurrence of abnormal hairi- 
ness, as Halban first pointed out. Especially distinct is the increased growth 
of a previously existing rudiment of the beard. Halban cites a very interesting 
case of Slocum’s. A woman carried three children normally and also had an 
abortion at the sixth or eighth week. In each pregnancy the beard grew on 
1 Basal metabolism in late pregnancy is increased.—Baer (J. L ). Basal metabolism in 
pregnancy and the puerperium. Am. J. Obst. and Gyn., Vol. II, Sept., 1921, pp. 249—256. 
2 See the hypothesis as to the genesis of the pigmentation in the chapter on the suprarenal 
apparatus. 390 
THE DISEASES OF THE SEXUAL GLANDS 
the cheeks and chin. But also the downy hair on the entire body, especially 
on the abdomen and on the linea alba, grew stronger during pregnancy. These 
hairs fell out again after the labor. Halban could even demonstrate the in- 
creased growth tendencies of the hair in animal experiment. After shaving 
of the abdomina of pregnant animals the hair grows faster there than on the 
abdomina of nonpregnant animals similarly treated. He refers these anomalies 
in the hairiness to the internal secretory activity of the chorionic epithelium; 
it would also be likely, however, that this comes into relationship with the 
hyperplasia of the suprarenal cortex that occurs in pregnancy, as is pointed out 
by Glynn. This hyperplasia of the suprarenal glands has been demonstrated 
by Iiaberer and Stoerck. 
I would attribute especial value to the fact that during pregnancy the 
interstitial glands develop enormously. This fact shows that also in the sexual 
glands of the female there is a certain independence of the function of the 
interstitial glands from that of the generative glands. While the activity of 
the follicular apparatus becomes inhibited, the interstitial glands show his- 
tological signs of an increased activity. According to my view the clinical 
symptoms correspond to those of the histological finding. As I already em- 
phasized in the article on ductless gland diseases in Mohr-Staehelin’s handbook 
(Vol. IV), I cannot subscribe to the opinion upheld especially by Tandler and 
Grosz that during pregnancy the “internal secretory” activity of the ovary is 
inhibited by the persistence of the corpus luteum. By “internal secretory,” 
activity is understood by these authors a function that in fact can only depend 
•on the interstitial glands. Against an inhibition of the interstitial glands speaks 
however, the fact that during pregnancy the secondary sexual characters 
throughout do not retrogress, and on the contrary there is found, in agreement 
with histological findings, strong accentuation of them. Entirely especial, 
however, are the views concerning the relation of the sexual glands to the hypo- 
physis, which had led to the rapid entrance into the literature of what I consider 
an incorrect view. Therefore I must enter into this question more in detail. 
The hypophysis in woman during pregnancy enlarges considerably. Its 
weight can rise to two and one-half times as much as normal. Enlargement of 
the anterior lobes is exclusively responsible for this increase in weight, this 
lobe becomes more juicy and essentially softer. It shows the occurrence of 
enormous numbers of pregnancy cells, which develop from the so-called chief- 
cells. In the later stages of pregnancy more than four-fifths of the organ may 
consist of the new formed cells. Comte, and Launois and Moulon first pointed 
out this enlargement of the hypophysis, and Erdheim and Stumme, whose exposi- 
tion I follow, carefully studied these alterations in a great number of cases. 
Then enlargement of the hypophysis during pregnancy is sometimes so con- 
siderable that in rare cases even a pressure-action on the chiasma seems to be 
possible, v. Reuss described repeated temporary blindness during pregnancy, 
while Bellinzona and Tritondani report bilateral narrowing of the visual field. 
Actually there exist a series of manifestations that point to an increase in func- 
tion of the hypophysis during pregnancy. To these may belong the osteophyte 
formations on the internal surface of the skull that are associated with marked 
hyperemia of the dura. In addition they are found also on the upper jaw, on THE GENERATIVE APPARATUS 
391 
the nose, and on the frontal and parietal bones (Manau), further the develop- 
ment of substance devoid of calcium in the pelvis. Breus and Kolisko observed 
increase of the growth of the pelvis during pregnancy. Tandler and Grosz 
point out that in gravid persons there is a coarsening of the facial features, espe- 
cially of the soft parts of the nose, lips, and moreover that a thickening of the 
hands is not rare, manifestations that remind one of a slight grade of acromegaly. 
I refer in the chapter on the hypophysis to the case of Marek, in which we can 
indeed speak of a transitory forme fruste of acromegaly. As far as the growth of 
hair on the linea alba is concerned, I should rather ascribe it to the hyperplastic 
alterations of the suprarenal cortex. Into association with increase of function 
of the hypophysis may be brought also the observation of Halban that in youth- 
ful persons whose epiphysial junctures are not yet fully closed, the growth can 
proceed in fits and starts during pregnancy. I shall refer to this later. 
We see therefore that in pregnancy an increase of the function of the hypo- 
physis is associated with an increase of function of the interstitial glands, as is 
also the case in acromegaly. There remains only one point that also seems 
very much to support the view of Tandler and Grosz. Tandler and Grosz con- 
cerned themselves with the observation that the extirpation of the ovaries, 
hence a removal of the internal secretory activity of these organs, leads to 
enlargement of the hypophysis, and they thus regard the cause of the tall growth 
in the castrated to an increase in the function of the hypophysis. Fischer 
first reported that in capons and castrated male cattle the hypophysis is often 
twice as large as in cocks and uncastrated male cattle. Moreover, Jutaka Kon 
states that in eight castrated women the hypophysis was found enlarged and 
rather heavy. The enlargement affected the glandular part alone and on 
histological examination there was found the picture of true hypertrophy. 
Finally Tandler and Groszseveral times observed a strikingly large sella turcica 
in “Skopzen.” [See p. 402.] So far as the findings in the hypophyses of cas- 
trated animals is concerned, there is found, however, the statement that mani- 
festations of an apparently degenerative kind (vacuole formation) are often 
observed. I am very sceptical with regard to the finding at Jutaka Kon. At 
least one cannot draw from it the inference as to an increase of function of the 
hypophysis, for nobody would state that symptoms occur in castrated women 
that indicate such an increase. In male late castrates may be observed such 
an enlargement of the sella turcica, as in one of the cases I reported (castration 
in the twenty-sixth year of life), or in the case of Rieger (epistolatory communi- 
cation). Further, Tandler and Grosz have already stated that no enlargement 
of the sella was found, and further on I shall report four cases of eunuchoidism, 
in which the sella was found to be normal in size or strikingly small. Finally 
as far as the tallness of eunuchs and eunuchoids is concerned, I would refer it 
not to an increase in function of the hypophysis, but to a persistence of the 
epiphysial junctures. As we have seen in the chapter on the hypophysis early 
acromegaly does not always lead to tallness, also not when the epiphysial junc- 
tures have not closed prematurely. Nor are there to be found in eunuchs or in 
eunuchoids any other signs of a hyperfunction or an increased function of the 
hypophysis; I call to mind only the so characteristic behavior of the carbohy- 392 
THE DISEASES OF THE SEXUAL GLANDS 
drate metabolism in acromegaly. The view of Launois and Roy that when the 
epiphysial junctures are open, functional increase of the hypophysis leads to 
tallness or to gigantism, and when closed, to acromegaly is to my mind as unten- 
able as the opinion that falling away of the sexual glands prdouces increase of 
function of the hypophysis. If we follow both views to their ultimate conse- 
quences, we arrive at the postulate that castration after epiphysial closure must 
call forth acromegalic manifestations, as is evidently not the case. And I 
believe therefore that Halban's symptom of increase of growth in youthful 
gravida does not depend so much on increase of hypophysial function as much 
more on the periodically increased vitality of the whole organism when the 
epiphysial junctures are open. 
Let us now return to the behavior of the ductless glandular apparatus in 
pregnancy. I must here mention the fact known already in antiquity that dur- 
ing pregnancy there is increase in volume of the thyroid gland. There de- 
velops a parenchymatous struma that feels soft on palpation. There is indeed 
no doubt that this increase in volume is associated with a slight increase in 
function, which is even a partial phenomenon of the increased vitality. 
An increase of function of the parathyroids and of the pancreas can be 
inferred by us only indirectly, from the fact that the latent insufficiency of these 
glands tends to be manifest during this period; we have grounds for assuming 
that this occurs as a consequence of increased demands and therefore that 
normally the function of these ductless glands is increased. 
We will now describe the changes undergone during pregnancy by the 
mammary glands. First of all I will make some remarks as to their develop- 
ment. Halban, whose important works we have to thank for our information, 
distinguishes four periods of growth impulse separated in point of time. The 
first falls about in the time between the eighth and ninth lunar months [of 
embryonal life]. The second occurs at the time of puberty, the third always 
recurs at the premenstrual periods, and the fourth, especially intensive, occurs 
during pregnancy. The ovaries constitute the trophic center for the first 
three growth impulses. This may already be seen by the fact that in distur- 
bances in the development of the ovaries the breasts too remain undeveloped 
(Foges). The growth impulse during puberty leads as is known to a noticeable 
development of the glandular parenchyma. The growth impulse in the pre- 
menstrual periods can in rare cases be so strong that in virginal individuals 
colostrum may be secreted, and later, during the menstruation, milk may appear 
{Scanzoni, Gauthier). The most intensive impulse of growth occurs during 
pregnancy. The breasts swell and toward the end of pregnancy may yield 
colostrum on expression. There is no doubt but that this impulse for growth 
is set free by hormones. This is shown by observations on Siamese twins, 
Blazek; when the one became pregnant the breasts of the other swelled also, 
and after confinement, secretion of milk occurred in both {Schauta); Grigori and 
M. Cristea could make the same observation on parabiotic animals. For the 
hormone theory speaks also the observation of Ribbert that transplanted mam- 
mae secrete milk after birth. The ovaries are not necessary for the pregnancy- 
hyperplasia of the mammae, as also in spite of castration undertaken in the THE GENERATIVE APPARATUS 
393 
early stages of pregnancy, the development of the breasts proceeds in a normal 
manner, and the women are able to suckle their children. Mainzer has collected 
sixteen such cases from the literature and Halban has added three more. It 
looks very much now as though the removal of the ovary later exercises 
favorable influence on milk-production, as breeders state that castrated cows 
yield abundant milk. Noteworthy in this respect is the case of Foges. After 
a labor a woman experienced a secretion of milk for seventeen years. During 
this time constant amenorrhea existed. After seventeen years of amenorrhea 
a new conception occurred. After the labor the milk-secretion continued again 
for six years. 
Milk usually comes on two or four days after labor. This whether the 
birth takes place at normal time or whether there has been a miscarriage. 
Secretion of milk has even been observed after an abortion as early as the 
second month of pregnancy. As the pregnancy-hyperplasia of the breasts 
is independent of the ovaries. Starling and Lane-Claypon have regarded the 
fetus as the source of the mammary gland hormone. Actually they even suc- 
ceeded in inducing growth of the mammary glands by injection of extract 
of embryos into the peritoneal cavity of rabbits that had not yet been covered. 
Also Biedel and Konigstein lend themselves to this view, as has also Fod who 
recently on the ground of his experiment has upheld the opinion that the mam- 
mary glandular harmone was not specific in kind. Against this, Halban has 
upheld the view that the pregnancy-hyperplasia of the breasts is produced by 
a hormone, that proceeds from the chorionic epithelium of the placenta. / al- 
ban bases his view on the following observations. The pregnancy-hyperplasia 
of the breasts can still develop if the fetus has been dead a long time but the 
placenta remains living. If, however, the placenta too dies, the further develop- 
ment of the mammary glands ceases and milk begins to flow. Halban further 
observed two cases of cystic mole, in which secretion of milk began after expul- 
sion of the mole. Halban says that the chorionic villi develop from the fer- 
tilized egg and in spite of enormous growth until the end of pregnancy undergo 
but little differentiation. By the copulation of spermatozoa and ovum is ex- 
plained the fact that the hormonopoietic action of chorionic epithelium is 
stronger than that of the ovum alone. Hardly any objections can be raised 
against Halban’s clinical observations. On the contrary it seems to be not 
refuted that also from the fetus may mammary glandular hormones proceed, 
as indeed the chorionic epithelium may live without the fetus, but not the fetus 
without chorionic epithelium. Hence it seems to me that the views of Halban 
and of Starling are not irreconcilable. 
Yet a few remarks concerning the onflow [“Einschiessen,” literally a shoot- 
ing in] of the milk, which, as previously mentioned, usually occurs on the 
second to fourth day after delivery. It was formerly regarded that the cause of 
the onflow was the act of suckling, but Halban has pointed out that suckling 
during pregnancy may indeed induce the secretion of colostrum, but never calls 
forth the production of milk (cases of Duval and of Hildebrand). The onflow 
of milk also occurs in cases in which the child has never been put to the breast. 
On the other hand (apart from such cases as the case of Foges cited above) 394 
THE DISEASES OF THE SEXUAL GLANDS 
the act of suckling or of drawing off the milk is requisite for the continuance of 
the milk-secretion. From a series of clinical observations, Halban draws the 
conclusion that the onflow of milk always coincides with the removal or the 
death of the placenta. Again, the extirpation of the ovaries at a time other 
than during pregnancy may increase the existing secretion of milk, while, as is 
known, the occurrence of menstruation during lactation inhibits the secretion 
of milk, and indeed in the premenstrual period, and also that amount of its 
solid constituents, especially the casein, the fat, and the salts, are diminished 
(N. Davis). Indeed, even at the beginning of the climacteric there may exist 
for a time with the introduction of the ovarian function painful swelling of 
the breasts and excretion of milk. Halban reports such a case. Halban 
therefore concludes that the ovary is growth-inducing and secretion-inhibitory 
on the mammary glands, just as is the placenta, only less so. 
Finally there remains to be mentioned the pregnancy reactions of the 
fetus described by Halban. The uteri of new-born girls regularly show con- 
siderable hyperemia and histological alterations of the mucous membrane that 
bear great similarity to those of menstruation. There may even occur genital 
hemorrhage, that have nothing to do with menstruatio prsecox, as the latter 
usually set in much later, at a time that ovaries have shown signs of maturity. 
The uterus of the new-born girls shows almost always a slight involution that 
is usually completed three weeks postpartum. Moreover, the mammary glands 
of new-born girls and boys show signs of epithelial proliferation, indeed, even 
the secretion of colostrum (witch’s milk). Further, the blood shows a slight 
grade of hyperleucocytosis and increased coagulability. Finally the prostate 
of the new-born boy shows a slight hyperplasia, which is then affected by involu- 
tion. Halban correctly brings all these manifestations in analogy with the 
pregnancy-reactions and ascribes them to the hormonopoietic function of the 
chorionic epithelium. 
After labor, as is known, there occurs in the mother a rapid retrogression 
of all the profound alterations just described. The neutrophilic hyperleuco- 
cytoses give place to a leucopenia with mononucleosis, the tachycardia tem- 
porarily to a bradycardia. With the onset of the milk, numerous eosinophilic 
cells make their appearance in the blood (Blumenthal). According to Novak 
and letter there are found in the early puerperium different irritative symptoms 
of the entire vegetative system; then the signs of an increase in the functions 
of the ductless glandular system gradually vanish. 
Surveying now the alterations described, which take place in the organism 
of pregnant women, we find that they are entirely analogous to those which 
occur in the premenstrual period, while those of the puerperium are analogous 
to those of the menstrual period. As is known, labor takes place at the men- 
strual term. Hence seems justified the dictum of W. H. Freund that ‘Tabor 
is a menstruation, in which a fully developed egg is extruded.” While, how- 
ever, the phenomena of the premenstrual period proceed from the ovary, 
there can be no doubt at all that the similar, but potentized, manifestations of 
pregnancy proceed from the developed egg. It therefore seems to me that the 
conclusion lies at hand that all the manifestations of the premenstrual period are THE GENERATIVE APPARATUS 
395 
set free by the maturing follicle, which only renders intelligible the fact that 
the extirpation of the ovaries during pregnancy has no influence on this phe- 
nomenon, as the maturing ovum no longer is found in the ovary, but in the 
uterus. From this we see that if we ascribe to women an interstitial gland, it 
can have very little to do with the phenomenon during pregnancy. It takes 
part in hyperplasia and in increase in function only in the same manner as do 
the other ductless glands, and the stronger emphasis of many of the so-called 
sexual characters may stand in connection with it. The most important 
prevailing alterations of pregnancy are at all events independent of it. 
At the climacteric the interstitial glands show certain regressive changes; 
they are, however, retained in part, while ovulation ceases entirely. The 
lipoidemias that Neumann and Hermann observed in postclimacteric women are 
in my opinion to be referred to the falling out of the function of the follicular 
apparatus. As is known, libido may be retained for a still longer time. The 
function of the sexual glands is usually associated with an increase in the fatty 
layer of the abdomen and mammae. As is known there occur during the transi- 
tion period numerous nervous disturbances, that point to extraordinary chang- 
ing and manifold conditions of excitation in the vegetative nerves. Manifold 
symptoms of a psychical hyperirritability are added, an existing hysteria 
becomes worse, and when a predisposition to a psychosis exists this may 
develop to a climacteric psychosis, which, however, has no specific character 
{Krafft-Ebing). 
We now have to consider the question as to whether the generative appa- 
ratus in man too possesses an internal secretion. We have already seen 
that there are clinical observations to the effect that the function of the gen- 
erative apparatus does not develop (the kryptochides inguinales of Variot), 
while the interstitial glands and with them also the masculine habitus are 
well developed, and that on the other hand similar results have been brought 
about by experiments. It would now be proper to investigate whether such 
sterile but otherwise masculine individuals possess the same libido as normal 
individuals. The cardinal point is the fact whether the developmental dis- 
turbance sets in in early youth, or that experimental attack is made on quite 
young animals. For experience teaches that if once the generative apparatus 
has been fully developed and has functionated normally then also after com- 
plete extirpation of the sexual glands can the libido be retained for a long time. 
It seems to me important, however, that also in such cases the libido is mostly 
released only through external influences. On the whole it seems to me, 
although I cannot demonstrate this with certainty, that a normally strong 
sexual instinct is present only when the function of the generative gland is 
normal, and in this circumstance speaks for the hormonopoietic function of the 
generative glands. 
The known stimulating action on the central nervous system, which 
expresses itself in tendency to movement and in a heightened muscular tonus, 
which comes to expression also in a spiritual sense in higher creative activities, 
and which characterizes especially’ the period of “ Sturm and Drang,” I would 
refer more to the hormonopoietic activity of the generative glands. What has 396 
THE DISEASES OF THE SEXUAL GLANDS 
been done experimentally on this question does not lend itself to the support 
of this view. On the whole the numerous reports as to the stimulating action 
of testicular extract and of spermin Poehl have not been written with the neces- 
sary critique; the careful investigations of Zoth and Pregl, which showed an 
increase of the muscular capacity, were made with extracts of whole testicle, 
so we are unable to say what part the generative glands had in producing the 
effect. 
While in man the function of the generative glands is a more continuous 
one, there exist in the most of male animals the same cycle as in the female. 
As is known, the complete extirpation of the sexual glands prevents a recurrence 
of rut. Although in some cases the wave of rut remains for some time longer, 
I would not lay as much stress on this fact as Halban does. Here also must we 
consider that the organism had been accustomed to the rut-wave for a long 
time. As certain cohabitation experiments show, however, it is possible that 
it is promoted psychically by the rutting female. I believe also here the ques- 
tion permits of discussion as to whether many of the rut phenomena usually 
grouped with secondary sexual characters, that are necessary for the act of 
copulation, as for instance, the hypertrophy of the arm musculature and the 
thumb callosities in frogs, are set free by the generative glands. I have been 
unable to find any experimental investigations that help to clear up this 
question.1 
1. THE MALFORMATIONS 
It is not my intention to enter into a comprehensive exposition of the 
malformations accruing to the sexual glands. I shall only choose those types 
that seem to me important for the discussion of the problems stated above. 
1. Aplasia of the Sexual Glands 
Halban has collected from the literature the reports of cases of congenital 
amorphia or aplasia of the ovaries. They all come from the older literature, 
so that Tandler and others have expressed doubt as to the exactness of the ob- 
servations. It is true that this doubt does not extend to the observations on 
anorchia that were made on boys shortly after birth. In such cases are always 
found also anomalies of the internal genitalia—anomalies such as lack of the 
epididymis or of the funiculi spermatici or the vesicular seminales. When, 
however, we hear in many of the observations in old literature as to aplasia of 
the sexual glands that the external and internal genitalia were quite well 
developed, or that in the male individual a beard was present, such a doubt is 
well justified. It is at all events very striking that no such observations have 
been made in the last decade, although the number of sections has enormously 
increased. From the observations on anorchia in new-born children the most 
that can be mentioned is that also without sexual glands there is possible a 
development, if only a disturbed development, of the male or female accessory 
genital apparatus, and perhaps other characteristics of the male sex. 
Also the observations that Landau and Peck publish concerning the exist- 
ence of individuals of a neutral sex do not seem to me to be free from objec- 
1 See Lipschiitz, loc. cit., p. 382. HERMAPHRODITISM 
397 
tions. I quote the following two cases that Peck regarded as especially 
important. In the case of v. Swinarski-Pfannenstiel there was a fifty-five- 
year-old unmarried “woman,” who had never menstruated. The general 
habitus was masculine, the clitoris 3 cm. long, both ovaries were considerably 
enlarged, the superficies smooth, no corpora lutea were to be seen, and on 
microscopical examination the ovaries were found to be entirely “parenchy- 
maless.” The internal genitalia were those of the female. The case of 
Howitz was that of a forty-nine-year-old unmarried “woman.” The hairi- 
ness and form of the pelvis were masculine; the large and small labia were 
present, the clitoris was 6 cm. long and 2 cm. thick. The urogenital sinus 
was smooth, and on its floor was found an opening through which one could 
pass a thin sound into the 7 cm. long vagina. Between the thirtieth and for- 
tieth years of life blood issued from the vagina at intervals of one to several 
years. At the site of the ovaries on each side was to be found a body of the 
shape and size of an almond. There was no follicle formation in the ovaries, 
and the stroma was strikingly hard. In this case which had come to advanced 
age one could not say with certainty that the follicular apparatus had always 
been entirely absent. The absence of menstruation does not allow of the 
statement that at least for a time there did not exist a tendency [start, Ansatz] 
for menstruation. Also statements to the proportioning of the body are not 
given. Finally an examination of the suprarenal cortex in such cases would be 
very desirable. It seems to me therefore that such cases should not enter into 
our discussion. 
2. Hermaphroditism 
We distinguish a hermaphroditismus verus and hermaphroditismus spurius 
or pseudohermaphroditism. Cases of hermaphroditismus verus, in which ova- 
ries as well as testicles are capable of functionating, are as yet unknown in 
man. But there are cases of so-called ovotestis; I will cite some examples. 
A case of Salen was that of a forty-three-year-old “woman.” Menstruation 
had existed since the seventeenth year, the clitoris was 5 cm. long, the vagina 
6 cm. long, the labia majora were of normal development, the habitus was 
feminine. The ovotestes show in the ovarian part Graafian follicles and 
typical ovules, in the testicular part seminal tubules, Ley dig s interstitial cells, 
but no sperm. The case of Simon was that of a twenty-year-old “man.” 
The individual felt as if he were a man. The sexual inclination was mascu- 
line. Menstruation has existed for three years, the secondary sexual characters 
were mixed, with the feminine predominant. The labia majora were well 
developed, the penis was 6.5 cm. long, the glans was not perforated. There 
were found tubes, parovaria, and ligamenta lata; vasa deferentia and epididymis 
were without connection with the testicular part of the ovotestis. In the 
latter were found typical sexual glandular tissue of both sexes, but no sure 
signs of function. 
In pseudohermaphroditism there are found sexual glands of one sex and 
the sexual characters of the other. We distinguish pseudohermaphroditismus 
internus, if only the internal sexual passages of the other sex are present, and 398 
THE DISEASES OE THE SEXUAL GLANDS 
a pseudohermaphroditismus externus, if only the external sexual passages of the 
opposite sex are present, and a pseudohermaphroditismus completus when both 
external and internal sexual passages of the other sex are present. Further, 
according to the prevalence of the sexual glands a pseudohermaphroditismus 
jemininus or masculinus. 
As an example of the pseudohermaphroditismus completus I cite the 
case of Heyn. The habitus of a forty-six-year-old individual was entirely 
feminine. The person married at the age of twenty-one years, sexual inter- 
course was entirely normal and was attended with orgasm and discharge. 
There was found a vaginal cul-de-sac; uterus, ovaries, prostate were absent. 
Testicles were present on both sides. 
In pseudohermaphroditism are found all conceivable varieties. There 
are cases of somatic pseudohermaphroditism in which not only the sexual 
organs but all the psychical characteristics of the other sex prevail, v. 
Neugebauer has collected twenty-five such cases. Further, there are cases in 
which the secondary sexual characters, such as hairiness, voice, dimensioning 
of the body, belong partly to one and partly to the other sex, and there are 
cases in which the sexual glands and genitalia belong to one, the secondary sexual 
characters to the other sex (pseudohermaphroditismus secundarius, Ila-lban). 
Finally there are observations concerning unilateral pseudohermaphro- 
ditism. In man so far as is known, this has been observed in a very rudi- 
mentary form only. Halban cites cases of unilateral development of the 
breasts in women. There are, however, numerous such observations on 
the part of zoologists. Delbet saw butterflies that possessed on the one side 
an ovary, and on the other a testicle, and in which one-half of the body was 
colored like that of a female, the other side like that of a male. I further 
cite the known observation of Weber. A finch possessed testicle and male plu- 
mage on one side, an ovary and female plumage on the other. 
Let us now survey the rich material of facts, from which I have chosen 
only a relatively few illustrative examples, but examples that are important, 
and let us proceed on the basis of these to enter into the discussion of the 
problems mentioned above. 
Let us turn first to the relation between sexual glands and the secondary 
sexual characters. I would here sketch again, in outline, the different views. 
We have seen that in this respect two views stand bluntly opposed to each 
other. According to one the sexual characters exist from the beginning, 
there exists a male, a female, and hermaphroditic predisposition, and the 
sexual glands exercise only a protective stimulus on the development of the 
sexual characters. According to the other, it is the sexual glands alone that 
form the sexual characters. The authors that adhere to the last opinion, show 
that indeed already in the first embryonal stages there are differences to be 
observed between the male and female sex, but that the sexual glands have 
begun to develop already at this time and begin to exercise their influence. 
It will be seen at the first glance that multiplicity of the phenomena is 
not explained in a satisfactory manner by the last-named assumption. How 
shall we explain the coming about of complete hermaphroditism in which HERMAPHRODITISM 
399 
the sexual glands of one sex lead to the development of the sexual characters 
of the other, if the sexual glands exert a specific sex-determining formative 
stimulus? Even less explicable according to this hypothesis is the occurrence 
of unilateral hermaphroditism. In this connection, no matter from which 
point of view we regard the matter, we cannot circumvent the opinion of 
Halban. For this opinion speaks also the circumstance that in hermaphrodit- 
ism the heterosexual characters are enormously developed even at the time 
of puberty, and the known fact that unioval twins are always of the same 
sex. Only in the last analysis does this solution meet with great difficulties. 
According to it we should suppose that the protective influence of the 
sexual glands would be always active if it met with a heterosexual predispo- 
sition. According to this we would expect that when the sexual glands are 
extirpated in a not yet fully developed animal, and the sexual glands of the 
opposite sex are implanted in this animal, the original predisposition would 
come to development even then. Steinach has followed this method. He 
implanted ovaries into previously castrated young males of guinea-pigs and 
rats. The transplants “took,” and not only the interstitial glands developed, 
but also the primary follicles, to large follicles with normal ova, and there 
occurred in entirely normal manner the formation of atretic follicles of corpora 
lutea. In these animals not only did the penis cease developing, but it was 
even set back in its development. If a tube and a piece of the uterus were 
transplanted with the ovary, these developed to mature organs. Moreover, 
there came about an enormous development of the mammary glands, that in 
form and size were entirely like those of the normal female, and indeed even 
exceeded them in size. Furthermore, the animals remained behind in growth, 
the body showed entirely the proportioning of the female; also the growth of 
hairs and the layer of fat showed the texture of that of the females, and there 
was a reversal of the psychical sexual characters. 
If Steinach’s experiments were to receive full corroboration, were someone 
in converse manner successful in bringing to previously castrated females the 
male sexual characters by implantation of testicles, we would have to agree 
that they would stand in contradiction to Halban’s view. I believe, however, 
that we would not be making allowance for the difficulty of the problem, if 
we were to regard it as entirely solved by this view; for Steinach’s experi- 
ments do not explain the occurrence of heterosexual characters in the pres- 
ence of the sexual glands of the other sex. The observations belonging to 
this problem have led Biedl to assume an hermaphroditic mapping-out [Anlage] 
of the sexual glands. The occurrence of heterogenous sexual characters 
is explained by Biedl by his supposing that the internal secretory part of the 
sexual glands that belongs to the opposite sex gains the upper hand. Biedl 
thus explains the occurrence of certain masculine characters in old women 
after the menopause. 
On cessation of the activity of the female sexual glands, there can occur, 
according to Biedl, a reversal of the sexual characters in that the existent 
male sexual glands continue to functionate. I would here agree with Novak 
in not considering the illustration that Biedl employs as convincing. The 400 
THE DISEASES OF THE SEXUAL GLANDS 
occurrence of the so-called old woman’s beard is not a male sexual character. 
Its occurrence is explained much more adequately by Halban, who points out 
that the individual sexual characters possess very different tendencies to growth 
and that the development of the beard in women is very much delayed. 
In the same manner I do not regard the localization of the deposits of fat in 
old men as a female sexual character, but rather as the sign of the beginning 
dissolution of the activities of the sexual glands, only as the suggestion of a symp- 
tom that in eunuchoidism is exhibited in early years in a pronounced manner. 
It therefore seems to me that the only possibility is to look for the solu- 
tion of the problem in another direction; we should not endeavor to crowd 
all of the manifestations into one of the views set forth, but should consider 
the question as to whether the genesis of the sexual characters is not deter- 
mined by a number of factors. We cannot discard the assumption of a pre- 
existent tendency for certain sexual characters without doing away with the 
problem altogether. Before all, however, we should think of the possibility 
that the sexual glands actually give off the formative stimulus for many 
a sexual character, especially if we take the viewpoint that some of the sex- 
ual characters come under the dominating influence of the interstitial glands, 
others under those of the generative glands. I have previously set forth 
that if we ascribe to women an independent function of the interstitial and 
the generative glands, the development of the mammary glands seems to 
stand only under the formative stimulus of the follicular apparatus or of 
the ovum. From this standpoint it is worthy of note that Steinach in his 
experiments transplanted not only the interstitial glands but also the follicular 
apparatus. We can readily imagine that the interstitial glands alike, whether 
they come from man or woman, exercise the same protective stimulus on certain 
presexistent masculine or feminine sexual characters; but no one would expect 
the same action from the masculine as from the feminine generative glands. 
Finally we should think of the possibility that the development of many 
of the sexual characters comes entirely or partially under the influence of 
other ductless glands. A new viewpoint has lately opened in this direction, 
a viewpoint that also seems adapted for showing the occurrence of many 
a heterosexual character in a new light. I refer to those observations that 
were described in detail in the consideration of tumors of the suprarenal 
cortex. Women who have developed entirely normally up to or beyond the 
age of puberty become, on the development of such a tumor, amenorrheic; 
the uterus atrophies, and there develops a hypertrichosis. Mustache and 
beard grow, and hairs on the trunk become abundant; in short, the distri- 
bution of hair assumes quite the masculine type. The supposition that this 
heterosexual hairiness is to be referred to a hyperfunction of the suprarenal 
cortex is very probable, suggesting the thought that also in the virile type 
of hairiness that is observed in acromegalic women, or even in normal women 
during pregnancy there is the same cause—for hyperplasia of the suprarenal 
cortex is observed in both conditions. 
Why, however, do we find, in those cases in which the suprarenal tumor 
develops in earliest youth, a premature development of the genitalia with THE EUNUCHS 
401 
marked accentuation of the sexual characters without reversal to the hetero- 
sexual type, while, when it occurs in women who are already matured, the 
activity of the sexual glands fails? In explaining this fact I would refer once 
more to the relations in acromegaly. Here, in addition to marked accen- 
tuation of many sexual characters, in addition to the masculine type, we 
find either, mostly only temporary, increase of the activity of the genera- 
tive gland (even with secretion of colostrum) or, what is more frequently the 
case, the failure of this from the beginning. In this there seems to me to 
lie an analogy with the behavior of the generative glands in tumors of the 
suprarenal cortex; we may assume that hyperfunction of the suprarenal 
cortex always leads to a marked development of the hairiness on the trunk, 
but that an increase of the activity of the generative glands enters in only 
when there is an especial vitality of these glands, while in the cases in which 
vitality fails, there is rapid exhaustion. In the very strong impulses in 
childhood there would come about a pronounced increase (premature develop- 
ment), and in already matured individuals an exhaustion. In acromegaly, 
in which this impulse is very much less feeble, a temporary increase of function 
may first occur, even in late years, although in most cases the exhaustion 
appears in the foreground already from the beginning. 
These observations and convictions ascribe to the suprarenal cortex 
an important trophic influence on a very important sexual character, namely, 
the hairiness. This supposition finds a certain support in embryology and 
histology. Let us recollect that the suprarenal glands as well as the inter- 
stitial glands are of mesodermal origin, that both proceed from immediately 
contiguous parts of the celom, and that the histological picture of cortical 
cells and the interstitial cells present a great similarity. Also Glynn inclines 
to the assumption that the suprarenal cortex is a trophic center for the growth 
of beard and the hairiness on the body, and believes that we should properly 
expect that in man the suprarenal cortex is better developed than in woman. 
As is known, this is really not the case. I would not, however, ascribe any 
great significance to this absence of better development in man. As we can- 
not quite discard the assumption of a masculine or a feminine predisposition 
[Anlage] for the body, it is explicable that with normal impulses the mascu- 
line or feminine type of hair distribution will exist. When, however, the 
impulse is considerably increased, then the virile type in man is potentized, 
while in women the virile type is approached or attained. Even under phy- 
siological conditions, namely, in pregnancy, is there an approach to the virile 
type. This idea also includes the explanation of why in pseudohermaphrodit- 
ismus femininus the suprarenal cortex is usually found so hyperplastic. 
II. AGENITALISM OR HYPOGENITALISM 
i. The Eunuchs 
Occurrence.-—The manifestations of agenitalism or hypogenitalism 
occur in the form of a pure physiological experiment in eunuchs and in “Skop- 
zen.” Castration, as is known, was very much practised in antiquity; even 402 
THE DISEASES OF THE SEXUAL GLANDS 
until a short time ago it was carried out in Italy for “musical purposes,” 
and in the Orient it is to-day carried out on the watchers of the harem, and 
in Russia on the religious sect, the “Skopzen,” on religious grounds. All 
these forms affect male individuals. As to castration of females there exists 
only a very inexact report from India by Roberts. 
Symptomatology.—An excellent exposition of the symptomatology has 
been given by Tandler and Grosz, which I shall in great part follow. The 
action of castration is different according to whether it has been done in early 
youth or after the entrance of puberty. 
We shall first pay attention to the manifestations of loss of sexual glands 
in males. When the castration occurred in earliest youth, the development 
of the accessory genital apparatus is extremely deficient. Penis, prostate, 
and seminal vesicles remain small (.Pelikan). When castration has taken 
place in later years the penis becomes only slightly smaller, while the pros- 
tate shrinks to a greater extent. As is known, castration has been done 
for prostatic hypertrophy; I shall consider in detail later the action of late 
castration. 
In early castration all sexual instinct is absent, and the small penis that 
remains never becomes erect. As the castration is not always complete, 
it may happen some of the eunuchs may still experience a slight degree of 
libido, on account of which some of the harem-watchers in the Orient had 
their penis removed with the testicles. A. Marie reports the case of a forty- 
year-old Egyptian eunuch who had been castrated in childhood, but who 
showed illusory ideas that had an erotic content. 
If castration has been carried out after development of puberty the 
sexual instinct—Mobius calls it the cerebral sexual instinct—is retained 
for a long time; copulation is still possible and there occurs an ejaculation 
of prostatic secretion. 
According to Gall, the cerebellum should atrophy, and indeed in uni- 
lateral castrates the opposite half of the cerebellum. This statement has 
been contradicted, although Mobius pointed out that no certain contradictory 
evidence has been advanced. According to a personal communication of 
Prof. Tandler, however, the statement of Gall is certainly not in accordance 
with fact. 
The statement as to the characters of castrated individuals varies very 
much. For the most part it is stated that castrates lack the courage, the 
passions, and the aspiration of a normal man; they are described as tricky, 
revengeful, and cruel. On the contrary the intellectual capabilities are not 
diminished, as many eunuchs have attained to influential positions. It 
is hard to judge these statements, as in the most of the famous eunuchs, the 
history lacks exact knowledge as to the time and the completeness of the 
castration. Mobius points out that castrates lack the higher artistic endow- 
ments, for the virtuosity of castrated singers cannot be regarded as such. 
At any rate, animal experimentation shows that castrated animals (oxen, 
geldings, capons) lack the courage, the animation, and passions of normal 
male animals. THE EUNUCHS 
403 
Noteworthy is the influence of castration on the skeletal formation and 
the development of the secondary sexual characters. Castration in early 
years leads in man and animals to increase in length {Godard, Pelikan, Pittard, 
Becker, Lortet, Pirsche, Sellheim, Tandler and Grosz, and others). Eunuchs 
of 200 cm. in height are observed often. The tallness first sets in at the 
time of puberty. The closure of the epiphyses is delayed. Many epi- 
physial junctures may remain open until a high age. The ossification of the 
cranial sutures is also delayed. Signs of the frontal, cranial, sagittal, and 
lamboid sutures are retained for a long time. Therewith the skeleton shows 
especial characteristics; the head is small, the tabular part of the occipital 
bone is, according to Gall, flattened. The spinal column is especially short, 
the extremities are lengthened, especially in their distal parts, thus causing a 
certain preponderance of the lower length over the upper length and a rela- 
tively large span width. Often there is genu valgum. The breadth of the 
shoulders is diminished, the pelvis shows a mid-form between masculine and 
feminine type, and remains infantile. In the same cases the sella turcica is 
remarkably large. I have already remarked that I cannot infer from this an 
increase in function of the hypophysis. In the tall eunuchoids the sella 
turcica, as we shall see later, is not enlarged, but rather smaller. The larynx 
remains small, does not ossify, shows childish dimensions, in which the lam- 
inae thyroidise encroach upon each other at a wide angle and the prominentia 
laryngea is indistinct; the voice does not change, and the childish soprano 
is retained. The bones, especially the long tubular bones remain delicate, 
and the sites of the muscular insertions are only very feebly developed. The 
tonus of the muscles is slight, the phenomena of movement should take place 
more slowly. The muscles are permeated with fat. The metabolism of 
the muscles must become essentially altered through the castration, for on 
castration the meat of male animals takes on the characteristic odor, an 
experience that is extensively made use of by breeders. 
The skin is strikingly delicate and pale and in older castrates shows the 
fawn-yellow coloration and wrinkling. It is very poor in pigment. The 
distribution of fat is very characteristic, fully corresponding to that which will 
be found described under dystrophia adiposo-genitalis. Hence there are 
pads of fat in the hypogastric region, and on the mons Veneris, the latter of 
which is bounded above by a horizontal fold; also on the nates, on the hips 
and thighs, on the mammary glands and laterally on the upper eyelids which 
may hang down like bags. In many cases there occurs pronounced adiposity. 
Tandler and Grosz distinguish between a tall and a fat eunuch type, although 
in the first the characteristic distribution of fat is always indicated. The 
muscle meat is, as in the castrated animals, permeated with fat. The tonus 
of the musculature is slight. 
Finally the secondary sexual characters are deficient. While the hair of 
the head is dense, such individuals are beardless, and show only lanugo hairs 
on the face, especially on the chin and the upper lip; in later life, individual 
bristly hairs may develop, similar to those that grow in old women, on the 
lateral parts of the upper lips. The trunk remains completely hairless and 404 
THE DISEASES OF THE SEXUAL GLANDS 
the axillary hairs are absent or are sparse. The pubic hairs are absent, or 
consist in only a few sparse hairs at the root of the penis. Also the peri- 
neum remains hairless. The involution of the thymus gland is slight. 
We know much less concerning the results of castration in the youthful 
female organism. According to the inexact statements of Roberts the female 
castrates grow to be tall, the accessory apparatus of the genitalia remain 
entirely undeveloped, the secondary sexual characters and the breasts do 
not develop. With this rather agree the animal experiments of Hegar, Kehrer, 
and others, and the observation on female eunuchoids that will be mentioned 
later. 
2. Late Castrates 
Castration in man after the onset of puberty is carried out but very rarely. 
In the most cases the indication for it is found in tuberculosis of the testicles. 
Later, in late eunuchoidism, we will learn about the group that depends on a 
traumatic foundation. As, however, in most of these cases the sexual glands 
remain behind in the body and are only shrunken. I classify these cases 
with late eunuchoidism, as it seems to me of like significance whether the 
shrinking of the testicle is the result of a traumatic action or of another disease 
process. 
If castration in man takes place at a relatively early age there occurs a 
pronounced regressive alteration of the genital apparatus, and at least a 
partial retrogression of certain secondary sexual characters, and finally a dis- 
tribution of fat that is similar to that of eunuchs. It is remarkable that 
I was unable to find in the literature an exact description of such a late eunuch. 
From the older literature I quote that of Martin: In war, a piece of shell 
tore away the penis and testicles of a married man. Soon afterward the 
man lost his beard and his breasts began to increase in circumference. More 
frequently is found the statement that on castration in already fully developed 
individuals a retrogression of an already developed accessory genital apparatus 
and of the secondary sexual characters does not occur. 
A short time ago I was able to observe carefully a suitable case, and I 
herewith report it: 
Observation XLVII.—Kr. J., forty-nine years old. Entered the clinic July, 1912. 
In the eighteenth year of life he had gonorrhea and bilateral orchitis. In the nineteenth 
year of life he acquired lues. In the twenty-first year of life there began a swelling of the 
cervical lymphatic glands and at the same time a caries of the lower jaw; the latter continu- 
ing three years and disappearing after operative procedure. In the twenty-sixth year of 
life, both testicles were removed on account of tuberculosis. A year after the operation 
the patient suffered with cardiac palpitations, that later disappeared. In the thirty- 
seventh year of life he developed a goiter after a trip to the Steiermark, which goiter later 
receded. For several years he has had attacks of typical bronchial asthma. 
Since the castration the patient has gradually gained about 30 kg. The potentia 
coeundi still exists, but coitus is carried out but very rarely; ejaculation takes place, but 
since the operation libido has been very slight. 
The mustache, which even before was not developed very strongly, has become very 
much more sparse since the operation, so that there exists on the upper lip only a small LATE CASTRATES 
405 
strip of sparse hairs, as is seen in the accompanying photograph. The beard on the cheek 
is now so sparse that the patient has to shave himself much less frequently than formerly. 
The hairiness of the mons Veneris is very sparse, it is a little denser at the root of the penis. 
Here it terminates above in a horizontal line. 
The penis is only 3 cm. long, the foreskin has become too long and, therefore, shows 
numerous transverse wrinklings. In an erect condition the penis is only 4cm. long. 
The hairiness in the axillae, on the trunk and on the perineum and on the extremities is 
entirely absent. 
The patient is rather fat, the breasts are pronouncedly rich in fat, and the hypogastric 
region and the mons Veneris are also rather fat. 
The case reported is not entirely free of object- 
ions, as it might be supposed that the previous 
gonorrhea and luetic infection and the tuberculosis 
may have damaged the sexual glands seriously even 
before the castration. Nevertheless the state- 
ments of the patient that the alterations described 
took place only after the operation are very 
precise. 
In the female sex castration after puberty 
has been carried out frequently by the gynecolo- 
Fig. 69.—Late castrate. 
Fig. 70.—-Genitalia of a late castrate, 
gists. It leads regularly to atrophy of the uterus and vagina. Menstruation 
remains absent. The external genitalia, especially the clitoris, shrink, the vagina 
becomes narrower. In female animals the sexual instinct ceases. Bucura 
experimented on rabbits. If after the castration the female did not admit 
the male, this was a sure sign that the operation had succeeded. Also after 
castration in women is the sexual sense reduced. Gloevecke found this in 
78% Pfister in 73% Alterthum in 68%. In women who have been having 
sexual intercourse for a long time, libido may be retained for a while. In rare 
cases (Mandl and Burger, Pfister) the libido may be increased for a time after 
the castration. 
After the castration the skin becomes lighter on account of loss of pigment 
{Pfister). The hair of the head becomes luxuriant. There is no distinct 406 
THE DISEASES OF THE SEXUAL GLANDS 
influence on the shape of the breasts; but the nipples show a slight grade of at- 
rophy, and the areolae become light-rose in color through partial loss of pigment. 
As in man, there is in woman after castration a tendency to corpulency. 
Considerable increase in weight was found by A Iterthum. in 29.5% by Glaevecke 
in 57-5%- 
The behavior of the respiratory metabolism after castration has become 
a subject of lively discussion. Lowy and Richter found in female castrated ani- 
mals the basal metabolism lowered about 20% in the males about 14%. On 
administration of ovarian substances it again rose to normal. Again, Luthje 
has pointed out that the slight reduction of the basal metabolism was to be 
referred to the greater phlegma of the animal, v. Noorden has subjected the 
experiments that exist in the literature to a thorough criticism, and comes 
to the conclusion that a reduction of the basal metabolism has not as yet been 
strictly demonstrated. The clinical observation of an increased deposit of fat 
after castration is ever known “on account of the broad basis on which it rests, 
unquestionable.” Recently, further investigations by L. Zuntz have been 
made on three women who were castrated on account of gynecological com- 
plaints. During the first week Zuntz found no distinct reduction of the basal 
metabolism. In all cases there was found, after a long time, a slight fall of the 
oxygen consumption, as much as 20%. The administration of oophorin was 
not able to produce a distinct addition to the oxygen consumption. We shall 
see later that also in eunuchoidism, in the few investigations that have been 
made up to the present, the respiratory metabolism was found to be rather 
normal. There is no ground, however, for the fact that the corpulency that 
develops after castration in a great majority of cases does not depend directly 
on the loss of the sexual gland, as small turnings of the scale not demonstrable 
by our present methods may amount to something in the course of years; and 
as the disturbance in the regulation of the fat metabolism does not depend 
exclusively on the basal metabolism (see Chapter XIV). 
Very little is known as to the other alterations of the metabolism that occur 
after castration. Also the action of the sexual glandular substances introduced 
in the organism has not been sufficiently studied up to the present. As we 
have seen before, its influence on the respiratory metabolism is still subject to 
controversy. Many authors (.Matthis, Neumann and Vas, and others) found 
under the influence of oophorin a slight increase in the elimination of nitrogen, 
and an increase of the elimination of salts, especially of the elimination of phos- 
phorus through the intestine. 
Cristojoletti saw after the administration of ovarian substances the glyco- 
suric action of adrenalin become weaker. 
In woman, the acute loss of the sexual glands leads, as is known, to a series 
of manifold excitatory states of the vegetative nervous system. Drawing 
pains, emotional excitements, feeling of anxiety, headache, fainting spells, 
heat and feeling of cold, disturbance of the intestinal tract, weakness of memory, 
and mental depression occur. The wave-movement ceases. The manifestations 
become intelligible when we consider what distinct revolutions occur in the 
female organism after castration. EUNUCHOIDISM 
407 
Cristofoletti saw after castration (also in animal experiments) increase of 
the glycosuric action of adrenalin. Alder found delay in the coagulation-time 
of the blood and reduction of the calcium in the blood. 
As is known, all these manifestations occur also at the climacteric. “Cas- 
tration produces an artificial climax, that is like the natural one, and often tran- 
scends it in pathological manifestations” (IT. H. Freund). 
The treatment of eunuchoidism will be considered further on. 
3. Eunuchoidism 
Dystrophia adiposo-genitalis, gerodermia genito-distrofico, obesite d’ori- 
gine genitale. 
Definition.—Eunuchoids we term, according to Tandler and Grosz, indi- 
viduals who, without being castrated, entirely simulate in their clinical manifesta- 
tions the true eunuch type, or at least are extraordinarily similar to it. They 
are either tall, or if complications are absent, are at least not stunted in growth; 
they show the typical fat distribution of eunuchs, and eventually pronounced 
obesity; the epiphysial junctures persist abnormally long, the skeletal dimensions 
are characterized by an especial length of the extremities, and furthermore the 
individuals show a definite psychical habitus. Finally there is found a more or 
less pronounced disturbance of development of the genitalia with faulty development 
of the secondary sexual characters. It is probable that in such cases we have to do 
with a developmental disturbance beginning primarily in the sexual glands, and 
indeed especially the interstitial glands, as functional disturbances of the generative 
glands alone do not lead to eunuchoidism. 
Historical and Case Histories.—Such a case was first termed eunuchoid 
by Griffith. A sharp delimitation of the clinical picture occurred only a short 
time ago, when Tandler and Grosz first reported a series of cases and then 
described the clinical picture thoroughly. Even before Tandler and Grosz, 
however, a great number of such cases had been reported in the literature under 
very different names. 
Meige mentions a case of Reichlin’s that was a pronounced eunuchoid. 
Moreover Tandler and Grosz regard as an eunuchoid the case of Redlich. Simi- 
lar cases were described by Kisch. Kisch distinguishes between hereditary 
and acquired obesity and divides the hereditary obesity into two forms, one of 
which develops in early youth and which becomes prominent later, and in 
which only the predisposition to obesity is inherited. Then Kisch mentioned 
that the hereditary obesity “acquires a quite characteristic nutritive expression 
of degeneration.” The description of these types that Kisch furnishes suits 
entirely, as Tandler and Grosz points out, the eunuchoid type. Among two 
hundred thirty-eight cases of obesity, Kisch saw it twenty-four times, seventeen 
of these cases developing at an early age. 
Pirsche cites the case of Papillaunet and adds three observations of his 
own. Other cases have been reported by Etienne, Jeandelize and Richon 
(man fifty-nine years old, 174 cm. tall, preponderance of the lower length, 
epiphysial junctures incompletely closed, the testicles—one cryptorchiditic— 408 
THE DISEASES OF THE SEXUAL GLANDS 
very small and fibrous, seminal vesicles and prostate also small and fibrous, 
penis 4 cm. long); and by Duckworth (thirty-seven-year-old man, 171.7 cm. 
tall, 179 cm. span width, considerable preponderance of the lower length, 
marked fibrosis of the testicles, the prostate, and the epididymis, already 
described by Griffith)', already Duckworth mentions the similarity to “cryptor- 
chid conformation.” Very worthy of mention 
are the cases of Sainton of five brothers (and 
sisters), three were eunuchoids, and besides this 
an uncle and great-uncle. The case described 
was 172 cm. tall. The lower length predomin- 
ated considerably. The thymus gland was not 
persistent. I believe that also the case of Babon- 
neix and Paisseau (case I) and that of Lemos 
Magahaesl belong to this group; also the case of 
Thibierge and Gastinel (termed gigantism with 
infantilism). 
Neurath furnishes the description of an 
eleven-year-old tail-grown girl with typical 
“eunuchoid” obesity, that is very likely a case 
of eunuchoidism. 
Also the case of Porhon and Mihaelesco 
described by these authors as “ cas d’ infan tilesme 
dysthyreoidique et dysorchitique” seems to me 
to belong to this group, as also the case of “an- 
orchidia” of Launois and Roy. 
Also the case of “ cryporchides abdom- 
inaux” Variot; also a case of Apert, also case I 
of Babonneix and Paisseau would fit in this 
group very well. 
Of special interest is the case of Josefson 
and Lundquist that affected a female eunuchoid, 
I shall consider this in detail later on. I also 
mention here briefly the case of Peritz. 
During the course of the last few years, I 
have seen four cases, which I shall report, before 
entering into the description of the symptom- 
atology. 
Observation XLVI1I.—B. Sch., thirteen and one-half years. First observed November, 
1910. Father had lues at the age of twenty years. His Wassermann still positive. As a 
child the patient had an umbilical hernia, and a left-sided inguinal hernia, also slight con- 
stipation. The umbilical hernia healed three months after birth, the inguinal hernia only 
after some years, three years ago operation on the tonsils. 
Before this, always sore throat and snorings. For about three years gradual onset of 
obesity. In addition vomiting sometimes, especially after breakfast. When the vomit- 
ing has finished, appetite returns. The boy now weighs 55kg. The body build is slender. 
The skin pale, soft, satiny, facial complexion pale, marked collection of fat on the 
Fig. 71.—Case of eunuchoidism 
(Observation XLVIII). EUNUCHOIDISM 
409 
Fig. 72.—Sella turcica in eunuchoidism (Observation XLVIII). 410 
THE DISEASES OF THE SEXUAL GLANDS 
breasts, in the inguinal region and on the mons Veneris. The penis is quite small, as is also 
the'scrotum; the right testicle is about the size of a plum-kernel, the left is about half the 
size and is not quite descended. Examination of the eyes shows entirely normal rela- 
tions. Likewise the X-ray examination of the skull [i.e., normal]. Sella turcica rather small. 
Temperature 36.2°, circumference of the head 54 cm. 
Erythrocytes, 5,290,000 
Hemoglobin, 95 per cent. 
Leucocytes, 10,700, of which: 
Polymorphonuclear neutrophiles, 49.6 per cent. 
Large mononuclears, 3 per cent. 
Lymphocytes, 42.4 per cent. 
Eosinophiles, 5 per cent. 
Genu valgum on each side. 
The boy is well developed mentally, but lazy. 
He is silent, especially in intercourse with com- 
panions of the same age. 
Thyroid small, hardly palpable. Liver and 
spleen not enlarged. 
Thyroid gland treatment. Loss of about 3 kg. 
June, 19x1. The boy has grown, still very fat, 
typical distribution of fat. The testicles are not 
better developed. The right testicle has a long- 
itudinal diameter of about 25 mm., the left of about 
18 mm., the latter is fully descended. 
Leucocytes, 10,800, of which: 
Polymorphonuclear neutrophiles, 50.94 percent, 
Lymphocytes, 31.26 per cent. 
Large mononuclears, 12.8 per cent. 
Eosinophiles, 3 per cent. 
Eye examination normal. 
January, 1912. A new X-ray examination of 
the skull showed that size of the sella turcica had 
not essentially altered. The examination by a per- 
imeter showed an entirely normal visual field. The 
thyroid treatment was tried once more, which, how- 
ever, soon led to slight signs of hyperthyroidism and 
hence had to be abandoned. The patient was then 
ordered radium baths three times a week with 
100,000 Mache units per bath, which perhaps exer- 
cised a favorable influence. At all events there 
became apparent a distinct progress of the develop- 
ment, as even the patient thought in June, 1912. 
The patient was now 174 cm. tall and still somewhat 
fat. Abundant fat deposits were to be found in the 
hypogastric region. The pubic hairs were now well 
grown, but still showed a horizontal boundary above. 
The trunk was still fully bald, and only in the axillae 
on both sides were a few sparse hairs to be seen. 
The size of the penis and the testicles corresponded 
to the age of the patient. It was stated that pollutions had not as yet occurred. The 
voice had changed and the patient complained only very rarely of headaches. Some ade- 
noid vegetations in the nose were now removed. 
Summary.—Here was a typical case of eunuchoidism. The headaches and the occa- 
sional vomitings at first awakened the thought of a hypophysial tumor; but the X-ray 
Fig. 73.—Case of eunuchoidism 
(Observation XLIX). EUNUCHOIDISM 
411 
examination of the skull and the observations, continued for three years, and especially 
the absence of an inhibition of growth, ruled out this possibility, the inhibition of develop- 
ment seemed to be only transitory, that has recently been made up for very considerably. 
Observation XLIX.—Dat., from Jerusalem, twenty years old. Entered the clinic 
December, 1905. Typhoid fever at the age of sixteen years; since this time chronic enteritis. 
Total length 159 cm., circumference of head 57 cm., of breast 74 cm., of abdomen 87 cm., 
anterior superior spine to internal malleolus 88 cm., acromion to styloid process of radius 
57 cm., acromion to oleocranon 35 cm. 
Distantia spin, 26 cm. 
Distantia crist, 27 H cm. 
Distantia trochant, 29 cm. 
Slender build, marked emaciation, except that there are fat deposits on the hips and 
mons Veneris. Milk-teeth in part retained. The penis and scrotum quite small. Testicles 
Fig. 75.—Genitalia in case M. W. (Observation L.) 
Fig. 74.—Eunuchoidism (Obser- 
vation L). 
on both sides in the inguinal canal; very few hairs at the root of the penis. No hairs in the 
axillae, no beard. Never erections, no libido. 
Marked hyperextensibility of the joints, especially the phalangeal joints of the fingers 
The fingers can be bent backward to a right angle, and the knees can rest comfortably 
in the axillae. Fingers are very long and slender. 
Sexual life entirely absent. 
X-ray examination shows that the distal epiphysial junctures of the ulna and radius, the 
proximal of the first metacarpal bones and proximal of the phalanges are still open; the bones 
seem rarefied. 
The sella turcica is rather small. 
Striking is a short, round, and sharply delineated calcification in the anterior part of the 
sella turcica immediately beneath the clinoid process. 412 
THE DISEASES OF THE SEXUAL GLANDS 
Ftg. 76.—Sella in a case of eunuchoidism (Observation L). EUNUCHOIDISM 
413 
Slight genua valga. 
Voice high. 
Indistinct prominentia laryngea. 
Thyroid not palpable. 
Test for alimentary glycosuria (ioo and 150 gm. dextrose respectively) negative. 
Observation L.—M. W., twenty-three years old. March, 1903. Genitalia hypoplastic, 
as far back as patient can remember. Deposits of few 
on the mons Veneris and hips, which during the last fat 
years have become more strongly developed. Never 
libido; erections often since the eighteenth year, during 
which the penis becomes about 3 cm. long. Has never 
had sexual intercourse. Recently, several pollutions. 
Patient is 169 cm. tall. 
Length of lower extremities (from ant. sup. spine 
of ileum to int. malleolus) 87 cm.; length of the upper 
extremities (from head of humerus to end of third finger) 
76 cm. Span width 184 cm., genu valga. Copious de- 
posits of fat on the hips, on the outer sides of the thigh 
and on mons Veneris. Mammae not very rich in fat. 
No beard hairs at all. Abundance of hair on head. 
Hairs in axillae sparse; pubic hams present, not very 
luxuriant, bounded above by a horizontal line. No hair 
on the linea alba. No hairs on the thighs. Genitalia 
hypoplastic. Penis small, scarcely 1)42 cm. long. Each 
testicle about size of a bean, soft. 
X-ray.—Sella turcica normal, the distal epiphysial 
junctures of the radius and ulna, and the proximal of 
the first metacarpal phalanges are still open. 
Leucocytes, 7600 of which 46% are neutrophilic 
polymorphonuclear cells. Voice higher. Prominentia 
laryngea not palpable. Thyroid gland not distinctly 
palpable. Test for alimentary glycosuria (100 and 150 
gm. dextrose) negative. Character: Silent, not commu- 
nicative, somewhat shy. Intelligence normal. 
Observation LI.—H. Ad., twenty-eight years. En- 
tered clinic April, 1912. The patient had nine brothers 
and sisters, five of whom died shortly after birth. One 
sister had chlorosis. One brother when a child appar- 
ently had laryngospasm. Since his sixteenth year the 
patient has suffered with a gradually increasing chronic 
exudative articular rheumatism. He states that once 
during an exacerbation of the joint affection, he lost 
much weight. Then in the twenty-first year he was 
at a bath-resort and in a short time, gained 42 to 48 
kg. Later this became obesity. Then during another 
attack of articular rheumatism he again lost weight. 
Now the body weight is 66% kg. 
The patient states that he has experienced 
sexual sensations since the twelfth year of life. Later 
he often had erections, in which the penis became quite stiff. His inclination was 
always for young boys, however, and occasionally he practised active pederasty. Since 
his sixteenth year, his inclination gradually turned to women, but the libido was never 
very strong. He had love-episodes but he never attempted coitus, as he knew that he was 
impotent. Later, never pollutions; the penis has always been very small. 
Fig. 77.—Eunuchoidism (Observa- 
tion LI). 414 
THE DISEASES OF THE SEXUAL GLANDS 
The patient is 176 cm. tall, of typical eunuchoidal form and dimensions. The span width 
is 185% cm., the lower length nearly 100 cm. The thorax is small in relation to the pelvis, 
the head is small, the prominentia laryngea is only indicated. Bilateral genua valga. 
The patient is very intelligent but very taciturn speaking only when he is spoken to. 
The [mental] attitude is often depressed. 
The voice is high, the thyroid gland not distinctly palpable. Typical distribution 
of fat, and a thick pad of fat on and superior to the mons Veneris. Marked fat collection 
in region, which is separated from the mons Veneris by a deep fissure, also 
fat on the outer sides of the thighs and on the buttocks. The breasts are very rich in fat. 
On the hips are striae (the results of former obesity). 
Hair.—No beard, no axillary hairs, hairs on the mons Veneris only sparse, forming a 
horizontal line above. No perineal hair. Hair on the trunk otherwise absent. 
Fig. 78.—Genitalia in Case H (Observation LI). 
The penis is 3 cm. long, as in a five-year-old boy. The testicles are palpable in the 
scrotum, above the size of beans, very soft. The prostate is very small. 
The breadth of the heart as shown by X-ray examination is only cm. 
The X-ray examination of the skull shows a small but otherwise well formed sella 
turcica. X-ray examination of the hand shows that the proximal epiphysial junctures 
of the phalanges are still open, and that the distal are closed. Open are the proximal of the 
first metacarpal and the distal of the radius and ulna. 
Blood examination: Erythrocytes, 5,800,000. 
Hemoglobin, 75 per cent. 
Leucocytes, 5500, of which: 
Neutrophiles, 59 per cent. 
Lymphocytes, 16)4, per cent. 
Large mononuclears, per cent. 
Eosinophiles, 3 per cent. 
Examination of the respiratory metabolism (Dr. Bernstein). 
CO2 in cc. O2 in cc. 
176.5 221.0 
C02 02 RQ 
2.67 3.31 0.8088 EUNUCHOIDISM 
415 
Fig. 79.—X-ray picture of the hand in eunuchoidism (Observation LI). 416 
THE DISEASES OF THE SEXUAL GLANDS 
According to this the oxygen consumption is entirely normal. 
Test as to alimentary glycosuria (ioo and later 200 gm. dextrose negative). 
Summary.—Typical case of eunuchoidism, in which a slight function of the sexual 
glands was present at the time of puberty, which, however, soon disappeared. 
Symptomatology.—The form of eunuchoids is characterized by its slender- 
ness. Even in fat individuals the bony build is slender, and especially the 
tubular bones are striking by their length. The head is small, the hands 
are slender and long. This is well shown in the accompanying photographs. 
Tallness is the rule in most of the cases. There are cases known that were 
nearly 200 cm. tall. As far as I can judge by the literature, individuals with 
eunuchoidism who are not pronouncedly tall are never, on the other hand, 
small. In the case I reported the height is never below what corresponds to 
the age. Only case Da is small, but here the parents are very small. Hence 
there usually exists abnormal tallness and at all events never, unless especial 
complications should exist, stunting of growth. We shall see later that this 
is important for differential diagnosis from hypophysial dystrophy. 
The dimensions of the skeleton in eunuchoidism are characterized by the 
especial length of the extremities. There is almost always found an excess 
of the lower length over the upper length and of the span width over the body 
length. I quote some examples. In the case of Duckworth the body length 
was 171.7 cm., the span width 179 cm. in Observation LI, H., the length 
was 176 cm., the span width cm., the lower length 100 cm. In 
Observation L, the height was 169 cm., the span width 184 cm. The tallness 
the preponderance of the length of the extremities is brought about by an 
abnormally long remaining open of certain epiphysial junctures, namely, 
those which usually ossify the latest. According to Tandler and Grosz they 
are chiefly the following: The sternal end of the clavicle, the proximal end 
of the humerus, the distal ends of the radius and ulna, the distal of the tibia 
and fibula, the crista ilei, the tuber ischii. Often at the site of the coronal 
and the parietooccipital sutures is found a tertiary suture formation. The 
root of the nose is often deeply saddled. On the contrary the bone-nuclei 
are apparently always correspondingly well-developed. At least in Observa- 
tion Sch, I could find at the fourteenth and at the sixteenth years of his life 
that there was a development of the bone nuclei corresponding to his age. Also 
in Observation W. M. (twenty-three years) and in Da (twenty years) the bone 
nuclei are already developed very well. 
At later years the junctures may be fully closed (Case Thibierger and Gastinel). 
The sella turcica, so far as observations have been made on it is normal 
in size or rather small (Tandler and Grosz, also the author’s observations). 
This agrees with the observations of Eppinger, that in women with infantile 
genitalia, the sella turcica is rather small. In my case a small focus of calci- 
fication was found on X-ray examination (Observation Da). 
Almost always there are genua valga. These were always present in my 
cases. Moreover, I could often observe the hyperextensibility of the joints, 
especially of the phalanges of the fingers (see case Da). At the diaphyses 
the bones are commonly rarefied. EUNUCHOIDISM 
417 
The dentition is sometimes retarded. In Observation Da, milk-teeth 
were present at the twentieth year. 
The larynx remains cartilaginous and retains the dimensions of child- 
hood. The angle of the laminae thyroidae remains wide. The prominentia 
laryngea is only slight. In highly pronounced cases voice remains high and 
is usually shrill. 
All cases show the typical distribution of fat, that is, pads of fat on the 
mons Veneris and the hypogastric region, which latter is separated from the 
mons Veneris by a deep furrow. Moreover, there are copious fat deposits 
on the buttocks and on the outer sides of the thighs, and fat deposits in the 
breasts. Tandler and Grosz distinguish, as in true eunuchs, a tall and a fat 
type. The tall individual always shows the eunuchoid distribution of fat, 
however. Also in these individuals, who from some reason or other have lost 
weight, is the distribution of fat always at least indicated by an inclination 
to become fat. When the conditions are favorable, the obesity develops 
surprisingly rapidly (see Observation H). It may attain an excessive 
degree. Tandler and Grosz report a case in which a 6 kg. pad of fat was removed 
by operation from the hypogastric region, which removal seemed to make the 
patient easier. 
The hair of the head is abundant. There often lanugo hairs on the 
face, especially in front of the ears and on the chin and upper lip. There are 
no mustache and beard. In later years occur on the lower jaw sparse bristly 
hairs, such as are seen in old women. The hair in the axillse is absent or 
only sparse, that on the mons Veneris is limited to a few short hairs at the 
root of the penis. When they are more abundant in this situation they are 
limited above by a horizontal line. There are no hairs on the perineum; nor 
on the trunk and extremities. 
The skin is remarkably delicate, pale, velvety, and sometimes has a fawn- 
yellowish color. The face in older individuals often shows folds and wrinkles. 
As a rule the musculature is but little developed, and shows but slight tonus. 
In most cases the thyroid glands seem to have a slighter volume, at least 
the statement is repeatedly made that the thyroid was not palpable. 
The genitalia are pronouncedly hypoplastic. The penis is always very 
small and sometimes quite buried in the fat pad on the mons Veneris. The 
scrotum is small and smooth and hairless. The prostate is small. The 
testicles are small, soft, and sometimes not larger than a pea. Sometimes 
they are not or only partially descended on one or both sides. In this case 
the inguinal canals are open. Autopsies were made in the case of Etienne, 
Jeandelize and Richon, and in the case of Duckworth and of Tandler and Grosz. 
In the case first named the testicles were very small, fibrous (3 gm.), the inter- 
stitial glands were degenerated. Also the prostate was very fibrous. On 
microscopical examination, Tandler and Grosz found sparse seminal canals and 
sparsely developed interstitial substance. Also the seminal vesicles were small, 
but the epididymis on the other hand, well developed. 
Cases of female eunuchoidism seem to be rare. Josefson and Lundquist 
have reported such a case, which I shall quote somewhat in detail. 418 
THE DISEASES OF THE SEXUAL GLANDS 
Thirty-four-year-old woman who had kept on growing from the fifteenth year on 
(the growth had been especially active up to the twenty-fourth year); she was 183.6 cm. 
tall (upper length 118 cm.), she had never menstruated and had felt only slight inclination 
for men; the mammae were small, flat, without palpable glandular substances, the nipples 
very small; she had rather a mannish appearance, but a feminine voice. The form of the 
pelvis was rather womanly. The epiphysial junctures were closed, the sella turcica not 
enlarged. Examination of the genitalia showed very small labia minora, a hypertrophic 
clitoris, the vestibule was rather narrow, the internal genitalia were not palpable. No 
introitus vaginae or hymen. 
In eunuchoids the genital function is always markedly reduced or entirely 
absent. In many cases, however, erections are possible despite the smallness 
of the penis. I refer to the Observations Da and H. In many cases libido 
is entirely absent, although it may be present slightly. In one of my cases 
the inclination was at first homosexual. In many cases potency can exist 
for some time, but this becomes less after some years and disappears. In 
other cases the inhibition of development and disturbance of function occurs 
chiefly at the time of puberty and later becomes compensated (transitory 
eunuchoidism). We may regard both as formes frustes. As a case of the 
first form I would regard case II of Josefson and Lundquist. It was that of a 
forty-five-year-old man who had been married since the thirty-sixth year and 
who was entirely impotent for three years. The breasts had been very rich in 
fat ever since youth and the pubic hairs ended above in a horizontal line, the 
voice had not changed, the hairs of the beard and in the axillae were very sparse, 
trunk hairless. 
Eunuchoids of the male and female sex are always sterile. At least no 
case of procreation or conception is known. 
In woman, the breasts are poorly developed or fatty, but poor in glandular 
substances; in man they often contain much fat. 
Observations on the respiratory metabolism have as yet been confined to 
Observation H and to a female eunuchoid of L. Zuntz’s. The value of O2 
requirements is entirely normal. Of course from which we are not justified 
in concluding that in such cases we may not have had a slight degree of endo- 
genous obesity, as small differences may not be evident on investigation, 
and yet through summation may favor deposition of fat. It is certain that in 
all these cases there is present an abnormal disposition for the deposition of 
fat, as was observed for example in the case of H. At all events the cause 
may be due chiefly to the slight inclination for movement and to the individual’s 
phlegma. 
Test for alimentary glycosuria was undertaken in three of my cases, with 
150-200 gm. dextrose, and always resulted negative. Hence the assimilation 
limits for carbohydrates seem to be high. 
Guggenheimer reports a case in which at an old age diabetes developed. I 
cannot see here an especial connection with eunuchoidism. In eunuchoidism 
(as in normal individuals) there may very well set in a degeneration of the 
pancreatic insular apparatus. Another case of eunuchoidism with diabetes 
seems to be the “giant” described by UhthojJ. This patient at the age of six- 
teen years suffered an attack of pneumonia. From then on abnormal growth. EUNUCHOIDISM 
419 
He was 194 cm. tall, hands and feet were not especially large. There existed 
bilateral cryptorchidism, the pubic hairs were sparse, and he had never been 
potent. 
The purin metabolism has been studied (not published) in one case only, 
Observation H of Nowaczinski and myself. The endogenous uric acid elimina- 
tion was normal. Purin administered exogenously was well eliminated. 
Perhaps this behavior is of differential diagnostic importance as against hypo- 
physial dystrophy. 
The blood examined in my case showed normal values for erythrocytes 
and hemoglobin. The leucocyte count was near normal; in all cases there 
existed a pronounced mononucleosis. Lately also Guggenheimer has found 
the marked predominance of lymphocytes in several cases of eunuchoidism; 
in one case he saw hyperleucocytosis with predominance of the mononuclear 
cells.1 
The thymus gland showed abnormally slight involution (Kolisko, and 
Tandler and Grosz). 
The findings in the internal organs show no essential alterations, except 
such as must be regarded as coincident. In one case the heart shadow as 
shown by the X-ray was seen by me to be strikingly small. 
Perhaps the excitability of the vegetative nerves in cases of eunuchoidism 
is somewhat reduced. This was tested in some cases with pilocarpine and 
adrenalin, yielding a slight, but distinct, reaction. 
The development of the intelligence in such individuals is mostly entirely 
normal. Feeble-mindedness, which has been observed in some cases, is to 
be referred to other coincident developmental disturbances. On the contrary, 
certain common traits do exist in the psyche of eunuchoids. Eunuchoids are, 
as Tandler and Grosz notice, strikingly quiet, but little communicative, and often 
but slightly independent. At any rate this mental condition is not to be 
designated as infantile. The masculine quality is all that is lacking. 
Occurrence and Pathogenesis.—Eunuchoidism, at least as far as its pro- 
nounced forms are concerned, occurs essentially more frequently in the male 
sex. Thus far the only typical incontestable case in woman has been reported 
by Josefson and Lundquist. Perhaps to this may be added the previously 
quoted cases of Swinarski, Pfannenstiel, and of Howitz. But here there are no 
statements as to the proportions of the body, which would be very important 
for the diagnosis. Animal experiments show us that castration in early life 
produces long-legged individuals in the female also. We know very little as 
to the cause of the developmental disturbances in the sexual glands. As was 
] Guggenheimer states that in two cases of eunuchoidism he found hyperglobulia. He mentions, 
moreover, that in these cases after the injection of adrenalin there never occurred an increase of 
erythrocytes, but even diminution of these. He says that he could not “corroborate” the hyper- 
globulia after injection of adrenalin as observed by Bertelli, Schweiger, and myself. This expres- 
sion seems to me out of place. We have never asserted that we saw hyperglobulia after the injec- 
tion of the doses of adrenalin used in man. The hyperglobulia observed by us in the dog after 
larger doses had already declined after twenty-four hours. Guggenheimer, however, tested very- 
small doses of adrenalin twenty-four hours after injection. The individual values for the ery- 
throcytes in Guggenheimer’s case also varied appreciably in the days uninfluenced by adrenalin. 420 
THE DISEASES OF THE SEXUAL GLANDS 
mentioned previously, eunuchoidism in the male sex is very frequently asso- 
ciated with cryptorchidism. This may be either abdominal or inguinal. It 
may well be regarded as a partial manifestation of the developmental disturb- 
ances and not as its cause. Moreover the developmental disturbance may 
very well be congenital if it first manifests itself at the age of puberty. It is 
also conceivable that traumatic and infectious insults in early youth may 
damage the sexual glands and thus lead to eunuchoidism. This is especially 
true of mumps, perhaps also of scarlet fever, measles, etc. We shall meet 
with these etiological factors again in the consideration of late eunuchoidism. 
Not rarely, eunuchoidism is hereditary. The case concerned in direct repro- 
duction can be only the lightest cases, those principally associated with obesity 
in childhood. On the contrary, it is conceivable that cases that do not repro- 
duce may now and then crop up in a family. Such a familial occurrence has 
been reported by Sainton. Of five living brothers and sisters, three were 
eunuchoids and besides this an uncle and great uncle. 
Grandfather 
Great-uncle 
Uncle 
Mother 
¥ 
Died early 
Very noteworthy is the observation that eunuchoidism and chlorosis 
can occur in the same family (Tandler and v. Noorden) (see also Observation H). 
Differential Diagnosis.—Differential diagnostically, infantilism and hypo- 
physial dystrophy come chiefly into consideration. The former in the pure 
forms shows retention of the childish dimensions. Also the psyche remains 
infantile; but the psyche of male eunuchoids although mannish, can hardly be 
called childish. Peretz and Wolf are wrong in their attitude against the de- 
limination of the eunuchoid type. When they call eunuchoidism a pure form 
of infantilism, they are confused as to the meaning of the diseases. Both the 
female individuals that Peretz describes are to my mind not eunuchoids, but 
infan tiles (see Chapter XII, Infantilism). Naturally there occur also mixed 
forms of infantilism and eunuchoidism, hence cases of infantilism in which the 
development of the sexual glands not only remain at a childish stage, but their 
function is much more seriously disturbed. It must not be forgotten that 
normally the interstitial glands functionate also in children, even if a sub- 
ordinate degree only. Such cases show in addition to the infantile features 
also more or less distinct eunuchoid dimensions and the typical distribution of 
fat such as is not a feature of true infantilism. The four female cases of Wolk 
are not true eunuchoids. One of them is apparently a true dwarf, the others 
are cases of infantilism, or at least transitional cases which tend nevertheless 
more toward infantilism. 
The differentiation from hypophysial dystrophy is on the whole not 
difficult. Common to both are the genital disturbance and the association of 
fat distribution or obesity. Hence there are an eunuchoid and hypophysial 
form of dystrophia adiposo-genitalis. The two forms are different from each 
other: EUNUCHOIDISM 
421 
1. By the growth in height. In the hypophysial form, so far as it sets in 
in childhood, is found pronounced inhibition of growth; in the eunuch- 
oidal form is found even tallness, or at least no growth disturbances. 
2. Eventually through the behavior in metabolism. In the severe forms 
of hypophysial dystrophy the basal metabolism is usually dis- 
tinctly reduced in the end; in the eunuchoid form the reduction is 
perhaps not considerable enough to become demonstrable. The 
answer to these questions will depend on further investigations. 
3. Through the cerebral manifestations in hypophysial dystrophy. 
Here in most cases are found signs of a hypophysial tumor or of, at least, 
a tumor in the hypophysial region, or at least signs of increased brain 
pressure. One should not forget, however, that cases of eunuchoidism 
at the time of puberty not at all rarely complain of headaches; and 
occasional vomiting may occur (two cases under my observation). 
In such cases the X-ray examination of the sella is very important. 
At all events there are also processes that may destroy the hypophysis 
without distinctly altering the sella and producing symptoms of brain- 
pressure; for examples gummata or chronic inflammations. Such proc- 
esses indeed set in after completed development. Hence here comes 
into consideration the differentiation from late eunuchoidism or from 
multiple ductless glandular sclerosis. 
The blood examination in the hypophysial as well as the eunuchoid form 
mostly shows a pronounced mononucleosis. Hence here there is no dis- 
tinguishing factor. We can at most say that in the hypophysial form, at least 
in the severe cases, the hemoglobin and the erythrocyte count are often more 
markedly reduced. 
Prognosis and Treatment.—Very important is the observation of Tandler 
and Grosz, that in the eunuchoidism that sets in early, developmental dis- 
turbances of the sexual glands are often only temporary (prepubertial eunuch- 
oidism). Hence such cases may be improved. One of my cases showed such 
a condition. At the sixteenth year (Observation Sch) the voice had changed, 
the genitalia had developed almost normally, but as yet there had occurred 
no pollutions. In these cases the obesity is only improved for the abnormal 
distribution of fat still exists. In such cases we would recognize the develop- 
mental disturbances later in life by the distribution of fat, and probably also 
by the hair condition. Also it is very probable that in these cases the function 
of the sexual glands disappears prematurely. Case II of Josefson and 
Lundquist seems to point in this direction. 
Rapid improvements have been reported from the thyroidin treatment. 
Apert mentions a case complicated with cryptorchidism in which after one- 
half year’s treatment with thyroidin, the penis had distinctly grown, the 
testicles had lowered, and the weight had increased about kg. 
Also Parhon and Mihailesko report a similar case in a fourteen-year-old 
youth with left-sided inguinal cryptorchidism and obesity; under thyroidin 
treatment the genitals took on a rapid development. 422 
THE DISEASES OE THE SEXUAL GLANDS 
There is no doubt that we are often able to improve with thyroidin the 
fat types of obesity. Thus for example in Observation Sch, there occurred 
without limitation of diet, after the administration of even small doses of 
thyroidin, a rapid reduction of 3 kg. in weight. A considerable improvement 
is also reported by Lemos Magelhaes. In a case of adipositas nimia who 
weighed 160 kg. there occurred under thyroidin treatment a reduction of 
kg. Then intoxication symptoms appeared. I do not feel justified, however, 
in referring offhand, as do Apert, Parhon and Mihailesko, the improvement in 
the genital sphere to the thyroidin treatment, or in constructing, because of the 
improvement, an etiological connection. To me the reports do not seem con- 
vincing that these cases were cured by thyroidin, because as has just been 
mentioned, there have been sometimes observed in this growth period improve- 
ments that are spontaneous. But we must accept a certain stimulating action 
of thyroidin. 
Not much has been reported as to other methods of treatment. I do not 
know that extracts of sexual glands have been used. As radium emanations 
have a certain stimulating action on the sexual glands—Freund and I saw several 
times through radium treatment an increase of the potency, a recurrence of 
the periods at the climacteric or an aggravation of dysmenorrheic complaints— 
in one case (Observation Sch) I used the radium emanation, perhaps with 
good results. Such a result is to be expected only in youthful cases. In 
another case (Observation H, twenty-eight years old), who on account of his 
joint affection was treated for a long time, all action on the sexual glands 
remained absent. 
The transplantation of the sexual glands has not to my knowledge been 
tried in the treatment.1 
4. Late Eunuchoidism 
Historical.—The first excellent description of this disease we find in 
Larrey in his “Campagne d’Egypte: de l’atrophie des testicules.” Larrey ob- 
served in several soldiers who had followed the campaign in Egypt with Napo- 
leon and later, in soldiers of the Imperial Guard, simultaneously with gradually 
occurring atrophy of the testicles with retrogression of the penis, disappearance 
of the libido and the potency, falling out of the pubic and axillary hairs, develop- 
ment of a falsetto voice, and certain alterations of intelligence and psyche. 
Larrey sees the cause of the disease in the deleterious influences of the climate, 
or in sexual abuse, or in alcoholism. Lately interest has again been turned 
toward this subject by Gandy who described three cases, that he termed infan- 
tilism reversif ou tardif. Of Gandy’s cases I would regard two as typical cases 
of late eunuchoidism. The third belongs to multiple ductless glandular sclero- 
sis. Gandy seeks the cause of the affection chiefly in a dysthyroidism, while 
Claude and Gougerot describe a series of cases that they refer to an insuffisance 
pluriglandulaire endocrinienne. Cordier and Rebattu treat the subject in a large 
study of these cases; they again uphold the designation “infantilisme regressif 
type Gandy.” 
1 See addendum.—Editor. LATE EUNUCHOIDISM 
423 
Recently I have published a study on this subject in which I pointed out 
that the manifestations in this disease, so far as they connected with the geni- 
tals, are like those of eunuchoidism; and I selected from the group the pure 
cases of “late eunuchoidism” [“Spateunuchoidismus”] from late eunuchoidism 
which is only the partial manifestation of a very complex clinical picture. 
Definition.—I term “late eunuchoidism” a clinical picture that comes about 
by the fact that in an already matured organism in which also the functions of the 
sexual glands have attained their full development, there occurs atrophy of the 
accessory genital apparatus (in man retrogression of the penis, scrotum, the pros- 
tate, etc.; in woman the labia major a and the uterus), and retrogression of the secon- 
dary sexual characters {mustache, beard, hairiness of the axillce and the pubis, 
the trunk and the extremities). Moreover there develop more or less distinct 
collections of fat on the breasts, the mons Veneris, and the hips, and often certain 
alterations of the psyche. The typical eunuchoidal alterations of the skeleton 
can no longer go on developing, especially where the development of the skeleton 
has been already closed off; that is where the epiphysial junctures have already 
united. 
There is regularly found a high-grade affection of the sexual glands, that must 
be regarded as the cause of the manifestations described. 
Case Reports.—I have already treated in my publication the case histories 
of this affection somewhat in detail. Since the time I wrote my article I have 
found still more cases in the older and newer literature. As I would describe 
the clinical picture in detail and delimit it as precisely as possible, I will here 
make a complete report of the case histories. Then I shall classify the cases 
according to their etiology, as nearly as possible. Moreover, I would here 
state that the position of a series of cases is still uncertain. I shall come back 
to these cases in the consideration of multiple ductless glandular sclerosis, 
and here set forth only those cases which I regard as pure cases of late 
eunuchoidism or at least as cases in which the manifestations of late eunuch- 
oidism stand quite in the foreground. 
A. Cases that depend on a traumatic foundation. 
Observation of A chard and Demanche.—Sixty-eight-year-old man. Pale tinge, the 
skin of the entire body pale and dry. Hair of head abundant, skin of the face and trunk 
and extremities completely bald. Eyebrows sparse. The breasts not essentially enlarged. 
The scrotum small, both the testicles small, the cremasteric reflexes very weak. Intelli- 
gence normal. Easily excitable disposition; at the twenty-fifth year of life, the man had 
sustained an injury, due to the tread of a foot, in the scrotal region. The testicles had be- 
come swollen, as the result of the injury, and later atrophied. Beard and cranial hair, 
that previously had been abundant, became at the same time always sparser, the muscu- 
lar strength decreased, a certain amount of libido was retained, but ejaculations had never 
occurred. 
Observations of Gallavardin and Rebattu.—Twenty-six-year-old man, 174 cm. tall, 
looks like a fifteen-year-old youth. Preponderance of the lower length over the upper 
length (femur + tibia = 90K cm.). The distal epiphyses of the radius and ulna have 
not as yet united. The voice that previously had been mannish, is now shrill, the skin 
is white and delicate, scrotum and penis are very small (as in a six- to ten-year-old boy). 
At eighteen and one-half years of age the man had received a violent knock in the 
scrotal region, after which for three hours he was unconscious. After this there developed 424 
THE DISEASES OF THE SEXUAL GLANDS 
a considerable swelling of the testicles and bloody suffusion of the skin of the scrotum; 
these phenomena disappeared after three months. Later the testicles became small, the 
penis atrophied, the secondary sexual characters and the libido disappeared, and complete 
impotence appeared. The photograph accompanying the report of the case shows well 
the enunchoidal fat distribution. 
Observation of Cordier.—Twenty-nine-year-old man, looks like an eighteen-year-old 
youth. Genitalia and prostate markedly atrophic, secondary sexual characters and libido 
have almost disappeared. The man married at the age of twenty-five years, is the father of 
one child. At twenty-five and one-half years a trauma that affected the testicles. Gradual 
falling out of the hairs of the mustache, the beard since then has become very sparse, marked 
reduction of libido. 
Observation of Stieda.—Thirty-year-old man. At the age of fifteen both testicles 
bruised. From then on the testicles became gradually smaller, he first remained behind 
in growth and then grew appreciably between the twentieth and thirtieth years. The 
voice was only somewhat rough, and the potentio coeundi remained, although there was 
no ejaculation of semen. The mammary glands grew somewhat in circumference. Accord- 
ing to his statement a growth about the size of a thaler appeared at their site on each side. 
The man remained beardless, there was hair on the mons Veneris but the upper border of 
this hair was horizontal. Height 175 cm., the extremities were remarkably long, the breadth 
of the shoulders was slight, the pelvis broad, the larynx small, internal and external genitalia 
had remained behind in development. The testicles were about the size of beans, the 
epididymises were about just as large. 
Observation of Riedinger.—The patient in his twenty-first year suffered a severe injury 
in which the anterior perineal region was bruised and the scrotum torn, and the testicles 
and prostate severely injured. The penis had previously been of normal size (examined 
by Rieder). Erections were still possible the first year after the injury, but there were no 
signs of ejaculations. Now erections only very seldom, no sexual intercourse any more. 
The man is 163 cm. tall, the lower extremities (from the trochanters down) are 86 cm. 
long, the skin is pale in color, the skin of the face lax and wrinkled. He appears much 
older than he is. The skin is otherwise lax and flabby. He is very thin; the accompanying 
photograph allows one readily to recognize, however, the abundance of fat in the breasts 
and on the mons Veneris. The penis is 6 cm. long, reduced in all its dimensions. The 
pubic hairs are very sparse and the upper border of the pubic hairiness is horizontal. The 
hairs in the axillary and anal region are also sparse. No beard (before the injury there 
was a beard). The voice is mannish, lately a goiter has developed. The sella turcica, as the 
author kindly informed me in a written communication, is not enlarged. 
Own Observation LII.—Forty-two-year-old man, rather corpulent, breasts very rich 
in fat, mons Veneris and hips somewhat richer in fat. Sparse hairiness of the axillge, 
Genitalia rather well covered with hairs. Both the testicles as large as peas, very soft, 
the scrotum small, without tension, cremasteric reflexes absent. Bilateral scars in the 
inguinal regions as the result of operation. 
Four years ago, after operation for bilateral inguinal hernia there developed on each side 
an enormous hematoma, which after some time disappeared. Only a few weeks afterward the 
patient noticed diminution of potency, which later disappeared entirely for a time. The 
libido did not disappear entirely, later erections were again possible and coitus was performed 
a number of times per month. According to statement, only a slight ejaculation occurred. 
The cause of the atrophy of the testicles in these cases may very well be regarded as a 
circulatory disturbance, whether through injury of the arteries, or compression due to 
shrinking of scar tissue, whereby damage was done to the nutrition of the testicles. 
B. Cases that depend on an orchitis due to syphilis, gonorrhea, or mumps. 
Perhaps some of the cases described by Larrey belong to this group. 
Observation of Coffin.—Male individual, after bilateral luetic orchitis the testicles 
shrank to the size of beans. The voice became higher, obesity developed, the beard fell LATE EUNUCHOIDISM 
425 
out, the muscular power diminished, erections and ejaculations ceased, the penis became 
smaller, finally to the size of that of a six- or seven-year, old child. The breasts became 
larger. 
Observation of Charcot.—Soldier. After bilateral mumps, orchitis, atrophy of the tes- 
ticles to the size of beans. Libido disappeared, complete impotence, the breasts increased 
in size. 
Observation of Lereboullet.—Twenty-seven-year-old man, skin pale, eunuchoid form, 
breasts well developed, penis and testicles very small, impotence. Beard absent, the 
patient was formerly very potent and the beard well developed. The voice mannish. 
At twenty-four years, mumps with bilateral orchitis, later gradual atrophy of the testicles. 
Observation of Dalche.—Thirty-six-year-old man. Color of face pale, hair of beard 
abundant. Hairs of beard, of axillae and of genitalia are entirely absent. Testicles very 
atrophic, libido absent, complete impotence, intelligence weak, forgetfulness, tendency to 
weep, apathy; often chills. At twenty years lues, at thirty years bilateral orchitis, since that 
time development of the genital atrophy. Later also slight swelling of the legs and of the 
face. Polyuria. In this case the eunuchoidism is certainly in the foreground. But in 
addition there exist symptoms (and indeed chiefly symptoms of failure) on the part of the 
other ductless glands. 
Observation of Dupre.—Forty-five-year-old man. Abundance of hair on head. Mus- 
tache much reduced, very little pubic hair, pallor of the face; penis and testicles small, 
soft, libido absent, impotence. Formerly gonorrhea and syphilis. At the thirtieth year 
gradual testicular atrophy and development of the symptoms described. 
Observation of Gandy.—Forty-six-year-old man. Color of face pale-yellowish, sec- 
ondary sexual characters very sparingly developed. Genitals markedly atrophic, some 
collection of fat on the trunk. Impotence. Formerly entirely normal, lues at the thirty- 
third year. About this time beginning of the retrogression of the genitalia, and secondary 
sexual characters, temporary polyuria (in the thirty-sixth year), also temporary swelling 
of the face. 
Observation of Gandy.—Forty-two-year-old man. Face very pale, wax-like, skin of 
the forehead arranged in fine parallel folds, skin of the trunk delicate, voice monotonous, 
no hair at all on lips or trunk, penis and testicles very small, prepuce long and folded, cremas- 
teric reflexes absent, no libido; impotence, memory somewhat weakened, apathy, blood- 
pressure reduced. At thirty-two years of age bilateral gonorrheal orchitis; from about this 
time began atrophy of the genitalia and impotence. At the twenty-ninth year states that 
he is somewhat stronger; pad-like swelling of the skin of the face, the hands, and the back 
of the feet. 
Gandy regards this case as “ dysthyreoidie + dysorchidie.” I believe, however, that, 
in spite of this, late eunuchoidism stands in the foreground. 
Apparently also the observation of Foges belongs here. After bilateral leutic orchitis 
there developed a “gynakomastie.” The mammary glands were removed, microscopical 
examination showing only fat and no glandular substances. Sexual sensation was much 
reduced. 
C. Cases of other etiology. 
Observation of Cordier and Francillon.—Thirty-five-year-old man. 175K cm. tall, 
lower length go}4 cm. hence distinctly predominating. Epiphyses united, eunuchoid 
distribution of fat, skin pale, diffuse pigmentations. Hairs representing beard absent, hair 
on cheeks sparse, atrophy of the genitals, libido present but coitus rare and incomplete. 
Weakness of memory. Patient is quarrelsome, easily excited, slight anemia with hyper- 
leucocytosis and mononucleosis (phthisis pulmonalis is present, however). Typhoid fever 
at about twenty-four years of age. Before development was entirely normal and potency 
was normal. Several months after the typhoid gradual development of genital atrophy 
and impotence; temporarily, also, complete loss of libido. Great bodily weakness, that 
later improved. Since that time increase in height about 3 cm. 426 
THE DISEASES OF THE SEXUAL GLANDS 
Observation of Gougerot and Gy.—Fifty-two-year-old man, quite normal up to forty- 
eighth year (except that he had had gonorrhea); about this time a hard to define acute 
infectious disease, after this asthenia, polydipsia, polyuria, atrophy of the genitalia, im- 
potence, loss of libido, retrogression of the secondary sexual characters, pigmentations on 
the forehead, hands and feet, cachexia. 
Observation of Galliard.—Fifty-seven-year-old man, face very pale, mustache and beard 
very sparse, no hair in the axillae, scrotum and penis small, testicles very small, im- 
potence. At fifty-three years eczema, “since that time development of the phenomena 
described.” 
Observation of Belfield.—In a man twenty-seven years old there developed at the same 
time with a polyuria a “retrograde puberty,” atrophy of the testicles and the external 
genitalia, retrogression of the secondary sexual characters, etc. The hair of the head 
remained abundant. Examination took place when the man was thirty-nine years old. 
X-ray showed sella turcica, normal. Thyroidin therapy and later adrenalin were used 
without results. Later was administered dried suprarenal gland, containing both cortex 
and medulla. After four months the daily amount of urine had been reduced to one- 
half. The body hairs had grown distinctly, the testicles were twice as large, and coitus 
already had been several times performed. 
I would here refer to the observation of Josef son and Lundquist (case 2). We can regard 
this case as a transition between eunuchoidism and late eunuchoidism. I have described 
this case in detail in a previous section. 
Finally, more on account of the curiosity, I will report an observation described by 
Hammond. The Pueblo Indians in New Mexico seem to have cultivated the so-called 
mujaderes for purposes of pederasty. For this purpose already fully developed men are 
excessively masturbated and at the same time are made to ride enormously. This treat- 
ment causes an atrophy of the testicles and epididymises, the penis becomes smaller, libido 
disappears, the testicles are insens tive to pressure, the mammae enlarge, the individuals 
become fat, the voice becomes higher and the bodily strength decreases. Hammond himself 
has examined two such individuals. WThile in many respects the story sounds fabulous 
(one of the mujaderes stated that he had suckled children), the agreement with the picture 
of late eunuchoidism is so complete that I had at least to mention the observation. 
Symptomatology.—Late eunuchoidism is found almost exclusively in 
men. There have been individual cases reported in women but these are not 
pure cases. As we shall see later they belong to the group of multiple ductless 
glandular sclerosis. The cause of the disease in man is either violent trauma 
effecting the testicles or their vicinity, or, as in my case, probably, a damage to 
both spermatic cords through shrinking of scar tissue; or a bilateral high-grade 
orchitis on a syphilitic or gonorrheal basis, or mumps orchitis; or it may be 
due to severe infectious disease—typhoid for example—or to an infectious 
process of an unknown nature, affecting the entire organism and probably also 
the testicles. At the close of these deleterious influences, or also in certain cases 
quite spontaneously, without distinct recognizable cause, in individuals who 
previously had been entirely normally developed, in whom especially the 
secondary sexual characters were completely developed and in whom the genital 
function has been entirely normal—there develops quite gradually an atrophy 
of the entire genital apparatus and at the same time a retrogression of the 
secondary sexual characters. 
Finally there seem to be cases in which there exists from youth a ecrtain 
lessened valuation of the rudiments of the sexual glands and soon an exhaustion 
(case of Josef son and Lundquist). LATE EUNUCHOIDISM 
427 
The ages of the affected individuals are very different. In the case de- 
tailed the beginning of the disease fell between the eighteenth and fifty-third 
years of life. 
The alterations in the genitals must be regarded as manifestations of 
retrogression and not, as Claude and Gougerot believe, as mere atrophy. In this 
view I am entirely in accord with Gandy. The retrogression of the testicles 
may be astounding. The testicles are estimated as at the size of hazel-nuts, 
cherries, beans, and peas. The diminution of volume is naturally less where 
connective tissue has formed at the site of an infectious process; and here too 
there is not such a diminution in consistence; in most cases has been emphasized 
an especial softness. The scrotum can be as small as that of an eight- to ten- 
year-old boy; and it loses its tension and its pigments. Also the penis can 
reduce in size to such an extent that it looks like that of an eight- to ten-year- 
old boy. The picture is therefore entirely similar to that of early eunuchoidism. 
Also the prostate takes part in the atrophy. 
We have already described the manifestations that occur after castration 
in the matured woman. Retrogression of the genitalia occurs, mostly an in- 
creased fat-deposit and loss of pigment, but not a falling out of the pubic and axil- 
lary hair. We shall consider later under ductless glandular sclerosis those cases in 
which retrogression in the hairiness occurs simultaneously with spontaneous 
atrophy of the ovaries. 
In late eunuchoidism the function of the genitals suffers severe damage. 
In man complete impotence with entire incapability of cohabitation can occur 
under circumstances. Libido is here entirely lost; but in other cases only 
impotence occurs, while libido remains in enfeebled form. In the formes 
frustes the capability for cohabitation still remains; except that in these cases, 
as Cordier and Rebattu point out, much stronger stimuli are needed to induce 
erection. The cremasteric reflexes are either weaker or entirely wanting. 
Hence the functional disturbance also corresponds entirely with that of early 
eunuchoidism. 
The same is true for the coloration of the face. The pallor of the face 
and the delicacy of the skin and body are noted in all cases. There is often 
found a yellowish tinge; and (in one case) folding of the skin of the forehead 
(as in eunuchs). Puffiness of the skin of the face is very rare indeed among 
the cases reported. 
The hair of the head remains abundant, but as a rule is rather dry. (The 
cases with patches of alopecia do not belong to pure late eunuchoidism.) 
In severe cases the hair of the body falls out entirely. The mustache, 
that previously may have been very luxuriant, falls out entirely or at least 
thins out very much. The same is true of the beard; often is found the state- 
ment that the patients who previously had to shave several times a week, 
shave much less frequently. Thinning out of the lashes and the eyebrows 
does not indeed belong to the pure picture of this disease. Also the trunk 
and the extremities may become entirely bald. The axillary hairs, the hairs 
on the scrotum, the perineum, and on the root of the penis, may fall out 
altogether. 428 
THE DISEASES OF THE SEXUAL GLANDS 
Very important for the comprehension of the disease picture are the 
alterations of the form. As has previously been mentioned, it is in itself sug- 
gestive that where the beginning of the disease falls at an age where all the 
epiphysial junctures are closed, a development of the eunuchoidal skeletal 
type is no longer possible. Of especial importance, therefore, are the observa- 
tions of Gallavardin and Rebattu, of Cor din and Francillon, and of Stieda. In 
the first case a youth of eighteen and one-half years old suffered a knock in the 
scrotal region, and in the second the beginning of the disease lay in the twen- 
tieth year. In the first case there was only a suggestion of the eunuchoidal- 
skeletal type (predominance of the lower length over the upper length), and 
the epiphysial junctions that close at a later period were still open at the 
twenty-sixth year. In the second case there was a further growth of about 
3 cm. at the twenty-fourth year. The case of Stieda’s sustained a trauma in 
the fifteenth year of life. He first remained behind in growth and then grew 
appreciably between the twentieth and the thirtieth years. Here, therefore, 
the epiphysial junctions had remained open abnormally long. Here also 
there came about the development of the eunuchoidal dimensions. 
The influence on the weak parts is noted more frequently. In many cases 
the statement is made that there appeared at the beginning of the disease 
an adiposity; in other cases that the breasts had become fatty, or the hips 
rounded, or that the mons Veneris had become richer in fat. In several 
cases, in which the typical distribution had not been noted especially, it could 
be recognized in the illustrations that accompany the reports. 
In the majority of cases it is furthermore stated that the voice which had 
previously been mannish, altered in the course of the disease. A falsetto 
voice did not develop, as in eunuchs and early eunuchoids, but the voice 
placement was high and the voice shrill. 
In the pure cases there is no alteration of the intelligence. The apathy, 
[mental] heaviness, forgetfulness, that are stated to have occurred in indi- 
vidual cases, may well be referred to the general prostration following several 
general infectious diseases or perhaps to a slight myxedematous component. 
We shall again see such manifestations under multiple ductless glandular 
sclerosis. In pure cases the statements as to alterations of the moral and 
psychical attitude are on the contrary very frequent; statements that such 
individuals like early eunuchoids, are psychically more easily excited, and 
given to sudden anger and to lying. In two cases also has been noted tem- 
porary polyuria (Gougerot and Gy, and Dalche). In the first case the late 
eunuchoidism came after an acute infectious disease, in the second after lues. 
We shall often meet with these symptoms in the consideration of multiple 
ductless glandular sclerosis. Perhaps it is of hypophysial origin. 
Are we now justified in separating out these cases as an especial clinical 
formation and giving it the name ‘Tate eunuchoidism?” As has been men- 
tioned, Gandy regards them as “ dysthyreodie + dysorchidie.” Gallavardin 
and Rebattu express themselves more in favor of [an affection of] the sexual 
glands, Cordier and Rebattu distinguish between an “infantilisme regressif 
myxedemateux et non myxedemateaux.” Claude and Gougerot finally LATE EUNUCHOIDISM 
429 
group all these cases under "insuffisa nee pluriglandulaire.” The confusion can, 
I think, readily be overcome if we place in the foreground the classification of 
these cases according to their etiological factor, and separate out, before 
everything else, those cases which have the value of experiments, namely, 
the traumatic. Where acute infectious diseases or noxi of a more general 
nature have led to degeneration of the sexual glands it is very well intelligible 
that also other ductless glands can suffer damage, and that other features 
often hard to define become associated with the picture of a disease that is 
due to falling-out of the sexual gland. 
As to the significance of thyroid insufficiency in this disease picture, we 
can become clear on this point, if we have recourse to the experiments. If 
in an individual who has attained complete maturity, the thyroid gland is 
completely extirpated, there come about disturbances of the genital function, 
but never any such retrogression of the genitalia as has been just described. 
The thyroprivic disturbance of the genital function can be promptly over- 
come by thyroidin medication, while all statements are in accord that thy- 
roid medication does not improve the disturbance of sexual glandular function 
in late eunuchoidism. In spontaneous myxedema of adults the behavior 
in these respects is not always as clear as in operative myxedema. It should, 
however, be considered that the disease process that in this condition is respon- 
sible for the sclerosis of the thyroid gland very readily and very often involves 
other ductless glands, and that here we are no longer dealing with mere action 
at a distance. 
Can we show by experimentations the significance of the sexual glands 
for this clinical picture in a clean and clear-cut fashion? To answer this we 
must have recourse to the known experiments of Ancel and Bouin. In male 
grown animals the ligation or transection of the vas deferens, or patho- 
logical stenosis of the exit-ducts of the sperm, leads to degeneration of the 
germinative part of the sexual glands, while the interstitial substance is 
retained. The animals become sterile but they are not impotent, and retain 
their masculine appearance. If, however, the “interstitial glands” are 
brought to degeneration the animals lose their masculine appearance and 
become similar to castrates. In this manner there is therefore produced an 
experimental late eunuchoidism. I refer moreover to late castrates whom I 
have described above. The same value for the pathogenesis is afforded by 
the very numerous cases of pure traumatic late eunuchoidism; they show that 
severe injuries of the male genitalia may lead to the full symptom-complex of 
late eunuchoidism; also in these cases there does not exist the slightest basis 
for regarding the condition as a primary affection of the other ductless glands. 
The question as to whether the loss of both sexual glands leads regularly to the 
development of late eunuchoidism does not seem to me entirely solved by the 
material up to the present time, although I regard it as very likely. Widal and 
Lutier have reported a case with marked testicular atrophy, in which the man- 
ifestations of late eunuchoidism did not seem to be present. Cordier and Rebattu 
discuss the possibility whether in these cases there were still present functionally 
capable islands of Leydig ’s interstitial cells or ectopic sexual glandular tissue. 430 
THE DISEASES OF THE SEXUAL GLANDS 
Much less clear are the alterations in women. That premature menopause 
and hyperinvolution of the uterus through repeated births or prolonged 
lactation does not lead to any change in the secondary sexual characters 
is readily intelligible, as there need not be associated with the retrogression 
of the follicular apparatus a retrogression of the interstitial substance. 
On the contrary it is really not intelligible why the loss of the whole 
ovaries exercises such little influence on the axillary and pubic hair. The 
few cases of pronounced regression of this hair seem to me to belong under 
the caption multiple ductless glandular sclerosis. 
The differential diagnosis has especially to consider the diseases of the 
hypophysis that first develop in later years after the attainment of the com- 
plete cessation of growth and complete maturity of the body. In this case 
there is no disturbance of growth, as occurs in the differential diagnosis between 
the eunuchoid and the hypophysial dystrophia adiposa-genitalis. Where 
symptoms of brain-pressure are present and the X-ray shows alterations 
of the sella turcica, the diagnosis is at once cleared up. Sometimes difficult, 
however, is the delimitation from atrophic and inflammatory sclerotic pro- 
cesses in the hypophysis. Perhaps points of differential diagnostic value 
can be obtained from the examination of the respiratory gaseous exchange 
and of the purin metabolism. The history also ought to be important; the 
fact that the patient has sustained a luetic, gonorrheal, or mumps orchitis 
should at any rate lead to the suspicion of late eunuchoidism. The differential 
diagnosis with respect to multiple ductless glandular sclerosis will be con- 
sidered later. 
The treatment has not up to the present yielded anything reassuring. 
That thyroid medication fails is indeed only too comprehensible. But also 
the administration of sexual glandular substances has led to only transitory 
results, or, as in the case of Dalche, led to improvement of symptoms that 
probably were not to be referred to the lack of the sexual glands (forgetful- 
ness, general weakness, chills). In the valuation of therapeutic results, we 
should not forget that in certain cases spontaneous improvement is possible, 
such as also occurs in early eunuchoidism. 
5. Treatment of Sexual Glandular Insufficiency 
The drug therapy of sexual glandular insufficiency has as yet had in man 
no decisive results. The feeding with testicular substance is but little carried 
out, and the reports as to the result of injection of sexual glandular extracts 
disagree. Spermin (.Poehl) may have a certain stimulating action on the 
nervous system, but profound symptoms of insufficiency are hardly improved 
thereby. 
For want of a better treatment, thyroid treatment has been recommended 
—a therapy that plays a part in the treatment of all ductless glandular affec- 
tions, to a certain extent, erroneously. In eunuchoid obesity, thyroid medi- 
cation has on the whole a good result and is certainly to be recommended if 
it be employed with necessary caution. It is also conceivable that through TREATMENT OF SEXUAL GLANDULAR INSUFFICIENCY 
431 
stimulation of metabolism often a certain furthering influence is exerted on 
the sexual glands, but we cannot expect decisive results as to this point. In 
such cases treatment with hypophysis tablets seems to be entirely value- 
less. I do not know whether anybody has as yet employed pituitrinum 
infundibulare. As I have mentioned already, perhaps employment of radium 
emanations would be of some value, but as yet no experiments with them have 
been reported. I shall not go further into the question of the other roborant 
and tonic treatment methods. 
The organotherapy of the symptoms due to loss rest on a much broader 
experience as far as is concerned with woman. The medication with ovarian 
substances was introduced by Regis and has been especially recommended by 
Jacobi, Chrobak, Landau, and others. Various preparations have come into 
the market; oophorin tablets, ovaraden, ovarin, ovarial tabloids, etc. Ordi- 
narily 3 to 6 tablets are administered daily. As has been mentioned, Lowy 
and Richter found in their experiments a stimulation of the respiratory metabol- 
ism; but this result seems to be inconstant, as other investigators did not 
find it. Also there did not always occur an improvement in the nervous 
symptoms. Bucura points out that this may be due to the unreliability of 
the preparations used. He believes that it is not a matter of indifference 
whether the preparations are obtained from the ovaries of young or old animals, 
and whether they are taken during the rutting season or the interval. He 
mentions experiments with the milk of rutting animals. As yet the involution 
of the uterus after castration cannot be prevented by the use of ovarian sub- 
stances (Jentze and Beutner). Frankel proceeding from his view that the 
corpus luteum possesses an internal secretion, has introduced lutein tablets 
into therapy. 
Very promising are the experiments on transplantation of the sexual 
glands. Ribbert was the first who succeeded in transplanting testicles. Foges, 
after autotransplantation of the testicles in young fowls, saw rather good 
development of secondary sexual characters. Steinach succeeded with the 
same experiment in rats and guinea-pigs. The interstitial cells and the Ser- 
toli’s cells were retained, but seminal cells were entirely absent. I do not 
know whether homiotransplantation of the testicles has succeeded. If it 
were to succeed, a favorable influence on eunuchoidism would not be impos- 
sible. The transplantation of the testicles, epididymis, and vas deferens, and 
therewith the possibility of semen production, is still the task of the future. 
[See addendum.] 
Much more noteworthy are the experiments with transplantation of 
the ovaries. Here also the successful experiment is that of autotransplanta- 
tion which was done by Ribbert. Knauer then showed that in grown rabbits 
involution of the uterus could be prevented by the autotransplantation. An 
essential progress was made by the experiment of Halban, who in new-born 
guinea-pigs transplanted the ovaries under the skin. After one and one-fourth 
years there was still present parenchyma capable of functionating. Graafian 
follicles and even mature ova had developed and the tube that had been 
transplanted at the same time had matured in normal manner. The breasts, 432 
THE DISEASES OF THE SEXUAL GLANDS 
as well as the uterus, had developed normally. In the castrated control 
animals the breasts remained rudimentary and the genitalia were markedly 
hypoplastic. In woman, also, transplantation has occasionally been followed 
by good results in operations on the genitalia. It is true that transplants 
often show regressive manifestations, but a part of the parenchyma may, 
however, still be retained, and on account of this the involution of the uterus 
and the nervous symptoms due to the loss are prevented. In autotrans- 
plantation in the neighborhood of the tube, even maturation of the ovum 
and pregnancy have occurred. 
Still more significant are the experiments with homiotransplantation of 
the ovaries. I refer to the collected statistics of Novak. It is true that in 
most cases the result lasted only for a short time, but in animal experiments 
numerous results of longer duration including maturation of the ovum and 
conception have occurred. On experiments in man, I mention the two cases 
that follow. Cranner transplanted into a twenty-one-year-old woman, who 
had never menstruated and who possessed rudimentary mammae, the ovary 
of an osteomalacic woman. Menstruation then set in and the breasts devel- 
oped. Still more remarkable is a case of H alliday-Crom. In this case 
amenorrhea had set in after labor and symptoms of absence developed. The 
small cystic ovaries were removed and a foreign ovary implanted. The woman 
again menstruated four months after the operation, and four years after the 
operation she conceived and bore a normal child. This case was earnestly 
discussed before the Edinburgh Obstetrical Society, and cannot well be denied. 
There is indeed in this case no doubt that if there has been no error of obser- 
vation, this woman bore the child of another woman. Serious objections 
might be raised against such procedures on ethical and forensic grounds. 
III. HYPERGENITALISM 
Definition.—We have come to know hypergenitalism already in the 
chapters on the hypophysis and in the consideration of suprarenal cortical 
tumors. There are also cases of premature development of the genitalia 
associated with temporary excessive development of the organisms, in which 
the epiphysis or the suprarenal cortex do not come into consideration as 
etiological factors, but in which we must assume, with great probability, a 
primary disturbance of the sexual glandular function in the sense of a pre- 
mature occurrence or an excessive increase. 
Pathologico-anatomical Findings.—A portion of these cases show malig- 
nant tumors of the sexual glands. Neurath collects five cases from the litera- 
ture, four ovarian tumors (two established at autopsy, two at operation) and 
one testicle tumor (operation). In another the sexual glands were described 
as only extraordinarily large. I must state that in two cases hydrocephalus 
was reported. One of the cases was reported by Wetzler; also in a case of 
Pellizzi’s did there exist, besides pronounced hypergenitalism and excess- 
ive growth, hydrocephalus with convulsions. Whether these were cases 
of primary hypergenitalism cannot in the present state of our knowledge be 
answered. HYPERGENITALISM 
433 
Symptomatology —The premature sexual development is found in both 
boys and girls. Neurath, who has written an excellent essay on this subject, 
quotes forty-three cases of premature sexual development in boys. In such 
individuals an excessive development of the genitalia may occur already in 
the first year of life. 
I quote the following examples. The case of Bernhardt-Ziehen was that of a three- 
year-old boy in whom an enormous growth had set in at the eighteenth month. At two 
years the pubic, axillary, and beard hairs were present. At two and one-half years the legs 
had hair on them; he was 103 cm. tall, the circumference of the skull was 53 cm., the body 
weight 49.5 kg. He looked like a seven- or eight-year-old boy. He was again examined at 
the age of eight years. He was then 138 cm. tall (116 cm. is the height for this age). The 
circumference of the skull was 56.5 cm. The sexual parts were developed like those of a 
grown man. He looked as if he were twenty-five to thirty years old. His intelligence was 
fairly well developed, he was lively, showed inclination for the female sex, but otherwise his 
demeanor was childish. As another example I cite the case of Hudovernig and Popovicz. 
In a later investigation of Hudovernig the boy was five and one-half years old; at one and 
one-half years he sustained a febrile disease (meningitis). The abnormal growth had 
existed since that time. He was 137 cm. tall and weighed 35.5 kg., this corresponding to 
the age of fifteen or sixteen years. The penis is 9 cm. long, the testicles very well developed. 
The psyche is infantile. The intelligence is rather behindhand. Skull and face were rather 
asymmetrical. The X-ray examination showed that the ossification was as well advanced 
as that of a fifteen- or sixteen-year-old boy. Also the skull bones were well developed, and 
the sella turcica seems to have been enlarged, although the observation is not convincing. 
The boy was first treated with thyroidin tablets or with thyroidin tablets plus potassium 
iodide. This did not affect the excessive growth. Later ovarian tablets were administered. 
This time the growth was somewhat less (only 3.x cm. in nine months as compared with 
5 cm. in the six months of the first period and 5 cm. in the ten months of the second period). 
In the third period the boy seemed to have become psychically more quiet. Hudovernig 
assumes that the ovarian tablets have retarded the excessive growth. I doubt this. If 
we calculate the growth per month we obtain for the first period 0.95 cm., for the second, 
0.5 cm. and for the third, 0.3 cm. There is hence found a gradual decrease of the excessive 
growth, which surely, as we shall see later, is to be referred to the gradual closing of the 
epiphyses. Finally I would mention the case of Stone, which is especially interesting from 
the fact that also the father of the boy showed a premature development. 
These cases all have in common the premature and excessive development 
of the genitalia and of the secondary sexual characters, premature change of 
voice, and the excessive body development. Already in the first year there 
occur erections, ejaculation—Pellizzi demonstrated spermatozoa in his cases—• 
and eventually premature sexual instinct. The development of the internal 
genitalia often hurries the development of the whole body. As far as the latter 
is concerned, the osseous system and the musculature are mostly affected in 
like manner. There therefore occurs a transitory gigantism; as, however, the 
epiphysial closure is rather hastened, the body growth finally attained is not 
abnormal, but mostly rather small. The psychic and intellectual development 
of such individuals do not keep pace with the body development; they for the 
most part show a childish demeanor, corresponding with their age, which de- 
meanor has a characteristic stamp only through the premature sexual life. 
The assumption of such cases as primary hypergenitalism is often uncertain 
without autopsy findings, although such a primary hypergenitalism may be made 434 
THE DISEASES OF THE SEXUAL GLANDS 
secure by operation in certain cases. I mention especially the case of Sacchi. 
It was that of a nine-year-old boy who had developed normally until his fifth 
year; in that year there set in an excessive growth and especially a premature 
development of the genitalia and of the secondary sexual characters at the same 
time a tumor of the left testicle developed; at nine years of age the boy weighed 
44 kg. and was 143 cm. tall. The lower length was 77 cm. Hence the boy 
showed childish dimensions, and was in this respect different from other cases of 
true gigantism which, as we shall see later, shows either normal or eunuchoid 
dimensions. The testicular tumor, which was an alveolar carcinoma, was 
removed. One month after the operation the beard hairs fell out and the ab- 
normal hairiness of the extremities retrogressed; the hairs on the mons Veneris 
remained. The penis became smaller, the previously low voice became childish, 
and the pollutions and erections ceased. 
In the female sex such cases are mostly described under the title men- 
struatio praecox. The older literature is found in Kussmaul and v. Haller. 
Neurath counts eighty-three cases from the literature. The external genitalia 
develop in an abnormal manner, mostly more strongly than the internal. The 
secondary sexual characters (hairiness, etc.) and the development of the 
mammae are always abnormally premature. As in the male sex, excessive 
growth of the body is found to be more or less pronounced. Also the dentition, 
the change of teeth, and the appearance of the bone nuclei and the closure of the 
epiphysial junctures are premature. 
I cite the following: The case of Geinitz was one of menstruation praecox in an eighteen- 
month-old girl. The uterus had attained the size of that of a twelve- to fourteen-year-old 
girl. The case of Klein, of menstruatio praecox (two and one-half years), the vulva had 
grown to the size of that of a fourteen-year-old-girl. Stocker describes twin sisters, of whom 
one had been larger since birth. In the first, menstruation began before the end of the first 
year. The flow occurred regularly every four weeks, lasting three days. At eight years 
of age the child had the size and appearance of a twelve-year-old girl; she measured 139 cm. 
and weighed 34% kg., while the twin sister was 121 cm. tall and weighed 20 kg. The case 
of Neurath was that of a six-year-old girl who exceeded in size and weight her eight-year-old 
sister. The ossification conditions corresponded to those of the tenth or eleventh year. 
Recently there has been reported a case of Wolf concerning a girl four years and one month 
old. The size had been large since birth. The child had menstruated since the second year. 
She looks like a seven-year-old girl. The hair of the head is long. The height is 121 cm., 
the weight 26 kg., the span width 114.5 cm. (hence potentized childish dimensions). The 
intelligence corresponds to the age. The mammae are very well developed. The mons 
Veneris is covered with hair. The ossification corresponds to that of a ten year-old-child. 
Especially instructive is the case of v. Haller. In this the menstruation set in at the age of 
two years; at the age of eight the girl became pregnant and shortly afterward the excessive 
growth stopped. She lived to be seventy-five years old. This case shows that premature 
closure of the epiphyses may also occur in the female sex. Finally the case of Riedel shows 
that in certain cases a primary hypergenitalism may be demonstrated also in females. 
In this case of precocious menstruation (six-year-old child) the uterus was the size of a seven- 
teen-year-old girl. There was a sarcoma of the ovaries; on the removal of the sarcoma, the 
menstruation ceased. 
Treatment.—Up to the present, the treatment, as far as tumors were 
demonstrable, has been surgical operation. In many cases, as is shown in the 
above reports, the results were remarkable. Whether X-ray, radium irradia- CHLOROSIS 
435 
tions, or mesothorium irradiations have been tried as yet in certain cases, I 
do not know. Also in cases without demonstrable tumors it is conceivable 
that injections of thorium X or actinium X might induce an inhibition of the 
abnormal sexual glandular development and thus influence the premature 
development of the organism. 
IV. CHLOROSIS 
The circumstance that the beginning of chlorosis always falls at the time 
of puberty or during the time of maturation of the female organism following 
puberty, together with the circumstance that in chlorosis, disturbances in 
the genital sphere are found almost regularly, shows that this disease, at least 
to a certain extent, belongs in the chapter on the sexual glands. Opinions are 
at variance in regard to the nature of the tunctional disturbances. Therefore 
I avoid placing chlorosis in one of the divisions of hypogenitalism or hyper- 
genitalism and give it a position by itself. 
Historical.-—Virchow on the ground of pathologico-anatomical findings 
assumed a congenital deficient development of the vascular system. Immer- 
mann supposed a weakness of the blood-forming organs that is in part congeni- 
tal and associated with the hypoplasia of the vascular system, and in part 
acquired and temporary. The disease begins in puberty because at this time 
especial demands are made in blood-forming apparatus, v. Bunge places in the 
center of the pathogenesis a disturbance in the iron metabolism. The maternal 
organism gives to the child organism a very great amount of iron. This is 
stored up not during pregnancy but already at the time of puberty, whereby 
there occurs a poverty of the blood in hemoglobin. Zander regards the cause of 
chlorosis as a disturbance of the absorption of iron, other authors as chronic 
constipation, and as gastroptosis through the wearing of tight corsets, etc. 
Basing his views on the theory of Immermann, v. Noorden for the first time ex- 
plains a disturbance of the activity of the ductless glands as essential for the 
coming into existence of chlorosis. According to v. Noorden chlorosis depends 
on an in part congenital, in part acquired, weakness of the blood-forming organs, 
in consequence of which there occurs in the period of sexual ripening disturb- 
ances in the blood-formation proceeding from the female sexual organs. Nor- 
mally impulses flow from the female sexual glands to the blood-forming organs. 
Loss or weakening of the internal secretion of the ovaries leads to chlorosis. 
Grawitz sees the cause of chlorosis in a disturbance of the relation of liquid 
interchange between blood and tissues. This depends on deficient function of 
the vasomotors. He therefore regards chlorosis as a neurosis. 
Very recently, Morowitz, on the ground of observations in which the rest 
of the chlorotic symptom-complex is associated with an approximately normal 
blood condition, upholds the view that the blood-changes in chlorosis constitute 
only a symptom and not the essence itself of the disease; he points to the 
frequency of thyroid glandular swelling and believes the cause to be a disturb- 
ance in the reciprocal action of the ductless glandular system. Kottman 
observes that there is a deficient iron-assimilation on account of a weakening of 
the internal secretion of the ovaries. Finally we mention the theory of Charrin 436 
THE DISEASES OF THE SEXUAL GLANDS 
and Villemin that chlorosis is a menstrual auto-intoxication. Villemin assumes 
in addition that the internal secretion of the corpus luteum possesses hemolytic 
properties. 
Symptomatology.—Chlorosis is a disease that inclines very much toward 
relapses. The first attack of chlorosis usually occurs between the fourteenth 
and twentieth years of life. Cases of so-called tardive chlorosis (Hayem, 
Rieder) are extraordinarily rare. Lately also cases of infantile chlorosis have 
been described (Rist, Hutinel, Stoltzner, et al.). Because of the uncertain con- 
nection with these cases with true chlorosis, v. Noorden proposed for these cases 
the name chlorotoid. Also the connections of the extraordinarily rare cases 
of conditions similar to chlorosis occurring in the male sex (for example, the 
cases of Formanoli, Ferrari, Byrorn Bramwell) are contested by most of the later 
authors, v. Noorden and v. Jagic believe that in such cases we are dealing with 
sexual neurasthenics who are insufficiently nourished. A great role in chlorosis 
is played by heredity. Often many sicknesses are found in the family of the 
patient. In rare cases there is observed in the same family simultaneous occur- 
rence of chlorosis and of prepubertal eunuchoidism (Tandler, v. Noorden; see 
also Observation LI). 
Chlorosis usually sets in with a series of subjective complaints; attention 
is attracted to the color of the face. These symptoms consist in ready fatiga- 
bility, cardiac palpitations on slight bodily exertions, slight dyspnea, headache, 
sensations of cold—especially tendency to cold hands and feet—eventually seeing 
black, flickers before the eyes, ear noises, vertigo, fainting-spells, pressure in 
the gastric region, nausea, etc. 
Examination of the heart often shows in advanced cases slight broadening, 
soft systolic murmurs, the known humming-top murmur over the jugular, 
furthermore in a great number of cases acceleration of the pulse, great excita- 
bility of the cardiac activity and of the vasomotors. Further is found a marked 
laxity of the arteries (crural double tone). According to the investigations of 
Bihler and v. Noorden there is always a reduction of blood-pressure. 
Breathing is mostly somewhat accelerated and superficial, with high posi- 
tion of the diaphragm. 
As far as the digestive tract is concerned, it should be mentioned that there 
is frequently a slight degree of hyperacidity. According to v. Noorden, consti- 
pation is not much more frequent than in normal girls. The respiratory gas 
exchange is usually slightly increased. The condition of nutrition is as a rule 
not bad. Investigations as to the assimilation limits for carbohydrates gave 
an increase, or at least no decrease. After the ingestion of 150 gm. of grape- 
sugar, there never, in the experiments of v. Noorden and v. Jagic, occurred 
glycosuria except in one case that at the same time showed symptoms of 
Basedow’s disease. Also Chatin came to the same result. It should further be 
mentioned that not rarely chlorotics show a higher level of their body 
temperature. 
In not very rare cases there are found pigmentations of the skin. 
The examination of the urine shows no abnormal constituents. Also 
the products of destruction of hemoglobin are not eliminated in abnormal amount. CHLOROSIS 
437 
I now enter on a description of the blood findings; on account of the poverty 
in hemoglobin there occurs in the severe cases a greenish-pale facial color, that 
has given to the disease its name. There are, however, numerous cases that 
on account of the reddening of the cheeks make a florid impression. Here the 
disease is unmasked by a close examination of the mucous membranes and 
careful examination of the blood. The chlorotic blood-finding is characterized 
by a relatively very marked poverty of the blood in hemoglobin and a relatively 
slight reduction of the erythrocyte count. Hemoglobin amounts as low as 
50 per cent, are very frequent, those and as low as 30 per cent, not rare. When 
there is high-grade poverty of the hemoglobin there is found more or less dis- 
tinct poikilocytosis; and in addition isolated nucleated erythrocytes. In the 
lighter forms the count of the red blood cells is normal or only slightly reduced, 
only in the severe forms do reductions as low as 60 per cent, occur. In the 
severe cases the specific gravity of the blood is markedly reduced, while that of 
the serum is essentially unaffected. With regard to the leucocytes there is a 
slight relative mononucleosis. 
Recently, as was mentioned at the beginning, Morowitz has called attention 
to the fact that in rare cases that otherwise show the symptom-complex of 
chlorosis, the blood is found to be normal or nearly normal. Already Laache 
had described such cases, also several statements have been made by O. Naegeli 
and Grawitz, while lately Seiler, Groag, Dubnikoff, and others have described- 
such cases. Handmann even found twenty-three cases with normal blood find- 
ings among forty-four cases of chlorosis. 
It is furthermore very noteworthy that the investigations so far made as 
to the quantity of blood in chlorosis have shown a plethora. While according 
to the investigations of Smith the total amount of blood in normal individuals 
is about 5 per cent, of the total body weight, this author found in chlorotics 
with 29-50 per cent, hemoglobin the blood amount to be 7.5 per cent, and 14.3 
per cent. The lower the hemoglobin percentage, usually that much larger the 
amount of blood. Plesch and Oerum using other methods came to a like result. 
It should further be noted that in pernicious anemia Smith and Plesch found 
subnormal values [for the quantity of blood]. 
In connection with this subject it might be well to mention the alterations 
in the water metabolism that are observed in chlorotics. v. Romberg, v. Noorden, 
and Rethers frequently observed in chlorotics a tendency to the retention of 
water, while on the other hand we often see under the influence of iron-therapy 
a rapid loss of weight with moderate polyuria. As has been mentioned, prod- 
ucts of decomposition of hemoglobin are not, in chlorosis, eliminated in the 
urine. Therefore we cannot regard an increased destruction of the blood-color- 
ing matter as a cause of the poverty in hemoglobin. 
Not at all rarely the thyroid gland shows a swelling. Giudiceandrea, 
Archangeli and Bastianelli found it in half the cases. Handmann found it in 
twenty-four times among forty-four cases, three times with distinct Basedow’s 
symptoms, v. Noorden and v. Jagic report an interesting case in which the 
development of the anemia was associated with a swelling of the thyroid gland 
and on a relapse led to an acute Basedow’s that lasted for several days. As the 438 
THE DISEASES OF THE SEXUAL GLANDS 
statements as to the involvement of the thyroid increase in so astonishing a 
manner (since the time that attention has been directed to the fact), we must ask 
ourselves whether the pseudochlorosis described by Fr. v. Muller does not stand 
in an intimate relation with true chlorosis, v. Muller states that in regions 
where goiters are frequent, there are not rarely found pale, readily fatigable, 
girls with abnormally irritable heart-action, in which manifestation of Base- 
dow’s disease later became more distinctly conspicuous. 
Finally I come to a description of the alterations of the genitalia, after which 
I shall add some remarks as to the disease’s pathogenesis. I shall try to sepa- 
rate those changes that are due to an alteration of the glands of generation and 
those to changes of the interstitial glands. 
Disturbances of development are found in the genitalia in chlorotics not 
rarely. Deficient development of the external genitalia, deficiency in the 
prominence of the mons Veneris, flat nates, small labia majora are found, while 
labia minora and clitoris are uninvolved; eventually, narrow vagina, faulty 
development of the uterus, breasts, etc., are sometimes observed. The statisti- 
cal reports of Stieda, and of H. W. Freund and v. Noorden show that a relatively 
larger percentage of chlorotics have such developmental disturbances in more 
or less pronounced manner. There are undoubtedly a not inappreciable num- 
ber of chlorotics whose genitalia are developed normally. As especially note- 
worthy I would emphasize that the hairiness of the genitalia, the mons Veneris, 
and the axillae corresponds to the age of the individual and further that a 
delayed closure of the epiphysial junctures and corresponding eunuchoid 
dimensions of the body is not to be observed in chlorosis. Tandler states 
on the contrary that he has observed very frequently in chlorotics a very 
frequent premature epiphysial closure, and as a result of this, an especial 
short leggedness and also a certain prematurity, as shown by other sexual 
characters. 
As far as the function of the generative glands is concerned, almost all 
the statements are concerned with menstruation, while, as is intelligible, 
ovulation evades observation. Disturbances of menstruation are relatively 
very common. I here quote some examples from the statistics. According 
to Stieda only seven chlorotics among twenty-three had menstruated regularly. 
According to Otten, among four hundred forty-eight cases there were only 
one hundred eighty-six who had menstruated regularly before and during the 
illness. In the first edition of v. Noorden’s monograph, 60.7% of one 
hundred seventy-three cases showed weakness of menstruation. In the newer 
statistics of v. Noorden and v. Jagic that embraces two hundred fifty cases 
this figure was raised even to 77.2% and twenty-six of the cases had not 
menstruated before the onset of chlorosis. There are, however, cases with 
entirely normal menstruation, and furthermore cases with abnormally strong 
menstrual hemorrhage. Trousseau has described such cases as menorrhagic 
chlorosis. In such cases the ovaries were found to be enlarged and there was a 
great abundance of follicles, v. Noorden and v. Jagic on the basis of their 
compilation came to the conclusion that in chlorosis menstruation shows no 
characteristic behavior. CHLOROSIS 
439 
Pathogenesis.—If we now survey what I have just said as to the relation 
of the sexual glands and the primary and secondary sexual characters, we find 
it hard to accept the theory that chlorosis is a functional disturbance of the 
interstitial glands, especially if we compare it with those manifestations which 
are described in the rare cases of female eunuchoidism. There is indeed no 
doubt that in chlorosis there occurs an enfeebled development of the primary 
and secondary sexual characters, but in such cases this is mostly only of a slight 
grade, and just the essential symptoms of failure (deficient hairiness, delayed 
epiphysial closure) are absent practically always; indeed on the contrary, 
according to Tandler, as has been mentioned, the development points to a 
degree of prematurity. Also animal experimentations have as yet failed to 
furnish any support for the assumption of a diminished activity of the interstitial 
glands. According to the investigations of Monaro, and of Breuer and v. Settler 
the extirpation of the ovaries in young dogs in a state of development indeed 
leads to a temporary commensurate sinking of the amount of hemoglobin and 
count of erythrocytes, never, however, to the blood picture observed in chloro- 
sis. If I here use the methods that I employed in the exposition of the tests 
of the sexual glands for separating the symptoms that depend on the functional 
failure of the interstitial glands from those to the functional failure of the gen- 
erative glands, I may suppose a slight strengthening of the function of the 
interstitial glands; it is, however, a priori improbable that these stand in the 
mid-point of the pathogenesis. I believe that there is applicable an hyothesis 
that at least has the advantage that it is not contradicted by any of the known 
facts. In chlorosis, as has already been mentioned, the behavior of menstrua- 
tion shows nothing characteristic. We find that although in the majority of 
cases there is a weakening of the menstrual process, there may be a normal 
course or an essential strengthening. This is what is told to us with regard 
to menstruation, but not in regard to ovulation. We know only that there is 
no menstruation without ovulation. It is known, however, that under circum- 
stances ovulation proceeds without menstruation, and it does not seem to me 
that anything stands in the way of the proposition that under circumstances 
it may go on in an increased or precipitate manner. The assumption of precipi- 
tate ovulation in chlorosis is, however, though it seems fascinating, not at all 
unconditionally necessary. To me the assumption seems enough that the 
violent revolutions that go on in the feminine organism at the time of puberty 
or with the setting in of a strengthened activity of the follicular apparatus lead 
in non-vigorous individuals to a temporary or longer continued exhaustion of 
the organism. We have seen in the description of the physiology of the sexual 
glandular apparatus that ripening of the follicle in the premenstrual period 
leads to a heightened vitality of the whole organism. Hence there proceed 
impulses from the follicular apparatus that spur on all the organs and especially 
the entire ductless glandular system to a heightened activity. Would it not 
be conceivable that in a predisposed individual, in whom these impulses are 
perhaps increased by precipitate ovulation, there may appear an exhaustion? 
On the basis of this supposition I shall now proceed to analyze the 
symptom-complex of chlorosis. Let us first consider the genital disturbances. 440 
THE DISEASES OF THE SEXUAL GLANDS 
The assumption of an increased activity of ovulation does not seem to me 
to stand in contradiction to the diverse behavior of menstruation. On the 
one hand it explains cases with increased menstrual bleeding, and on the 
other that after a time a feebler organism no longer reacts to every impulse 
of the growing follicle, or at any rate not with the corresponding alterations 
of the uterine mucous membrane. It is therefore not at all necessary to con- 
sider that the internal secretion of the corpus luteum normally is cast off through 
menstruation and that with the continued absence of menstruation with 
progressive ovulation an autointoxication becomes established (Villemin). 
Otherwise we would have to have a chlorosis in every case of amenorrhea, and 
the cases of chlorosis with excessive hemorrhage would not be explicable at 
all.1 An increased activity of the follicular apparatus would also exercise a 
certain reinforcing action on the function of the interstitial glands, thus ex- 
plaining unforcedly the symptoms of prematurity that are seen in certain cases. 
Through my assumption, a case of childish gigantism with sexual pre- 
maturity and chlorosis, observed by Hastings Gifford, does not seem so in- 
explicable. The author had observed this case between the second and the 
eighteenth years. Menstruation began at the age of thirteen months and from 
then on came at irregular intervals up to the eighth year of life, after which it 
was regular. With the menstruation at the thirteenth month occurred also a 
rapid growth; at three and one-half years of age the child was already 146 cm. 
tall and weighed 41 Yi kg. X-ray plates of the hand showed a development that 
corresponded to that of an eight-year-old girl; the sexual development was 
that of a thirteen- to fourteen-year-old child. The intelligence had remained 
somewhat behind. From the sixth to the twelfth year the girl was always under 
treatment for recurring chlorosis. From then on recovery set in. 
We have further seen that in the premenstrual period the activity of the 
ductless glands is increased, so that there is hence in chlorosis either an in- 
crease in the activity of the ductless glands, or, in those whose activity comes 
most in demand, an exhaustion. Very significant in this respect seems to me 
the behavior of the thyroid gland. I refer to findings described under sympto- 
matology and the frequency of slight symptoms of Basedow’s disease. From 
this standpoint it is indeed intelligible that a newer attack of chlorosis, that 
perhaps takes place with the maturation of a follicle, leads, when a correspond- 
ing disposition is present, to temporary symptoms of Basedow’s disease (see 
the cases of v. Noorden and v. Jagic). 
A second ductless gland whose activity seems to me to be very significant 
is the chromaffin tissue. We have seen that under normal conditions there 
occurs in the premenstrual period an increase of blood-pressure, and we have 
expressed the opinion that impulses proceed from the ripening follicle which 
increase the activity of the chromaffin tissue and raise the vascular tonus. 
Plainly this organ can become relatively rapidly exhausted, the exhaustion 
leading to an influencing of the vasomotor system in the sense of an irritable 
weakness. The laxity of the arteries as well as the low blood-pressure belongs 
1 The assumption of Villemin depends in addition on the incorrect hypothesis that in chlo- 
rosis there is an increased blood disintegration. CHLOROSIS 
441 
to the constant symptoms of chlorosis. We may indeed go further and try to 
explain the blood alterations, at least in part, from this point of view. Height- 
ened tonus of the vessels leads to hyperglobulia through transudation of the 
plasma into the tissue. (I refer to the discussions on the subject of tetany, and 
those concerning the significance of the chromaffin tissue for the regulation and 
distribution of blood-pressure.) It is therefore to be expected that on decreased 
vascular tonus there will be an increase in the amount of the blood; as the blood 
becomes thereby poorer in erythrocytes, it is to be assumed that erythrocytes 
that are then poorer in hemoglobin are given off to the blood paths. Just 
these conditions obtain in chlorosis, increased amount of blood, slightly reduced 
erythrocyte count, more markedly reduced amount of hemoglobin. In a 
group of cases the functional breadth of the bone marrow may fully suffice for 
this regulation, in another group it soon, according to this view, becomes 
exhausted, the exhaustion leading to poverty in hemoglobin. In addition to 
this it is possible that direct impulses go from the follicular apparatus to the 
bone-marrow and on increased activity of the former favor the exhaustion of the 
latter. As according to this hypothesis we are dealing only with an exhaustion 
due to the large demands, it is intelligible why in the autopsies on cases of 
chlorosis the bone-marrow was found to be normal (Birch-Hirschfield, Grawitz). 
Perhaps other symptoms of chlorosis point to a lessened valuation of the chro- 
maffin tissue, signs such as slight mononucleosis, the not rare pigmentation, and 
indirectly the high carbohydrate tolerance, which up to the present have been 
observed by all investigators. The investigations as to the blood sugar have 
not as yet been made. At all events it would not be unintelligible why chlorosis 
develops just in individuals with hypoplasia of the vascular system, which, as 
is known, is associated with hypoplasia of the chromaffin tissue; the corrobora- 
tion of our views would be an instance of the penetrating vision of the past- 
master, Virchow. 
This hypothesis seems to me also to explain why chlorosis is found almost 
exclusively in the female sex. If we were to assume the insufficiency of the 
interstitial glands, it would be indeed unintelligible why in eunuchoidism, in 
which the symptoms of insufficiency are so conspicuous, we meet with no 
chlorosis. The interstitial glands have the same function in both cases; the 
follicular apparatus is something specific for woman. The revolutions that 
take place in the female at the time of maturity are different from those that 
occur in man and are much more powerful. 
The experimental basis for this view is yet to be laid. Whether the im- 
plantation into young animals of ovaries taken in marked ovulation will be 
able to produce a picture similar to chlorosis, is at all events questionable; 
just as castration, which according to the view set forth would bring the 
chlorosis to a standstill in a short time, is impracticable. We must, however, 
consider whether a very cautious X-ray irradiation of the ovaries would not 
act favorably on the chlorotic process.1 Perhaps this view furnishes the key 
11 would here call attention to the later views as to the cause of uterine hemorrhages. Pankow 
pointed out that metritis and chronic endometritis could not be the cause of the profuse menstrual 
hemorrhages. The chronic inflammation may very well be associated with profuse bleeding, but 442 
THE DISEASES OF THE SEXUAL GLANDS 
for the solution of the problem of iron therapy. As is known, iron has an 
almost specific action in chlorosis, while in the other anemic processes it mostly 
fails. Morawitz has concluded that the iron does not act principally on the bone 
marrow, but somewhere else in the body. From the standpoint mentioned, 
it would be well to investigate whether ovulation or the giving-off of hormones 
is not inhibited by the great amount of iron ingestion. At all events it seems 
to me that such a specific influence of iron on the ovaries is not at all necessary. 
The difference of chlorosis from anemia consists in the fact that the bone marrow 
in the former is not diseased, but simply gives out because of increased demands, 
in the course of which exhaustion the formation of the red cells is less affected 
than that of the hemoglobin. It is thus readily understood why in chlorosis 
abundant administration of iron works better than in the anemias. With the 
increase of the hemoglobin may be exercised a favorable influence on the entire 
organism and indirectly on the sexual glands. 
Appendix. Osteomalacia 
In way of an appendix, some remarks as to the relations between osteo- 
malacia and the ductless glands might find place here. There are no doubt 
a number of, in part, important facts that point to the involvement of the 
ductless glandular system in the development of the osteomalacic process; 
the most important of these observations are the following: 
1. Osteomalacia occurs almost exclusively in women, and indeed, in the 
overwhelming majority of cases, during pregnancy. 
2. Castration leads very often to a rapid cure or at least a considerable 
improvement of the osteomalacic process (Fehling). Also after labor 
or after artificially induced abortion, osteomalacia tends to cure or 
at least to improve, just to relapse at the next pregnancy. 
3. The curative or ameliorative action of castration can in such cases 
v enter in without the interruption of the pregnancy (cases of Cramer, 
Walcher, Cristofoletto). 
4. Frequently symptoms are found in osteomalacia that point to an 
involvement of the other ductless glands. Thus, for instance, osteo- 
malacia is not rarely complicated with Basedow’s disease (Latzko), 
or with Basedow’s and tetany (Koppen, v. Recklinghausen). Mohius 
reports a case of Basedow’s that later went over into myxedema, and 
then later acquired puerperal osteomalacia. Moreover, there is found 
in osteomalacia frequently, perhaps regularly, a hyperplasia of the 
parathyroids (Erdheim, Strada, et al.). This hyperplasia of the para- 
thyroids does not tend to occur in senile osteoporosis. 
5. In osteomalacia the glycosuric action of adrenalin and apparently 
also its action on the heart and vessels is strikingly slight (Cristo- 
it does not condition it. Pankow seeks the cause rather in a different functional size of the ovaries 
conditioned by “disturbances in the reciprocal relations of the ductless glands to each other.” Per- 
haps the assumption of a deficient or increased ovulation would suffice, as the climacteric hemorrhages 
have been favorably influenced by X-ray irradiation (Doderlein), which restricts the process of 
ovulation. OSTEOMALACIA 
443 
foletti, see also Reinhardt, Merletti, v. Neusser, Englander, et al.). This 
is also true for osteomalacia during pregnancy, because otherwise 
in pregnancy the action of adrenalin is especially powerful. Further- 
more, long-continued injections of adrenalin in many cases of osteo- 
malacia have exerted favorable influence (Rossi). Cristofoletti has 
collected forty-seven cases of osteomalacia that were treated with 
adrenalin. Of these, eleven were gravid and thirty-five nongravid 
women. Of the gravid women 45 per cent, were cured, and about 18 
per cent, improved. Of the non-gravid women about 17 per cent, were 
cured, and 40 per cent, improved. 
6. In some cases of osteomalacia improvement follows the injection of 
pituitrinum infundibulare (Bondi, Pal). Lately Pal has reported 
concerning excellent influencing of the osteomalacia, in two cases, 
through injections of pituitrinum glandulare. 
Three forms of osteomalacia are to be distinguished. The puerperal form 
which is by far the most frequent. The rheumatic form, which is rare, which 
mostly does not follow a severe course and which occurs also in women inde- 
pendent of a preceding labor; it is also observed in man. Finally the senile 
form. 
The views as to the bone processes in osteomalacia are many. One group 
of authors imparts the most important value to the decalcification of the 
completed bones, another group to the apposition of especially calcium-poor 
bones. Likewise is there division of the authors as to whether rachitis and 
osteomalacia are two different disease conditions or constitute one and the 
same disease process, that leads when it develops in youth, to rickets, and when 
it develops in the fully developed organism to osteomalacia. Cristof oletti sets 
forth the facts that speak against the unitary theory, as well as gross anatomical 
difference: The endemic occurrence of osteomalacia that is independent of the 
extension of the rachitis, the occurrence in grown people, and finally the cardinal 
symptom of osteomalacia, the pain, which is absent in rachitis. The fact also 
seems to me noteworthy that osteomalacia mostly affects persons who were 
not rachitic in youth. 
As might be expected, investigations as to calcium metabolism in osteo- 
malacia show great disturbances. Almost regularly is found negative calcium 
equilibrium. Especially is the elimination of calcium through the intestine 
increased. That therewith the phosphorus is also eliminated in increased 
amount in the feces is not characteristic for osteomalacia, as the calcium 
carries with it the phosphorus. The calcium contents of the blood in os- 
teomalacia is somewhat raised (Capellani). We can see a certain relation 
between pregnancy and osteomalacia in the fact that osteophytes that 
normally form during pregnancy are very poor in lime. 
Of the hypotheses that are at hand as to the pathogenesis of osteo- 
malacia, I mention those only which concern the ductless glands. The 
assumption of a specific thyrogenic disturbance cannot be accepted as correct, 
nor can the view that goiter formation and the osteomalacia have a causal 444 
THE DISEASES OF THE SEXUAL GLANDS 
connection. Among thirty-four cases of osteomalacia, Bossi saw not one 
with a goiter; and I can also very well reject the supposition of a primary 
functional disturbance of the chromaffin tissue. The sexual glandular hy- 
pothesis has attracted the most adherents. Through the favorable results of 
castration, Fehling was furnished the occasion for regarding the cause of 
osteomalacia as a hyperfunction of the ovaries. Cristoj'oletti modified this 
hypothesis by assuming that the internal secretory function of the ovary lasts 
during pregnancy, and that this leads to a hypofunction of the chromaffin 
tissue. 
For an especially functional disturbance of the interstitial glands speaks 
the finding of Wallart that the interstitial substance in osteomalacia is especi- 
ally strongly developed. The assertion of Siegert and M. B. Schmidt that infan- 
tilism and osteomalacia belong together is made scarcely plausible by this fact 
alone. As, however, also in normal pregnancy the interstitial glands are more 
strongly developed, it is questionable whether we may estimate the value of the 
findings of Wallart as high, although I am unable to bring anything else against 
them. 
I would not ascribe the hypofunction of the chromaffin tissue so great a 
value as does Cristojoletti. As signs of it, Cristojoletti quotes: The hypereosino- 
philia, the absence of the adrenalin glycosuria and the eventually present pig- 
mentations. But why, then, do we never find osteomalacic manifestations in 
Addison’s disease? The combination of hypofunction of the chromaffin tissue 
with pregnancy cannot be such an important factor, for there are cases of 
osteomalacia without pregnancy. Moreover the relations of the chromaffin 
tissue to the calcium metabolism are still rather questionable. 
To my knowledge, there are no existing observations as to whether there 
is in pregnancy a continuation of ovulation. After all, the assumption of a 
hyperfunction of the ovaries is up to the present the only one that can be sup- 
ported by numerous and good observations. It is at all events surprising that 
the osteomalacic process is as well influenced by both castration and by normal 
or artificially induced labor. We may, however, suppose with Halban that the 
activity of the ovary and that of the chorionic epithelium become summated, 
and that it is therefore sufficient to limit only one of these factors. Also the 
hyperplasia of the parathyroids perhaps is explained by this hypothesis. Al- 
ready during normal pregnancy are greater demands made on the parathyroid 
glands, still greater demands may lead to hyperplasia (confer the chapter on 
the parathyroid glands). 
The observations of Pal, that extracts of the anterior lobe of the hypo- 
physis influence osteomalacia favorably, turn our attention to the hypophysis. 
Perhaps in osteomalacia the normal hyperplasia of the anterior lobe during 
pregnancy fails to take place. Up to the present, all these theories are hypothe- 
ses, as between the described and the supposed alterations in the function of the 
ductless glands and the profound disturbance in the osseous system there is 
still a very wide gap. 
In a thorough monographic dissertation on osteomalacia and rachitis, 
G. Pommer has upheld the view that both diseases depend on an affection of the ADDENDUM 
445 
central nervous system. Considering the intimate relationship between the 
central nervous system and the function of the ductless glands this supposition 
seems to me to deserve more attention than it has thus far found. 
Addendum 
Whitehead reports the histological examination on the testicle of the case 
of E. M. Prince. As Prince's case is very interesting, it will be quoted in extenso: 
The patient, apparently a girl, eighteen years of age, consulted Prince 
stating that she had never menstruated, and that she suffered from headaches 
supposed to be due to that fact; she had withdrawn from the college she had 
been attending because of the headaches which were worse about every twenty- 
eight days. She appeared to be a healthy, robust girl, refined and intelligent. 
There was a heavy growth of hair upon the head, the voice was soft and feminine 
and the breasts well developed, rather larger than ordinarily seen in a girl of 
her age. The hips were typically feminine, the mons Veneris was rather scantily 
covered with hair, the labia majora were normal; the clitoris was not enlarged 
and the hymen was unruptured. No uterus could be made out by rectal exam- 
ination. The vagina was about 2 in. long, and terminated in a blind pouch. 
In the upper part of each labium majus a body could be felt which was freely 
movable. The diagnosis made was congenital abscess of the uterus with hernia 
of both ovaries. At the operation (exploratory laparotomy) a small body the 
size of a pecan nut was found at the usual site of the uterus, and to the left of 
this there was found an apparently normal ovary with rudimentary tube. At 
a subsequent operation the two bodies in the labia majora were removed and 
were found to be testes, a diagnosis which was afterward confirmed by a 
pathologist. 
In this case the secondary sexual characters were of the female type. 
A weak point in the case is the absence of the microscopical examination of 
the bodies believed to be ovaries. 
Losert reports a case of true lateral hermaphroditism in man. There 
were, however, no spermatozoa in the part that resembled a testis. He includes 
as true hermaphroditism the four cases collected by Pick (cases of Simon, 
Salen, Ujfreduzzi, and Gudernatsch, and the cases since reported by Kleinknecht 
and by Photakis). In none of these cases, however, were functionating germinal 
elements of both sexes present. 
Saenger reports seven cases of eunuchoidism which had come under his 
personal observation, and concludes that the condition is by no means so rare 
as is generally supposed. His last case is especially interesting in that the 
subject was an kyphoscoliotic acromegalic individual aged thirty-three years, 
who developed a late eunuchoidism in consequence of a gangrene of the testicle; 
after the injury there was a failure of potency, a falling-out of the hairs of the 
beard and pubic regions—and in part also of the eyebrows—but there was no 
eunuchoidal distribution of fat, nor gigantism. 
All references to the subject of the sexual glands would be incomplete 
without mention of the name of Leo Loeb, whose researches on the function 
of the corpus luteum are epoch-making. According to Loeb the corpus luteum 446 
THE DISEASES OF THE SEXUAL GLANDS 
supplies to the uterus a sensitizing substance which prepares it to respond with 
the production of the maternal placenta, if there is added an external stimulus 
of a mechanical nature. 
Loeb has recently fortified his position in an article in “Science.” He 
regards it as certain that the living corpus luteum has the function of inhibiting 
ovulation and of being the decisive factor in the mechanism of the sexual cycle. 
His work has been accepted by gynecologists. Zeitzschmann who has reviewed 
thoroughly the subject of the menstrual cycle publishes the result of his survey 
in the following scheme: 
Endocrine Gland 
Ripening follicle. 
Corpus luteum. 
The developing embryo. 
Functions 
First formation of the uterine mucosa, in 
animals up to and with rut. 
1. Continued formation in the uterus to its 
height, and transition to pregnancy condition. 
2. Prevention of the formation of further 
follicles. 
Retention of the corpus luteum. 
Seitz, Wintz, and Fingerhut have been able to isolate from the cow’s corpus 
luteum two bodies. One of these, a luteoproteid, has hemorrhage-checking 
properties; the other, a lecithin albumin, has, in animals, a stimulating influ- 
ence on the genitalia. When injected subcutaneously in amenorrheic women, 
it brought about menstruation. 
The subject of interchange of sexual character in animals by transplanta- 
tion of the glands peculiar to the opposite sex has been well dealt with in the 
volume by Lipschutz. Here Steinach’s work on this subject is given an im- 
portant place. Steinach’s later work has concerned itself with the so-called 
rejuvenation of animals by tying off the vasa deferentia. The aim of this is to 
induce a destruction of the germinal elements and a proliferation of the so- 
called interstitial cells. Similar results have been ascribed to the irradiation 
of the testicles and the ovaries in animals and in man. It is not at all assured 
that these tying-off and irradiation experiments do not proceed from a faulty 
assumption. In spite of many facts that speak for the position of the so-called 
interstitial glands as furnishing the so-called internal secretory substance of the 
testicle, many arguments speak against this assumption. The principle 
antagonists of the assumption are Schmaltz, Stieve, Bucura, Benda and Zietzsch- 
mann. Schmaltz regards the interstitial cells as of mesodermal origin, and 
therefore, says he, they do not furnish a secretion. Bucura regards the follicular 
epithelium and the Sertoli cells as furnishing the internal secretion, Stieve the 
follicular epithelium and the spermiogenetic elements. Stieve recently worked 
with stuffed geese and found that these possess more interstitial cells and 
show less sexual activity than normal geese. 
Steinach’s work as applied to human beings has been tried in Europe with 
varying success. It has not as yet met universal favor in America, and certainly 
much critique must be exercised before either vasotomy or irradiation is 
applied in a wholesale manner at clinics. In this country Wolharst reports his 
results with vasotomy in three cases of senility and in three cases of premature ADDENDUM 
447 
senility, with sexual impotence. He states that in the actually senile patients, 
the most striking result is the marked decrease in blood pressure, and a feeling 
of well-being that is appreciably noticeable. In these cases the sexual function 
seems to have become extinct and has not been influenced by the operation. 
In the prematurely senile cases, there is occasion to believe, he says, that the 
sexual function was stimulated materially by the operation. 
It must not be forgotten that it has been long recognized that vasotomy 
influences the size and function of the prostate gland. This was well recognized 
by the late J. William White who proposed ligation of the vas in certain cases 
of enlarged prostate gland. May it not be that certain of the good effects of the 
ligation in the successful cases reported may have been due to secondary effects 
from the changes in the prostate gland? 
The work of Steinach has been criticised from another standpoint by 
Fiebinger. According to this author the “senile” rats Steinach worked with 
were not really “senile” but were suffering with a parasitic skin disease, which 
improved after the operation on account of better hygienic care of the animal, 
or other cause. 
That the interstitial cells probably do not possess endocrine properties is 
well shown by the work of Nonidez in fowls. He has shown that the mature 
cock-feathered male fowl lacks a specific interstitial tissue influencing the 
secondary sexual characters. “Since these elements are the only kind of 
granule laden cells present in the ovary and testes and are connected with 
typical eosinophile granulocyte by a closely graded series of stages, it is safe to 
assume that they do not constitute tissue endowed with a specific endocrine 
function. A further proof of this is found in the fact that the granule laden 
cells are not restricted to the gonads, but occur elsewhere in the general mesen- 
chyme. At least it cannot be proved that the cells present in the glands differ 
from those in the other organs in any constant fundamental characteristic.” 
The question of gland transplantation is another matter. Already Falta 
remarked upon the fact that generative organ transplants are apt to “take” 
(see Chapter I). In America Lydston has been one of the pioneers in testicle 
transplantation. One of his most recent articles is that in the New York 
Medical Journal, Feb. 5, 1921, where he reports on two cases, one in a case of 
hypopituitarism, and the other a case in which both testicles were lost through 
tuberculosis. Concerning the first patient Lydston writes: I now have had 
sufficient experience with such cases to warrant the statement that none of these 
patients when operated on by sex-gland implantation will fail of excellent 
results under reasonably favorable conditions. It is my belief that practically 
all, if not all, such subjects, if operated on, at or about the usual age of puberty, 
can be taken through puberty and will show sex development, with correspond- 
ing secondary masculine sex characteristics approximating the normal more or 
less closely,” and concerning his second case: “As to the permanency of 
cases like the foregoing, I beg leave to submit that even where, after a greater 
or less interval, a repetition of the implantation is demanded, the operation 
is still a great step in advance in the treatment of a class of cases hitherto 
regarded as hopeless. One of the remarkable features of the case under con- 448 
THE DISEASES OF THE SEXUAL GLANDS 
sideration is the age of the patient [thirty-six years] and the length of time that 
had elapsed since his own testes were removed [six years before operation]. There 
is no question in my mind as to the uniform success of a properly performed 
implantation in such cases when performed at a reasonably early period after 
the loss of the patient’s own glands. I am convinced, also, that by implantation 
performed at varying periods the results can be sustained indefinitely.” 
Lichtenstern, to quote an abstract in the J. Am. M. Ass., relates that the 
implanted testicle was cast off or absorbed in four cases in which he implanted 
a testicle in the scrotum after resection of the tuberculous testicle. In another 
case both testicles had been destroyed by a shell wound, and the man presented 
the typical symptoms of total castration. Lichtenstern slit a testicle and im- 
planted each half separately on scarified muscle-tissue in the inguinal region, 
under ether, and kept the man in bed for twelve days. The results in this 
and in twenty-one other cases since 1915 confirm the therapeutic effect of free 
testicle transplantation, and that this technique offers favorable conditions 
for survival, and for the continued functioning for years of the implanted 
testicle. He adds that Lydstori’s high percentage of cases in which the testicular 
tissue was cast off is due to Lydston’s method of implantation in the scrotum. 
Conditions here are far from being as favorable for vascularization as in a bed cut 
out for it in the fascia over the oblique muscle in the inguinal region, slightly 
scarifying the muscle. The implant can be a retained testicle from another 
person who has one normal testicle. The father or brother will sometimes give 
a testicle for transplantation especially when it is explained that only a half or 
third of the testicle is required. In one of his cases the testicle was derived 
from an operation elsewhere, and had been kept on ice for several hours. The 
results were faultless, as also in a case in which he implanted a testicle taken 
from a ram. 
The ovary has been transplanted with success, as is mentioned in the text. 
The subject has been written about recently by Clark in “Progressive Medi- 
cine.” Tuffier has grafted or shifted the ovary in 230 cases. The results were 
better in the younger women. Menstruation was never restored with an ovary 
grafted from another women (20 cases); but in 76, 71 per cent, of the 73 women 
whose ovary had been shifted, menstruation returned in from five to seven 
months. The menses were not so regular as in normal conditions, and did not 
usually continue very long. 
The extract of corpus luteum and the extract of the whole ovary have been 
used with success in gynecology and obstetrics. J. C. Hirst among others has 
used them successfully. An account of his experiences is to be read in his 
article. He finds that results are not invariable with any extract, but that 
some success may be expected, except with “ovarian residue which is not very 
happy in its effects,” results are often slow; they are more prompt in the meno- 
pause with the whole ovarian extract, and in the nausea of pregnancy with 
corpus luteum extract. The preparations were often used hypodermically or 
intravenously. He uses ovarian extract intravenously in all cases of hysterec- 
tomy. Corpus luteum, which was useful in the vomiting of pregnancy, should 
not be used intramuscularly or intravenously when the patient has a goiter. ADDENDUM 
449 
Hutchinson and Patet, who have studied osteomalacia in Bombay, state 
that the large preponderance of osteomalacia among Mohammedan women in 
Bombay proves definitely that lack of fresh air and exercise—the result of the 
purdah system—is by far the most potent factor in the production of the 
disease. There is no evidence to show that dietetic deficiency is a cause of 
osteomalacia, as the disease is not uncommon among the wealthier classes of 
the community; among the poorer the deficiency of animal fat in the diet is 
common to all. There is no reason to believe that child marriage and prolonged 
lactation are important factors. The fact that the disease has sudden onset 
associated with fever in many cases and the rapid softening of the bones suggest 
a possible infective condition. 
The knowledge of the relation of possible sexual glandular diseases to 
dementia precox, as suggested by positive Abderhalden reactions when ex- 
tracts of the sexual glands are tested against the sera of dementia precox 
patients is as yet very obscure. The results of such tests against the sera of 
shlorosis patients, would, in view of the author’s views on the cause of chlorosis, 
be very interesting. This may have been done, but the editor does not know 
of such work. 
Whitehead, (R. H.). The structure of a testis from a case of human hermaphroditism. Anat. 
Record, Vol. VII, 1913, p. 83. 
. Losent (/.). Ein Fall von Hermaphroditismus verus beim Menschen. Beitrage zur klin. Chir- 
urgie. Vol. CXXII, 1921, pp. 411-417. 
Saenger (A.). Ueber Eunuchoidismus. Deutsche Zeitschrift fur Nervenheilkunde. Vol. 
LI, H. 3-6, 1914, pp. 178-197. 
Loeb (L.). The experimental production of the maternal placenta and the function of the 
corpus luteum. J. Am. M. Ass., Oct. 30, 1909, Vol. LIII, No. 18. 
Loeb (L.). Corpus luteum and the periodicity in the sexual cycle. Science, N. S., Vol. XLVIII, 
No. 1237, Sept. 13, 1918, pp. 273-277. 
Seitz (L.), Wintz (H.), and Fmgerhut (L.). Ueber die biologische Funktion des Corpus luteum, 
seine chemischen Bestandteile, und deren therapeutische Verwendung bei Unregelmassigkeiten der 
Menstruation. Mimchen. med. Wchnschr., 1914, LV. pp. 1657-1661, 1734-1738. 
Zietschmann (0.). Ueber Funktionen des weiblichen Genitale bei Saiigetier und Mensch. 
Vergleichendes iiber die cyclischen Prozesse der Brunst und Menstruation. Archiv f. Gynak., 
Vol. CXV, No. 2, 1921, pp. 201-252. 
Lobert (/.). Ein Fall von Hermaphroditsmus verus lateralis beim Menschen. Beitrage zur 
klin. Chirurgie, Vol. CXXII, 1921, pp. 411-417. 
Loeb (L.). Corpus luteum and the periodicity in the sexual cycle. Science, N. S., Vol. XLVIII, 
No. 1237, Sept. 13, 1918, pp. 273-277. 
Lipschiitz (A.). Die Pubertatsdriise and ihre Wirkungen. Bern, Bircher, 1919. 
Steinach (E.). Verjiingung durch experimentelle Neubelebung der alterden Pubertatsdriise. 
Berlin, Springer, 1920. 
Schmaltz (R.). Das Geschlechtsleben des Haussaugetiere. 3rd edition, Schoetz, Berlin, 1921. 
Stieve (H.). Neue Untersuchungen iiber die Zwischenzellen. Verhandl. der anat. Gesellsch., 
Jena, 1921, Vol. LIV, Erganzungsheft, pp. 63-76. 
Bucura (C. /.). Zur Theorie der inneren Sekretion des Eierstocks. Zentralbl. f. Gynaekol, 
Vol. XXXII, Part 2, 1913, pp. 1839, seq. 
Benda (C.). Bemerkungen zur normalen und pathologischen Histologie der Zwischenzelle des 
Menschen und der Saugetiere. Archiv fiir Frauenkunde, etc., Vol. VII, No. 1, pp. 30-40. 
Zietzschmann (C.). Ueber Funktionen des weiblichen Genitale bei Saugetier und Mensch. 
Vergleichendes iiber die cyclischen Prozesse der Brunst und Menstruation. Archiv f. Gynak., 
Vol. CXV, No. 2, pp. 201-252. 
Fiebinger (/.). Ueber die Rattenraude und ihre Beziehung zu den Steinachschen Verjungs- 
versuchen. Wiener klin. Wchenschrift, Vol. XXXIV, No. 30, July 28, 1921, pp. 364-366. 450 
THE DISEASES OF THE SEXUAL GLAND 
Wolbarst (A. L.). A report on the Steinach operation in senility and premature senility. 
N. Y. Med. J., Vol. CXV, No. 9, May 3, 1922, pp. 543-545. 
Lydslon (G. F.). Two remarkable cases of testicle implantation. N. Y. Med. J., Vol. XCIII, 
No. 6, Feb. 5, 1921, pp. 232-233. 
Nonidez (J. F.). Studies on the gonads of the fowl. 1. Hematopoietic processes in the gonads 
of embryos and mature birds. Am. J. of Anat., Vol. XXVIII, 1920-1921, pp. 81-113. 
Lichtenstern (R.). Transplantation of testicle. Seitschrift fur urologische Chirurgie, Vol. VI, 
No. 5-6, June 13, 1921, p. 305, seq. Quoted in J. Am. M. Ass., Vol. LXXVII, No. 9, Aug. 27, 
1921, p. 743. 
Clark (J. G.). Ovarian transplantation. Progr. Med., 1921, Vol. II, p. 228, seq. 
Tuffier (J.) Etude chirurgicale sur 230 greffes ovariennes, Bull, Acad, de m6d. Par., 1921, 3s, 
Vol. LXXXVI, pp. 121-124; abstract in J. Am. M. Ass., Vol. LXXVII, No. 12, Sept. 17, 1921, 
p. 974. 
Hirst (J. C.). The comparative value of whole ovarian extract, corpus luteum extract, and 
ovarian residue in menstrual disorders. N. Y. M. J., Vol. CXIV, No. 7, Oct. 5, 1921, pp. 391-394. 
Hutchinson (H. S.) and Paid (P. T.). A preliminary study of the etiology of osteomalacia in the 
city of Bombay. The Glasgow Med. Jr., Vol. XCV, No. 4, April, 1921, pp. 241-255. CHAPTER XI 
PLURIGLANDULAR DISEASES 
Multiple Ductless Glandular Sclerosis.—Gigantism 
Already in the first chapter we pointed out how that in recent time 
there has been a growing tendency especially in the French literature to regard 
individual diseases of the ductless glands as pluriglandular diseases. The 
number of contributions as to pluriglandular disease has shown a steady growth. 
I have already stated my opinion that I regard this tendency as mistaken. 
It must have the result that the individual typical disease pictures will become 
more and more confused and that the laborious acquisitions [to our knowledge] 
will again become lost in the general chaos. In order to make manifest my 
viewpoint on this question, I would again briefly capitulate what I have 
already stated in detail in the first chapter as to the physiological and patho- 
logical correlations. The disease of an individual ductless gland regularly 
has as a sequel disturbance in the other ductless glands, that eventually may 
be recovered from if the gland primarily affected becomes healthy or if, for 
example, its absence of function [Ausfall] has been made good by therapy 
(physiological correlations). By pathological correlation I mean the phe- 
nomenon that the disease that has first involved one gland involves, in its 
further course, other members of the ductless glandular system. In the 
majority of cases, it may readily be seen what ductless gland was first involved; 
for the most part indeed the disease of that ductless gland stands so much to the 
fore, that in this case also I would rather avoid the designation pluriglandular 
disease. Much more do I consider it correct to reserve this term for those 
cases in which the clinical picture shows that the disease process embraces the 
whole ductless glandular system or at least a large part of it. Multiple ductless 
glandular sclerosis must be designated as such a pluriglandular affection kclt’ 
etjoxyv. In such cases we have to deal with general symptoms of deficiency 
[of function, Ausfallerscheinungen] on the part of the system of ductless glands. 
The question as to whether the antitype exists, that is, if there occurs a 
generalized hyperplasia of the ductless glandular system with corresponding 
manifestations of increased function, seems to me not yet ripe for discussion. 
There is no doubt that hyperplastic changes in the thyroid gland and in the 
suprarenal cortex are not rarely a concomitant of acromegaly. But in this 
case there is no occasion to doubt the diagnosis acromegaly on this account— 
so much is the picture dominated by symptoms on the part of the hypophysis. 
The only disease that perhaps belongs here is gigantism. Later I shall expound 
in detail that I cannot regard gigantism as simply an acromegaly of child-life, 
as Launois and Roy assert. The enormously increased tendency to growth of 
the entire body seems to signify to me much more a rendering potent of the 
451 452 
PLURIGLANDULAR DISEASES 
entire ductless glandular system, that is mostly followed by a rapid exhaustion, 
in which some glands, as for example the sexual glands, even at the beginning of 
the disease, show signs of a decay [of function] or of a remaining backward in 
development. One aspect of the problem seems to me not as yet explained, 
namely, whether we are justified in regarding the potentizing of the ductless 
glandular system as alone the cause of the increased tendency to growth, or 
whether we must not assume that from the beginning there was an abnormal 
tendency [mapping-out, Anlage] of the entire organism, including the ductless 
glands. It seems to me, however, that the inclusion of gigantism among the 
pluriglandular diseases seems best adapted for our purpose. 
Multiple Ductless Glandular Sclerosis 
Historical.—A number of the cases that I shall group under this term 
appear in the literature under very diverse designations. In the descrip- 
tion of late eunuchoidism it was mentioned that the cases of multiple ductless 
glandular sclerosis all are associated with more or less distinct symptoms of 
late eunuchoidism, that however these symptoms constitute only a partial 
manifestation of the picture, far richer in symptoms, of multiple ductless 
glandular sclerosis. A uniform conception of this disease picture has not 
as yet permeated the French literature. Gandy describes as infantilism 
reversif ou tardif a part of the cases here set forth by myself and ascribes an 
important etiological factor to a disease of the thyroid gland. Cordier and 
Rebattu place the sexual glands as the central figure of the pathogenesis and 
distinguish between dysorchidie and dysorchidie-dysthyroidie. The works 
of Claude and Gougerot mark an essential advance, these authors in 1907 
having described this clinical picture under the terms insufhsance pluriglan- 
dulaire endocrinienne. To my mind, however, Claude and Gougerot have 
lately gone too far, in that they had especially also later French authors have 
included under this designation cases whose position [thereunder] have seemed 
to me uncertain. I have already dealt with this in detail in the first chap- 
ter. There I have classified together under the term multiple ductless glandu- 
lar sclerosis those cases in which a primary simultaneous disease, or almost 
simultaneous disease, of several glands exist, cases that we must regard as 
correlated to the inflammatory sclerosis and atrophy of the ductless glands 
as found at autopsy. 
There are, of course, cases of spontaneous myxedema or of Addison’s dis- 
ease that likewise depend on inflammatory sclerosis of the ductless gland con- 
cerned. Mostly, however, we are in a position sharply to differentiate the 
disease pictures. In the cases about to be described we are dealing with a 
symptom-complex that already in vivo suffices to let us refer the diagnosis 
to a more or less generalized sclerosis of the ductless glands and justifies us 
in picking out this disease-form as an entity. 
Definition.—As multiple ductless glandular sclerosis I term that clinical 
picture which is brought about by a probably infectious, for the most part not 
as yet more well-defined, disease process—a disease process that involves several MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 
453 
ductless glands simultaneously, and leads to high-grade sclerotic atrophy and 
hence to manifestations of deficiency on the part of these glands. Thyroid gland, 
sexual glands, hypophysis, and suprarenals are mostly involved. Correspond- 
ingly are found more or less pronounced the manifestations of hypothyrosis, of 
late eunuchoidism, and hypophysial insufficiency, combined with a syndrome 
similar to Addison’s disease (hypotonia, pigmentations, etc). Especially brought 
into prominence is a progressive [i.e., uncontrollable] cachexia, that develops 
to a high grade. 
Case Histories.—Of the cases reported in the literature I regard the fol- 
lowing as belonging to multiple ductless glandular sclerosis. At all events 
I must mention that some of these cases are not exactly enough described, 
so that their membership in the group is not quite certain. 
Observation of Rumpel.—Man, thirty-six years old. Great weakness, backs of hands 
and feet thick and puffy, pronounced cachexia, and considerable anemia, skin dry, weak- 
ness of memory, frequent chills, temperature abnormally low, penis of normal size, scrotum 
very small, testicles much atrophied, but still sensitive. Cremasteric reflex weakened, 
libido absent. Scanty axillary and pubic hair; also the hair of the head is thinned out; 
subcutaneous fat-tissue increased, especially on mons Veneris; polyuria and polydipsia; 
gonorrhea at the age of twenty-four years. Beginning of the disease in the thirtieth year 
of life with gradual loss of the sexual instinct, with thickening of the skin of the dorsa of the 
hands and feet, lessening of memory, falling out of hair, etc. Thyroid treatment without 
result. No autopsy. 
Observation of Ponfick.—Man, forty-seven years old, cobbler, married since twenty-third 
year of life, has six children. Since the thirty-second year has had a gradually-increasing 
fullness of the face, working ability decreased, the cheeks become puffy, the lips swollen, 
the skin rigid and pale as wax, the hair of the head thinned out, the hair on the cheeks is 
entirely absent. Also the mustache is thinned out. Mimicry slow, speech scanning, 
hearing diminished, skin slightly colored cyanotic, scaly, the hairiness of the trunk and 
extremities has decreased markedly, the genitalia are almost entirely devoid of hair. Hemo- 
globin 55 per cent. Essential improvement on thyroid medication, gain of weight, 8 kg., 
hemoglobin rises again to 75 per cent. In spite of continuation of the thyroidin treatment, 
later much pufiflness of the face, diarrheas, hemoglobin again falls, hearing becomes worse 
(sclerosis of the middle ear), body weight sinks lower, although thyroidin is no longer given. 
Death from pneumonia. Thyroid 10.2 gm., therefore only a third of the normal weight. 
The isthmus and the parts bordering on it well retained, however, and show tissue that is 
entirely capable of functionating. Periarteritis hemorrhagica. Suprarenals generally 
thinned, cortex somewhat smaller. Hypophysis: in the sella turcica a large cavity, the 
posterior lobe well retained, the peduncles of the hypophysis penetrate the cavity (hydrops 
ex vacuo), dura grown fast to the underlying tissue. Destruction of the glandular lobe. 
Callous thickening in the retained part. Rigidity of the fiber masses. 
Observation of Gouilloud.—Woman, thirty-seven years old, mother of three children, 
severe hemoptysis at the thirty-third year, at the time cessation of menses, which have never 
been right since; the temperament, which was formerly very lively, has altered, the patient 
is apathetic, forgetful, childish mentally. Cachexia for the last half year. Face pale. 
Lashes have in part fallen out. Also the hair of the head is thinned out and has lost its 
color. Also the hairs of the axillae and on the pubis have fallen out. The hands are cold, 
backs of the hands edematous. The thyroid is apparently smaller than normal, the uterus 
entirely atrophic. Improvement by thyroid therapy doubtful. 
Observation of Djemil Pascha.—Man, eighteen years old, testicles began to atrophy 
three years ago, the potency became lost. The mamillae began to increase in volume, also 
the breasts became larger, the pitch of the voice was higher. After operative removal of 
the breasts libido returned, the testicles became larger again, pollutions occurred; later, 454 
PLURIGLANDULAR DISEASES 
increasing paleness and puffiness of the skin of the entire body, apathy, increasing cachexia, 
dryness of the hair. Medication with thyroidin unsuccessful, death, no autopsy. 
Observation of Claude and Gougerot.—Man, forty-seven years old, formerly very potent, 
father of three children, alcoholism. At forty-two years, probably tetany, also perhaps 
nephritis. During convalescence falling out of the hair of the head, the testicles atrophied, 
complete impotence, the voice altered, and also the external genitalia became atrophic. 
Hairs of the beard very scanty. Pubic hair and axillary hair absent. Skin dry, apathy, 
pigmentations on the skin and mucous membranes, low blood-pressure, asthenia, gradual 
diminution in the size of the thyroid gland, high-grade cachexia, tuberculosis of the lungs, 
death. Autopsy showed tuberculous foci in lungs, liver and kidneys. The thyroid very 
small, only 12 gm. The testicles very atrophic (22 gm.), prostate and seminal vesicles also 
atrophic. Hypophysis small and sclerotic. Histological examination of the skin; atro- 
phy of the epidermis; hair follicles, sweat glands and sebaceous glands atrophic. 
Observation of Gandy.—Man, thirty-three years old, formerly gonorrhea, father of two 
children; was very potent; at twenty-seven years, polyuria, headaches, severe sweats, 
puffiness of the face, falling out of hair, nasal hydrorrhea. Later retrogression of the second- 
ary sexual characters and atrophy of the genitalia. Looks like an eighteen-year-old youth. 
Skin of the face, pale, subicteric, skin dry, slightly scaly. Hairs of beard very scanty. 
Trunk and extremities bald. Scrotum and testicles quite small, the latter insensitive. 
Penis 6-7 cm. long. Complete impotence. Prostate also atrophied. Cremasteric reflexes 
absent. Perineum and genitalia have lost their pigment. Autopsy: Inflammatory sclerosis 
of the thyroid (7 gm.), the testicles very small (8-10 gm.). Interstitial substance has dis- 
appeared entirely. Meningitic changes at the base of the skull, with edema of the brain. 
No statement as to hypophysis. 
Observation of Brissaud and Bauer.—Twenty-nine-year-old woman, heart failure, em- 
bolism, tuberculosis, peritonitis. First menses at the age of fifteen. Birth of child at the 
age of twenty. From that time has not menstruated. Infantile appearance, face very 
pale, slightly swollen, breasts little developed. Hair of head dry and thinned out, likewise 
the eyebrows, entire absence of pubic and axillary hair. Voice monotonous. Apathy, 
headaches, anemia, and cachexia. Autopsy. Thyroid 15 gm. apparently normal. No 
statement as to microscopical examination. Left side salpingitis and oophoritis. Right 
ovary much sclerosed, very small. Uterus like that of a little girl. No statement as to the 
pituitary. 
Observation of Sainton and Rathery.—Woman, thirty-two years old, syphilis at the age 
of twenty-five. Very distinct myxedema, appears very infantile, absence of pubic and 
axillary hairs. Hair of head thinned out, dry. Apathy. Speech slow, almost complete 
amaurosis, pulse 66, improvement as a result of thyroidin medication. Autopsy. Thyroid 
gland sclerosed, 12 gm., thymus large, suprarenals sclerosed. Genitalia atrophic. Ovaries 
very small, sclerotic. Uterus infantile. Soft malignant, cystic degenerated tumor of the 
hypophysis. 
Observation of Josser and.—Man, thirty years old, five years ago influenza and articular 
swellings, later great loss of body weight, marked weakness, the mustache fell out, also the 
axillary hair and the eyebrows; the skin of the penis became thick, and inelastic, atrophy 
of the testicles, loss of libido and of potency. Extreme weakness, then some improvement. 
Anemia, senile appearance. Testicles the size of hazelnuts, bilateral hemianopsia, apparent 
increase in size of the hands and feet. 
Josserand mentions in brief a second case who at the age of thirty-five passed safely 
through an attack of influenza, and later became senile. 
Observation of Gougerot and Gy.—Man, fifty-two years old, formerly very strong, very 
potent, at the age of forty-one years a “hard to define” infectious disease, with pains in the 
limbs and in the abdomen, vomiting and numbness, lasting two and a half months. Later 
asthenia, and temporary polyuria. From this time on libido and potency gradually les- 
sened and finally disappeared. Hairs of the beard fell out, axillary and pubic hairs are almost 
entirely absent. Senile appearance, testicles atrophied, sensation of cold, tuberculosis of the MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 
455 
apices, lupus on the nose, erysipelas, later pneumonia. Autopsy: Thyroid gland highly 
sclerosed, right lobe 6 gm., left lobe 5 gm. Testicles likewise sclerosed, right 18 gm., left 
20 gm. Suprarenals sclerosed, chiefly in the cortex; pancreas also sclerosed, likewise the 
hypophysis (0.3 gm.), and the parathyroids. Also liver, spleen and kidneys sclerotic. 
Personal Observation.—Observation LIII.—Forty-year-old man (history partly elicited 
from the wife of the patient). Father of the patient died at the age of sixty years of carci- 
noma of the stomach, mother at forty-five years, of tuberculosis. One brother also died 
of tuberculosis, otherwise no tuberculosis in the family. One uncle died of diabetes. No 
gout, no obesity, no Basedow’s, in the family. The patient himself had in his youth passed 
through measles and scarlet fever. At twenty years of age, catarrh of the pulmonary apices, 
that became healed. The patient then remained healthy up to his thirty-fifth year. Sexual 
life was fully normal. He married at the age of twenty-eight years and has three healthy 
children. Hair of the head abundant, and there was a fair amount of hair on the trunk and 
extremities. Abundant beard. Axillary and pubic hair abundant. Potency and libido 
entirely normal. Had never engaged in [sexual] excesses; at the age of twenty-two years 
gonorrhea and slight orchitis. He was never especially strong muscularly, was always rather 
thin, but he felt well and could always fulfill his now and then exacting duties as a tradesman. 
At the age of thirty-five years be became ill rather acutely with fever, lancinating pains in 
the extremities, pains in the back and neck (he cannot say whether the thyroid was swollen). 
The physician diagnosed influenza and ordered aspirin. For some days later there also 
existed diarrhea. The fever rose as high as 39.s°C. Later when the acute manifestations 
had retrograded, there occurred edema of the legs, the face, and also the backs of the hands 
and feet. Albumin was found in urine and the physician diagnosed nephritis. The patient 
felt very weak, after about eight weeks improvement occurred, but the weakness persisted; 
convalescence continued for an unusually long time, for several weeks still the patient 
suffered from great muscular weakness, he became thin, and the edematous swellings dis- 
appeared very slowly. After three months the patient had recovered, yet he never felt 
entirely well since that illness. The potency gradually became lost, and about three- 
quarters of a year after the illness the testicles seemed to him to be smaller. Also the 
penis was smaller, the hair of the head had become thinned out immediately after the ill- 
ness, so that some bald spots had formed. Now also the hair of the mustache and beard 
began to fall out, and the axillary and pubic hair and the hair on the trunk gradually dis- 
appeared. Since this time the patient has been an invalid. Later, the physicians regarded 
the nephritis as cured; although the puffiness of the skin never left entirely. The patient 
is very apathetic, tires very easily, shivers, is never quite warm, has never attained his former 
body weight, mental work exerts him very much, he sleeps poorly at night, suffers from pres- 
sure in the head, sometimes complains of drawing pains in the back and legs; lately the 
swelling of the face has again become distinct. Also the pallor of the face has increased. 
He has visited different bath resorts and taken many medicines, among them iodine and 
arsenic. The bowel movements often occur at intervals of four to five days. Recently, 
albumin has again been found in the urine. 
The patient came under my observation in May, 1911. Medium height, cachectic 
appearance, looks very much older. Face pale with a light yellowish tinge. Distinct 
puffiness of face, especially about the eyes, on the cheeks and lips. Light livid discoloration 
of the middle of the cheeks. On the upper lips mustache hairs very scanty; chin and cheeks 
bald. Hair of head thinned out, dry, and brittle, at certain places much more scanty, 
especially on the occiput. The trunk is bald, there are no hairs in the axilla; at the root 
of the penis a few scant)" hairs only, the perineum is almost free from hair. Tongue perhaps 
somewhat thickened. Teeth poor, partly carious, the crowns much worn away, transverse 
folds on the forehead, skin in the supraclavicular fossae shows slight pad-like thickening, 
elastic; also the skin on the backs of the hands and feet is more elastic, otherwise skin on 
trunk is rather rich in fat. Several lens-shaped specks of pigment on the mucous membrane 
of the cheeks. Many places on the skin more strongly pigmented, as in the folds of the 
palm of the hand, also in the vicinity of the nipples, on the backs of the hands, forearms, also 456 
PLURIGLANDULAR DISEASES 
about the waist. Breasts not enlarged. Mons Veneris rather rich in fat; no especial 
deposition of fat on hips. Findings as to cranial nerves entirely normal, except that Chvostek 
II distinctly positive. Trousseau negative. Pupils react promptly. Eye-grounds normal. 
Patellar reflexes weak. Size of heart normal to percussion; faint, weak, systolic murmur 
at Erb’s point. Pulse 68, tension slight, blood-pressure (Riva Rocci) 65, liver not enlarged, 
spleen not distinctly palpable, neighborhood of the kidneys on each side not especially sensi- 
tive to pressure. Penis small, about 7 cm. long. Skin on penis folded. Testicles on each 
side about the size of a bean, soft, epididymis also small, somewhat hardened. Scrotum 
small, soft. Examination per rectum shows that the prostate is very small. Examination 
of the blood: leucocytes 12,000 of which 51 per cent, are neutrophiles and 5 per cent, eosino- 
philes. In the urine no sugar, traces of albumin. Slight dullness over the right apex, very 
few rales. Vesicular murmur somewhat weakened. Therapy. Thyroidin tablets 0.1 
gm. t.i.d. After two and one-half months report by letter that the myxedematous manifes- 
tations have improved, but the deterioration in strength has progressed. 
Symptomatology.—The cases described show a very noteworthy agree- 
ment with one another. It is therefore not difficult to delineate the clinical 
picture of the condition. All cases show in pronounced manner the symp- 
toms of late eunuchoidism, an exact description of which I need not enter into 
here. This syndrome, however, constitutes only one, although one of the 
most emphatic expressions in the total picture of the disease. To it is added 
in all cases a most irresistibly progressive cachexia, and mostly also, as far 
as investigations have determined, a pronounced anemia. Hence it occurs 
that such patients in spite of the boyish beardlessness of face, do not, as in 
late eunuchoidism appear younger than they really are; for the most part 
they rather appear prematurely old, and in some cases the face has 
even a senile appearance. There never occurs the development of an adi- 
posity of the type shown by eunuchoids. For the most part there rather occurs 
an increasing emaciation, which is associated with a feeling of weakness 
and with chills, and which persists in spite of all attempts at feeding up. 
Then there occurs more or less pronounced pufhness of the skin of the face, 
especially of the cheeks, and of the skin of the backs of the hands and feet, 
in many cases quite pronounced myxedema, which partially but not entirely 
retrogresses on thyroidin medication. There usually are added to the falling 
out of the hair on the face, trunk and extremities, thinning out of the hair 
of the head, eventually falling out of the hairs in spots, such as is seen in 
true myxedema, also thinning out of the eyebrows, eyelashes, and symp- 
toms that also do not belong to true late eunuchoidism. Also brittleness 
of the nails was observed in my case. The loosening of the teeth, and especially 
the marked wearing down of the crowns, as I saw in my case, perhaps too belong 
to the clinical picture. In many cases are found in addition to the pufhness 
of the skin, pronounced atrophy of the rest of the skin, and marked dryness 
and exfoliation. There further develops in the majority of cases pigmentations 
of the skin, especially in places exposed to light or where the clothing presses, 
sometimes, too, distinct pigmentations of the mucous membrane as in Addison’s 
disease; in other cases a pigmentation that is more brownish is noticed. Almost 
in no case are absent asthenia that increases to high-grade prostration of 
strength, mental sluggishness and apathy, further a feeling of pressure in the 
head, forgetfulness, insomnia, and eventually transitory rheumatoid pains in the MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 
457 
limbs. In addition there exists hypotonia. The sugar content of the blood 
has not as yet been investigated. In cases in which the blood has been 
examined have been found in addition to the anemia, slight leucocytosis with 
mononucleosis and eosinophilia. Temporary polyuria has been reported 
remarkably frequently (Rumpel, Gandy, Gougerot and Gy). Occasionally 
also occur tetanic convulsions (Claude and Gougerot), or at least the symptoms 
of a latent tetany. 
The tracing of the relationship of the numerous symptoms to the diseases 
of the individual ductless glands often meets, as will be understood, with diffi- 
culties. It seems to me that the simplest to explain is the syndrome that we 
learned to know in the exposition of late eunuchoidism, and that comes about 
through the degeneration of the sexual glands. It should only be mentioned 
in addition that in the cases that affect women, the retrogression of the 
genital apparatus and of the secondary sexual characters are present in a pro- 
nounced manner. At all events we cannot in the cases with pronounced retro- 
gression of the genital apparatus, and especially of the hair of the mustache, 
exclude the possibility that a degeneration of the suprarenal cortex does not 
play a role. In male individuals, it appears to me only necessary to assume 
such an involvement of the suprarenal cortex in the crassest cases, as in trau- 
matic late eunuchoidism, in which the etiological factor is quite clear, quite 
severe manifestations of retrogression may occur. In women, however, 
there may perhaps be ascribed to the suprarenal cortex a greater signifi- 
cance in this direction, for we see after castration very slightly pronounced 
the ordinary retrogression of such secondary sexual characters as the hairi- 
ness of the axillae and of the genitalia. 
The changes in the hair of the head are to be referred to a degeneration 
of the thyroid gland, as are also trophic disturbances of the nails, probably also 
of the teeth, and further the apathy, headache, forgetfulness, etc., finally the 
myxedema of the skin. At all events it seems to me questionable whether the 
myxedematoid consistence of the skin is always of purely thyrogenic origin, 
as thyroidin medication very often does not fully control it. Such myxedema- 
toid alteration of the skin is found not infrequently in the hypophysial dystro- 
phia adiposo-genitalis; further such alterations occur not rarely if cachexia 
develops in Basedow’s disease. I refer to the chapter dealing with this subject, 
and would like only to express the conviction that in such cases the skin changes 
may be brought into relationship with a (even simultaneous) degeneration of 
the glandular hypophysis. 
The sclerosis of the hypophysis may also very well play a part in the rapidly 
progressive cachexia. That there does not ensue a distinct development of 
hypophysial obesity is intelligible when we consider the general cachexia in 
multiple ductless glandular sclerosis. If individuals who are not yet fully 
developed were to become the subjects of this disease, the absence of the 
eunuchoidal tall height would also be intelligible, as the action of the insuffi- 
ciency of the sexual glands on the development of the skeleton might be com- 
pensated by the insufficiency of the hypophysis. I would bring still another 
symptom into relation with the hypophysis—the transitory polyuria. As is 458 
PLURIGLANDULAR DISEASES 
known we find this symptom quite commonly in diseases of the hypophysis, 
or in pathological processes at the base of the skull. We may readily conceive 
that sclerosing processes that have become established in the anterior lobe of 
the hypophysis temporarily act as irritants on the posterior lobes or on the pars 
intermedia. From this standpoint it seems to me worthy of mention that two 
of the cases of late eunuchoidism reported in the tenth chapter, in which we 
found transitory polyuria, developed after an acute infectious disease or after 
lues. Here the polyuria may well be regarded as hypophysial. 
Fig. 8o.—Case with insufficiency of sev- 
eral ductless glands (Observation LIV). 
Fig. 8i.—Slightly myxedematous facial expression. 
Hypotonia, high-grade asthenia, and the pigmentations serve as manifesta- 
tions of absence or deficiency [Ausfall] on the part of the suprarenals or, much 
more, the suprarenal medulla. Finally the tetanic spasms that occur point to 
an involvement of the parathyroid glands in the disease process. Here perhaps 
it may be thought that the lowering of the thyroidal and suprarenal activities 
can antagonize the occurrence of distinct tetanic symptoms even where there is 
high insufficiency of the parathyroid glands. I know that much that is hy- 
pothetical is bound up with these attempts at explanation. In one point, how- 
ever, I believe I can scarcely err, namely, in the supposition that the rapidly 
progressing cachexia that is observed so frequently finds its explanation not in 
the functional disturbance of one ductless gland, but in the progressive degenera- 
tion of the ductless glandular system. MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 
459 
The etiology of multiple ductless glandular sclerosis of the ductless glands 
seems to be of diverse nature. In many of the cases acute infectious diseases 
have preceded the beginning of the disease. Thus in the case of Josserand, 
influenza; in the case of Gougerot and Gy a “hard to define acute” illness 
occurred, as in my case also. The case of Sainton and Rathery was syphilitic. 
In the case of Claude and Gougerot, and in that of Brissaud and Bauer there 
existed at the same time tuberculosis. Histologically, in the cases in which 
there were autopsies, there was found a simple sclerosis; except in the case of 
Claude and Gougerot, where there was found in addition tubercle in the thyroid 
gland. It is indeed very likely that the ductless glandular sclerosis may depend 
very often on a tuberculous foundation, as Poncet and Leriche mention, although 
I cannot follow the connection of ideas of these authors when they ascribe to 
cases of dystrophia adiposo-genitalis, yes even to cases of acromegaly, a tubercu- 
lous foundation. 
In many cases the disease picture of multiple ductless glandular sclerosis 
develops quite spontaneously, without a preceding or an accompanying disease. 
The opinion of Claude and Gougerot that there exists in such cases a congenital 
weakness of the ductless glandular system, so that a not well-definable deleteri- 
ous agent brings this system to degeneration, is not improbable. In such cases 
the organism, especially that which is still in a state of development, may come 
to a temporary manifestation of insufficiency on the part of the ductless glandu- 
lar system. 
I would regard the following as such a case: 
Observation LIV.—J. K., seventeen years old (first medical clinic). One year ago 
typical tetany, two months ago typical epileptic attacks for the first time. Now tetany 
again. Of medium height, pale color of face, skin somewhat dry and exfoliative. Face 
distinctly myxedematous, especially the eyelids. On the backs of the hands slight myxede- 
matous swellings. Hairs of the beard and axillae are entirely absent, as is also the hairiness 
of the linea alba and the calves. Scanty hairs at the root of the penis. The testicles are 
very small and soft. As yet no libido, never erections nor pollutions. Finger nails very 
compact, strongly curved, and ridged longitudinally. Teeth throughout strikingly small 
and poorly developed, terrace-like striations on the enamel (whether he had tetany in child- 
hood cannot be elicited). Ossification normal. Blood-pressure 65. On the administration 
of even 200 gm. dextrose, no glycosuria. Neutrophile cells 54 per cent. Typical tetanic 
attacks. Slight apathy; on thyroidin medication the myxedematous symptoms disappear 
entirely, the blood-pressure soon rises to normal, the blood picture becomes normal. 
After a year the case was examined by Redlich. There were new attacks of tetany, also 
epilepsy. There was nothing to be seen of the myxedematoid symptoms, the secondary 
sexual characters had for the greater part developed, and the sexual life had begun to assert 
itself. 
Thus in this case there existed, in addition to typical tetany and epilepsy, 
a simultaneous disturbance of the function of the thyroid gland and of the 
sexual glands. Perhaps the suprarenals (pronounced hypotonia) were also 
involved. Probably the inhibition of development of the sexual glands was 
not occasioned directly by the disease of the thyroid. For this speaks the fact 
that thyroid-gland therapy immediately brought the manifestations of hypo- 
thyroidism to disappearance, while the insufficiency of the sexual glands gradu- 
ally disappeared spontaneously. 460 
PLURIGLANDULAR DISEASES 
Claude and Gougerot believe that also alcoholism may furnish an etiological 
factor. In this respect two cases of general hemochromatosis, concerning which 
Falk has reported, are of interest. As is known, there are found in such cases 
pronounced sclerosis of the liver and mostly also of the pancreas. In both the 
cases, as I myself had occasion to observe, there was also a premature diminu- 
tion or cessation of the genital function, without the history furnishing a basis 
for a preceding disease of the genitalia. In both cases there was found an almost 
complete falling-out of hair on the trunk and the extremities, and also that in 
the axillae and on the pubis. The histological examination of an excised piece 
of skin showed, in addition to collections of pigmentation, abundant connective- 
tissue proliferation of the cutis; and in places the sweat-glands and the hair 
follicles were replaced by connective-tissue strands. Falk believed that this 
sclerosis was also the cause of ffhe falling-out of the hair. I incline more to the 
supposition that the involvement of the sexual glands in the general sclerosis 
had led to a retrogression of the secondary sexual characters. 
For this assumption I find support in the investigations of Weichselhaum 
and Kyrle. In individuals, wfio do not as yet stand under the influence of the 
senium, Weichselhaum and Kyrle found on account of alcoholism cirrhotic 
alterations of the testicles, affecting interstitial cells as well as the glands of 
generation. 
In the broad field of multiple ductless glandular sclerosis belongs perhaps 
a disease that v. No or den has described as degeneratio genito-sclerodermica. 
It affects young, previously healthy, girls, in whom after a previously normal 
development the menstrual periods suddenly cease at the termination of an 
acute infectious disease. There are marked emaciation and loss of appetite, 
a premature senility occurs, and there develop trophic disturbances of the skin; 
in some cases in which the condition was looked for, the body of the uterus was 
found to be atrophic. 
Further I would mention for consideration whether such a multiple ductless 
glandular sclerosis does not exist in many cases of pedatrophy. Thompson 
has described a noteworthy case in which sclerotic processes were found in 
all the ductless glands. 
Finally I might here mention an apparently rather typical disease picture 
of which Sir Jonathan Hutchinson, Hastings Gilford and recently Variot and 
Pironneau have furnished examples. Hastings Gilford designates these cases 
as “ progeria,” Variot and Pironneau as “nanisim type senile.” As we shall 
see directly much speaks against our classifying, without other consideration, 
these cases with multiple ductless glandular sclerosis. I would say, how- 
ever, that at least an indirect connection with the ductless glandular system is 
here possible, and that the inclusion of the condition at another place appears 
to me less to the purpose. 
I will here shortly report the three cases described up to the present. In the case of 
Hastings Gilford the observation extended between the fourteenth and eighteenth years 
of life of the individual. A photograph of the individual taken at the second year 
of life shows that the hair of the head was markedly thinned out already at that time at 
the later investigations he showed a marked remaining behind in growth and in MULTIPLE DUCTLESS GLANDULAR SCLEROSIS 
461 
entire development. At fourteen years of age the boy was 113 cm. tall, weighed 16 kg. 
He was extremely thin, so that the cartilages of the nose and the veins and the tendons of 
the entire body were very prominent. The head was rather large, the facial skeleton 
relatively small. There were on the head only a few thin hairs, the eyebrows and the 
lashes were absent, almost completely, as were also the hairs of the trunk. The lower jaw 
was ill-developed, and there was especially a poor development of the clavicles. The mus- 
culature was poorly developed, the genitalia were about one or two years behind in their 
development, the skin was thin and dry, the nails were short and the anterior fontanelle 
had not as yet closed, and certain of the temporary teeth were still present. There was a 
falsetto voice; the intelligence was rather well developed. The individual made quite a 
senile impression. At the age of eighteen, the boy died with symptoms that gave thought 
to the diagnosis of “thymic or cardiac asthma.” At autopsy was found an enlarged thymus 
gland and atheromatous alteration of the mitral and aortic valves; the coronary arteries 
were highly sclerotic. The capsule of the spleen was thickened, the kidneys were fibrous, 
the walls of the intestines and stomach were so atrophied that they were almost trans- 
parent. The liver was relatively large, the brain normal. The long tubular bones were 
rather slender, but the ends much thickened. Especially the condyles of the femurs and the 
arterial ends of the clavicles were swollen up. Ossification had been premature. Micro- 
scopically the ductless glands (thyroid, hypophysis, testicles and suprarenals) were apparently 
normal, there was no microscopical examination. 
Hutchinson observed a three-and-a-half-year-old boy with the same disease. Hastings 
Gilford saw this case when it was fifteen years of age and kept in touch with it to its death two 
years later. There existed extreme emaciation, so that the bones and the tendons were very 
prominent. The abdomen was large, the condyles of the tubular bones were rather thick- 
ened, especially the distal epiphyses of the femurs, so that the patellas were pushed forward. 
The fingers were short, the size of the hands corresponding to that of a three-year-old child. 
The ossification represented that of a twenty-year-old youth. There were symptoms of a 
mitral and aortic failure, and death occurred with symptoms of a cardiac syncope. There 
was no autopsy. 
The case of Variot and Pironneau was that of a fifteen-year-old girl. She weighed only 
11.65 kg.—like a two-year-old child—was 102 cm. in height, size and dimensions corre- 
sponding with those of a five-year-old child. The appearance was entirely senile. Apart 
from isolated hairs on the head, the hair was entirely absent, even the hairs of the eyebrows 
and lashes. The skin was thin and folded, the panniculus adiposus was entirely absent. 
The muscles were relatively well developed, and stood up prominently through the thin 
skin. The nails were very small, the tooth formation was very bad, and second dentition 
was just appearing. Many teeth have fallen out without especial pain. The develop- 
ment of the genitalia had remained behind, and the breasts especially had not developed. 
The intelligence was rather good. Up to the fifteenth month development had been entirely 
normal, and from this time it had remained behind. X-ray examination showed that the 
lower jaw was very atrophic and that the epiphysial junctures had for the most part closed. 
Gilford Hastings reports also a case of Ransom that possibly belongs here. It was concerned 
with a twenty-seven-year-old girl who was 135 cm. tall and weighed 16 kg. The father.had 
been a heavy alcoholic. The girl’s intelligence was feebly developed. Diarrhea had 
existed from youth, and later there had been a diabetes. The genitalia in their development 
represented those of a ten-year-old girl. The ovaries were absent. The girl was markedly 
emaciated and looked pronouncedly senile. At autopsy there were found fibrous changes in 
the spleen, lymph glands, the pancreas, kidneys, suprarenals, thyroid, hypophysis, etc. 
The heart weighed 6 oz. (about 176 gm.) and there were atheromatous changes in the aortic 
and mitral valves and in the aorta. 
[A case of apparent progeria (case of Rand)—not however typical—there is no baldness— 
is pictured by Ilarvier in “ Sympathetique et Glands Endocrines,” Vol. IX of Sergent, etc.’s. 
‘‘Traite de Pathologie Medicale,” etc. Paris, Malone, 1921.—Editor.] 462 
PLURIGLANDULAR DISEASES 
The cases cited show the greatest similarity to one another. Already 
Eastings Gilford remarked that his case and that of Hutchinson were so similar 
that the father of the first when shown the photograph of the second believed 
momentarily that it was that of his child. Also the case of Variot and Piron- 
neau was similar to the first two, as is seen in the photographs these authors 
publish; it is also remarked by them, although their case is that of a girl. 
In all cases the disturbance in development began in the earliest youth. In 
all the inhibition of growth was very considerable, so that we could really speak 
of dwarfism. In all there was extreme emaciation, with the skin thin folded. 
In all were the muscles rather prominent. The osseous system showed the 
characteristic alterations. The dimensions remained childlike. The lower jaw 
was rather poorly developed, apparently also the upper jaw, causing perhaps the 
aquiline nose observed in all. The long bones were relatively slender, the ends 
of the bones thickened, the closure of the epiphyses was rather premature. 
The genitalia remained backward in development in all cases; and finally the 
absence of hair is common to all, affecting not only the hairiness belonging 
to the so-called secondary sexual characters, that on the lip, chin, axillae, pubis, 
and trunk, but also the hair on the head, lashes, and eyebrows. This increased 
the senile appearance, which in all these cases is of high degree. 
That here we are dealing with a morbid entity can in all likelihood be as- 
sumed from the similarity of the cases and the course of the disease. On the 
contrary the pathogenesis of this condition and the role of the ductless glandular 
system in the same seem to me to be as yet but little clear. Variot and Piron- 
neau point out that in the case of Hastings Gilford the suprarenal showed 
fibrous degeneration, and see in the disease picture the sequel of a suprarenal 
insufficiency’s setting-in in youth. Apert goes still further and sees the cause 
in a damaging of the suprarenal cortex. On account of the characteristic 
disturbances in the hairiness and in the genital sphere he sees in this disease 
a countertype to that of tumors of the suprarenal cortex. Hastings Gilford 
believes on the contrary that we are to ascribe to the hypophysis a “growth 
center” of considerable importance. The results of the one autopsy done on 
these cases up to the present are insufficient, as there was no microscopical 
examination of the ductless glands. It was mentioned only that the suprarenals 
were sclerosed. In the case of Ransom, that does not belong with certainty to 
this group, the other ductless glands were also apparently sclerosed. If now 
also the microscopical examination in such cases would also furnish an extensive 
sclerosis of the several ductless glands, it would not necessarily be shown the 
disease of the ductless glands was primary; it would also be possible that we 
might be dealing with a diffuse sclerotic process involving the entire body, that 
has also involved the ductless glandular system, such a general process as we 
regarded above as possible for hemochromatosis and which is perhaps also 
true for pedatrophy. 
Then we would be dealing with a secondary sclerosis of the ductless glandu- 
lar system, that at all events lends to progeria many of the striking features of 
ductless glandular sclerosis, and which may play the chief role in the enormous 
cachexia and the senilism of these individuals. GIGANTISM 
463 
In the clinical picture of progeria are some features that seem to me 
hardly compatible with the assumption of a ductless glandular sclerosis. 
In the three typical cases the intelligence was fairly well developed, which 
rules out a strong involvement of the thyroid gland. Especially, however, 
does it seem to me that the premature ossification points to a sclerosing 
process independent of the ductless glandular system, as otherwise we would 
expect considerable retardation of ossification. The severe disturbance in 
the development, or the retrogression of the hair, can indeed very well be 
brought into relation with an involvement of the suprarenal cortex; it is, 
however, conceivable that it has its foundation in a severe atrophy of the 
skin. It was already in the first chapter pointed out that we must not re- 
gard old age, as Lorand does, simply as a gradual degeneration of the ductless 
glandular system; but consider that the ductless glandular system, like the 
rest of the organs takes part in a general involution of old age. It seems to me 
that the same thought can be applied also to premature and to childish senility. 
Differential Diagnosis of Multiple Ductless Glandular Sclerosis.—The 
cases out of the literature that I have quoted show a remarkable agreement 
with each other, so that for the most part the diagnosis does not meet with 
difficulty, especially so in that the retrograde processes in the genitalia and 
the secondary sexual characters constitute especially striking symptoms. 
The delimitation from pure late eunuchoidism may indeed become difficult. 
Marked puffiness of the skin, thinning of the hair of the head in patches, 
and of the hair of the lashes and eyebrows, speak against late pure eunuch- 
oidism, as do also marked emaciation and cachexia. For the delimitation from 
pure myxedema I regard as important the partial or extremely deficient 
results attending thyroid-gland therapy. Concerning the diagnosis from pure 
Addison’s disease nothing further need be said. As far as diagnosing it from 
hypophysial dystrophia adiposo-genitalis is concerned, I do not know that in 
this disease such a high-grade atrophy of the genitalia of adults occurs as was 
described under late eunuchoidism; naturally the absence of symptoms of brain 
tumor is also important, although it must be remembered that in the case of 
Sainton and Rathery there was found at the same time a malignant cystic 
degenerated tumor of the hypophysis. Therefore it seems that a combination 
of multiple ductless glandular sclerosis and hypophysis tumor may occur. 
Up to the present the treatment has been of little avail. In the cases of 
Rumpel and of Djeinil Pascha the use of thyroid gland was negative, and in 
Gouilloud’s case doubtful. French authors have tried a combined ductless 
gland therapy (thyroidin, hypophysis substance, sexual gland substance, and 
suprarenal substance), and have sometimes seen temporary improvement of 
individual symptoms under the influence of these, yet the progressive cachexia 
can for the most part not be essentially influenced. 
Gigantism 
Historical.—It can be readily understood that gigantism usurped the 
interest of the laity and physician from early times. Indeed a philanthropist 
even founded a prize in order that by the intermarriage of giants a larger 464 
PLURIGLANDULAR DISEASES 
and stronger race would be produced. For the first valuable scientific obser- 
vations concerning this interesting phenomenon we are indebted to C. v. 
Langer. v. Langer distinguished between normal and pathological 
giants. He described three skeletons of normal giants, one from the Berlin 
Pathological Institute, one from the Hunterian Museum, and one from Trinity 
College, Dublin. These giants enjoyed good health until a high age; they showed 
in general normal dimensions of their skeletons corresponding to their size, 
therefore rather large skull and a relatively large upper body, the upper 
length somewhat exceeding the lower length. In the other group, the 
pathological giants, v. Langer first pointed out that here certain pathological 
alterations of the skeletons were present, such as relatively small cranium 
with enlarged sella turcica and enlargement of the facial skeleton with enor- 
mous lower jaws, widening of the pneumatic spaces, increased development 
of the insertions of the muscles, certain abnormalities of the pelvic girdle, fre- 
quency of genu valgum, in short a series of alterations that to-day we would 
designate as acromegalic, v. Langer pointed out that from illustrations also 
degeneration of the soft parts, such as enlargements of the tongue and the lips, 
had existed. 
Then Sternberg in a detailed work pointed out the frequency of the com- 
bination of acromegaly and gigantism. According to Sternberg about 40 
per cent, of all giants are acromegalics, and about 20 per cent, of all acro- 
megalics giants. This question entered upon a new stage when especially 
the French school sought to define the relation between acromegaly and 
gigantism. After Massalongo had designated acromegaly as late gigantism, 
Brissaud and Meige came forward with the teaching that acromegaly and 
gigantism are one and the same disease and depend on the same cause, namely, 
an alteration of function of the hypophysis, which leads in youthful individuals 
to gigantism, and in older individuals, those in whom the epiphysial junctures 
have already ossified, to acromegaly. These authors also support the view 
that only the acromegalic giants should be termed proper giants, and that 
gigantism should always be regarded as the disease. This opinion, which was 
actively contradicted by Pierre Marie, Launois and Roy have tried to support 
in several researches and in their monograph. These authors show, in con- 
vincing fashion, that the greater part of the giants thus far observed have been 
acromegalics, or have later become acromegalic. Also Biedl has relegated the 
subject of gigantism to his chapter on the hypophysis. 
Symptomatology and Types of Gigantism 
According to the opinions thus far existing in the literature, as to the 
pathology of gigantism, it is not possible to define it uniformly. The difficulty 
begins already with the question as to which individuals should be regarded as 
giants. Bollinger proposed regarding as tall, human beings whose height 
reached 205 cm., and only speaking of giants when the height exceeded 205 cm. 
This classification is naturally quite arbitrary. According to it a whole group 
of the cases reported in the literature would no longer be regarded as belonging GIGANTISM 
465 
to giants. Just as arbitrary seems to me the opinion occurring in the French 
literature that only those giants that bear acromegalic features should be 
regarded as true giants. Even though well-proportioned, non-acromegalic 
giants are apparently among the greatest rarities, yet, according to the definite 
statements of v. Langer and Virchow, their existence is not to be doubted. 
Therefore it seems to me to the point to adhere to the old classification of 
Langer and to distinguish between normal and pathological giants. Moreover 
we find described in the literature a group of cases, whose height lay between 
190 and 200 cm.; cases that showed no acromegalic features, but on the other- 
hand, all the signs of typical eunuchoidism. Here, therefore, there lies before 
us all the signs of a potentizedform of eunuchoid tallness, and for this the designa- 
tion eunuchoid gigantism seems to me not without foundation. The cases 
coincide in part with those cases which Launois and Roy have called infantile 
gigantism. Considering the fact that I have sharply separated eunuchoidism 
from infantilism—I shall come back to this differentiation in the next chapter— 
I must regard the designation eunuchoid as more precise than infantile. I 
would here point out that a portion of the giants described by Launois and Roy as 
infantile are not pure eunuchoids, but already bear the acromegalic features. 
Finally, as to what concerns the acromegalic giants I shall take pains to show 
that here there are very diverse types, those types in which from the beginning 
acromegalic manifestations are distinctly prominent; those types which to use 
an expression of Launois and Roy “ acromegalize” only later; those types which 
possess the eunuchoid features or even pronounced eunuchoidism from youth 
on; those types to whom a kind of late eunuchoidism comes only later, and 
finally those types in whom the eunuchoid features are entirely absent, in 
whom, moreover, the function of the sexual glands and genitalia are entirely 
normal, or even perhaps temporarily abnormally increased. 
In the great multiplicity of the manifestations of gigantism a uniform 
exposition of the symptomatology is scarcely possible; it seems to me more 
to the purpose to adduce examples of the various types from the literature, 
whereby I would mention that all possible transitions between the groups occur. 
I will not enter further into the subject of normal giants. In the historical 
introduction I have already mentioned the most important facts. 
Of the eunuchoid giants I mention the twenty-seven-year-old man 
described by Launois and Roy. (Soc. de Biol., 10 Jan., v., 1903.) In this 
individual the increased growth in height apparently began after an attack 
of typhoid fever. 
I shall now adduce a series of cases relating to acromegalic giants, in 
whom the function of the sexual glands was normal. As the first example I 
communicate a case that I myself had occasion to investigate. 
Observation LV.—-B. O., “Bulgarian giant,’’born in Gross-Wenkheim near Bad Kissingen, 
thirty-seven years old. The male members of the family are almost all rather tall. The 
tallest was his father’s brother, who measured 186 cm. His father measures 180 cm. B. O. 
states that he first began to exceed his school companions in growth at the seventh year of 
life. At twelve years of age he measured about 206 cm., and at twenty-four years of age had 
attained his full height (212.5 cm.). He served in the “Bayerischer Leibregiment” and was 
at that time examined by the chief physician, Dr. Seggel. At that time he was entirely well, 466 
PLURIGLANDULAR DISEASES 
Fig. 82—Gigantism (Observation LV) and hypophysial dwarf (Observation XLIV). The normal 
individual measures 183 cm. GIGANTISM 
467 
and had grown completely used to the military service. He says that as a young man he 
weighed 145 kg. Especially in his eighteenth to nineteenth years had his appetite become 
enormous. He says that it was easy for him to devour at one meal 1 kg. of meat with copious 
additional fare. The highest weight was 195 kg. He had never suffered from headache. 
According to his statement the sexual development was entirely normal. In 1900 he married 
a woman who was 187 cm. tall. After one year she bore an entirely normally carried child, who 
died after four weeks. Then later the woman had two premature deliveries, about in the fifth 
month. The potency up to this time had, according to his statement, not diminished. Six 
years ago he suffered from influenza and since that time “has had to do with a cough.” 
The apex of the right lung is defective. 
The man now measures 210 cm. As a distinct kyphosis exists, it is very probable that his 
statement that he formerly measured 212.5 cm. is perfectly correct. The span width 
reaches 220 cm., the breadth of the shoulders 52 cm., the circumference of the chest 118 
cm., of the waist 100 cm. Distance from the anterior superior iliac spine to the floor 
124 cm. 
There exists, as already mentioned, distinct kyphosis, the enormous shoulder blades 
project prominently. The clavicles enormously developed. The circumference of the 
upper arm measures 29 cm., formerly when the patient was very muscular it reached 
68 (?) cm. 
The distance of the external malleolus of the wrist-joint to the point of the middle 
finger is 27 cm. 
The greatest circumference of the hand is 30.5 cm. The greatest circumference over 
the metacarpopharyngeal joint is 27 cm. 
The middle finger, from the metacarpopharyngeal joint to the point of the finger is 14 
cm., the circumference of the thumb 9 cm. 
Distance between the anterior superior spine and the upper border of the patella is 
57 cm.; length of foot 33.5 cm. Circumference around the ankle-joint and heel 43 cm.; 
length of great toe 9.5 cm.; circumference of the same n cm. The head is enormous. 
The fronto-occipital circumference reaches 67 cm. The occipitomental circumference 
73.cm. The superciliary arches project markedly, as do also the malar ones. There exists 
distinct prognathia. The anterior upper incisors are 1.5 cm. from each other. The set of 
teeth is normal; only one tooth is absent. The tongue is disproportionately large. The 
palate is in proportion. The least circumference of the neck is 42 cm. The pomum Adami 
projects markedly. The thyroid gland is palpable and is in proportion. The voice is 
very deep and low. The hairiness is very abundant. The mustache is well developed, 
the man must shave every two days. The chest and the linea alba are extensively pro- 
vided with hair. Also the hairiness on the genitals and the perineum, and in the axillae is 
abundant. The genitalia are proportioned to the other relations. Heart dullness; upper 
border of the fifth rib, left sternal border, cm. to the left of the border of the sternum. 
Heart sounds clear. Slight tachycardia (105). 
The orthodiagram shows a greatest heart breadth of 13 cm., breadth of the aortic 
shadow 7 cm. These measurements are relatively very small. Tuberculous affection of 
both apices. The stomach is enormously large, sac-like, reaches 20 cm. below the navel. 
The ordinary bismuth meal is just enough to fill the fundus of the stomach. 
Blood examination: Hemoglobin (according to Sahli), 80 per cent. 
Erythrocytes, 5,720,000 
Leucocytes, 5600, of which: 
Neutrophilic polymorphonuclear, 65 per cent. 
Lymphocytes, 20 per cent. 
Large mononuclears, 9 per cent. 
Eosinophiles, 6 per cent. 
The examination of the urine shows sugar o, albumin o, urobilin o, indican +. 
Eye examination (Dr. Ulbrich). The pupillary distance is 72 mm. (normal about 65 
mm.). The length of the palpebral fissures 33 mm. (normal 28 mm.). 468 
PLURIGLANDULAR DISEASES 
On the contrary we find the globes lie abnormally free on all sides and that the width 
of the cornea is not greater than the normal average (n mm.). Eye-grounds normal. 
Visual field and color field normal. 
The X-ray plate of the hand shows entirely normal ossification. The enlargement 
affects bones and soft parts rather to a like degree. 
The X-ray plate of the head shows enormous relations. We see the frontal and the 
maxillary sinuses considerably broadened and, further, the distinct prognathia of the lower 
jaw. The bones of the cranial vault are enormously thickened, the sutures markedly 
projecting, especially striking is the enormous external occipital protuberance. 
The sella is markedly enlarged and deepened; the posterior clinoid processes are dis- 
tinct, and the anterior less evident. The introitus of the sella is relatively not very wide 
(Fig. 83). 
We are hence dealing in this case with a typical acromegalic giant. The 
acromegalic tendency became evident at a rather early age and seems to have 
progressed very gradually. At least this man can give no sure statement as 
to when the coarsening of the features and the prognathia began to develop. 
He states that his hands and feet have not become essentially larger in the last 
ten years. We have better data so far as the kyphosis is concerned. During 
the military service, hence fourteen years ago, this did not exist. Another 
point is furnished by the diminution of muscular strength, the strength at about 
the twentieth year must have been enormous. The pulmonary tuberculosis 
that has developed in the last year can surely be held responsible for only a 
small portion of the decay. Signs of increased intracranial pressure are not as 
yet present in this patient; with which the X-ray findings—these show espe- 
cially a deepening of the floor of the sella, are in accord. Especially important 
in this case is the behavior of the sexual glands. The functions of the genitalia 
up to the present time have been entirely normal. At all events up to his 
thirtieth year the patient was capable of reproduction. At most we could say 
that the early death of the first child and the two following premature deliveries 
on the part of his wife point to a diminished valuation of the semen, but this 
assumption does not seem to me to be well considered. In agreement with the 
sexual potency we find the dimensions of the skeleton normal, and the hairiness 
even abnormally strongly developed. 
Also the giant of Huchard and Launois had two children. In this case 
the abnormal increase in growth began in the twelfth year of life. At the 
age of eighteen he was 197 cm. tall. The genitalia were entirely normally 
developed. He attained the age of sixty years and at that time showed typical 
acromegalic manifestations. The sella turcica was the size of a nut. Sclero- 
sis of the anterior lobe was found at autopsy. This case has been brought 
forward as a demonstration against the hyperfunction theory of acromegaly. 
Incorrectly however, for we may well imagine that in late life the acromegalic 
manifestations must not necessarily retrogress when there occurs without any- 
thing else a secondary sclerosis of the hypophysis. 
The case of Buday and Jancso showed an abnormal increase of the 
potency that was at all events short in duration. At seventeen years of 
age this patient was very potent, and performed coitus four to six times 
every night. From the twentieth year on he gradually became impotent. GIGANTISM 
469 
It is noteworthy that this case was only 103 cm. tall when he was twenty 
years old. Now he first began to grow appreciably, and at the age of thirty- 
five years had attained the height of 198 cm. He now showed distinct acrom- 
egalic symptoms; there was found a large tumor of the hypophysis, the genitalia 
were atrophied, the length of the lower part of the body was very consider- 
able, there existed a genu valgum, the epiphysial junctures were ossified 
(the abnormal growth has ceased for two years). In this case we have the 
sort of late eunuchoidism combined with acromegaly. It is very noticeable 
that in spite of the increased sexual function, the epiphysial junctures remained 
open between the seventeenth and twentieth years. 
I would regard the case described by Cushing as one in which the late 
eunuchoidism began later. This thirty-five-year-old patient came from a 
healthy family. The father was six feet tall. At the age of thirteen years 
the patient first began to grow enormously rapidly; at the age of nineteen 
years he was 6 ft. 4 in. tall, weighed 200 lb. and was of extraordinary strength, 
and he was intelligent, a good student, and “aside from an uncontrolled 
libido sexualis” had good manners. Especially noteworthy seems to me 
the fact that only latterly did the obesity that occurred assume the eu- 
nuchoid type (as far as I can see from pictures). This is true also of the absence 
of beard, and the eunuchoid hairiness. “He has practically no beard, and 
except for a scant pubic growth of feminine distribution, the skin of the trunk 
and extremities is practically hairless.” The hair of the head was abundant. 
Also in the case described by Levi and Franchini did there occur a late 
eunuchoid obesity. 
The abnormal growth began in this person, who was sixty-five years old, at the age of 
eight to ten years, the secondary sexual characters were apparently normally developed at 
the time of puberty, there were few erections, however, and there never had existed an 
especial libido. The external genitalia were normal, as was also the mental development. 
He was always weak muscularly, in the last few years obesity developed, the distal parts of 
the extremities showed a considerable enlargement, there existed cervicodorsal kyphosis, 
in short the signs of an acromegaly that had gradually developed over a long period of 
time. The epiphysial junctures were closed. 
I now adduce several examples of the eunuchoid type, in which the symp- 
toms of deficiency on the part of the sexual glands already exerted an influ- 
ence on skeletal formation in early youth. Here belongs the giant Charles 
described by Launois and Roy. In the thirtieth year of his life, his height 
was 204 cm. The lower length was considerably more than the upper length. 
The penis was small, the testicles were very small, and the prostate also was 
small. He had had on several occasions erections, but never ejaculations. 
The hairiness of the trunk was typically eunuchoid. The epiphysial 
junctures were entirely open. In later life, acromegalic features made their 
appearance. 
A pronounced case is reported by Cushing that on account of the mon- 
strosity present I shall herewith adduce; thirty-six-year-old man; he was 
already as a boy abnormally tall, and from the fifteenth year on grew enor- 
mously. For ten years he has been sick and weak. At autopsy the body meas- 470 
PLURIGLANDULAR DISEASES 
ured 251.5 cm., the skin is delicate, hairiness of the head good, no growth of 
beard, no axillary hairiness, sparse hairiness of the pubic region. The genitalia 
are small, the testicles atrophied. The distal epiphysial juncture of the radius 
is still open, no alimentary glycosuria. Distinct symptoms of acromegaly are 
present. The sella turcica is very much enlarged (2.2 to 2.7 cm.) and the 
hypophysis consists, in great part, of a cyst. 
Again, in such eunuchoid giants the acromegalic alterations may be very 
significant. There are also known female eunuchoid giants. As example I 
adduced Lady Aama, described by Woods Hutchinson. She was about seven- 
teen to nineteen years old, 244 cm. tall, and the lower length far exceeded 
the upper length; hands and lower jaw were very large. The genitalia were 
infantile, the mons Veneris was poorly developed, the labia majora were 
flat, the clitoris was well developed and resembled a poorly developed penis. 
The ovary on each side was very small, and changed into glandular masses. 
The hypophysis was enlarged, the sella turcica was destroyed, the mammae 
were entirely hypoplastic. 
I believe that the examples I have furnished suffice to show the enormous 
multiplicity of the manifestations of the pathological forms of giant growth. 
The symptoms of eunuchoidism or late eunuchoidism are combined with 
those of acromegaly in the most diverse ways. If we disregard, however, 
the quite rare cases of pure eunuchoid gigantism, we find indeed that the mani- 
festations of eunuchoidism and late eunuchoidism, are very common, while 
the manifestations of acromegaly are present almost always regularly, or 
that they develop later. In this connection the classification of pathological 
giants of Launois and Roy is very correct, even if it is not just to the uncom- 
monly numerous types. 
Pathogenesis.—If we now turn to a pathogenesis of gigantism, our 
first task will be to test whether the formula of Brissaud-Meige, which also 
has been adopted by Launois and Roy, is in the position to explain the mani- 
fold types of gigantism. Brissaud and Meige have expressed the opinion 
that gigantism is nothing other than an acromegaly beginning in early youth, 
that is, before the closure of the epiphyses. A great difference between acromeg- 
aly and pathological gigantism exists, first of all, in the behavior of the sexual 
glands. I must here again point out the fundamental difference in the relation 
of the glands of generation and the interstitial glands in typical acromegaly. 
The first show temporary increase of their function, but then there very com- 
monly occurs very premature disturbances or entire loss of their function, 
whereas the function of the interstitial glands is rather more emphasized, 
or at all events, apart from very rare cases, shows no disturbance in the course 
of the disease. In gigantism we see this behavior in but a few cases. In the 
majority of cases the manifestations of eunuchoidism are prominent from the 
beginning, or later there occur manifestations of late eunuchoidism. In 
the description of early acromegaly a similar behavior of the sexual glands 
has been noted. 
There cases were described in which also the interstitial glands showed dis- 
turbances of their function, in this respect lending countenance to the Brissaud- GIGANTISM 
471 
Meige’s formula. There also we learned about sure cases of acromegaly, that 
came to manifestations of acromegaly while the epiphysial junctures were still 
open. Increase of function of the hypophysis alone, hence, does not lead to 
gigantism. We must assume in addition to it a potential tendency to growth, 
that may be either proportionate (normal giants), or as it is mostly, dispro- 
portionate, partly through a preponderance of the function of the hypophysis, 
partly through an insufficiency of the interstitial glands and probably also 
through many other factors. While in acromegaly we certainly find a tend- 
ency to hyperfunction and hyperplasia of other ductless glands in which, 
however, always the increase in function of the hypophysis remains quite in 
the foreground, in gigantism the tendency to increase in function of the whole 
ductless glandular system seems to belong quite to the essence of the disease. 
It would seem that in addition to the hypophysis all the ductless glands are 
involved in a predominant manner in the hyperplasia—the suprarenal cortex, 
probably also the chromaffin tissue, etc. How enormous the pancreas may 
become is shown by the autopsies of the giants Bassoe Peter and of the Tam- 
bourmajor. The pancreas of the former weighed 275 gm., that of the latter 
250 gm. Also the sexual glands may be involved in this hyperplasia. In 
addition to this tendency to hyperplasia there exists, however, a lability, a 
ready exhaustibility of the hyperplastic ductless glandular system; this 
seems to affect the most readily the sexual glands, in which degenerative 
processes may be established prematurely, indeed under circumstances the 
sexual glands (and especially the interstitial glands which, indeed differ from 
the other ductless glands in that they attain full maturity not until the time 
of puberty) may be disturbed in their development from the beginning. 
Also the development of the nervous system may suffer damage from this fact. 
The monstrous eunuchoid giants are the most deficient mentally. In addi- 
tion to the sexual glands the other ductless glands mostly rapidly show signs 
of decay. The frequency of diabetes in youthful giants is known. In the 
great decrepitude and muscular weakness perhaps there is involved a degen- 
eration of the chromaffin tissue. Even in the hypophysis, such degenera- 
tive processes frequently occur, if the individuals attain a high enough age. 
I refer to the case of Iluchard and Launois in which the hypophysis was found 
to be sclerotic, or to that of Cushing in which the hypophysis was in great 
part converted into a cyst. How rapidly the decay can enter in just these 
monstrous giants is shown by numerous cases in the literature. The enormous 
muscular power of which these individuals were wont to be so proud gives 
place in a few years to a great weakness. The ductless glandular system has 
exhausted itself and the organism fades rapidly like a plant driven to rapid 
growth by artificial means. Mostly the invalidism is rapidly made an end 
to by an intercurrent disease. Woods Hutchinson tells of eight giants that 
died on the average in their twenty-first year of life. 
Investigations of the respiratory metabolism of giants, as well in the 
time of bloom as in that of decay, would be very important. I do not know 
of any of them. With regard to the other metabolism investigations, there 472 
PLURIGLANDULAR DISEASES 
are only the statements of Levi and Franchini, who in one case found increase 
of the elimination of amino-acids, ammonia, and neutral sulphur. 
On the basis of what has been said above, I would assume in gigantism 
an abnormal mapping-out [Anlage] of the whole ductless glandular system, 
and would not, as have other authors, simply include it in the chapter on 
acromegaly. We know indeed that there are other forms of gigantism setting 
in in early life in which not the hypophysis, but other ductless glands (the 
epiphysis, the suprarenal cortex, the sexual glands) occupy the chief role 
in the pathogenesis. In such cases there may indeed appear even simul- 
taneous manifestations of hypophysial insufficiency (confer the case of 
Raymond and Claude). But as I mentioned already at the beginning the con- 
ception does not seem to me established as yet. I must leave open the question 
as to whether the hyperplastic mapping out of the entire ductless glandular 
system is only a partial phenomenon of an abnormal mapping out of the 
entire organism. We know indeed of a gigantism of individual extremity 
masses. I refer to the communications of Fischer, Manasse, Wiedenmann, 
Grunjeld, et al. We cannot hold the ductless glandular system responsible 
for such an abnormal growth tendency, even though there are found, also 
not rarely, certain anomalies of this system, e.g., cryptorchidism on the 
same side. 
Addendum 
Gigon has published recently a report on a series of three giants of whom 
one (a male) was acromegalic. Another (female) was almost perfectly formed, 
although her axillary and pubic hair was scant, and her pelvis was somewhat 
of the masculine type; her bones were normal, except for a cartilaginous exos- 
tosis. The third case (a girl, eleven years old), was tall for her age (162.5 cm.), 
showed premature puberty, hypergenitalism, mental precocity, early ossifica- 
tion of the epiphyses; pineal tumor was thought of but not definitely diag- 
nosticated. Gigon suggests the name “macrosomia essentialis” for the “true” 
or “normal” giant. 
Gigon (A.). Ueber Zwergwuchs und Riesenwuchs mit einem Beitrag zum Studium verwandter 
Entwicklungsstorungen im Organismus. Schweizer Archiv fur Neurologie und Psychiatrie, Vol. 
IX, Part 2, pp. 283-302 and Vol. X, Part 1, pp. x 13-129. CHAPTER XII 
VEGETATIVE DISTURBANCES, NOT DIRECTLY DEPENDENT ON 
DISEASES OF THE DUCTLESS GLANDS 
The words “vegetative disturbance” [Vegetationstorung] to my knowl- 
edge originated with Kundrat. By them we understand any inhibition of 
development. Since the time it was known that the growth, and especially 
the normal development of the organism was guaranteed only by a normal 
development of the ductless glandular system, modern investigation has 
been directed toward seeking the cause of the different vegetative distur- 
bances in the ductless glandular system. In the foregoing chapters an entire 
series of vegetative disturbances were comprehended, which to-day we are 
justified in regarding as referable to a functional disturbance of individual 
ductless glands. It seems important for the following exposition, again 
briefly to sketch what these are: 
1. Absence of the thyroid leads to dwarfism; in this is found characteristic 
disturbances of ossification, consisting in a high-grade remaining behind in 
development of the bone nuclei, and in the closure of the epiphyses, further 
in a disturbance in development of the bone marrow; what, however, has 
already been formed of the bones is of abnormal hardness; further there are 
found disturbances in the dentition, and in development of the central nervous 
system, whereby the development of the intelligence suffers. Further there 
are found the characteristic myxedematous alterations of the skin, and dis- 
turbances in the development of the genitalia. 
2. The vegetative disturbances in endemic cretinism is not dependent 
alone on the goitrous degeneration of the thyroid gland. It is far more likely 
that the deleterious agent acts also directly on the central nervous system 
and on other ductless glands, for instance, the hypophysis. Thereby the 
vegetative disturbances are extremely manifold, the individuals remain very 
much behind in growth, but the disturbance in ossification is not disproportion- 
ate; one time the developmental disturbances of the central nervous system 
may stand in the foreground, another time the inhibition in growth, and 
another time perhaps the disturbances in the development of the hypophysis. 
3. Pronounced inhibition of development is found also in diseases of the 
hypophysis that develop in early youth. In this case there occur, at least 
in a suggestive manner, eunuchoid dimensions on account of a prominent 
developmental inhibition of the sexual glands, and further there occurs eunuchoid 
distribution of fat. Disturbances in the development of the bone nuclei 
and of the epiphysial junctures occur distinctly only in most severe cases. 
The intelligence develops normal, although these individuals show the charac- 
teristic temperamental attitude. 
473 474 
VEGETATIVE DISTURBANCES 
4. Again, disturbances in the development of the suprarenal cortices per- 
haps also lead to definite vegetative disturbances; very little clearness as to this 
point exists, however. 
5. Isolated disturbances in the development of the sexual glands leads to 
eunuchoidism with characteristic distribution of fat, characteristic dimensions 
of the skeletons, remaining open of the epiphysial junctures, especially those 
that close latest under normal conditions, and a characteristic psychic attitude 
with normal development of the intelligence. 
There remains now a group of vegetative disturbances that of late have 
frequently been brought into association with the diseases of the ductless glands. 
In some of these the relation to the ductless glandular system is not yet sure, 
in others, the disturbances on the part of the ductless glands constitute only one 
component of the clinical picture. Finally in others I would deny the connec- 
tion. In this great group of vegetative disturbances I would include true 
infantilism, true dwarfism, chondrodystrophy, rachitic dwarfism, and Mongo- 
lism. In the exposition of each disease, its relation to the ductless glandular 
system will be especially considered. We shall not enter further into the subject 
of dwarfism in microcephalus and porencephalus. I have described dwarfism 
with hydrocephalus in the chapter on hypophysial dystrophy. 
I. INFANTILISM 
Historical.—The first cases of human beings who for their life time re- 
mained in a childish stage of development [pathologically] were described by 
Dancel and Baillarger. The case of Dancel was that of a woman twenty-four 
years old who was 94 cm. tall and showed a mental and physical development 
of a four- to five-year-old child. Lasegue coined the name infantilism [-us]. 
He understood by it a condition of persistence in the adult of the psychical 
and physical characteristics of a child. The first exact description was made 
by Lorain. He describes a form of infantilism that he describes as “Charac- 
terisee par la debilite, la gracilite et la petitesse du corps, par une sorte d’arret 
de developpement, qui porterait plutot sur la masse de l’individu que sur un 
appareil speciale: en un mot des subjets atteint d’une juvenilite persistente 
qui retarde indefiniment chez eux l’establissement integral de la puberite.” 
Lorain and his pupil Faneau de la Cour already stated that the different 
harmful influences that may affect the juvenile organism may lead to 
infantilism. 
The question has been especially discussed in the French and Italian 
literature, ever since Brissaud set forth a form of infantilism that he referred 
to as insufficiency of the thyroid gland in child life. Brissaud considers that 
the type Lorain constitutes a dystrophic condition, and is brought about and 
maintained by a chronic congenital or inherited disease during the period of 
growth. 
The views of Brissaud have been adopted in recent time by Bauer. Bauer 
regards only the type Brissaud as true infantilism and separates all other forms 
from the type Brissaud as “chetivisme.” Hertoghe and Ausset-Breton go still INFANTILISM 
475 
further than Brissaud; they see in all forms of infantilism an expression of a 
congenital damaging of the function of the thyroid gland and thus seek to estab- 
lish all forms on a uniform basis. 
Ferranini was the first to oppose this view. Ferranini separates the two 
forms of infantilism, and regard the type Lorain as the sequel of a developmental 
deformity, and the type Brissaud as the sequel to the standstill of development. 
Ferranini sets forward the significance of the congenital or early inherited heart 
defect in the pathogenesis of infantilism (cardiodystrophic infantilism). Carre 
and Gilbert and Rathery hold similar views. In recent time, especially E. Levi 
has opposed the views of Brissaud, in that he mentions that not all the true 
infantilisms are to be referred to an insufficiency of the thyroid gland. The 
type Lorain should also be regarded as true infantilism. Before this Sante de 
Sanctis had already again sharply separated the two types and emphasized the 
significance of various factors for the genesis of the type Lorain, factors such as 
hypoplasia of the vessels, chlorosis, disposition to tuberculosis, hereditary 
syphilis, malaria acquired in early youth, pellagra of the parents {Agostini), 
etc.; furthermore, de Sanctis separated the true form of psychic infantilism 
from idiocy. Then, too, de Sanctis was the first to attempt to explain the gene- 
sis of the type Lorain through alterations in the ductless glandular system. The 
delay in the physical and psychical development is never the result of isolated 
alteration of an individual ductless gland, but is produced by a “deviation 
de la fonction harmonique formative-protectrice de toutelesglandes a secretion 
interne.” In an interesting study, R. Anton has described the psychic side 
of infantilism. General infantilism was defined by Anton as “a developmental 
disturbance, that causes the entire organism to remain behind at the child type, 
but prevents the reproduction of the individual in the sense of the species. 
Thereby not only the physical earmarks, but often also the psychical characteris- 
tics of the child persist.” 
With general infantilism Anton includes: 
(A) The infantilism with myxedema and cretinism. 
(B) Mongolism. 
(C) Infantilism through absence or atrophy of the genitalia. 
(D) Infantilism with primary lesion of the visceral glands, especially the 
suprarenals, the thymus gland, and the pancreas. 
(E) Infantilismus dystrophicus, with the following etiological variation: 
Infantilism in vascular aplasia. 
in primary brain lesions, unilateral or bilateral; 
in hereditary syphilis; 
in alcoholism or other poisonings (lead, mercury, etc.) of the parents; 
in other diseases and metabolic disturbances that are acquired early, 
such as tuberculosis, chlorosis, and cardiac defects; 
through deformities due to bad hygienic surroundings and to insufficient 
nourishing of the child. 
Of partial infantilism, I mention especially the infantilism consisting in 
an atrophy of the genitalia, and the pure psychical infantilism. 476 
VEGETATIVE DISTURBANCES 
I would finally especially emphasize here the excellent studies of di Gasperos. 
Here we find five cases described in detail, which, as we shall see later, are fine 
examples of true infantilism. Di Gasperos handles with special care the psy- 
chical side of the problem. 
Schuller divides infantilism into two forms: He distinguishes a dystrophic 
form conditioned by hereditary diseases, or diseases acquired in early youth, 
and a form whose pathogenesis is seen to depend on a lesion of a definite duct- 
less gland (thyroid, hypophysis, etc.). 
The regular undevelopment of the genitals in the type described by Lorain 
has induced many authors to term “infantilism” the most varying pathologic 
states in which the genitalia remain more or less hypoplastic. Thus we find 
in the literature numerous cases of true gigantism published under the title 
infantilism plus gigantism. Further we find published numerous cases of infan- 
tilism whose description would correspond to that which in a former chapter 
we have regarded as eunuchoids, or cases that at all events must be regarded as 
transition forms between eunuchoids and true infantiles. This is especially 
the case in the new expositions of the subject by Peretz and by Pende. In the 
work of Peretz we find nearly all the ductless glandular diseases associated with 
developmental disturbances classified as infantilism. Even infantile features 
are ascribed to hypergenitalism. Gandy terms “infantilism reversif ou tardif” 
cases in which after completed development a retrogression of the genitalia 
and the secondary sexual characters begins (confer “late eunuchoidism,” 
Chapter X). The ductless glandular theory has found an especially ardent 
advocate in Pende, who assumes as the cause of infantilism a disease of the 
ductless glandular system. He bluntly calls infantilism a disease of the duct- 
less glandular system, and arrays himself against the opinions advocated by 
Anton and others, that there is also an infantilism that is dystrophic ectoglandu- 
lar, and independent of a disease of the endocrine glands. 
We see then, that there is hardly an idea in the medical literature concern- 
ing which there is more confusion than that pertaining to infantilism. 
The name infantilism can surely readily give occasion to misunderstand- 
ings because in any kind of inhibition of development, infantile features may 
be retained. I believe, however, that a clear definition is possible if we limit 
ourself to the thought that the childish organism is characterized not only by 
the still undeveloped genitalia and the childish mentality, but, as already 
Breus and Kolisko mention, by definite childish dimensions. 
Definition.—We may therefore briefly define a pure infantilism as a 
standing still at the infantile stages of development, considering especially the 
following factors: the genitalia and the vita sexualis remain undeveloped, or develop 
deficiently; and the same is true of the secondary sexual characters; the involution 
of the lymphatic apparatus is deficient, the growth is deficient, ossification, that 
is, the appearance of the bone-nuclei and the closure of the epiphyses is delayed, 
and the childish dimensions of the body are retained wholly or in part; that is 
the lower length of the body equals the upper length or, what is commoner, 
exceeds it only a little, the form of the pelvis is neither [of the] masculine or 
feminine [type], but infantile, and finally the psyche remains behind [in develop- INFANTILISM 
477 
ment]. Such individuals show throughout no gross defect in intelligence, but 
their minds remain childish. 
Important for the definition of infantilism are the following considerations, 
which serve to render precise the position of the ductless glandular system in 
the pathogenesis of infantilism. If the in- 
fantilism comes about through a standstill 
of the entire organism at a child stage of 
development, then it is intelligible that also 
the sexual glands do not develop further. 
Up to the present however we have not suffi- 
ciently considered that the sexual glands 
occupy a separate position in the ductless 
glandular system, in that, though they func- 
tionate from early youth and influence the 
development of the organism, yet they attain 
their complete maturity only at the age of 
puberty; the other ductless glands are already 
fully developed in the new-born. At the 
same time, the remaining behind of the 
development of the sexual glands in infant- 
ilism is only a subordinate symptom of the 
entire clinical picture. We therefore do not 
find in infantilism such profound develop- 
mental disturbances as in eunuchoidism. 
The genitalia are quite childish and the sexual 
glands Junctionate like the sexual glands of 
children, while in eunuchoidism the sexual 
glands eventually do not functionate at all 
or slight islands of the sexual gland tissue 
have developed further, corresponding with 
the age, whereby there occurs an entirely in- 
sufficient function, a function that, on account 
of the faulty development of the accessory 
apparatus, is lacking; thus we see that the 
sexual glands of infantilism or the infantile 
genitalia are essentially different from those 
of eunuchoidism. 
Thus if true infantilism comes about 
through the standing-still of the whole 
organism at a juvenile stage of develop- 
ment, the ductless glandular system remains 
just as childish as the skeleton or the hematopoietic apparatus or the central 
nervous system; therefore the inhibition of the ductless glandular system is 
only coordinated with that of the entire organism; as, if these premises hold 
good, we are not justified in classing infantilism with the primary ductless 
glandular diseases; on the other hand, it does not then seem to me justifiable 
Fig. 84.—True infantilism (Observation 
LYI). 478 
VEGETATIVE DISTURBANCES 
to designate as infantilism sharply delimited clinical pictures that depend on a 
primary disease or developmental disturbance of a definite ductless gland, pic- 
tures such as juvenile myxedema, juvenile hypophysial dystrophy, or 
eunuchoidism. 
Before I enter into the symptomatology of true infantilism and the bases 
of the view just expressed, I would like to report some typical cases of true 
infantilism. 
Fig. 85.—X-ray picture of the hand in true infantilism (Observation LVI). Delay of the closure 
of the epiphysial junctures. 
Observation LVI.—J. H., twenty years old. At the age of seven years, commotio 
cerebri through fall from a tree. Present manifestations of a benign pyloric stenosis with 
dilatation of the stomach and hypersecretion. For one-half year tetany. 
Total length, 142)42 cm.; lower length, 69 cm.; span width, 143 cm. 
The patient looks like a boy thirteen years old. Facial expression and psychical attitude 
entirely childish. Abundance of hair on head. Beard hair absent, hair in the axillae and 
on the mons Veneris absent, soft downy hair on face. Penis small. Both testicles small. 
No libido, rarely weak erections which have appeared only recently, no ejaculations. The 
epiphysial junctures of the skeleton of the hand are almost all still open. For two years 
tetany, at the close of which slight manifestations of hyperthyrosis. INFANTILISM 
479 
Observation LVII.—W. K., eight years old. Entrance into the clinic Nov., 1910. At 
the age of four years gradual deterioration of the gait. The child also remained backward 
mentally, and repeated for the third time his first class in school. 
Typical progressive muscular atrophy, the description of which we may omit here. 
Typical length, 117 cm. Circumference of head, 51 cm. Circumference of breast, 57 
cm. Circumference of abdomen, 55 cm. From coracoid process to olecranon 25.5 cm. 
From iliac spine to internal malleolus 56 cm. 
Both lobes of the thyroid distinctly palpable. 
The tongue is large, always is seen to a certain 
extent between the teeth. Root of nose not retracted, 
skin everywhere elastic, feels moist. Cryptorchidism. 
Pilocarpine 0.01 gm. elicits minimal sweats, minimal 
salivation. 
0.001 gm. adrenalin shows strong action on the 
pulse and on the blood-pressure, distinct diuretic action, 
no glycosuria. 
Leucocytes, 9400, of which: 
Neutrophiles, 55.1 per cent. 
Large mononuclears, 8.3 per cent. 
Lymphocytes, 33.3 per cent. 
Eosinophiles, 3.3 per cent. 
From Nov. 14 on, one thyroidin tablet a day. On 
Dec. 18, 0.001 gm. adrenalin. Strong action on the 
pulse and blood-pressure; now 1.43 gm. sugar in the 
urine. 
Under the influence of the thyroidin medication 
which now has lasted about six weeks, the pulse-rate 
increases hardly at all, no manifestations of intoxication. 
On entrance the X-ray examination of the skeleton 
of the hand showed the following: The distal epiphysis 
of the ulna, which should be deposited normally at 
seventh year, is here entirely absent. 
The bone nuclei of the skeleton of the wrist are 
abnormally small. 
At the end of a six weeks’ thyroidin medication 
X-ray examination was again made, without showing 
any change worthy of mention. 
In this case we are dealing with a typical 
progressive muscular atrophy, setting in early 
and associated with an inhibition of develop- 
ment. This is both physical (abnormal small- 
ness, cryptorchidism, etc.) and mental. The 
large tongue gives rise to a thought of myxe- 
dema, but on careful searching no other signs of myxedema were found. Six 
weeks of the thyroidin medication causes no acceleration of ossification. 
s; 
Observation LVIII.—R. R., twenty years old. Entered May, 1912. Several cases of 
tuberculosis in the family. The girl learned to walk only three years ago S nee childhood 
conjunctivitis eczematosa. From youth she has remained behind in growth and in mental 
development; at present she has the psyche of an eight- to ten-year-old child. Although, on 
account of her eyes, she never went to school, she can read and write and takes an interest in 
household affairs. 
Fig. 86.—Infantilism in progressive 
muscular atrophy. 480 
VEGETATIVE DISTURBANCES 
127 cm. tall. Span width, 128 cm. Lower length (ant. superior spine to ext. malleolus) 
63K cm. 
Very sparse growth of hair in axillae and on the genitalia. 
Adenoids in nasopharyngeal space. Glands of the neck, the elbow, and the groins 
somewhat enlarged. Slight horizontal furrowing of the teeth. Since, sabre-sheath form of 
the bones, but otherwise no signs of severe rachitis. 
The mammae on both sides developed distinctly, 
little glandular substance palpable. First menstrua- 
tion two days ago, weak. 
Leucocytes, 7700, of which: 
Neutrophiles, 61 per cent. 
Lymphocytes, 32 per cent. 
Large mononuclear, 5 per cent. 
Eosinophiles, 2 per cent. 
X-ray examination. Sella turcica normal, no 
peribronchial lymph glands. 
Coarse nystagmus on both sides, the eye grounds 
show medullated nerve fibers, otherwise they are 
normal. 
X-ray examination of the skeleton of the hand. 
The ossification corresponds to about that of a fifteen- 
to sixteen-year-old individual. 
Observation LIX.—B. B., fourteen years old. 
Entered May, 1912. It was stated that in the first 
year the head and abdomen were very large, later 
good development, could walk at two years, could 
speak at three. Remaining behind in corporeal de- 
velopment, especially since the first year of life. 
Mental development fairly good. Psyche childish. 
Length of body, in cm., lower length, 62 cm., span 
breadth, 113.5 cm., length of arm, 38 cm. 
Slender, weakly child, thin, looks like a child eight 
years old. Pallid. The head, relatively large (circum- 
ference, 54 cm.). Frontal protuberances somewhat 
prominent. 
Adenoid vegetations in nasopharyngeal space, 
tonsils enlarged; in the neck, in the groins, every- 
where, are palpable glands up to the size of a bean. 
Distinct parallel furrows on the incisor teeth o ' 
the lower jaw. Slight form of pectus carinatus. Some 
lordosis of the lumbar spine. Slight affection of the 
apices of the lungs on both sides. 
Erythrocytes, 2,800,000, 
Hemoglobin, 60 per cent. 
Leucocytes, 10,400, of which: 
Neutrophiles, 52.0 per cent. 
Lymphocytes, 41.1 per cent. 
Large mononuclears, 2.5 per cent. 
Eosinophiles, 4.0 per cent. 
Mast cells, 0.5 per cent. 
Slight poikilocytosis. X-ray examination. Vault of cranium thin. Sella turcica 
normal. No basis for thymus-rest. Right divergent strabismus, both papillae somewhat 
washed out and pale, otherwise eye grounds and vision normal 
X-ray examination of the hand; the skeleton of the hand about corresponds with that of a 
ten-year-old boy. 
Fig. 87.—Infantilism (Observation 
LIX). INFANTILISM 
481 
Symptomatology.—Ordinarily the disturbance in growth in true infantilism 
is very significant. The skeleton shows a retention of the childish dimensions, 
that is the lower length does not exceed the upper length, or exceeds it only a 
little. The head is relatively large, the bones are slender, the navel is low, the 
pelvis is neither masculine nor feminine, but infantile. The occurrence of the 
bone-nuclei and the closures of epiphyses are delayed. 
The genitalia remain at a child’s stage of development, they have the size 
and dimensions of a child’s genitalia; we are not dealing here with a falling 
away of the genital function, but with a function which corresponds with that 
of the years of childhood. Correspondingly there is a remaining behind of the 
secondary sexual characters. Also the vita sexualis is that of a child. 
The lymphatic apparatus shows deficient involution. We find therefore 
commonly a relatively great count of lymphocytes in the blood, on which 
account there is not necessarily present a status lymphaticus, although it is not 
improbable that the damaging that produces the infantilism also often leads 
to a status lymphaticus. Moreover, the anemia that is not rarely found in 
infantilism can be regarded as a direct consequence of this deleterious influence. 
The hair of the head is usually abundant, the hair on the trunk is usually 
absent, but not always entirely absent. The hairiness of the pubis and the 
perineum is usually very sparse or is absent. The same holds good for the 
hair in the axillae. 
The internal organs are as a rule normal, so far as illnesses, occurring in 
early years, have not led them to infantilism. The vascular system seems in 
the most cases to show a slight grade of hypoplasia. Also the blood-pressure 
often lies on the lower borders of the normal. 
I am not aware as to the existence of investigations as to the respiratory 
metabolism. In the cases that I investigated the tolerance limits for carbo- 
hydrates approximate the normal. Functional testing of the vegetative 
nervous system sometimes showed slight diminution of the excitability. Not 
much importance can be attached to this. 
Characteristic for true infantilism is the retention of the childish features. 
We find the childish logic, the childish instinct for imitating, a certain anx- 
iety and non-independence. For example the case reported by me (Observa- 
tion LVI), acted like a boy when at his visits he was scolded for not having 
collected his urine. By the grown people of the clinic he was treated like 
a child. Ziehen points out in this regard that in infantilism the individual- 
izing association characteristic of children is retained. Also the psychical 
inhibitory apparatus is only deficiently developed. Di Gaspero attaches 
especial value to the retention of the childish ideas of value, and of the sug- 
gestibility of children. A careful description of the psyche of infantilism is 
furnished by G. Anton. “The mimicry, gesticulations, physiognomy, cor- 
respond to childish age phases, as do the pitch and the modulation of the 
voice. For the most part there is absent the childish gaiety and freedom, 
often there comes to expression feelings of insufficiency, timidity, and peevish- 
ness.” For the most part the attention may be readily drawn, but is readily 
deviable. Constant concentration is not to be attained. Complicated sense 482 
VEGETATIVE DISTURBANCES 
impressions produce a feeling of unpleasantness. “Often therefore they have 
acquired a routine in which complicated impressions and tasks are slipped 
by; their selection tends to the primitive, the simple.” I have attached value 
to reproducing the description of Anton, because it is enough to show that the 
psyche of persons with infantilism is essentially different from that of 
eunuchoids. 
Forms.—According to the intensity of the noxious agent that is to blame 
for infantilism, do different forms of this condition occur, from the quite 
excessive forms which in their corporeal and mental development remain little 
children all their lives, to the poorly pronounced formes frustes. Very impor- 
tant for the differentiation of the forms is also the consideration of the phase 
of development at which the noxus set in. “Every age period has its infan- 
tilism” {di Gaspero). When the noxus sets in relatively late there results a 
form which has been termed “ juvenilism.” In this the skeleton is no longer 
purely childish. The genitalia are relatively well developed, etc. We find 
very commonly the juvenile form of psychic infantilism in ordinary life {Anton). 
According to whether the inhibition of development has affected the more the 
skeleton, the psyche, or the genitalia, etc., we may speak of partial infantilism. 
An instructive example of a juvenilism furnished by a case briefly reported by 
Apert and Rouillard. In a thirty-eight-year-old man who had developed 
normally up to his sixteenth year, there occurred in the wake of a typhoid 
fever a remaining behind in corporeal and sexual respects, at this develop- 
mental period. There were present no signs of eunuchoidism. Apert and 
Rouillard attribute this inhibition in development to the thyroid gland. As no 
signs of myxedema were present, I would dissent from this view. 
The excessive form of infantilism might well coincide with the hypo- 
plastic dwarf of Breus and Kolisko. Breus and Kolisko indeed state that 
in the hypoplastic dwarf only the height is childish, the other dimensions 
only in part childish. Probably in such individuals the disturbance has its 
onset in fetal life or in early youth. 
Etiology.—The etiology of infantilism is very manifold. The most 
divergent toxic and infectious deleterious agents are blamed. Alcoholism, 
saturnism, nicotine-poisoning—agents that may also have affected the 
parents—further malaria, pellagra, syphilis (a fine example is furnished by 
Peretz), tuberculosis, abdominal typhoid in early youth (see the case of Apert 
and Rouillard)-, polyserositis (v. Neusser), deficient development of the cardio- 
vascular apparatus {Hodlmoser has communicated a pronounced pertinent case 
that was only 125 cm. tall with a lower length of 66 cm.), and further cardiac 
defects acquired in early youth {Gilbert and Rathery) (and in this nanisme 
cardiaque the genital disturbance may eventually become less pronounced), 
and the traumata that may affect the children in early youth (the case J. H., 
Observation LVI, suffered a commotio cerebri at the age of seven years). 
Jojjroy described two cases of paralysis generale juvenile with pronounced 
infantilism. I have reported such a case above (see Observation LVII, W), 
further it has been suposed that unfavorable conditions of life, and conditions 
of nourishment in early life are causal factors, and also disturbances of nutri- INFANTILISM 
483 
tion, chronic diarrheas, etc., existing since early life (see later concerning pan- 
creatic infantilism). The position of the cases with hydrocephalus does not 
seem to me assured as yet, in these cases consideration must be given especially 
to signs of hypophysial insufficiency, especially the distribution of fat. 
Also the liver diseases acquired in early life may lead to infantilism. 
Lereboullet described a case in which he ascribed hypertrophic biliary cirrhosis 
of the liver as the cause of the infantilism. The following case also perhaps 
belongs in this group. 
Observation LX.—G. A., twenty-one years old. Entered Nov., 1909. Since early 
youth strong imbiber of alcoholic liquors. In 1906, he fell in the water, after which pneu- 
monia, later pleurisy. Since that time has not grown much. For about two years, swelling 
of the abdomen, edema of the legs, and enlargement of the liver. The ascites subsided, the 
liver remained large and painful. 
According to his statement, for about three years after the time of puberty the patient 
had libido and erections, that later ceased. Never pollutions, never cohabitation. 
Very considerably enlarged liver, painful to pressure, pole of the spleen palpable, 
heart dullness somewhat enlarged to left and to the right. Extra-systoles, no ascites, no 
albumin. 
The physiognomy is juvenile, no beard, no axillary hair, sparse growth on mons Ven- 
eris. Testicles and penis of normal size. 
Differential Diagnosis.—If we confine ourselves to the symptoms just 
described, the delimitation of true infantilism from the diseases of the ductless 
glands associated with infantile features is not difficult. 
And yet on closer examination of the individual cases described under the 
same infantilism we find that very frequently later authors confuse infantilism 
with diseases of the ductless glands. Thus I would hold that in the communica- 
tion of Richon and Jeandelize the first of the cases described was probably an 
eunuchoid, the second a cretinoid, and the third perhaps a true case of infantil- 
ism. Another example: In the communication of E. Levi, I regard the first 
case as one of hypophysial dystrophy, the second is difficult to classify, the 
third is perhaps a typical case of true infantilism. 
I would detail somewhat more exactly the most important differential 
diagnostic features: 
Let us begin with the delimitation from infantile myxedema. In the 
French school two types of infantilism are distinguished, the Lorain’s type, 
which on the whole is true infantilism, and second, myxinfantilism. When 
however we go back to Brissaud’s original publication, we find that the char- 
acterization of myxinfantilism is very inexact. Here begins an error that 
has continued until the present and that may be regarded as the chief cause 
of the prevailing confusion. Brissaud describes myxinfantilism in the follow- 
ing manner: The face is round, the lips are thick, the nose small, the cheeks 
are thick, the genitalia infantile, the thyroid gland small, the ossification is 
delayed, dentition is retarded or fails, the neck is short, and there often exists 
lordosis of the lumbar spine; among the individuals belonging to this type 
there are also those whose health may be very good. Brissaud held the opinion 
that in the majority of cases myxinfantilism is not an etat morbide and he 
refers also partial infantilism to an insufficiency of the thyroid gland. As an 484 
VEGETATIVE DISTURBANCES 
example he quotes the cases of two sisters of whom the elder looked to be about 
three years younger than the other and showed an entirely childish habitus. 
He also quotes the case of a boy of sixteen years, who looked as if he were eleven 
years old, and whose psychical attributes corresponded with that of the latter 
age. At the age of ten years of life he had sustained an inflammation of the 
throat and a swelling of all lymph glands; Brissaud here regards it as established 
that at that time the thyroid gland was affected. The third case that Bris- 
saud cites is, on account of the inaccurate description, hard to classify. I need 
hardly detail more intimately that the belonging of the cases cited to infantile 
myxedema is at least uncertain, even unlikely. A priori we may withdraw 
from consideration, however, the classification on the etiological basis, accord- 
ing to Brissaud’s assumption that a severe disturbance of development could 
depend on a thyroid insufficiency without other symptoms of myxedema being 
present. The inhibition of ossification alone, on which some stress has been 
laid, is no certain sign of thyroid insufficiency. Meige and Allard point out, 
it is true, as the foundation of this assumption, a case of typical Lorain's 
infantilism in which ossification had advanced much further than in a case of 
myxinfantilism. E. Levi showed, however, that in the type Lorain the ossifica- 
tion is much delayed as compared with that of a normal individual of this age. 
It is certain that also in true infantilism there exists a certain inhibition of 
ossification, and that even a certain acceleration of ossification may follow 
thyroid gland therapy. But this does not furnish a certain demonstration of 
the thyrogenic pathogenesis of such cases, for, as Ferranini already mentions, 
the stimulation of the metabolism through the administration of the thyroid 
gland may help somewhat. To-day, when the manifestations of thyroid gland 
insufficiency in childhood are so carefully studied, we would require uncondi- 
tionally sure signs of childish myxedema if we were to call a case myxinfantilism. 
The delimitation of true infantilism from severe forms of childish myxedema is 
indeed readily made. The mitigated forms may be distinguished from it by 
the presence of myxedematous alterations of the skin, thickening of the tongue 
and lips, the umbilical hernia, disturbances of intelligence, apathy, and especially 
the result of thyroid gland therapy. 
Naturally there also occur mixed cases. Signs of thyroid gland insuffi- 
ciency may be added to those of true infantilism, temporarily or permanently. 
Perhaps such a case is described by Dupre and Pagniez. Here a myxedema 
began at the fifteenth year of life in a case of true infantilism. 
Again, the delimitation of true infantilism from eunuchoidism is not diffi- 
cult in most cases. It is quite unintelligible how Peritz can regard eunuchoid- 
ism as the purest form of infantilism. In eunuchoidism we have an isolated 
severe disturbance of the development of the sexual glands, and here the 
analogy with eunuchoidism ends, the dimensioning of the body [in eunu- 
choidism] has nothing in common with the childish dimensions. (There is 
significant predominance of the length of the extremities and small head [in 
eunuchoidism].) Also the psyche of typical eunuchoids is not childish through- 
out. The feeling of absent virility here often leads to timidity and eventually to 
deep mental depression, while the childish features [of the disease] are absent. INFANTILISM 
485 
Wolf, just as has Peritz, has spoken against the designation eunuchoid, with 
incorrectness. Of the four cases that Wolf communicates, case 3 probably 
belongs to true dwarfism, associated with genital disturbance (Paltaufs type). 
He is certainly not an eunuchoid, but a mixed form between true dwarfism 
and infantilism. The other three cases are however typical infantilism, dis- 
tinguished from true eunuchoids by their childish 
psyche and by the proportioning of their bodies. 
The delimitation of true infantilism from 
typical juvenile hypophysial dystrophy is easy. 
In this too is found the disturbance in growth, but 
to the disturbance is added the typical distribu- 
tion of fat, and the disturbance of development 
of the genitalia is much more severe and is even- 
tually retrogressive. There are also present 
symptoms of increased intracranial pressure. I 
would here point out, as I have already in the 
chapter on the hypophysis, that it is quite un- 
justifiable to refer off-hand to the hypophysis a 
disturbance of growth, if other manifestations of 
hypophysial insufficiency are not otherwise 
present. Aschner has described a sixteen-year- 
old dwarf girl, 132 cm. tall; the ossification and 
dentition were delayed, her proportions were 
childish, and psychically and intellectually she 
was childish. She became pregnant in conse- 
quence of a rape. This indeed does not speak 
much against existing infantilism of the genitalia, 
as under circumstances children may become 
pregnant before the onset of menstruation. 
Aschner rejects the expression infantilism as in- 
definite, and regards the cause of the disturbance 
of growth as hypophysial without furnishing any 
evidence for his opinion. I regard this case as 
true infantilism or as a hypoplastic dwarf. 
Naturally there are numerous cases that 
constitute transitional cases between true infant- 
ilism and the hypophysial or eunuchoid form of dystrophia adiposo-genitalis. 
As example I cite the following: 
Observation LXI.—B. A., sixteen years old; entered the clinic February, 1911. Father 
dead. Mother had had lues before the child’s birth. Wassermann reaction is still posi- 
tive. The boy, too, gives a positive Wassermann. The boy learned to speak and walk as 
late as three years old. At the age of eight, a fall from a second story. Unconsciousness 
for ten minutes, and, according to statements, no after effects. 
The boy is small, length of body 142.5 cm. Lower length 82L2 cm. Psyche childish, 
corresponding to that of a boy thirteen years old. 
Slight sinking-in of the bridge of the nose: Hutchinson's teeth. No hair at all in the 
axilla and on the pubis. On the breasts slight collections of fat, collection of fat on the 
mons Veneris. Penis very small, testicle small, in the scrotum on both sides. 
Fig. 88.—Mixed form between 
true infantilism and dystrophia 
adiposo-genitalis. 486 
VEGETATIVE DISTURBANCES 
Scoliosis of the thoracic spine to the left; left pupil twice the size of the right; both fail 
to react to light, patellar and Achilles reflexes very lively. Hyperesthesia of the whole left 
side of the body, sharply cut off at the median line. No other nervous condition found. 
Fundus normal; to X-ray examination sella turcica normal. 
The epiphysial joints of the hand-skeleton are wide open, and the sesamoid bones as yet 
show no bone-nuclei. 
Diagnosis.—Infantilism + dystrophia of adiposo-genitalis of a slight grade, in heredi- 
tary lues. 
In this case of hereditary lues the excess of the lower length over the upper 
length militates against pure infantilism. Further, the eunuchoid distri- 
bution of fat is plainly indicated. The developmental disturbance of the sexual 
glands is somewhat more pronounced, and is perhaps of hypophysial origin 
(congenital lues, different symptoms on the part of the nervous system); on 
the other hand these symptoms are slight in comparison with the inhibition of 
growth, and the psyche is decisively childish. 
Just a few words concerning the so-called pancreatic infantilism. Bram- 
well and later Rentoul have described such cases. In the case of Rentoul we 
are dealing with a girl eighteen years old, who from youth, suffered with 
diarrheas (fat stools?). She grew slowly up to the eleventh year, and then, 
with regard to growth, remained at a standstill to the age of eighteen. She 
looked like an eight-year-old girl. The stools improved very much on the 
administration of pancreatin; she now increased rapidly in weight and grew in 
four months about 2 in. I do not regard as appropriate the term “pancreatic 
infantilism.” Thereby we might be induced to attribute infantilism to a 
disturbance of the internal secretion of the pancreas, although in these cases 
we may be dealing with true infantilism brought about through nutritional 
disturbances. When the nutritional disturbance improves, the retardation of 
the development may in part be mitigated. Disturbance of the internal secre- 
tion of the pancreas does not lead as far as is known to infantilism. Youthful 
diabetics do not show infantile features. In several cases of juvenile diabetes 
I have convinced myself that ossification does not remain behind. 
The vegetational disturbances in early childhood through damaging of 
the suprarenal cortex are as yet too little investigated that we can delimit them 
from infantilism. I refer to the chapter on this subject. Apparently hypo- 
plasia of the chromaffin tissue likewise does not lead to true infantilism. Prob- 
ably such cases belong to the so-called hypoplastics of Bartels or to true status 
lymphaticus. 
Pathogenesis.-—As I already mentioned at the beginning, the tendency 
is coming more and more to the fore to regard the cause of infantilism as a 
disturbance of the ductless glands, or as a disturbance of ductless glandular 
correlations; the disturbances of the correlations is a favorite modern catch- 
word. This opinion I cannot share. I regard true infantilism as the vegetative 
disturbance dependent on an inhibition of development of the whole organism. 
But the developmental retardation of the ductless glands is coordinated with 
that of the entire organism. Hence there is found no disturbance of correla- 
tion among the ductless glands, but a function of them graduated for an organ- 
ism that remains childish, a function fully suited for the childish TRUE DWARFISM 
487 
conditions. In true infantilism, also the sexual glands functionate—for signs of 
eunuchoidism are absent—but they functionate like those of children. 
According as the damage has occurred in the fetal, the infantile, or the juvenile 
organism, do there occur fetalism, infantilism, or juvenilism. 
A damaging that in youth acts electively on the ductless glandular system, 
and injures it severely must, according to my view, lead to a vegetational 
disturbance that is similar to multiple ductless glandular sclerosis. It would 
condition cachexia and premature senility, but not infantilism. 
This conception of infantilism agrees with that of Anton, who rules out 
dystrophic infantilism from the true ductless glandular diseases. The dif- 
ference consists only in the fact that I limit the idea of infantilism still more and 
do not class with it the true ductless glandular diseases of childhood. 
I need hardly mention again that this view holds only for the typical 
forms of infantilism. There are perhaps as many transitional forms as typical 
forms that pass over into the ductless glandular diseases. These transitional 
forms may exist between infantilism and various other diseases—hypophysial 
or eunuchoid dystrophia adiposo-genitalis, or pronounced status lymphaticus, 
with marked hypoplasia of the chromaffin tissue, or true myxedema or cre- 
tinism, or other vegetative disturbances yet to be described (true dwarfism, 
mongolism, etc.). I believe it is better to be precise in the delimitation of true 
infantilism as in this way the transitory forms that are so frequent, are made 
easier to recognize and easier to analyze. 
Prognosis.—The later fate of true infantilism has not as yet been thor- 
oughly studied. It is known, however, that the patients show an especial 
disposition for various diseases and mostly die prematurely (di Gappero, W. A. 
Freund, Hegar, et al.). Especially does tuberculosis reap a rich harvest among 
them. Also their mentality seems to suffer under the rough influences of life 
and its severe conflicts. 
Treatment.—The treatment in the true forms as yet is almost hopeless. 
Thyroid gland medication, hypophysis medication, etc., may yield slight re- 
sults in the mixed forms. True infantilism usually shows a lower tolerance 
for thyroid preparations. 
II. TRUE DWARFISM 
True dwarfism as a proportioned nanism may be rather well delimited 
from the other vegetative disturbances that I have thus far described or will 
hereafter describe in this chapter; since all of these with the exception of true 
infantilism are disproportioned nanisms, while in true infantilism the childish 
dimensions are retained. In spite of the fact that we are considering true 
dwarfism in this connection, it constitutes no uniform affection. Indeed 
attempts have been made to distinguish two different types of true dwarfism 
that differ from each other in important points and perhaps are also to be 
separated etiologically. There exists, however, as we shall see, all possible 
transitions between these types. As long as we do not know anything certain 
concerning the etiology of true dwarfism a satisfactory terminology for all the 
cases that belong in this group is not possible. 488 
VEGETATIVE DISTURBANCES 
Historical.—In this short exposition I would not enter into the descrip- 
tions that exist in the old literature. It is to be supposed that among the 
numerous dwarfs that in former times were retained at the courts of nobility- 
on account of curiosity or that were exhibited in the show booths [as freaks] 
there were some that were true dwarfs. The descriptions of these are, however, 
very inexact. Therefore I shall limit myself to the fewer and more careful 
communications in the later literature. The first exact description of the 
skeleton of a true dwarf originates with A. Paltauf in the year 1891, whiles. 
Hansemann was the first to separate the two types of true dwarfism, v. 
Hansemann distinguished a nanosomia primordalis and a nanosomia infantalis. 
In the latter at the time of birth the individual is of normal size. Growth ceases 
only later, the epiphysial junctures remaining open; often the individual re- 
mains infantile. This form is identical with that described by Paltauf. The 
primordial dwarf is small from the beginning, although his development, apart 
from the smallness, proceeds in the normal manner. He is, therefore, a veri- 
table diminutive human being; Sainton and Launois distinguish this true dwarf- 
ism from the other vegetative disturbances, without, however, considering 
the other type. Also E. Levi who has published a thorough study of this form 
of dwarfism, has considered Paltauf s form insufficiently. 
A. The Primordial Nanosomia.—An excellent example of this form is 
the case described by Virchow and later by v. Hansemann. It was that of an 
individual twenty-two years old (who at the age of eleven years was investi- 
gated by Virchow) who was 114 cm. tall. He was entirely well proportioned, 
the intelligence was well developed, the genitalia were well developed, except 
that cryptorchidism was present. The epiphysial junctures had ossified. At 
birth he had weighed only 500 gm. This was doubted by v. Hansemann 
although it is certain that at the birth the parents were impressed with the 
abnormal smallness. He was the fifth child of twelve, and the first dwarf. 
Later three dwarf children followed, but they did not attain a high age. Be- 
tween them there were births of normal-sized children, that later also developed 
normally. 
To the primoridal dwarfs belong also the dwarf family Magri, studied by 
various Italian authors and exactly described by Taruffi. The husband and 
wife Magri were entirely normally developed; of thirteen children eight sur- 
vived, five were of entirely normal size, three extraordinarily small. Of these 
there was a girl 102 cm. tall, in whom menstruation occurred late but who was 
otherwise normal. A boy of no cm. of bright temperament, but bad charac- 
ter, married in his twenty-sixth year a woman of normal size and had by her 
two children—-a boy who was of normal size and a girl who was apparently a 
dwarf. The third dwarf child of the Magri husband and wife was 109 cm. tall. 
All three Magris grew taller very slowly. 
Very exactly studied are also the cases of Levi. These I shall now describe 
more in detail. The first was a forty-nine-year-old man, 109 cm. tall. The 
lower length was shorter than the upper length. The individual was small 
already at birth; the genitalia, the secondary sexual characters, and the intelli- 
gence developed fully. At the age of twenty, he married a woman of normal 489 
TRUE DWAREISM 
size, who after eight years bore a child of extraordinary smallness. Two years 
later there followed a still smaller child, who died at the age of ten years. At 
the age of forty-nine years the man was still sexually active. The second case 
of Levi was that of a twelve and one-half-year-old son of case I. He was 77 
cm. tall, and very intelligent. The third case was that of a thirty-three-year- 
old man, hi cm. tall, weighing 25 kg. The lower length was 64 cm.; the father 
was very small, the mother of normal size. The stunting of growth became 
prominent especially between the eighth and the tenth year. At the age of 
twenty-eight he married, and his child at two years old of extraordinary diminu- 
tiveness. In all cases the ossification and the closure of the epiphyses cor- 
responded to the age. Levi also emphasizes the fact that these cases, like the 
dwarf described by v. Hansemann, showed a slight retraction of the bridge of the 
nose and a slight degree of drum-stick fingers. 
The primordial dwarf is hence characterized by the fact that the dwarfism 
exists already at birth, that apart from the smallness the development proceeds 
normally, and that the genitalia, the ossification and the epiphysial junctures, 
and the intelligence develop rather normally. According to Hansemann 
“infantile” features are found only here and there, for example, cryptorchidism, 
or in the case of v. Hansemann enlarged thymus, or retention of the lobules of 
the kidney, abnormal length of mesocolon, funnel-shaped proximal end of the 
appendix, etc. Levi points out the slight retraction of the root of the nose and 
the slight degree of drum-stick fingers. 
B. Paltauf s Dwarf.—A. Paltauf described the skeleton of a dwarf who died 
at the age of forty-nine years; all the epiphyses were open. The individual 
was 112.5 cm. tall; he came from an entirely normal family; the intelligence 
was normal (he had taken part in two campaigns). He had twenty-eight 
erupted teeth; the thyroid gland was normal. A. Paltauf believes that in this 
case he was dealing with a nanosomia sui generis that depended on an earlier 
stage of the formation-age on account of the bones remaining at a standstill in 
development. Also the deformed cartilaginous base of the skull had ceased its 
growth, while the bones laid down in membrane grew further, thus allowing the 
normal development of the brain; although a slight cretinoid facial expression 
was thereby brought about. The skeleton is proportioned, but shows childish 
dimensions, the upper and lower lengths approximating those of a child {Breus 
and Kolisko). Such individuals may suddenly begin to grow again. A. 
Paltauf cites two instances, the English dwarf Jeffery, who began to grow again 
at the age of thirty years, and the Polish dwarf Borwilawski. The brothers 
and sisters of the latter were also dwarfish, but his children developed perfectly 
normal. I shall limit myself to the citation of the well-observed cases. 
The case of Schaafhausen was a sixty-one-year-old man, 94 cm. tall; 
several members of the family were also dwarfish, the genitalia were infantile, 
the facial expression childish. The sutures of the skull were all ununited, the 
epiphyses nearly all. The observations of Schauta, Ranke, and von Voil 
perhaps belong here also.1 Hitschmann describes a thirty-five-year-old man 
1 The case of His, quoted by Paltauf, belongs to the endemic cretins, that of Dalega to the 
sporadic cretins. 490 
VEGETATIVE DISTURBANCES 
who came of normal family and who developed normally up to the age of 
five years. Then growth was retarded, although up to the twenty-fifth and 
twenty-sixth years he did grow somewhat. He was 108 cm. tall, beardless, 
the voice did not change, the thyroid gland was normal. X-ray examination 
showed epiphysial junctures open O/2 cm.; the intelligence was normal. He 
was an actor with a Lilliputian troup. 
A second case of Hitschmann was that of a twenty-two and one-half-year- 
old singer; the inhibition of growth began at the tenth year. She was 125 cm. 
tall, slender, the intelligence was normal, the epiphyses were for the most part 
ununited. 
Joachimsthal describes several members of a Lilliputian troup, among 
whom was an individual thirty years old, in whom the stunting of growth had 
begun in the third year; at fifteen years of age, she was 90 cm. tall, and at 
thirty years 100 cm. tall. The facial expression was childish, the voice had 
not changed and the axillary hair was absent. All epiphysial junctures were 
open. The bone nuclei were about as well developed as those of a ten-year-old 
child. In an individual thirty-six years old the inhibition had begun at the 
age of seven. At the age of twenty-two he was 105 cm. tall and at the age of 
thirty-six, 128 cm. tall, the epiphysial junctures were open, the bone nuclei 
had developed further. In an individual thirty-three years old the inhibition 
had begun at the age of ten years, at twenty years he was 109 cm. tall, at thirty- 
three years 134 cm. tall; in a woman thirty years old the inhibition had begun 
at the age of eight years, at nineteen years she was 103 cm. tall, now 132 cm. 
tall. To the Paltauf’s type belongs probably the celebrated dwarf Helen 
Gubler called the “Puppenfee” [doll fairy]. At birth she wag normal. She 
ceased growing at the age of six years, and at twenty years was 106 cm. tall. 
If we survey the cases quoted, we find that the Paltauf’s type may be 
characterized thus: At birth the individuals are of normal size, and at first 
show a normal development. Only later, but at all events mostly in early youth, 
they suddenly cease growing. The epiphysial junctures remain open, and 
in all cases there occurs a quite slow further growth, the inhibition being broken 
through in exceptional cases only. The development of the bone nuclei 
is in nearly all cases delayed only a little, the development of the intelligence 
is normal. On the contrary the genitalia and the secondary sexual characters 
remain behind almost always. The cause of this growth disturbance is as 
yet not known. 
The typical Paltauf’s dwarf differs essentially from an individual with true 
infantilism. In the latter condition not all the epiphysial junctures remain 
open, but the ossification is highly retarded, so that we find ununited only 
those junctures that tend to close the latest otherwise. Then too the psyche 
of Paltauf’s dwarf is ordinarily not childish. I have therefore discarded 
v. Hansemann’s expression “infantile dwarf” and have chosen the expression 
“Paltauf’s type.” 
The distinction between the primordial dwarf and Paltauf’s dwarf, on 
the one hand, and high-grade infantilism on the other hand serves only for 
the typical cases. It will readily be seen that transitional forms between the THE RACHITIC DWARF 
491 
two varieties of dwarf and true infantilism occur. To quote some examples: 
Joachimsthal describes among his cases two thirty-six-year-old individuals 
of 114 cm. and 116 cm. heights respectively. With these, growth has remained 
at a standstill at about the tenth year. We can therefore not classify them 
with the primordial dwarfs. The epiphysial junctures were, however, closed, 
and both menstruated regularly since their twentieth year. In a female 
dwarf with retained epiphysial cartilages the sexual organs were developed 
quite normally. She conceived, and at Cesarean section was delivered of 
a child above the normal in weight and size. 
The circumstance that there are transitions between the primordial and 
the Paltauf’s type does not mean that they both rest on the same etiological 
basis. It would be very easy to assume that in the primordial dwarf the 
noxus took its effect in fetal life, in Paltauf’s dwarf, in postfetal life. This 
does not, however, explain the great difference in the relation of the genitalia. 
As will be seen by the example quoted, the familial hereditary occurrence is 
common to both types. In both types, too, the children of the person affected 
may develop normally. 
There therefore does not seem to me to lie at hand any basis for con- 
sidering true dwarfism as an affection of the ductless glandular system. I 
need hardly point out that there is no involvement of the thyroid gland. 
Aschner would indeed make the hypophysis answerable for dwarfism—certainly 
incorrectly—for all the symptoms characteristic of hypophysial dystrophy 
are absent. 
III. THE RACHITIC DWARF 
Dwarfism may be the result of a high-grade rachitis developing in 
children. According to Breus and Kolisko, in addition to the inhibition of 
growth in height, there are found regularly also curvatures—under circum- 
stances the bones are weak and flexible. “The disturbance of the periosteal 
ossification, in contradistinction of endochondral ossification, comes into the 
foreground.” Breus and Kolisko also state that in such cases the epiphysial 
junctures can often remain ununited; Gulecke, however, reports three cases 
of dwarfism who had suffered severe rachitis in early life and yet showed on 
X-ray examination premature synostosis of the epiphysial junctures. Gulecke 
assumes that the epiphysial cartilages were severely damaged by the rachitis, 
and that then reparatory processes set in which led to premature ossification. 
In fresh cases the X-rays show washing out of the boundaries between the 
bone nuclei and cartilage, and at the site of the epiphyses broad light zones 
apparently representing excessively proliferated cartilage (Joachimsthal). 
The behavior of the epiphysial junctures and the bone nuclei thus vary 
according to the intensity of the process, according to the liveliness of the 
proliferation of the abnormal cartilage, and the reparatory processes. Rachitic 
dwarfism is characterized by the never-ahsent signs of a previous rachitis and 
by the normal development of the intelligence and of the genital sphere. 492 
VEGETATIVE DISTURBANCES 
IV. CHONDRODYSTROPHY 
(A chondro plasia) 
Historical.—Chondrodystrophic dwarfs were known already in antiquity. 
Cestan and Meige, who have concerned themselves with the historical study 
of this disease, refer to the pictures of the Egyptian god Ptah and the goddess 
Bes, in which typical cases of chondrodystrophy are exhibited. Also the 
statue of Karakalla and several pictures by Velasquez show typical chondro- 
dystrophies. Formerly chondrodystrophy was regarded as congenital or fetal 
rickets (Sommering, II. Muller, Longer, and others). Virchow described a 
chondrodystrophic dwarf that he regarded as a case of endemic cretinism. 
In France, Porak denied the assumption of achondroplasia as fetal rachitis and 
set forth that it was concerned with an affection of the epiphysial cartilages 
that sets in in fetal life. Kaufmann in his known monograph lines himself 
against Virchow's explanation, Kaufmann and later Dieterle have done away 
for good with the conception of a thyrogenic disturbance, until Kaufmann 
originated the name chondrodystrophy, by which the condition is known in 
Germany. Kassowitz calls the disease “Mikromelie.” But this designa- 
tion is not precise, as there are different kinds of micromelie (shortness of the 
extremities) that have nothing to do with chondrodystrophy (osteogenesis 
imperfecta [Vrolik], phokomelie, etc.), and chondrodystrophy constitutes 
only one of these types. I refer the reader to the excellent dissertation of 
Siegert. 
Definition.—Chondrodystrophy is characterized by a growth disturbance 
of the cartilages at the ossification boundary of the cartilages, especially, those 
of the long bones setting in the earliest fetal life. Microscopically there is found, 
according to Kaufmann, either mucoid softening of the cartilages (malacic 
form), or only cessation of growth (hypoplastic form), or even considerable, 
but entirely disorderly, proliferation, which takes place in all directions instead 
of in the longitudinal direction, and thus leads to a moderate swelling out 
of the epiphyses (hyperplastic form). In older individuals, the cartilaginous 
zone of proliferation is bounded at the periphery by strips of connective tissue 
{Dieterle). Thereby the periosteal bone formation is not inhibited, and may 
even be excessive, as is also the formation of bone nuclei in the epiphyses, 
which may even show acceleration. The disturbance affects also the bones 
of the shill that are preformed in cartilage, and the vertebral column, while the 
growth of the bones preformed in membrane is not inhibited. 
Symptomatology.—From this growth disturbance there results a skeletal 
formation characterized by the following points: The base of the skull is 
markedly shortened by the inhibition of growth and the premature synos- 
tosis of the os tribasilare occipitalis and the os basilare occipitalis, as first 
described by Virchow. There is thus brought about a marked retraction 
of the root of the nose, such as is not observed in any other growth distur- 
bance. There are, however, rare cases of chondrodystrophy without this 
retraction. Eichholz has described three such cases belonging to one fam- 
ily. Then again the retraction of the root of the nose may exist, without 
there having taken place a coalescence at the synchondrosis (a case of E. CHONDRODYSTROPHY 
493 
Langenbach). The clivus is shortened—I here am following the description 
of Breus and Kolisko—the foramen magnum is very small; the base of the 
skull is usually supernormally large; there occur also hydrocephalic skulls in 
which ossification is rather retarded so that the fontanelles persist abnormally 
long. The form of the sella turcica may be quite abnormal (confer Observation 
LXIII). If the subject lives after the period of childhood, the development 
of the brain and the intelligence is normal. The upper jaws are broad, spread 
far apart, and the upper jaws project markedly. Dentition is entirely normal. 
The vertebral canal is narrowed, usually in the frontal diameter on account 
of premature coalescence of the nuclei of the arches and the bodies, but some- 
times generally. 
There exists lordosis of the lumbar spine and kyphosis of the thoracic 
spine. The thorax is narrowed in the sagittal diameter. In five skeletons 
of grown chondrodystrophic dwarfs, Breus and Kolisko found frontal stenosis1 
of the vertebral canal in every case. According to Dieterle the narrowing 
may also be conditioned by hyperplasia of the cartilage. This was true in 
pronounced manner in both of Lampe’s cases. In one of these the spinal 
medulla was markedly compressed on this account. 
In chondrodystrophy the ribs are broad and coarse, and at the junctions 
of the ribs the cartilages are often swollen-up (pseudo-rosary), in such a man- 
ner that the bony part embraces the cartilaginous. Siegert describes a marked 
swelling-out at the part of the rib bordering on the capitulum costis, with 
sharp-angled bowing and fungus-like swelling out of the epiphysis; the ster- 
num is broad and thick, body and xiphoid process are synostosed; the clavicles 
are short, and bent in the form of an S; the scapulae very small, their 
borders coarse, the pelvis generally narrowed, its inlet kidney-shaped. The 
promontory [of the sacrum] projects markedly, the ilia are thickened, 
shovel-shaped with thickened borders. Most characteristic of the micro- 
melic growth disturbance is the inhibition in growth of length of the extremi- 
ties, which is the proper cause of the dwarfism of the individual. Under 
normal conditions the lower length begins to exceed the upper length already 
toward the end of the first year of life, and the difference becomes more 
marked as the years pass. In the disease under consideration however the 
growth in length of the extremities remain so far behind that the relation of the 
upper length and lower length may reach 2:1. As the periosteal bone-forma- 
tion is not inhibited, the cortex of the diaphyses is very thick and very 
marked places for the insertions of the muscles develop; the muscles themselves 
are entirely normal, so that the chondrodystrophic dwarfs are very strong with 
regards to muscular force and are clever acrobats. According to Breus and 
Kolisko the fibula is less shortened than the tibia, so that it projects mark- 
edly below the lower end of the tibia, thus producing a varus position of the 
foot; the feet are shortened, also the upper extremities are essentially short- 
ened, likewise the hand, the breadth of which is however normal; the shortened 
fingers stand apart from one another (main a trident, Radspeichenform). 
1 In German edition “sclerosis,” according to the original article of Breus and Kolisko “stenosis.” 
Editor. 494 
VEGETATIVE DISTURBANCES 
The ossification of the epiphyses proceeds very irregularly. The epiphyses 
themselves may, as Siegert mentions, sometimes be more hyperplastic, 
sometimes more hypoplastic, in the latter case embracing the diaphyses. 
The closure of the epiphysial junctures may occur prematurely, especially 
those of the metacarpal bones of 
the hands and feet; at other places, 
however, the epiphyses may close 
abnormally late. In the seven- 
teen-year-old case I shall report 
later, the distal epiphysial junc- 
tures of the radius and ulna, and 
Fig. 89.—Chondrodystrophy (Observation 
LXII). 
Fig. 90.—Chondrodystrophy (Observation LXIII) 
the proximal of the first metacarpal and phalanges are as yet wide open, so 
that examination of the accompanying X-ray picture will show that the head 
of the metacarpal bone is swollen out, extremely coarse, and that the epiphyses 
are well developed, and in part—for example those of the radius—'misplaced. 
Hyperplastic and hypoplastic processes may often be seen in the same skeleton. CHONDRODYSTROPHY 
495 
There have also been described cases of partial chondrodystrophy. 
Dufour describes such a case, in which the upper extremities were hardly 
shortened, and also the trident form of the hands was not pronounced, while 
the lower extremities showed marked chondrodystrophic alterations. Espe- 
Fig. 91.—X-ray picture of the hand in chondrodystrophy (Observation LXIII) 
dally noteworthy is the case of unilateral chondrodystrophy described by 
Siegert in his monograph. 
The malacic form of chondrodystrophy is not capable of maintaining its 
life; both other forms may attain a high age. The aplastic form is recognizable 496 
VEGETATIVE DISTURBANCES 
by the absence of the vertebrae and cranial synostoses described, and further by 
a characteristic position of the joints by which the extremities maintain a curved 
appearance (Breus and Kolisko). The dwarfs are for the most part especially 
small. 
Fig. 92.—Sella turcica pressed flat in chondrodystrophy (retouched) (Observation LXIII). 
For the characterization of the chondrodystrophic dwarf, it is also men- 
tioned that they all show a great family likeness (Porak); that the gait in all 
is waddling, that the intelligence develops normally, and that finally the sexual 
glands and the genitalia develop and functionate normally. Indeed in many 
cases the genitalia are developed remarkably well. CHONDRODYSTROPHY 
497 
Here are set forth two cases observed at the first medical clinic. The 
notes concerning the first case, four years old (Observation LXII), have un- 
fortunately been mislaid. I can only show the characteristic illustration, 
that shows the characteristics of chondrodystrophic dwarf in pronounced 
manner. The root of the nose is markedly retracted; the extremities are 
enormously shortened, the skin has become too wide for its extremities, lying 
in thick folds. 
Observation LXIII.—U. W., seventeen years old. Father of the patient normally 
developed. The same is true of the father’s parents and three brothers and sisters (except 
that one sister has a syndactylism of three fingers). The mother of the patient seems to 
have had rickets in early life, but is of normal development. Of brothers and sisters of 
the patient only the youngest, a girl one year old, is living; she is entirely normal. The 
eldest child died at the age of fourteen years of tuberculosis, was normally developed. 
The second child died at three-fourth year, the third at one-fourth year, the fourth is the 
patient. The fifth and sixth died at one-fourth and one-half years, the seventh immediately 
after birth. 
The patient, like the rest of the children, was, according to statement, normal at birth. 
At six months of age he seems to have had pain in passing urine, and soon after the father 
observed that the child remained behind in growth, and only the head was much too large. 
The increase in the size of the head lasted until about the seventh year. He learned to speak 
at two years, the intelligence developed entirely normally. At about one-half year he has 
had paresthesia and fatigue in the legs. He began to walk with knees pressed together and 
for some weeks sitting down has been difficult too. 
Height 125 cm., span width 126 cm., acromion to points of finger 47 cm.; upper border 
of trochanter major to the heel 53 cm. Length of hands, 15 cm., breadth 10 cm.; length 
of feet 21 cm. 
The cranial skull is much larger than the facial skull, is somewhat quadrangular; root 
of nose deeply retracted. On looking to the left or upward, horizontal or vertical nystag- 
mus respectively. Chvostek’s phenomenon present on both sides. Slight dextroscoliosis of 
the thoracic spine. The hands are short and broad, the fingers alike in length, typical 
mains a trident. X-ray shows that the epiphysial junctures of the fingers are not as yet 
united. The sella turcica is pressed together in the vertical diameter, broadened in the 
horizontal. 
The musculature is normally developed, the genitalia hyperplastic. There is no axil- 
lary hair, nor hair on the linea alba. There exists a moderately large struma of rather soft 
consistency. 
There are spasms of the lower extremities. Legs adducted when at rest, with slight 
equinus position. Patellar and foot-clonus present, Babinski positive. Hypalgesia and 
hyperesthesia from about the height of the arch of the ribs downward, becoming less from 
the fossae of the ilia down; very slight on the feet. 
Summary: Typical Chondrodystrophy.—At first we thought of a hydro- 
cephalus, descending degeneration of the pyramidal tracts and spastic paresis 
of the extremities. Yet there were no other points for our adhering to the 
diagnosis hydrocephalus. It is possible that the spastic paresis was produced 
by narrowing of the vertebral canal by the chondrodystrophic process. I 
refer to the case of Lampe mentioned above. 
Occurrence.—Chondrodystrophy does not belong to exceedingly rare 
affections. According to Katolicky about 70 cases are known in adults. Siegert 
counts 53 females and 50 male cases. Several cases of familial or hereditary 
occurrence of chondrodystrophy are found reported in the literature. Porak 498 
VEGETATIVE DISTURBANCES 
mentioned a chondrodystrophic female dwarf who was delivered of a chon- 
drodystrophic child through Cesarean section. Porak also cites a case of 
Charpentier, a twenty-three-year-old chondrodystrophic female dwarf, whose 
sister, father and great-grandfather had been chondrodystrophic dwarfs. 
Poncet and Leriche observed two chondrodystrophic sisters, Decroly saw chon- 
drodystrophy in grandfather, father, and child. Also Eichholtz saw familial 
occurrence of chondrodystrophy. He saw two chondrodystrophic sisters, of 
whom one was a childless widow forty-two years old. The other, about forty 
years old, had an eighteen-year-old chondrodystrophic child. She was delivered 
through Cesarean section. Also the father of both women seems to have had 
Fig. 93.—Chondrodystrophic family (Father—Observation LXIV) 
chondrodystrophy. Siegert mentions that beyond these cases he could find 
no others of inheritance of the disease among the more than ioo cases reported 
in the literature. However, there are later observations. Franchini and 
Zanasi observed a chondrodystrophic man and wife. The woman became 
gravid and was delivered through Cesarean section. The child, which indeed 
the authors did not themselves see, was 80 cm. tall at the age of twelve years, 
and had an enlarged head and shortened extremities. It seems thus also to 
have been a chondrodystrophy, as the authors suppose with entire correctness. 
Glaessner showed two cases of chondrodystrophy at the Wiener Gesellschaft 
der Aerzte. They were father and son, fifty-six and twenty years old, ioi 
and 108 cm. tall respectively. It was elicited that for four generations, dwarf- 
ism always existed in the male members of the family, while the women were 
entirely normal. A fine example of inheritance of the disease was also observed 
in the first medical clinic. It concerned a father, son, and daughter. I here CHONDRODYSTROPHY 
499 
Fig. 94.1. 
Fig. 95.1 
Figs. 94 and 95.—Chondrodystrophic family (Son—Observation LXV and daughter—Observation 
LXVI). 500 
VEGETATIVE DISTURBANCES 
reproduce the photographs. The father was forty-nine years old, the son 
nineteen, the daughter twelve years old. The wife of the father was of normal 
height. (Observation LXIV, LXV, and LXVI.) 
Etiology.-—As I already mentioned at the beginning chondrodystrophy 
was first regarded as fetal rickets, an assumption that was already the experi- 
ments of Parrot and Porak showed unfounded. Virchow regarded as typical 
for endemic cretinism the premature synostosis of the os tribasilaris that 
occurs in chondrodystrophy and on this supposition turned attention to 
the thyroid gland etiologically. The assumption of insufficiency of the thyroid 
gland is recognized as incorrect, as the result of the works of Kaufmann and, 
later, Dieterle, in spite of which Ilertoghe, Stotzner and Moro again adopted the 
thyrogenic origin of chondrodystrophy. In all accurately investigated cases 
the thyroid gland is entirely normal, however {Dieterle, Breus and Kolisko, 
Kassowitz, etc.). The supposition of Moro that in his case there had occurred 
previously a dysplasia of the thyroid gland is not justified by anything. Also 
in the case reported by me, there was not a single symptom that belonged to 
the symptom-complex of hypothyrosis. Then again thyroid therapy is 
entirely without results, even in young individuals. Recently Sumita has set 
forth the untenability of thyroid-gland therapy. 
Lauze points out that the buffoons of kings were chondrodystrophic 
dwarfs who have been described as talented, loquacious, quick at repartee, 
“fond of everything that glitters,” and sometimes also maniacal. Lauze regards 
this mental condition as the result of hypersecretion of the interstitial glands. 
Euziere. and Delmas describe a case of chondrodystrophy with psychical 
characteristics such as Lauze has described; they regard these, however, as an 
expression of degeneration and do not believe that such psychical earmarks 
stand in causal associationship with chondrodystrophy. In the cases of 
chondrodystrophy observed by me I could not observe any of the mental 
characteristics described by Lauze. The hypothesis of Lauze should hardly 
gain adherents. 
Differential Diagnosis.—Nowadays we ought not to waste words con- 
sidering the differential diagnosis from cretinism. 
Another form of micromelic growth disturbance, osteoporosis congenita 
(Kundrat), is characterized by a disturbance of the epiphysial as well as peri- 
osteal bone formation. Clinically, it has up to the present been without 
significance as the infants have never been capable of maintaining life; except 
that Ilagenbach described a dwarf with tumor of the hypophysis, whose bone 
alterations Ilagenbach regarded as osteoporosis. Up to the present there are 
no tenable relationships between this disease and the ductless glandular system. 
V. MONGOLISM 
(Mongoloid Idiocy) 
Mongolism was first recognized as a disease sui generis by Langdon-Down. 
I shall here limit myself to a short delineation, paying especial attention to 
the differential diagnosis from infantile myxedema, in the course of which 
I follow the excellent descriptions of Bourneville, Kassowitz, Scholtz, and Siegert. MONGOLISM 
501 
Symptomatology.—The Mongoloid children show a great family likeness. 
The term Mongolism is used because the physiognomy of these children shows 
great similarity to that of the Mongolian races. While in infantile myxedema 
the skull is mostly large and pronouncedly brachycephalic, in Mongolism 
it is small and round, the palpebral fissures are small and lack myxedematous 
swelling, they are placed oblique, are slit-like and show epicanthus; 
the nose is small and sits like a button on the broadened and somewhat sunken 
nose-root (Kassowitz), while in infantile myxedema the root of the nose is 
Fig. 96.—Six and one-half-year-old girl (Mongolism) with three-year-old healthy sister. 
strongly retracted, so that the nasal cavities become apparent. Mongoloids 
often show a conjunctivitis. The zygomatic arches protrude somewhat, 
the forehead is low and flat, the mouth is small but becomes broadened when 
the patient laughs, the tongue is not enlarged, or not essentially so, is fissured, 
is always somewhat between the separated rows of teeth, the lower jaw as a 
rule projects beyond the upper jaw. The palatal arches are high, the cephalic 
hairs are soft and silk-like, while in myxedema they are rough and dry and are 
here and there absent. The ears are small and stand back, the lobules have 
developed in the form of a triangle (oreille mongolienne); while in myxedema 
the facial expression is morose and unintelligent, in Mongolism it is vacant and 
expressionless only in the first years of life. Later it is gay, comical, imbecile. 
I refer to the accompanying illustration. The cheeks lack the thickness of 
myxedema and usually show a macular redness. While in infantile myxedema 502 
VEGETATIVE DISTURBANCES 
or thyroaplasia the condition becomes recognizable only some time after birth, 
Mongolism may be recognized immediately “c’est un petit chinois.” The 
fontanelles and sutures are open abnormally long, dentition is somewhat delayed 
and somewhat irregular. The teeth are defective, and the set of teeth mostly 
shows numerous abnormalities. (Degenerationsgebiss-Tog/); growth in height 
is usually somewhat stunted, but there exists a difference from infantile myx- 
edema in that all these manifestations are very much less pronounced, and the 
bone nuclei usually appear at the normal time or just a little later. In many 
a case only isolated bone nuclei appear late (Vogt). Siegert even observed 
premature ossification of the epiphysial nuclei. Later there often occurs a 
stunting of growth, and even a case of Mongoloid dwarfism has been observed 
by Bourneville. The skin is smooth and moist; the pseudolipomata of infantile 
myxedema are absent, and there often exists marked obesity. The neck is 
regular, not shortened as in infantile myxedema. The thyroid is present. 
Very commonly the abdomen is thickened, obstipation exists, and umbilical 
hernias are not rare. Kassowitz found umbilical hernias forty-four times among 
fifty-five cases, and three times a hernia in the linea alba below the umbilicus. 
Both the accompanying illustrations, (Observation LXVII) for which I 
thank Dr. L. Mohr (Halle a. S), show the Mongolian expression of the face. 
[Timme1 reports changes in the sella turcica in a recent paper and has 
subsequently been corroborated by Tumpeer} Timme quotes Oliver for eye 
ground changes, as will be noted below.-—Editor.] 
The skeleton is proportioned, slender, the children learn to sit and stand 
late, the hands are rather small, awkward, the middle phalanx of the little 
finger is often shortened, the end phalanx atrophic; also the thumb is often 
very short (main mongolienne). Very commonly the joints are extra- 
ordinarily low, especially the joints of the hands and feet, but also the hip- 
joints. The musculature is often hypotonic. Often other anomalies of 
formation occur, such as congenital cardiac defects, and not rarely slight 
strabismus or nystagmus. [The cranial convolutions are of a simpler type 
than the normal. There is as a rule thinning of the cortex. According to 
Shuttleworth and Potts3 (quoting Wilmarth and Tregold) there is a notable 
diminution in the size of the pons, medulla and cerebellum.—Editor] The 
genitalia are different from those of infantile myxedema, in that they remain 
only a little behind in development. In males, the penis and scrotum are often 
strikingly small, as Kassowitz found nineteen times in thirty-nine cases, and 
Siegert in half the cases. Also there may be delay in descent of the testicles. 
Later the genital functions are for the most part normal, although libido may be 
very slight. The Mongoloids are usually short-lived, and very sensitive to 
tuberculosis. The mental development is most only delayed, or there may be 
slight imbecility—and but rarely pronounced idiocy. The children are rather 
1 Timme (TV.)-—The Mongolian idiot, a preliminary note on sella turcica findings. Arch. 
Neurol, and Psychiat., Vol. V, May, 1921, pp. 568-71. 
2 Tumpeer (/. II.).—Mongolian idiocy. J. Am. M. Ass., Vol. LXXIX, July 1, 1922, pp. 14-16. 
3Shuttleworth (G. E.) and Potts (TV. A.).—Mentally deficient children—their treatment and 
training. London, Lewis, 1922. MONGOLISM 
503 
lively, but their attention is fixed with difficulty; they have considerable insta- 
bility and pose readily. 
Hence there are very few features of infantile myxedema mixed in with 
Mongolism. These are eventually a slight degree of dwarfism, the delay of 
the dentition and closure of the fontanelles, the distention of the abdomen, 
the umbilical hernias, the constipation, the remaining behind in mental develop- 
ment, the anemia. There are, however, cases of Mongolism in which myx- 
edematous symptoms are more prominent; Vogt, Neurath, and others have 
described such cases.1 
Fig. 97.—Same case after thyroid treatment. 
Pathogenesis and Treatment.—From what has been said, we should 
expect that thyroid-gland treatment would have only a slight influence. 
Sometimes not even acceleration of the dentition and closure of the fonta- 
nelles follow. Only the umbilical hernia and constipation are improved 
rapidly. Kassowitz says that in young children treatment with thyroid 
gland will only anticipate the improvement that later occurs spontaneously. 
In the case shown above, the results of its use may be regarded as extraor- 
dinarily good. 
1 Basal metabolism was normal in six Mongolian idiots. Fleming (G. B.).—The respiratory 
exchange in cretinism and Mongolian idiocy. The Quarterly J. of Med. No. 61, Oct., 1922, pp. 11-21. 504 
VEGETATIVE DISTURBANCES 
Although according to what has been said there tends to be present in 
cases of Mongolism a slight temporary component of athyrosis, which may be 
more strongly pronounced in certain rare cases, yet there is not doubt that 
the clinical picture of this disease cannot be attributed to any disease of the 
thyroid. This is confirmed by the fact that in the few autopsies thus far 
recorded the thyroid for the most part was found to be normal (Neumann, 
Comby, Bourneville). Only Phillippe and Oberthur found in four cases inflam- 
matory sclerosis and Lange slight inflammatory changes. Bourneville in 
five cases, and Siegert in one case saw a persistent thymus. The findings 
in Mongolism do not present anything characteristic, and resemble those of 
idiocy (Scholz). Kassowitz considers the simultaneous affection of many 
ductless glands; which assumption lacks all objective evidence. Most worthy 
of remark in an etiological direction seems to me the oft repeated observa- 
tion that Mongoloids are the last born in a family numerous in children, 
or that the mother was very old or her strength had been reduced through 
illness. Shuttleworth therefore terms the Mongoloids the “products of 
exhaustion.” [Shuttleworth says they are ‘’unfinished” children; but he 
prefers the term “ill-finished” children introduced by John Thomson. Accord- 
ing to the figures of Dollinger2 the average age of the fathers of twenty-four 
Mongoloid was 39.2 years, the average age of the mothers 33.7 years (in five cases 
the mother was older than the father); the average age of the fathers in forty- 
eight other (non-Mongoloid) children was 33.6 years and of the mothers 27.7 
years. Thursfield3 in a study of forty-two cases of Mongolism could find no 
relation between Mongolism and the age rank of the child among the rest of 
the children of the family, nor were the mothers of some of them unusually 
old.—-Editor] 
In the differential diagnosis from infantile myxedema, the X-ray examina- 
tion, in addition to the Mongoloid expression of the face, is of importance. 
Addendum 
It is true that no term in medicine has been more abused than that of 
“infantilism,” and that any special work done on the individuals affected 
with infantilism must be accepted with caution if the type of infantilism 
and exact description of the individual be not clearly stated. The author’s 
attempt to delimit the affection is indeed very laudable; but it is true that the 
determination of the fine shades of distinction is often very difficult. Thus 
certain of the cases of pituitary tumor without apparent abnormal distribu- 
tion of fat have been classed under the general term “infantilism.” It is 
not at all certain that these cases would be included under any of the types 
mentioned by the author, although some do possess features that resemble 
closely the infantile types. Among these may be mentioned the type of 
1 Shuttleworth (G. E.) and Potts (W. A). Loc. cit. 
2 Dollinger (A.). Zur Aetiologie des Mongolismus. Ztschr. f. Kinderheilk. Orig. XXVII, 1920, 
PP*332-336. 
3 Thursfield (H.). Notes on Mongolism. The British Journal of Children’s Diseases. Vol. 
XVIII, Nos. 205-207, pp. 18-21. ADDENDUM 
505 
“fat boy” described by Cushing, which Cushing regards as on the whole a 
hypopituitarism. Probably it would be better to consider these as disease 
manifestations of the various glands or groups of glands, although not too 
much should be ascribed to subsidiary changes in glands that are involved 
in a minor or secondary manner. 
McKee, who has had an extensive experience with Mongoloids, claims 
to have attained very good results from the use of thyroid-gland extracts. In 
view of the fact that parents ask that such cases be treated, polyglandular 
therapy may be tried, not, however, with the expectation of much success. 
The cases shown in the picture in Falta ’s text apparently show some improve- 
ment. Hyman I Goldstein, of Camden, N. J., has told the author that the addi- 
tion of pituitrin to thyroid extract or thyroxin in his cases of cretinism seemed 
to be of value—and as will be set forth below these cases of cretinism seem to 
present some Mongoloid features. Goldstein himself states that one “has 
the appearance of a ‘cretinoid Mongolian idiot.’” 
In very many of these cases of Mongolism reported, evidences of heredi- 
tary lues were present. We do not believe that such cases should be considered 
in the same category with the cases in which lues can be ruled out as an etio- 
logical factor. Is it not possible that these cases of Mongolism represent a 
reversion to a primitive type in which Mongoloid characters are dominant 
(in a Mendelian sense) ? The occurrence of the bluish spots which are normal 
in true Mongolism is suggestive along these lines. The fact that Tumpeer 
has recently reported a case of Mongolism in a Mongolian throws no light on 
the subject. It will probably be found that Mongolian idiots are not rare 
among the Mongolian peoples. 
It would be well, however, that all cases be subjected to as many metabolic 
tests, and X-ray examinations as possible. As Shuttleworth points out mixed 
cases may occur and indeed are the rule. 
Shuttleworth and Potts have excellently summarized the difference between 
Mongolism and cretinism: 
Mongolism 
1. Characteristics noticeable from birth. 
2. Skull brachycephalic: contour 
rounded or short oval; longitudinal and 
transverse diameters nearly correspond. 
3. Palpebral fissures “almond shaped,” 
and more or less oblique upwards and out- 
wards. Frequent epicanthus. Strabismus 
common. Ciliary blepharitis frequent. 
4. Cheeks chubby, often florid. Com- 
plexion mottled. 
5. Lips often transversely fissured. 
Lower lip may be pursed up over upper. 
6. Tongue large and coarsely papillated, 
if not fissured. Tongue frequently pro- 
truded and drawn back. 
Cretinism 
1. Characteristics often not noticeable 
till sixth or seventh month. 
2. Skull dolichocephalic; flat at top. 
(fontanelles close late) expanded laterally, 
broad behind, often symmetrical. 
3. Palpebral fissures horizontal, but 
appear small owing to pseudoedema of eye- 
lids. Strabismus and ciliary blepharitis 
less common. 
4. Often circumscribed malar flush; 
complexion ashy or waxy. 
5. Lower lip often everted. Mouth 
open. Drivelling common. 
6. Tongue large, but not coarsely 
papillated or fissured. Tip of tongue 
thickened, and constantly protruding. 506 
VEGETATIVE DISTURBANCES 
7. Skin smooth in infancy, but furfura- 
ceous later; not redundant or “baggy.” 
8. Thyroid gland palpable to greater or 
less extent. 
9. No fatty tumors (pseudo-lipomata) in 
posterior triangle of neck. 
10. Long bones somewhat shorter than 
usual, but slender. 
11. Hands broad, thumb and little finger 
short, the latter often curved towards ring 
finger. 
12. Feet large and flat. Fissures between 
great and second toe often seen. 
13. Expression more or less vivacious and 
mobile, observant and imitative. 
7. Skin dry and scaly; forms folds here 
and there; being redundant and “baggy.” 
8. Thyroid gland impalpable to most 
thorough examination. 
9. Fatty tumors (pseudo-lipomata) fre- 
quently found in posterior triangle of neck, 
etc. 
10. Long bones, shortened and thickened, 
in some cases bowed. 
11. Hands broad, thick and stumpy with 
wrinkled skin. Fingers square at tips. 
12. Feet squat, skin redundant about 
ankles and dorsum of foot. 
13. Expression dull and immobile, unob- 
servant and apathetic. 
Similarities in Each Variety 
Deficient stature (more marked in cretins), flattened bridge of nose, with expanded 
alas, late and irregular dentition, deferred closure of fontanelles, retarded puberty (the 
last most marked in cretins). 
Goldstein has observed in the cases that he recently reported as cretinism 
the great space between the great toe and the next adjoining toe. It is possible 
that these cases showed some Mongoloid characteristics. The space suggests 
to the editor, as do the bluish spots, an atavistic tendency. If this is so, 
the relationship of Mongolism to achondroplasia (see below) is somewhat 
doubtful. The editor has, however, seen in young brothers signs of clavicular 
deformity with epicanthus, mutism, and a patch of gray hair on the frontal 
region. Pictures of these cases were shown before the Philadelphia Neuro- 
logical Society by Dr. A. E. Taft. 
Sternberg subdivides nanosomia infantalis. This condition consists in 
normal size of the individual at birth, stopping of growth prior to cessation of 
age of childhood, retention of the proportions appertaining to the age of child- 
hood for the life of the individual, absence of the consummation of develop- 
ment, remaining open of the epiphyses, failure of sexual maturity or faulty 
sexual maturity. One of the sub-divisions is nanosomia hypoplastica of which 
he reports a case. Pituitary dwarfism and thyrogenous dwarfism (with 
proportioned body-form—not cretinic) are the other types. One of the 
recent resumes of the subject of dwarfism and gigantism is that of Gigon, who 
reports one case of the adiposis-genitalis type, one case of Paltauf’s type, and 
one case of sporadic cretinism. 
The subject of dwarf growth especially that of achrondroplasia has 
also been dealt with by Maas. 
Jansen in studying the nature and cause of achondroplasia came to the 
conclusion that two principles which had hitherto passed unnoticed were 
underlying the facts, namely: 
1. Injurious agents affecting growing cell-groups enfeeble their power 
of growth. ADDENDUM 
507 
2. The measure in which growth is enfeebled is proportional to the rapidity 
of growth. He has written a book to work out these principles. (See references 
below.) He brings achondroplasia into relationship with dysostosis cleido- 
cranialis and with Mongolism, also with ancephaly, with congenital club-foot, 
and with congenital dislocation of the hip. He ascribes all of these conditions 
to “typical misdeeds of smallness of the amnion” (enhanced amniotic pressure). 
The work should be reviewed in conjunction with Jansen’s earlier work on 
achondroplasia. 
Borchardt has recently suggested the following classification of infantilism: 
1. Infantilism through abnormal growth tendencies. (Anlagen) i.e., 
hereditary infantilism. 
2. Through damage to the germ (alcohol, lead, X-rays). 
3. Through endocrine disturbances (a) dysthrogenous, (b) pituitary, (c) 
pluriglandular. 
4. Dystrophic (a) following early, even intrauterine, acquired infections 
(lues, tuberculosis, leprosy, malaria, pellagra, echinococcus), (b) following 
disturbances of nutrition, (c) following premature use of alcohol, (d) in 
congenital and acquired heart disease. 
Some of these classes should more appropriately be referred to classifica- 
tion under the diseases of the individual organs. 
Timme has recently brought into prominence a clinical complex in which the 
thymus gland seems enlarged and in some of which cases diseases of the various 
ductless glands and infantilism are associated. We are dealing here, it seems, 
with an infantilism of adult life. Timme ascribes much to the persistence of 
the thymus gland. Borchardt has pointed out in his article that infantilism may 
affect individuals up to any age (the ages of his cases varied between five and 
forty years). As has been stated in the addenda to some of the preceding chap- 
ters, the functions of the thymus gland are still sub judice and I think that in 
many of these cases much difficulty would be experienced in demonstrating an 
enlarged thymus gland either by percussion or by the X-ray—which brings up 
the questions, “What is the pathology of an enlarged thymus gland,” and “ What 
X-ray shadow does the thymus of a normal individual show?” Also, “How 
large is the so-called normal thymus at autopsy?” 
The subject of infantilism has been intimately associated with disturbances 
in various other ductless gland groups, so much so that it might be well to 
classify these cases under the main gland involved rather than to call them all 
infantilism. The thymus, as has been just suggested, has sometimes been 
regarded as being at fault. For this reason we shall consider here the subject 
of status thymo-lymphaticus once more, and pay more attention to the article 
of Haven Emerson’s, as mentioned in the addendum to the chapter on status 
lymphaticus. Emerson examined the autopsy records of 1000 cases of alco- 
holics who died in the wards of Bellevue Hospital, City of New York; of these 
780 were without any stigmata or physical characteristics which would mark 
them as abnormal, and the remainder showed signs of the so-called status 
lymphaticus. 508 
VEGETATIVE DISTURBANCES 
Emerson mentions that there was enlargement of the thymus gland out of 
proportion to the age in active cases. The question again is, “What is the 
normal size of the thymus gland?” and “Why should not the thymus gland as a 
lymphatic organ enlarge somewhat in these cases?” But that the thymus 
exercises any influence at all in the sudden death of certain of these patients, 
and on their susceptibility to infection is very doubtful. The alcohol these 
individuals may have imbibed may itself be a factor in the susceptibility, or 
again the alcohol may have been imbibed because of a defective constitution. 
The autopsy material in Emerson's cases should really have been controlled 
by an equal number of autopsies from the non-alcoholic wards of the hospital. 
In a way, nearly all autopsies in this country represent work on the so-called 
lower strata of society, at least such as have found their way as charity patients 
into public institutions, so that it is hard to say just what the age-size and age- 
weight of the organs of the average American is. (See addenda to chapters on 
the thymus gland and on status lymphaticus.) 
Emerson, in his final paragraph lumps lymphatismus, hypoplastic con- 
stitution, constitutional inferiority, status thymico-lymphaticus, or status 
lymphaticus, as apparently synonymous with the particular physical habit 
he dealt with. He has this to say, however, for the so-called constitutional 
inferior, “It should by no means be understood from this that all cases of 
status lymphaticus are undesirable socially, as they may be physically less 
capable in the struggle for existence than their fellows, for it is in the experience 
of all who observe these cases that there are among them leaders in scientific 
and artistic professions, and men of the highest standards of character.” 
The disease picture in women is described by Emerson thus, “For the 
identification of status lymphaticus among women we rely on the peculiar 
character of the skin of the body and extremities, the scantiness of the axillary 
hair pad, the scantiness of pubic and perineal hair, hypoplasia of the genital 
apparatus, and particularly slender thorax and extremities. Some women of 
decided status conformity have a marked growth of hair on the face and upper 
lip. As has been pointed out by Paltauf, Bartels and others, the status cases 
among women are in a high percentage of cases subject to the dangers of preg- 
nancy and the puerperium.” 
Perhaps some of the cases Emerson saw were cases of infantilism, perhaps 
also there was unnoticed ductless glandular disorders. The row of hyper- 
trophied follicles at the base of the tongue as described by PUbram as especially 
frequent in status cases (at autopsy) was not looked for especially—it seems, 
however, that the pharyngeal tonsillar tissue was enlarged. 
It probably is true that these individuals are less able as a rule to endure 
the stress and strain of life than are normal individuals, and they probably do 
constitute one type at least of so-called “constitutional inferior.” The limits 
of inferiority should be accurately defined, as well as the constitutional factors 
that make up “constitutional inferiority.” The conception of infantilism as 
a factor in constitutional inferiority brings us dangerously near to Freud and 
to the so-called inferiority of organs as promulgated by Adler. The question 
of this attitude of society to the constitutional inferior is a tremendous problem, ADDENDUM 
509 
one not to be answered glibly or dealt with in a facetious manner. What will 
society do to make the constitutional inferior a constituent part of itself, 
physically, mentally, morally, and socially? What will it do towards making 
him realize his responsibility and his niche in life, and his duties as a self- 
respecting citizen irrespective of his mere casting of a ballot? Probably if he 
is to be educated at all, his education should be social from the very beginning. 
Advanced ideas of social justice presented, however, in an extremely elementary, 
but accurate manner, should form the keynote of the early school curriculum; 
and as sociology is the acme of the hierarchy of the sciences, so elementary 
sociology, without bias or propaganda, should be introduced into the school 
system as early as the child can grasp social ideas. Any child capable of grasp- 
ing ideas at all must be capable of attaining to some ideas of social life and 
relationships; and proper, true, and accurate ideas of this nature should be 
instilled in him from the beginning. This, proper surroundings, and occupation 
may help to make a potential moron or constitutional inferior more useful to 
society in his later years. The problem is enormous and interests not only the 
physician and the psychiatrist, but the educator, the sociologist, the eugenist, 
and society at large. These remarks are not offered as a solution of the 
problem, but as a suggestion towards amelioration. 
Says Shuttleworth, “Take the ordinary feeble-minded child or youth away 
from the bad environment into which he so readily drifts, and place him in 
healthy and proper surroundings with good discipline; in a short time he will 
be quite a different creature,” and he quotes Miss Dendy as follows: “I am, 
however, as you say, sure that in the majority of cases children who have been 
supposed to be moral defectives do not merit that title at all, and do very well 
as soon as they are removed from the surroundings which have prompted 
their evil doings,” and she adds: “Many children have been sent to us at 
Sandbridge as incurably wicked, but we have had to discharge only one youth. 
He was more lunatic than feeble-minded, or rather, I should say, lunacy 
supervened on weakness of mind. Occasionally we have to isolate a child for a 
time, so that it may not contaminate the other children; but, luckily, bad 
habits are as soon forgotten as good ones. ” The work of Ilealy among juvenile 
offenders is well known. Shuttleworth does, however, show that in some cases 
nothing much can be done by quoting Barr, of Elwyn, Pa., to the following 
effect, “Many of the children are absolute criminals. Some are the victims 
of circumstances, but the absolutely bad children we cannot do anything with. 
We have fifty to seventy-five of them. I think our Government should take 
up the question of these children. I should have these form a national 
colony on the bad lands of the West, to be taken care of under military 
discipline. ” 
The term “intestinal infantilism” is sometimes used. It was described 
by Herter and is characterized by arrest in development of the body, the mainten- 
ance of mental powers and fair development of the brain, marked abdominal 
distention, moderate anemia, rapid onset of fatigue, and disturbance of intes- 
tinal function. This is associated with a failure of retention of calcium and 
magnesium salts over a prolonged period of time. Herter believes that the 510 
VEGETATIVE DISTURBANCES 
bacteriology of the stools in this condition is characteristic—a preponderance 
of the B. bifidus, with great diminution or entire absence of the B. coli. Holt 
considers the condition under chronic intestinal indigestion. 
Under the term renal infantilism there has been described a condition of 
stunted growth with lack of deposition of lime salts in the bone trabeculae, 
and interstitial nephritis. Cases have* been reported recently among others by 
Paterson, Fletcher, and Barber. Genu valgum is a common deformity in this 
condition. 
Gibson has described a condition which he calls muscular infantilism, view- 
ing it especially from the standpoint of metabolism. The patient could perform 
no unusual exertion, although symptoms of fatigue were not present. The 
patient’s bones were small, and he was very obese. Several of the patient’s 
family, including his mother and his grandmother, had the same disease. 
Creatin was present in the urine. The condition could not be ascribed to 
disease of any ductless glands. The case is interesting in that it shows that 
careful study would tend to eliminate as endocrine diseases some of the condi- 
tions now regarded as such. 
Cushing (H.). Concerning the symptomatic differentiation between disorders of the two 
lobes.of the pituitary body: with notes on a syndrome accredited to hyperplasia of the anterior 
and secretory stasis or insufficiency of the posterior lobe. Am. J. M. Sc., March, 1913, pp. 313-328. 
Tumpeer (I. H.). Mongolian idiocy in a Chinese boy. J. Am. M. Ass., Vol. LXXIX, No. 1, 
July 1, 1922, pp. 14-16. 
McKee and Wells. Practical Pediatrics. Philadelphia. P. Blakiston. 
Shuttleworth (I. E.) and Potts (W. A.). See foot-note, p. 504, this volume. 
Borchart. Ueber Abgrenzung und Entstehungsurachen des; Infantilismus. Deutches Archiv 
fur klin. Med., Vol. CXXXVIII, 3 and 4, 1922, pp. 129-143. 
Timme (PE.). See foot-note, page 50. 
Emerson (//.). See addendum to chapter on status lymphaticus. 
Pribram (H.). See addendum to chapter on thymus. 
Goldstein (H). Sporadic cretinism (infantile myxedema). J. M. Soc. New Jersey, Vol. XVIII, 
June, 1921, p. 184, et seq. Also, sporadic cretinism, with report of four cases. American Physician, 
1921. Oct., 1921, pp. 767-772; Nov., 1921, pp. 883, 892, 894, 896. 
Sternberg. Ueber echten Zwergwuchs. Zeigler’s Beitr. z. path. Anat. U. Z. all Path., Bd. 
LXVII, 1920, pp. 279-308. Cited in Centralblatt f. allg. Path, and path-Anat., Vol. XXXII, No. 6, 
Nov. 15, 1921, pp. 161-162. 
Gigon (A.). Ueber Zwergwuchs und Riesenwuchs mit einem Beitragzum Studium verwandten 
Entwich elungsstorungen in Organismus. Schweizer Archiv fur Neurologie and Psychiatrrie, 
Vol. XI, 1922, pp. 113-129. 
Maas (0.). Beitrag zur Kenntnis des Zwergwuchses. Ztschr. f. d. ges. Neurol, u. Psychiat., 
Berlin, 1920, Vol. CVII, pp. 196-231. 
Jansen (M.). Feebleness of growth and congenital dwarfism, with special reference to dyastosis 
cleido-cranialis. London, H. Fronde, Hodder & Stoughton, 1921. 
Jansen {M.). Achondroplasia, its nature and cause, etc. Leiden, Brill, 1912. 
Herter (C. A.). Infantilism from chronic intestinal infection, etc. Trans., Assoc. Am. Phys., 
Vol. XXIII, 1908, pp. 260-325. 
Holt (L. E.) and Howland (/.). The diseases of infancy and children. 7th edition, New York 
and London, Appleton, 1916. 
Peterson (D. H.). Three cases of renal dwarfism associated with curious bony changes. Proc. 
of the Royal Soc. of Med., Vol. XIII, I, 1919-1920. Section on Dis. in Children, pp. 107-118. 
Fletcher (H. M.). Case of renal infantilism. Ibid., pp. 118-121. 
Barber (H.). Renal dwarfism. Quarterly Journal of Medicine, Vol. XIV, 1920-1921, pp. 204- 
214. CHAPTER XIII 
THE DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
AND THEIR RELATION TO DIABETES MELLITUS 
A description of the pathology of the inner secretion of the pancreas 
offers beforehand many greater difficulties than that of other ductless glands, 
especially if the clinical manifestations are chiefly considered. The pancreas 
is not, like the other ductless glands, exclusively a gland with internal secre- 
tion. It belongs to the most important glands of external secretion; and 
anatomically shows chiefly the structure of one of these. Actually the physi- 
ology and pathology of the external secretion of the pancreas was for a long 
time the subject of investigation, before clinical observations and then the 
experiments on the total extirpation of the pancreas led us to regard it as 
possible that the pancreas might have an internal as well as an external 
secretion. 
Historical Development.-—Already Bouchardat had observed sclerotic 
alterations of the pancreas in some cases of diabetes mellitus, and on the 
ground of these observations had expressed the opinion that the cause of human 
diabetes depended on a disease of the pancreas. A secure experimental founda- 
tion for this view was first created by the celebrated experiments of v. Mering 
and Minkowski. These investigations showed that total extirpation of the 
pancreas in dogs, in addition to the disturbances of absorption due to the ab- 
sence of the pancreatic juice, leads regularly to an excretion of sugar, indeed 
even to a severe, fatally ending, diabetes. 
First through this discovery was the interest of pathological anatomists 
turned in general toward the pancreas. In the course of the next decade there 
followed numerous statements as to various alterations of the pancreas in 
diabetes mellitus, sclerotic changes, inflammatory processes, etc.; yet in spite 
of the weight of the experimental finding, we could not overlook the fact that 
in many cases of severe diabetes mellitus the pancreas showed no demon- 
strable pathologico-anatomical alteration, and that, on the other hand, in 
many cases of high-grade destruction of the pancreatic tissue, diabetes was 
entirely absent. The question assumed another aspect when attempts were 
made to bring the islands formerly described by Langerhans into relation 
with the inner secretion of the pancreas. While the glandular acini furnish 
the external secretion, the islands of Langerhans might constitute an em- 
bryologically independent tissue element distributed throughout the entire 
pancreas, which might give off directly into the blood path a hormone im- 
portant for carbohydrate metabolism. Especially important for this view 
was the observation of Ssobolew and of Schulze, that after ligation of the excre- 
tory duct of the pancreas, the acinic tissue gradually undergoes atrophy while 
the islands remain intact. Also the observations of the pathological anatomists 
511 512 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
show that the islands are much more refractory toward the action of various 
noxious agents than is the acinic tissue. This furnishes the explanation of the 
numerous cases of severe disease of the pancreas without glycosuria; on the 
other hand statements were constantly increasing, that in diabetes mellitus 
chiefly the islands were diseased, a tendency that was first inaugurated by Opie 
and quite particularly maintained by Weichselbaum. Up to the present the 
insular theory has not, however, won general recognition, as it is found on the 
pathological anatomical side that cases constantly occur in which in spite of an 
existing diabetes the insular tissue remains intact and even in certain cases is 
especially well developed. This finding has led many authors to the view that 
both tissue elements of the pancreas, acinic elements and insular apparatus, 
produce the hormone. In recent years the problem of the internal secretion 
of the pancreas has experienced further complication ;-the view has been ex- 
pressed that the significant influence that the pancreas exercises over digestion 
in the intestine depends not alone on the enzymatic properties of the intestinal 
juice but in part on the internal-secretory activity of the pancreas (Lombroso). 
Both tissue elements of the pancreas, according to this, are involved in both 
the external as well as the internal-secretory activities. This teaching has 
obviously caused much confusion.1 
Another aspect of the problem is the question how the pancreas takes part 
in the carbohydrate metabolism. Claude Bernard assumed that in diabetes 
there was increased sugar production. Minowski first expressed the opinion 
that on the absence of the pancreatic hormone the consumption of the sugar 
molecule in the body suffers harm. Naunyn inclines more to the view of a 
disturbance in glycogenesis (dyszoamylie). Luthje first furnished the certain 
demonstration that in addition to the carbohydrates also the protein is to be 
considered as a sugar builder. The increase in the sugar production has been 
more discussed again since the investigation of O. Lowi; Eppinger, Falta, and 
Rudinger assume in experimental pancreatic diabetes both reduction in the 
sugar consumption (removal of the specific internal secretion) as well as increase 
in the mobilization of sugar (consecutive increase of function of the chromaffin 
tissue), a view that I promulgated for human diabetes. On the ground of the 
investigations of Porges and Salomon, v. Noorden brought the increased sugar 
production again into the foreground, while lately Starling and Knouthon have 
advocated the exclusive disturbance of sugar combustion. 
As to what finally is the significance of the pancreas for the pathogenesis 
of human diabetes views diverge greatly. The discovery of sugar puncture 
by Claude Bernard led to the viewing of each case of diabetes as neurogenic. 
After the discovery of experimental pancreatic diabetes, attention was drawn 
on the contrary to the pancreas. Of course between the experimental pan- 
creatic diabetes and the genuine human diabetes there exist considerable dif- 
ferences. The intensity of the glycosuria is much higher in the latter. In 
association with Grote and Staehelin, I have pointed to the enormous increase 
in the decomposition of protein and the respiratory exchange of gases in 
experimental pancreatic diabetes. In genuine human diabetes on the other 
1 Since the isolation of insulin it may be regarded as definitely settled that the internal 
secretion is the product of the insular tissue.—Editor. ANATOMY AND EMBRYOLOGY 
513 
hand the demand for protein as well as the demand for calories is not increased. 
The supposition of Benedict and Joslin that the heat production in human 
diabetes is increased I cannot subscribe to, the reason for which I shall detail 
later. In consideration of these essential differences I have taken position 
as regards the pathogenesis of human diabetes in a direction contrary to the 
pancreatocentric; as also v. Noorden, on the ground of his clinical experience 
and the investigations carried out in his clinic, has upheld the view that in 
addition to the pancreas, a high value must be ascribed to the chromaffin 
tissue or the nervous system. 
In addition to the pancreas and the chromaffin tissue, the thyroid gland 
is certainly of importance in the genesis of many diabetic glycosurias. 
The manner of procedure in the following dissertations must, in order to 
render possible a condensed exposition of the manifold and complex questions 
deviate in some points the scheme followed thus far. After some introduc- 
tory remarks as to the anatomy and embryology of the pancreas the results 
of the experimental investigation will be given more space than has been the 
case in the other chapters. Especially will I treat in detail the metabolic 
disturbances that occur in animals after total extirpation of the pancreas. 
Also experimental nervous diabetes, so far as it has not already been con- 
sidered in the chapter on the suprarenals, will be dwelt on. In the clinical 
part, I shall first describe the gross anatomical disturbances of the pancreas 
and also the accompanying alterations of metabolism. Then will follow 
a short exposition of the clinical manifestations of genuine diabetes as far as 
is necessary to emphasize the points of difference from the changes in metabol- 
ism in experimental pancreatic diabetes. The pathological anatomy of genuine 
diabetes mellitus will be treated more in detail, including a consideration 
of the alterations of the pancreas, as well as those of the central nervous system. 
Only then will I enter into the question as to what role the inner secretion of 
the pancreas, or the pathologico-anatomical alterations of the insular apparatus, 
plays in the pathogenesis of diabetes mellitus. 
Anatomy and Embryology.-—The pancreas is a long-drawn-out cylindrical 
organ, situated behind the stomach just in front of the pars lumbalis of the 
diaphragm. We distinguish from right to left, the broad head lodged in the 
loop of the duodenum, the neck, the body, and the tail. The head is inti- 
mately adherent to the loop of the duodenum, while the left end (processus 
uncinatus) is more movable. On its anterior surface, the pancreas is covered 
with peritoneum. The length of the organ is about 19-22 cm., the weight, 
according to Vierordt, varies between 85 gm. and 105 gm., according to Orth, 
between 90 gm. and 120 gm. The pancreas is extraordinarily well vascu- 
larized. It receives a large branch (arteria pancreatico-duodenalis supe- 
rior) from the ramus gastroduodenalis of the hepatic artery, several branches 
from the splenic artery, and one branch (arteria pancreatico-duodenalis 
inferior) from the superior mesenteric artery. The pancreas is supplied 
by an abundant nerve plexus of branches from the vagus and from the sym- 
pathetic fibers that emanate from the sympathetic trunks or from the great 
sympathetic ganglia. 514 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
The glandular acini of the pancreas form large lobes bound together by 
loose connective tissue that are in turn made up of smaller lobules. The 
excretory ducts of the acini unite in the pancreatic duct or duct of Wirsung, 
which empties in common with the ductus choledochus into the papilla of 
Vater in the duodenum. A large excretory ductus pancreaticus accessorius, 
emanating from the head, unites with the duct of Wirsung. From the acces- 
sory duct there usually branches a duct uniting with the duodenum (ductus 
Santorini). Opie found this duct obliterated or markedly narrowed in numer- 
ous cases. Only in such cases was the secretion of the pancreas fully cut 
off from the intestine by closure of the principal duct. The closure of the 
accessory duct may lead to isolated sclerosis of the head of the pancreas. 
Further, we should consider that not infrequently accessory lobules of the 
pancreas are found in the duodenum. 
In the lobules of the glandular parenchyma are found imbedded between 
the individual acini cell groups that consist in polygonal cells with large round 
nuclei. These cells stain less distinctly than the cells of the acini. The pro- 
toplasm is lighter, it does not show the distinct zymogen-granules as does the 
glandular tissue. These cell groups, which occur in very different number 
and 'size, are named after their discoverer, the island of Longer bans. They 
are found in all kinds of animals (.Diamare), and in some they are very large 
and even visible macroscopically. They show an especial abundance of 
blood-vessels. The capillaries form a dense network interlarding the cell 
groups similar to what we see in the renal glomerules (Kuhne and Lea). The 
cell accumulations have no connection with the excretory ducts of the gland. 
They are never filled after the injection of the excretory ducts (v. Ebner). 
Many histologists state that the islands of Langerhans are surrounded by a 
capsule (Renaut, Opie, Flint, and others). Others combat the existence of a 
capsule (Diamore, Hansemann, and others). At any rate it should be men- 
tioned that in many species of animals (for example in the cartilaginous fishes) 
the capsules are found constantly {Rennie). 
Very different views have been expressed as to the nature of these pic- 
tures. Langerhans regarded them as nervous structures, later authors as 
lymph follicles. Finally the view was promulgated that they constitute a 
gland with internal secretion distributed throughout the entire pancreas, 
that gives off an internal secretion to the interlarding capillary network. 
According to the views of these authors the islands of Langerhans are com- 
pletely independent. On the other hand authors state that the insular tissue 
may shade off into the glandular tissue and vice versa. Laguesse first de- 
scribed intermediary forms between the gland cells and the island cells, and 
assumed that on certain functional demands there was a transition from the 
one kind of tissue into the other (balancement). Karakascheff is of the opinion 
that the islands constitute only a sort of reserve material, and that under certain 
conditions,—for example, in the giving-out of gland tissue,—there enters 
into play a regeneration of the parenchyma from the islands. On the other 
hand, Gutmann would see a changing of the parenchyma into insular tissue. 
Also Swale Vincent and Thompson suppose transitions between the gland DIABETES AFTER EXTIRPATION OF THE PANCREAS 
515 
cells and the island cells. The recent embryological studies and investiga- 
tions as to the regeneration processes in the pancreas do not seem to confirm 
the opinion of these authors. 
The pancreas is of entodermal origin. There are present three rudiments, 
a dorsal, made up of the epithelium of the primitive duodenum, and two ven- 
tral which proceed from the groove-shaped rudiment of the ductus choledochus. 
Laguesse first showed that the islands as well as the glandular parenchyma is 
of epithelial origin, and also showed that the islands separate out from the 
primitive cell columns at the same time as the glandular tissue. The newer 
investigations on human fetuses (Pearce, Weichselbaum and Kyrle, Mironescu) 
leave room for no doubt that the island tissue already in earliest fetal life 
develops from the epithelial cell columns just as do the acini. 
The youngest fetus in which the islands of Langerhans were observed was 
54 mm. long (Pearce). Weichselbaum and Kyrle did not find them present 
as yet in a fetus 50 mm. long. The islands are first found in the distal part 
of the pancreas. Also in adults they are more frequent in the tail of the pan- 
creas (Opie). v. Hansemann assumed that the islands were of mesenchymal 
origin, but Weichselbaum and Kyrle found them also later still in asso- 
ciation with the excretory duct of the pancreas, and hence regarded them as 
entodermal. Moreover, the observations as to the regenerative processes 
in the pancreas after abundant destruction of glandular tissue show that the 
islands always develop from the excretory duct (Ssobolew, Kyrle)] especially 
beautifully do the investigations of Kyrle show that on implantation of pieces 
of pancreas into the spleen, in the regenerative processes that soon make their 
appearance, the insular acinic tissues develop independently out of the epithe- 
lium of the excretory duct. 
I. EXPERIMENTAL PART 
A. Diabetes after Extirpation of the Pancreas 
We shall first describe carbohydrate metabolism after extirpation of the pan- 
creas. The complete extirpation of the pancreas causes in all kinds of ani- 
mals disturbances in the metabolism of sugar. It is true that in certain 
species of birds this does not go as far as glycosuria, but there results a hyper- 
glycemia. The significance of the pancreas for the metabolism of sugars is 
therefore universal. The extirpation of the organ in dogs has been studied 
the most exactly; I shall therefore make especially the observations in the 
experiments on dogs the foundation of the following dissertation. The com- 
plete removal of the pancreas in dogs always causes a diabetes. The nega- 
tive results that were obtained by certain investigators, especially those 
who preceded Mering and Minkowski, and referred to the facts that total 
extirpation of the pancreas is very difficult, and that sometimes slight remnants 
suffice to prevent the outbreak of the disease. Luthje has contributed still 
later reports in which in spite of complete extirpation, the glycosuria remained 
absent. There occurred, however, as Luthje himself stated, hyperglycemia 
after the operation, and later histological examinations of the duodenum 
showed that remnants of pancreatic tissue were present. In more than forty 516 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
experiments that we ourselves have instituted in the course of the last year, 
like Minkowski we never missed the occurrence of a severe diabetes. When 
about a third of the organ is left behind, diabetes usually remains absent, but 
can, however, develop later if the piece left behind undergoes inflammatory 
processes. If a still smaller piece of the pancreas is left behind, there occurs 
a light diabetes, that is, excretion of sugar occurs only when the carbohydrate 
metabolism is overstrained by the administration of a diet rich in amylaceous 
material (Sandmeyer’s diabetes). 
The sugar that is excreted in the urine after the total extirpation of the 
pancreas is grape-sugar. The sugar elimination usually starts only a few 
hours after the operation and in about forty-eight hours the diabetes is at 
its height. Before the death of the animal the excretion of sugar usually 
gradually sinks. The duration of life after the operation is at the most four- 
teen days. Exact information as to the intensity of the excretion of sugar 
is furnished by the excellent work of Minkowski. This author showed that 
administration of sugar raises the existing glycosuria by the amount admin- 
istered, and further that at the height of the disturbance in metabolism the 
amount of excreted sugar bears a definite relation to the amount of excreted 
nitrogen. This quotient, D:N, remains 2.8 to 3 [:i], just as well when the 
dog is fasting as when it is fed with meat or other protein body. Minkow- 
ski hence drew the conclusion that in this quotient is expressed the extent 
to which the animal organism is enabled to form sugar out of protein. The 
animals become poor in glycogen extraordinarily rapidly. After forty-eight 
hours the liver is almost free of glycogen and later becomes highly fatty. 
The glycogen is retained in the muscles for a long time, however. Even 
the leucocytes are strikingly rich in glycogen. Administration of grape- 
sugar cannot halt the disappearance of glycogen. The power of forming 
glycogen does not, however, disappear entirely, for on the administration 
of levulose a part of the same may be deposited as glycogen, in which case, as 
Eppinger and I observed, also the fattening of the liver is halted. A part 
of the levulose is excreted as levulose, another part as glucose. The ques- 
tion as to whether the increase in elimination of sugar conditioned by the 
administration of protein, depends on the direct formation of sugar from 
protein was discussed very energetically, especially through the numerous 
objections of Pjiuger, until Luthje ascertained that after abundant adminis- 
tration of casein the total amount of the excreted sugar far exceeds the pos- 
sible amount of stored glycogen. The administration of fat does not increase 
the excretion of sugar, yet it is to be considered that as a result of the absence 
of pancreatic juice, fat is very poorly absorbed. On the simultaneous admin- 
istration of pancreatin we have seen, however, in individual experiments 
appreciable, although only transitory increase in the D: N quotient (to 7). 
In addition to the glycosuria there exists polyuria and ketonuria. The 
occurrence of the latter is combated by many authors, although the experi- 
ments of Embden and Lattes let it be expected that in the pancreas-diabetic 
dog there exists a predisposition to ketonuria. If the blood of normal cattle 
was allowed to flow through the liver of a pancreasless dog, there was found DIABETES AFTER EXTIRPATION OF THE PANCREAS 
517 
as great an amount of diacetic acid as the liver of normal animals lets be 
produced only on the addition of the strongest acetone formers. Allard 
saw in addition to this, in pancreasless dogs, the occurrence of a not inap- 
preciable amount of diacetic acid and betaoxybutyric acid, especially when 
pieces of pancreas were placed under the skin of the abdomen and only later 
extirpated; when therefore the development of the diabetic disturbance of 
metabolism was retarded. In such animals ketonuria then develops rather 
rapidly and eventually leads to coma: • • 
Also the protein metabolism in pancreatic diabetes shows definite dis- 
turbances. Already Minkowski had shown that after removal of the pan- 
creas there occurs an increase of the protein decomposition. In collaboration 
with Grote and Staehelin, I showed that this increase is constant and its inten- 
sity conformable to law. The hunger protein metabolism after complete extir- 
pation attains to three or three and a half times the hunger protein metabolism 
before the extirpation. Mohr found less values; however, Eppinger, Rudinger, 
and I, in the later investigations confirmed our former statements. 
Also the excretion of salt is appreciably increased, according to the investi- 
gations of Whitney and myself. 
Finally the respiratory metabolism is essentially increased, according 
to the investigations of Grote, Staehelin and me, and of Mohr. Our investiga- 
tions were carried out in Jaquet’s respiratory apparatus. Already the appreci- 
able increase of the protein destruction would lead one to expect an increase 
of the caloric production, on account of the specific dynamic energy of protein. 
According to our investigations, however, the increase of the metabolism 
(about 42% in the experiments not complicated with fever) was higher than 
could be calculated from the destruction of protein. As increased metabolism 
might be anticipated also from the rapid losses of body weight, such as were 
ascertained in the later experiments I carried out with Eppinger and Rudinger. 
For the reason that bodies very rich in oxygen (sugar and ketone bodies) 
are excreted, the respiratory quotient is very low. In our experiments it 
averaged about 0.73. 
In the pancreasless dog the excitability of certain sympathetic nerves is 
increased. O. Lowi showed that the instillation of atropine into the eye of 
a pancreasless dog would produce mydriasis, a stimulus that had been below 
the threshold thus becoming operative. With this agrees the fact that sub- 
cutaneous or subperitoneal injection of adrenalin, increases, according to 
Eppinger, Rudinger, and my experiments, the D:N quotient. The amounts 
of sugar that raised the quotient to more than 2.8 were greater than those 
which under like conditions could be obtained by the injection of adrenalin 
into normal fasting dogs. Therefore the glycosuric action of adrenalin in 
pancreasless dogs is increased. As these experiments with adrenalin were 
undertaken at the height of the metabolic disturbance, therefore at a time 
when the glycogen constituent was already reduced to a minimal, it may be 
supposed that this increase is brought about, not only through the increased 
consumption of glycogen, or through a washing-out of circulating sugar, but 
also through an increased formation of sugar. 518 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
Then, too, other ductless glands influence the intensity of the pancreatic 
diabetes. The experiments on simultaneous extirpation of the thyroid gland 
or the parathyroid glands [together with the pancreas] show this. It is known 
that after thyroid extirpation the hunger protein metabolism is lowered. 
When the pancreas is simultaneously extirpated the hunger protein metabolism 
is about three to three and one-half times that of a thyroidectomized dog 
the same size, is therefore absolutely lower than after extirpation of the pan- 
creas alone. The excretion of sugar is, however, the same, so that the quo- 
tient of dextrose to nitrogen (I): N) is higher. In experiments in which, 
together with the pancreas, a large part of the parathyroid glands was extir- 
pated, we found further that the intensity of the diabetes was essentially 
increased. We observed quotients of 3.6, although the hunger protein de- 
struction (in relation to the body weight) was greater than was to have been 
expected in dogs of the same size after extirpation of the pancreas alone. 
Further, worthy of mention is the statement of Ziilzer that in an experiment 
on a dog in which the pancreas was extirpated and simultaneously the renal 
vein was ligated, the intensity of the excretion of sugar was very slight and 
transitory. 
We shall now enter further into the question as to how we may explain 
the occurrence of glycosuria after extirpation of the pancreas, or the regula- 
tory influence of the pancreas on sugar metabolism under normal relations. 
It is generally recognized that in the present state of our knowledge, the 
assumption of an internal secretion of the pancreas is not to be avoided. Opin- 
ions of former authors, that the irritation or injuries to the sympathetic nerve 
plexuses in the course of the severe operations determined the glycosuria, 
are contradicted by the transplantation experiments of Minkowski and Iledon. 
If the part of the pancreas lying in the mesentery of the duodenum is trans- 
planted with its vascular peduncle, under the skin, and if later the rest of the 
pancreas be removed, diabetes does not occur. A minimal [operative] attack 
then suffices to remove the transplanted piece and to call forth a diabetes 
in its fullest intensity. That the presence of pancreatic juice in the intestine 
is not necessary for the normal course of the carbohydrate metabolism 
is readily seen in the fact that administration of pancreatin essentially improves 
the absorptive disturbances, but rather increases the intensity of the excretion 
of sugar. 
The experiments detailed lead us to assume, as already mentioned, an 
inner secretion of the pancreas. We have not as yet succeeded, however, in 
isolating the internal secretion and defining it chemically.1 We are not even 
certain as to the path of the giving off of the same. Biedl showed in his inter- 
esting experiments on dogs that after leading off the lymph of the thoracic 
duct to the exterior, glycosuria can occur. Biedl concluded from that that 
the inner secretion of the pancreas is carried off by the lymph. Later Biedl 
and Offer stated that adrenalin glycosuria can be prevented by the simul- 
taneous injection of duct lymph. If the internal secretion of the pancreas 
were carried off by the lymph we would expect that on the administration of 
the lymph of normal dogs to pancreasless dogs the intensity of the metabolic 
1 It has been isolated—the insulin of Canadian investigators.—-Editor. DIABETES AFTER EXTIRPATION OF THE PANCREAS 
519 
disturbances would be essentially reduced, or that the excretion of sugar 
would completely disappear, at least for some time. In numerous investiga- 
tions as to this point we could not find these things. In large dogs that were 
fed abundantly with carbohydrates, the lymph from the thoracic duct was 
collected for some hours, and this lymph administered to pancreasless dogs 
either subcutaneously or by the drop-by-drop method into an exposed vein, 
without producing an essential influence on the quotient of dextrose to nitro- 
gen (D:N), although the experiments were conducted for hours only. When 
Biedl more recently states that he succeeded in similar experiments in depress- 
ing the D:N ratio from 1.8% to i.5~i.2% it seems to me that the 
the difference is much too small to decide as to this important question. Re- 
cently an attempt has been made by Tuckett to explain the glycosuria occur- 
ring in dogs with a lymph fistula, by the operative injury to the sympathetic 
nerve in the neck and also by the narcosis. This explanation, it seems to me, 
in consideration of the high percentage of sugar found by Biedl, does not appear 
satisfactory. If the internal secretion of pancreas is not carried off by the 
lymphatics—I leave this question open—there remains its transference by the 
pancreatic veins. 
We have for this reason collected the blood of the pancreatic veins of large 
dogs and injected subcutaneously the serum of pancreasless dogs. Also 
in these experiments were the results negative, v. Ehrmann has carried out the 
same sort of experiments with similar negative results. Not much can be 
concluded from these experiments. The pancreas is extraordinarily well 
vascularized; it may be that the amount of blood collected in a half hour 
does not contain enough internal secretion to produce distinct evidence. It 
should also be considered that under normal relations the blood of the pan- 
creatic vein is carried directly to the liver, whereas in our experiments it entered 
directly into the greater circulation. Finally we should consider the possibility 
that the internal secretion is bound in the blood corpuscles. The excellent 
vascularization of the pancreas may also furnish the foundation for the fact 
that we have not as yet succeeded in obtaining an extract of the pancreas that 
is active in influencing metabolism.1 The relations here seem to be similar to 
those affecting the likewise well-vascularized parathyroid glands. The pan- 
creas is also in respect to its internal secretion no storage gland as, for example, 
the thyroid is. Probably the internal secretion is carried off as it is formed. 
Zulzer, acting on similar considerations, has ligated veins of the pancreas, 
thus producing a stasis, and claims to have seen a favorable influence of the 
extract obtained from such a gland on the glycosuria of pancreasless dogs and 
on the ketonuria of human diabetes. It is true that the statements of Zulzer 
are not very convincing. The results in pancreasless dogs are very slight, and 
on the injection of the extracts into human beings shiverings are produced that 
influence the metabolism in a non-negligible way. 
The question as to which tissue element of the pancreas is to be referred 
the production of the hypothetical internal secretion has, since the discovery 
of the islands, been much discussed, especially with respect to human diabetes. 
I regard it as suitable to consider quite separately the results obtained in 
sentence no longer holds true.—Editor. 520 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
animal experimentation, as much speaks for the assumption that human dia- 
betes is not of a single nature and as the disturbances of absorption, observed 
after shutting-off of the pancreatic juice in the animals experimented on seem 
to deviate in many respects from those in man. Soon after the discovery 
of Langerhans’ islands the view was expressed that these pictures, which in 
their histological structure show a certain similarity to certain ductless glands, 
especially the suprarenal cortex and the parathyroids, produce the internal 
secretion of the pancreas, while the glandular parenchyma is concerned exclu- 
sively with the production of the external secretion. The view that was later 
upheld by several authors, namely, that the Langerhans’ islands could pass over 
into glandular parenchyma, or reversely; I have mentioned this in speaking of 
the anatomy and embryology of the pancreas; in which exposition, in considera- 
tion of all the data as to the histological and embryological observations, I have 
accepted the views of those authors who ascribe to the insular apparatus a 
morphological and embryological independence. Of especial importance for 
the insular theory, were, more recently, experiments that make a junctional 
independence in high degree possible. 
Already Katz and Winkler had observed that after ligation of a larger excretory duct 
the islands last for a while, while the glandular parenchyma in the part of the pancreas 
affected goes to pieces. The general attention was first, however, attracted to this 
subject by the mutually independent observations of v. Ssobolew and Schulze. Schulze 
ligated in guinea-pigs a large lobe of the pancreas and found that even after eighty days the 
islands were retained, while in the sclerotic tissue were found only traces of the acini. Fur- 
thermore, it should be mentioned that according to Schulze's investigation the islands 
undergo no alteration during fasting, while the pancreatic acini show alterations conditioned 
by the reduced function. Schulze concluded that the islands are entirely independent 
structures. Ssobolew experimented in rabbits, cats, and dogs. The results in rabbits were 
the clearest. The pancreas in rabbits, which lies flattened-out between the two layers of the 
mesentery possesses one excretory duct only. When this is ligated the pancreas shrinks 
markedly, owing to atrophy of the glandular parenchyma. It is true that Ssobolew found, 
between the thirtieth and the one hundred and twentieth day after the operation, slight 
sclerotic alterations of the islands in their clump of sclerotic tissue, but later the islands 
partially recovered; and they were retained even four hundred days after the operation. 
They also survived after analogous operations in dogs and cats. In dogs, Ssobolew found the 
atrophy of the glandular tissue less marked, as he supposes that it forms new excretory ducts. 
Tiberti found, after ligation of the excretory duct in rabbits, at first increased formation 
of zymogen-granules in the acini, that he regarded as hypersecretion, then hyposecretion, 
and finally complete cessation of granule formation. Later slight regeneration of the 
excretory duct made its appearance. In later investigations Tiberti found that the great 
part of the acini disappeared, and that pictures remain behind whose significance as remaining 
islands is not clear. In two rabbits, Tiberti found slight glycosuria five months after the 
operation. In dogs, according to Tiberti's investigations, the sclerosis of the pancreas is less 
distinct than in rabbits, since islands as well as acini are in part retained. 
Visentini ligated the excretory ducts of the pancreas in twenty-four dogs; he examined 
the pancreas two hundred and twelve days after the operation and found a gradually pro- 
gressing sclerosis. Even one hundred and twenty days after the operation individual 
gland-lobules were found; in two experiments after two hundred and sixty and two hundred 
and twelve days (respectively) the glandular tissue had entirely gone to pieces. In the 
dog that survived two hundred and twelve days there was found a slight glycosuria. 
Sauerbeck found after ligation of the excretory duct in rabbits gradually progressing 
sclerosis of the glandular parenchyma; the islands as in the investigations of Ssobolew showed DIABETES AFTER EXTIRPATION OF THE PANCREAS 
521 
transitory damages to their structure, owing to the sclerosing process. In this stage, Sauer- 
beck, in agreement with the older experiments of Hedon often observed glycosuria, sometimes 
considerable; in later stages the islands again showed their normal structure, and then no 
glycosuria existed. Lombroso found in forty-one pancreases of dogs that the ligation of the 
pancreatic duct did not lead unconditionally to sclerosis. Islands as well as acini could be 
in part retained. 
In ligation of the duct in rabbits, Lombroso and Sacerdote found that the islands were 
indeed retained, but that their number and size were diminished. 
Finally we should mention the investigations of Zuntz and Mayer. After ligation of 
the excretory duct of the pancreas, these authors found abundant retention of gland-acini 
in certain cases, showing more or less alterations of their structure. Very exceptionally 
indeed did the acini seem to have changed their structure. The islands of Langerhans 
likewise showed alterations of structure, “perhaps they seem smaller, but their number 
does not seem to have been diminished.” A portion of the island cells showed alterations 
even already after a few days; in every case the alterations of the islands developed much 
more slowly than those of the acini. 
Lombroso in his works and in a detailed review has subjected to criticism 
the experiments just referred to, and has concluded that the functional inde- 
pendence of the islands of Langerhans has not as yet been demonstrated. In 
this conclusion Lombroso's own views that to the external secretion of the 
pancreas must not be ascribed that freedom and independence of the internal 
secretion which we for a long time tended to ascribe to it, has had a great influ- 
ence. Before I discuss the question of the independence of the insular appara- 
tus, I must enter first into an account of the disturbances of absorption after 
extirpation of the pancreas or after ligation of its duct. 
Already Abelmann, whom we have to thank for the fundamental absorption experi- 
ments after extirpation of the pancreas, stated that it is true after total extirpation, the 
absorption of fat in the intestine almost completely ceases, although fat-splitting may be 
very good; that, however, the disturbance of absorption never reaches to this extreme 
grade when a part of the pancreas is left behind, even when its connection with the intes- 
tine is entirely broken up. Also after ligation of the excretory duct is the disturbance of 
absorption nevej intense. It has been attempted to explain this by the statement that in 
this case the pancreatic juice in is part absorbed, and reaches the intestine by way of the 
blood-vessels or that the dogs with pancreatic fistula lapped up the secretion that flowed 
out. (Sinn, Hess, Burckhardt, et al.) 
Besides this it is mentioned that in dogs there often occur accessory pancreases, and 
that in such cases therefore the complete cutting-off of the pancreatic juice from the intes- 
tine is very difficult. Sinn, and Hess found almost regularly in dogs a third excretory duct 
of the pancreas. According to these authors the ligation of all ducts is especially difficult 
intra vitam. When it really succeeds, there occurs within some weeks an almost complete 
necrosis of the pancreatic tissue. In these cases Hess, and Sinn, found no diabetes, in most 
cases, however, an appreciable temporary disturbance of protein and fat absorption. In 
some cases indeed the absorption was quite good. Lombroso in his numerous experiments 
has ascertained the following: The absorption of fat in dogs is rather good when the entire 
number of ducts are ligated, or when after a part of the pancreas has been transplanted 
and a fistula from this to the outside has been made, the other part of the pancreas has been 
extirpated. This also occurred, according to Lombroso, when the re-ingestion of the secretion 
was entirely prevented. 
In an experiment carried out in Minkowski's laboratory the disturbance of the absorp- 
tion of fat was indeed not inappreciable (up to 60%). When later the vascular 
nervous pedicle of the transplanted part of the pancreas was ligated and cut, a transitory 522 
DISEASES OE THE INSULAR APPARATUS OF THE PANCREAS 
glycosuria occurred, and the fistula secreted further. Only after extirpation of the remain- 
ing part of the pancreas did the diabetes and the disturbance in fat absorption reach its full 
height. In a second analogous experiment, glycosuria was present from the first, but the 
disturbance of absorption in this case was less (38.7%). Lombroso further showed 
that bile, saliva, and intestinal juice show no alterations in their enzymatic characteristic, 
and that therefore an excretion of absorbed pancreatic juice into the intestine was there- 
fore improbable. This was also confirmed by Zuntz and Mayer. Lombroso concluded 
from his experiments that the influence of the pancreas on the absorption of fat was also 
conditioned through an internal secretion. Fleckseder has instituted analogous experi- 
ments. He observed that the using up of fat and protein is somewhat diminished in the 
fistula animals, whether the secretion is let flow free from the fistula, or is let stagnate, 
whether it is re-ingested or not. Very interesting is an experiment of Fleckseder’s in which 
gradually, through increasing sclerosis of the piece of pancreas left behind, a diabetes devel- 
oped to full height, the secretion from the fistula stopped, but the absorption of fat was 
better than before. 
Lombroso in his review has, as before mentioned, doubted the significance 
of the ligation experiments for the functional independence of the pancreas. 
He considers that the disturbances of absorption that have just been mentioned 
point in the same direction, and concludes that islands as well as gland par- 
enchyma take part in the production of the internal secretion of the pancreas, 
and that this is of importance for the carbohydrate metabolism as well as for 
fat absorption. 
The amalgamation of both questions seem to be rather unfortunate. 
From the experiments just cited it seems that the two disturbances do not run 
a parallel course throughout. Thus we found, for instance, in one of Lombroso's 
experiments relatively good absorption in spite of existing glycosuria, and in 
an experiment of Fleckseder's right good absorption in spite of a fully developed 
diabetes. On the other hand we find in an experiment of Lombroso's a not 
inappreciable disturbance of absorption in spite of absence of a disturbance in 
carbohydrate metabolism. So much is therefore certain that, if an internal 
secretion of the pancreas actually essentially influences the absorption of fat, it is 
not identical with the pancreatic hormone regulating carbohydrate metabolism. 
As we shall see later, the same is true of the observations on human 
diabetes. 
In man the relations are on the whole much clearer than in the dog. Here 
we find cases with severe lethal diabetes and high-grade isolated disease of the 
insular apparatus; in spite of this, in these cases the characteristic, not-to- 
be-overlooked, fat stools are absent. On the other hand, when the pancreatic 
juice is completely cut off, fat stools occur, as we shall see later, which improve 
considerably on the administration of pancreatin. Characteristic of these 
pancreas stools in men is the deficiency of the splitting of neutral fat, whereas 
in the dog, according to the statements of all investigators the splitting of 
fats is not essentially disturbed even after the total extirpation of the pancreas. 
In reviewing the information at hand up to the present time, we find, 
according to my opinion that we can thus far say with certainty, only that the 
absorptive activity of the intestinal mucosa is somehow influenced by the pancreas 
even when the pancreas is entirely separated from the intestine, that, however, this 
influence is independent within wide limits of that of the carbohydrate metabolism DIABETES AFTER EXTIRPATION OF THE PANCREAS 
523 
through the pancreatic hormone. At all events, I do not regard it as proper that 
these not at all negligible relations should be used as a basis against the teaching 
of the functional independence of the glandular and the insular apparatus. For 
this independence speak the known transplantation experiments of Minkowski, 
Gley, Thiroloix, and Hedon. When we pass these in review from the standpoints 
above mentioned, we see that the production of pancreatic juice, therefore the 
function of the glandular parenchyma, is quite independent of the disturbance 
in carbohydrate metabolism. The glandular parenchyma of the transplanted 
piece may atrophy, the secretion from the fistula may stop flowing, and yet 
the diabetes remain absent. Only after extirpation of the sclerotic piece (with 
the retained islands) does the diabetes set in. On the other hand, there is 
known the experiments of Thiroloix in which diabetes set in after the trans- 
plantation, in which case therefore the islands probably suffered harm, while 
the secretion continued to flow from the fistula. 
I do not subscribe to the critical remarks of Lombroso directed against the 
remaining refractory of the insular apparatus after duct ligation. It seems to 
be intelligible that the chronic inflammatory processes that occur after ligation 
of the duct, may under certain circumstances damage also the insular apparatus 
and on account of this lead transitorily to glycosuria. There is no longer doubt 
as to the fact, now communicated from all sides, that also a long time after the 
ligation of the duct the entire glandular apparatus becomes sclerotic, the insular 
apparatus remains entirely or largely retained, and that on this account dis- 
turbances in carbohydrate metabolism remain absent. The experiments on 
pigeons that Lombroso quotes as support of his position are not convincing. 
In these experiments although the insular apparatus was apparently markedly 
damaged, the glycosuria remained absent. As Biedl has already pointed out, 
however, in many species of birds, the total extirpation of the pancreas does 
not lead to glycosuria, but only to hyperglycemia. The experiments on trans- 
plantation of the pancreas and the institution of a pancreatic fistula seem to me 
to be especially poorly adapted for the decision of this question. If the healing 
follows by primary intention the carbohydrate metabolism and also the insular 
apparatus do not alter. If, however, infection occurs and on account of this 
infection sclerosis of the pancreas sets in, naturally the insular apparatus can 
also be damaged, and often it would be very hard to estimate in such an altered 
pancreas the functional integrity of the tissue constituents still present. I 
have carried on some experiments that in spite of the unfavorable relations seem 
to me to point to the functional independence of the two apparati. 
Zuntz and Mayer found in their pretty experiments that the ligation of 
the excretory duct led in the dog first to a more or less well-expressed loss of 
body weight. Mostly the dogs rapidly regain their body weight and then 
live from then on like normal dogs. In other cases, however, the body weight 
falls still further, the emaciation terminating in death. Now Zuntz and Mayer 
found an almost complete disappearance of the glandular acini in these dogs, 
while in the dogs that recovered the disappearance of the glandular parenchyma 
proceeds much more slowly. Zuntz and Mayer conclude from this that in addi- 
tion to the production of the pancreatic juice and, of the still hypothetical 524 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
hormone regulating carbohydrate metabolism the pancreas has still another 
function, by which it becomes concerned with general metabolism. Cannot 
fat necroses, that are known to be difficult to avoid in the operation on the pan- 
creas, have played a part in the sudden death of the dogs? 
I should like to summarize the results of the experimental investigation 
up to the present in the following propositions. There is probably produced 
from the insular apparatus of the pancreas a hormone that is given principally 
to the venous blood and carried to the liver. When this hormone is absent, marked 
excretion of sugar and disturbance of glycogenesis occurs. Further, there occurs 
elimination of ketone bodies. The decomposition of protein, the excretion of 
salts, and the production of calories are greatly increased, as is also the excita- 
bility of the sympathetic nerves. 
According to my view, there speaks for a disturbance of glycogenesis, in 
addition to the marked poverty in glycogen, especially the fact that wTe have 
in partial extirpation of the pancreas (Sandmeyer’s diabetes) the occurrence 
of a glycosuria only on alimentary overfeeding. In the severest forms, at the 
height of the metabolic disturbance the glycogen formation in the liver seems 
markedly reduced. For this speaks the observation, as already Minkowski 
found, that the administration of dextrose raises the sugar-elimination to 
about the amount administered, and also the demonstration furnished by 
Grote, Staehelin and myself, that administration of sugar does not increase the 
respiratory quotient. That glycogen formation is not entirely in abeyance is 
spoken for, among other circumstances, by the fact that we may still obtain it 
on the administration of levulose. 
In my opinion there speaks for an overproduction of sugar the fact that 
also in fasting, when the alimentary influences are entirely ruled out, sugar 
production proceeds in the liver with the intensity that it does. 
Finally there remains for discussion the question as to whether the over- 
production in the liver is alone the cause of the sugar elimination, or whether 
also the combustion of sugar in pancreatic diabetes is diminished or increased. 
An attempt has been made to reach nearer the solution of this question by 
investigating whether muscular work will reduce the elimination of sugar. 
The basic investigations of Seo have shown that after incomplete extirpation 
of the pancreas sugar elimination as well as the quotient D :N diminishes 
under the influence of muscular work. After complete extirpation of the 
pancreas no such diminution occurs. If a shorter period be investigated, 
there rather occurs an increase in the quotient. If in such an animal the 
elimination of sugar at a later stage has started to fall, there occurs as a result 
of muscular work an increase in the quotient even above that regarded as the 
maximal boundary. From this Seo concludes that the increase in the consump- 
tion of sugar on account of muscular work is only possible when pancreatic 
tissue is still present in the organism. This conclusion is not, however, 
very convincing, v. Noorden explained analogous observations in human 
diabetes as a consequence of the oversensitiveness of the sugar-forming 
apparatus the steady appeal of which to the liver for new sugar during muscular 
work is answered in an excessive manner. DIABETES AFTER EXTIRPATION OF THE PANCREAS 
525 
The fact that the respiratory quotient after total extirpation of the pan- 
creas is maintained at a very low level, and, as previously mentioned, remains 
at this level in spite of administration of carbohydrates, was formerly regarded 
as a chief argument for the disturbance of carbohydrate combustion, v. 
Noorden mentions, however, that it has not as yet been shown that the substance 
that undergoes combustion in muscle is not a sugar. What has been shown is 
only that the excretory product is not a nutritional carbohydrate; it may 
however, be a fat. 
Also other authors express themselves as against a disturbance in sugar 
combustion. Chauveau and Kaujmann investigated the sugar contents in 
the arterial and venous blood of pancreasless dogs, and found that of the 
arterial blood higher. Investigations on the “sugar puncture” hypergly- 
cemia yielded the same result. Porges and Salomon found in their experiments 
that on exclusion of the entire portion of the body lying below the diaphragm, 
the respiratory quotient in the pancreasless dog rose as high or as even higher 
than in normal animals under the same conditions. As the combustion 
under these conditions takes place chiefly in the muscles, they assume that 
after removal of the pancreas, the muscles are in a condition to burn up sugar. 
Recently Knouthon and Starling have again entered the lists for a dis- 
turbance of the sugar combustion in the pancreasless dog. If a heart-lung 
preparation of a normal dog is transfused with normal blood, there occurs a 
strong consumption of sugar. If, however, the heart-lung preparation of a 
pancreasless dog is transfused with the normal blood, the consumption of 
sugar straightway becomes o. If dealbuminized pancreas extract be 
added to this blood, consumption of sugar reappears. Knouthon and Starling 
conclude from this that tissue and blood contain a substance ordinarily coming 
from the pancreas that is necessary for the sugar consumption in the tissues. 
The experiments of Knouthon and Starling may be interpreted in two 
ways. Either in normal dogs the sugar is burned, or its is polymerized and 
assimilated. According to the interesting experiments of Levene and Meyer 
the latter is not at all unlikely. For these authors showed that through 
the combined action of muscle-plasma and pancreas extract, the power of 
reduction of a sugar solution becomes reduced, but may be regained on cooking 
with acids. 
The experiments also make necessary a revision of the important investi- 
gations of Lepine on glycolysis. 
It is very unlikely that the combustion of sugar in the pancreasless dog 
ceases entirely. It must not be forgotten, that very intense grades of glyco- 
suria occur not only in human beings, but that forms of diabetes may also 
be produced in dogs, that are associated with a more intense elimination of 
sugar than is the case in pancreas diabetes. I refer to investigations of Lusk 
on phloridzin diabetes, in which the quotient 3.6 was regularly attained. 
Also in our investigations on simultaneous extirpation of the pancreas and 
thyroid gland, and especially of pancreas and parathyroid glands were the 
quotients high. Therefore in ordinary pancreatic diabetes it must either be 
that less sugar is formed, or that sugar is still consumed. 526 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
If we adopt the standpoint that the combustion of sugar in the muscles 
is only possible after preceding assimilation, the experiments of Starling would 
show that the glycogenesis in the muscles and probably also in other cells that 
otherwise contain glycogen is, without the pancreatic hormone, highly reduced. 
A certain grade of glycogenesis is always found remaining in the pancreatic 
diabetic dog, as already mentioned. If we assume that in the experiments of 
Porges and Salomon only the carbohydrates just assimilated are consumed to the 
last traces, we may readily bring this in harmony with the assumption that 
the assimilation of carbohydrates in the muscles of pancreasless dogs is dimin- 
ished. It seems to me therefore that the two series of experiments do not 
unconditionally contradict each other, if the fact is emphasized that in the 
pancreasless dog the formation of glycogen is disturbed not only in the muscles 
but also in the liver. 
It is very hard to explain the enormous increase of the protein decomposi- 
tion, the salt elimination, and especially also the caloric production, in the 
dog with pancreatic diabetes. I shall return to this in the theoretical con- 
siderations, later on. 
I might summarize what I have just detailed in the following hypothesis: 
The pancreatic hormone is an exquisitely assimilatory hormone, and governs 
glycogenesis in the liver and muscles. In the light grades of insufficiency the 
disturbance in carbohydrate metabolism occurs only when there are instituted great 
demands on glycogenesis in the liver (alimentary over-loading with carbohydrates). 
In the severer disturbances there occurs, in addition to the disturbance in anabolism, 
a marked increase in catabolic processes and thereby a faulty decomposition of 
higher and lower fatty acids (ketonuria). 
[Allen1 emphasizes the point that together with the anabolic processes in 
diabetes, catabolic processes go on at the same time. He credits Taylor2 with 
having also indicated this point. Allen ascribed both the catabolic and the 
anabolic role to the insular hormone.—Editor.] 
B. Experimental Nervous Diabetes 
Experimental nervous diabetes will be mentioned here only briefly. Many 
important facts have already been mentioned in the chapter on the suprarenals. 
We have to thank Claude Bernard for the fundamental experiment. A puncture 
at a definite place in the fourth ventricle leads in many animals to a glycosuria 
lasting several hours. Recently Aschner has shown that a similar sugar center 
lies also further centrally, in the subthalamic region. In sugar puncture the 
1 Allen, F.M., Experimental studies in diabetes. Series II. The internal pancreatic function 
in relation to body mass and metabolism. II. Changes in assimilation by alterations in body mass. 
Am. J. Med. Sciences, Vol. CXVI, No. i, Jan., 1921, pp. 16-32. 
2 Taylor, A. E., Tr. Coll. Phys. Philada, Vol. XXXVIII, 1916, p. 254. “The up-building 
processes of the body can never be dissociated from the pulling-down processes. There is no such 
thing as a disturbance in the burning of sugar, without an effect upon the anabolism of sugar in the 
tissues, and likewise no disturbance in the burning of fat without similar influence in the building-up 
process of fat. Fat and sugar are vital in the building-up of metabolism. We have every reason 
to believe that when the body cannot burn sugar and fat it cannot utilize sugar and fat in constructive 
anabolism.”—Discussion on one of Allen’s papers. EXPERIMENTAL NERVOUS DIABETES 
527 
stimulus travels over the paths of the sympathetic, and leads to an unburden- 
ing of liver glycogen and to hyperglycemia. If the conduction is interrupted 
in the spinal cord above the giving-off of the splanchnics, or if the liver is 
previously rendered sugar-free, as for instance, by strychnine, the puncture 
is of no avail. Until up to a short time ago this is as far as the mechanism 
of sugar puncture had been explained, nor did we know how the impulse was 
carried over the splanchnics to the liver. The investigations of the last few 
years have shown that the chromaffin tissue is to be regarded as the governing 
device. Already Blum had expressed the opinion that sugar puncture acted 
by way of the suprarenals. In common with Eppinger and Rudinger, I showed 
that in thyroidless dogs adrenalin glycosuria as well as “sugar puncture” 
glycosuria were not induced. Both were therefore prevented by the same 
factor. Waterman and Smith found after puncture a mydriatic substance 
in the serum. But to-day we must consider the methods used by these authors 
for the demonstration of adrenalin as insufficient. A further analogy between 
adrenalin glycosuria and sugar puncture lies in the appreciable hyperemia of 
the liver that occurs after such procedure, as Priestly and I have pointed out. 
After each procedure there occurs an increase in blood-pressure (E. Neubauer). 
For the convincing experiment we have to thank R. PL Kahn. He showed that 
after sugar puncture of the staining of the suprarenals to chrome dyes as well 
as the pressor power of the suprarenal extract decreases. If the puncture is 
done after previous section of both splanchnics the glycosuria remains absent, as 
is known, and the staining of the suprarenals to chrome dyes is retained. It was 
shown therewith, in confirmation of the experiments of Nishi, that the left 
splanchnic supplies both suprarenals, while the right splanchnic gives off fibers 
only to the right suprarenal; for on action of the right splanchnic the puncture 
makes both suprarenals poorer in adrenalin, while on section of the left splan- 
chnic only the right suprarenal suffers somewhat in its adrenalin contents. 
Electrical stimulation of the splanchnic (section of the nerves and stimulation 
of the peripheral stump) elicits glycosuria. Tschebokraroffi had previously 
shown that the adrenalin contents of the blood of the suprarenal veins is 
increased by electrical stimulation of the splanchnics. 
Therefore the action of sugar puncture may be explained by an afferent 
impulse conducted along the splanchnics, which leads to an unloading of the 
chromaffin. How adrenalin occasions a dissemination of the sugar from the 
liver is not as yet clear. E. Neubauer thought that the hyperemia of the 
liver was alone the cause of the dissemination of glycogen. I think, however, 
that against this speaks the fact that there are agents that bring about dis- 
tinct hyperemia of the liver without producing glycosuria. Such an action 
has pituitrinum infundibulare, for instance. The hyperemia of the liver may, 
however, very well favor the development of a glycosuric action, as has already 
been dealt with in the chapter on the suprarenals. We might suppose an 
activation of the diastatic ferment in the liver. Hofmeister reports recently 
that after the puncture, the glycogen for the most part is no longer found in the 
liver-cells, but in the efferent lymph and blood-vessels. Zulzer first propounded 
the view that adrenalin and the pancreatic hormone have an antagonistic 528 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
action. The poisonous action of adrenalin would be neutralized by the pan- 
creas hormone in the liver, v. Noorden expressed the view that both pancreas 
and chromaffin tissue influence the diastatic process in a contrary manner-—the 
pancreas inhibits, the chromaffin tissue accelerates it. v. Furth and Schwarz 
have taken justified exception to the experiment of Zulzer. A certain opposition 
in the action of the pancreatic hormone and of adrenalin is, however, unmistakable. 
The former works assimilatorily, governing the building up of glycogen, and the 
latter is dissimilatory, occasioning melting down of glycogen and decomposition in 
sugar. At all events we shall see later that the alimentary factor governed 
by the pancreas and the nervous factor working by way of the chromaffin 
tissue may be highly independent of each other. 
According to later investigations of Bernstein and myself, I might assume 
that as in the liver so also in the muscular system the same regulating powers 
that govern assimilation and dissimilation are opposed to each other. In a 
large series of experiments we saw the respiratory quotient rise in human 
beings after the injection of adrenalin (previously Roth and Fuchs had already 
reported on two experiments on patients with Addison’s disease). The rise 
in the respiratory quotient may be so appreciable that from it we may infer 
a combustion of an additional 30-40 gm. of sugar in the course of from half to 
three-quarters of an hour. As after injection of adrenalin there occurs also 
an impoverishment of the muscles in glycogen; I would consider most likely 
that under the influence of adrenalin the glycogen is everywhere mobilized and 
burnt1 in a precipitate manner, whereby a greater part of the sugar is furnished 
precipitately to the blood from the liver, producing hyperglycemia and gly- 
cosuria. Now it is very noteworthy that in severe cases of diabetes mellitus, 
that had been made sugar-free, we saw after injection of adrenalin considerable 
glycosuria, but no rise in the respiratory quotient. Hence there is absent in 
the severe diabetic the power to take into combustion precipitately mobilized 
sugar; of course the possibility should be considered that the sugar mobilized 
on account of adrenalin in the severe diabetic emanates not from glycogen, but 
from fat; in such a case the respiratory quotient should, however, sink. 
II. CLINICAL PARTS 
Although as yet the intimate process by which the pancreas enters into 
the regulation of the carbohydrate metabolism is only hypothetical, we have 
no reason for doubting the fact that the pancreas belongs to the most impor- 
tant regulators of the carbohydrate metabolism and plays a leading role in 
its disturbances. If now we try to enter further into the question as to what 
role the pancreas or its inner secretory function plays in human pathology, 
1 Such an increased combustion of carbohydrate seems moreover to be able to occur isolated 
in the muscles. I refer to the experiments with “pituitrinum glandulare” already quoted in 
the chapter on the hypophysis, in which there occurred a rise in the respiratory quotient, while 
all other actions were quite opposed to those of adrenalin (lessening of the volume of the liver, 
sinking of blood-pressure, no rise in blood sugar, but more often slight reduction, and finally 
reduction in the total caloric exchange). Also in two experiments on severe diabetics there was 
a rise in the respiratory quotients, while the reduction of the total gas exchange, showed with 
certainty that the agent was active. GROSS ANATOMICAL DISTURBANCES 
529 
we find that it is more to our purpose to view the problem from two different 
sides. On the one hand it will be necessary to pass in review the clinical 
pictures in which gross anatomical alterations of the pancreas have been 
observed, and to analyze which symptoms of the total symptom-complex 
can be referred eventually to the disturbance of the internal-secretory activity. 
A thorough description of these disease pictures does not lie within the province 
of the task I have set for myself, and is also not necessary for the purpose I 
am striving for; yet it seems to me desirable to delineate them, at least in coarse 
outlines. For as we have already mentioned in the consideration of the experi- 
mental physiology, there have been attempts to bring many symptoms that 
were formerly referred to as the external secretion of the pancreas into con- 
nection with the internal secretion. On the other hand I shall draw the essen- 
tial features of the metabolic disturbance that we designate diabetes mellitus, 
describe the pathologico-anatomical alterations found in the condition, and 
discuss what role the pancreas plays in it. 
It will be evident that there are a number of cases the analysis of which we 
can approach as well the one way as the other. 
A. Gross Anatomical Disturbances 
[An etiological classification of the diseases of the pancreas probably is not 
possible to-day.—■Editor.] As yet we know far too little in this respect. At any 
rate, the role played by infection is important. This may occur hematogen- 
ously, or by contiguity, in which case infectious processes of the neighboring 
parts affect the pancreas; and finally especially in gall-stone affections 
(.Hirschfeld) in which infection reaches it from the intestines through the 
ducts. The route last mentioned is by far the most frequent. An important 
role is played by diseases of the vessels of the pancreas and by cirrhotic process 
that depend on the chronic action of poisons (alcoholism, etc.). Also trauma 
may come into consideration as an etiological factor, especially in existing 
arteriosclerosis of the pancreas. Further we recognize a series of tumors of 
the pancreas under which carcinoma is by far the most common; further 
cyst formation, the genesis of which may be various, and finally a congenital 
failure of development especially of the insular apparatus (see genuine 
diabetes). 
An acute attack of the function of the entire pancreas may be observed 
under circumstances in apoplexy of the pancreas or in acute hemorrhagic 
pancreatitis. The first occurs chiefly in old corpulent drunkards with ad- 
vanced arteriosclerosis. In association with suddenly onsetting abdominal 
pains there occurs distention of the abdomen in the epigastrium, retention of 
feces, vomiting, and finally, with distinctly pronounced manifestations of 
ileus, death in the course of a few hours or days. Section shows enormous 
blood effusions in the pancreas, and eventually into the abdominal cavity, as 
the consequence of hemorrhage from the pancreatic vessels. The course of 
the disease is for the most part so fulminant, that glycosuria mostly does not 
occur even on complete destruction of the pancreas. 530 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
Acute hemorrhagic pancreatitis usually sets in with acute gastric distur- 
bances after indefinite prodromal symptoms that have lasted for some time; 
to the gastric disturbances are rapidly added distention of the epigastrium, 
violent pressure pains in the pancreatic region and high fever; either death 
follows rapidly under the manifestations of acute ileus and perforation peritoni- 
tis, or the case comes to remissions; then usually the disease lasts a longer time. 
Symptoms that depend on falling away of function of the pancreas are not rarely 
observed. In a case that proceeded rather acutely, I found 12% of sugar 
in the urine. In this case the reduction of the copper sulphate took place even 
in the cold. An interesting case with a chronic course is described by Albu. 
In a twenty-nine-year-old woman who had formerly often suffered with violent 
pains in the gastric region there gradually developed in association with rise in 
temperature a resistance in the epigastrium, fat-stools, and glycosuria. After 
a transitory improvement, the manifestations grew worse again, and a piece 
of necrotic pancreas tissue was removed on operation. A second operation was 
necessary on account of suppuration of the gall-bladder, after which the febrile 
process ceased, the fat-stools and the glycosuria disappeared; after some time 
there was a recurrence of the fat-stools, and of the sugar up to 5%. 
Acute hemorrhagic pancreatitis was first described by Balser. Later the 
clinical picture was accurately described chiefly by Korte. According to the 
recent experimental investigations it is to be assumed that there first occurs 
necrosis of the pancreatic tissue through infection from the intestine or through 
the pancreatic duct {Korte, Opie) on account of nutritive disturbances, and then 
goes on to fat necrosis through the action of the pancreatic juice. The fat 
necrosis probably travels further by way of the lymph channels, and then the 
pancreatic secretion gets into the circulation and acts toxic (Gulecke and 
v. Bergmann). Disturbances in sugar metabolism are to be expected only if 
the process involves the greater part of the gland and is not too fulminant. 
It is very probable the chronic inflammatory processes of the pancreas 
occur more frequently from infection through the pancreatic duct than we 
had previously supposed. Hirschfeld described three cases in which at the 
end of an influenza or of febrile angina there occurred either swelling of 
the liver and gastric distress, or colicky pains and glycosuria of 2 to 6%. 
After lasting one to five months the pains disappeared. Sometimes chronic 
pancreatitis occurs in cholelithiasis, although here the insular apparatus is 
affected only rarely. Mayo Robson found only four cases of diabetes (0.2% 
to 0.4% sugar) among sixty-five cases with stones in the ductus choledochus 
and with hard enlarged pancreas. In three cases the sugar vanished after the 
operation. Later one case passed into severe diabetes. 
Before I enter more intimately into chronic pancreatitis and pancreatic 
cirrhosis, I would mention a special form of it, namely, the luetic. The heredi- 
tary syphilitic form is apparently chiefly interstitial, and avoids the insular 
apparatus, on which account it almost always pursues its course without 
glycosuria. The syphilitic pancreatitis of adults is either gummatous (Herne- 
heimer, Hirschfeld), or interstitial. The latter form, if it progresses, may also 
temporarily damage the insular apparatus and thus lead to glycosuria. Chre- GROSS ANATOMICAL DISTURBANCES 
531 
litzer, Ehrmann, Albu, et al., report such cases. In the case of Chrelitzer, a 
relapse of lues occurred ten years after the primary affection. Simultaneously 
with the exanthema occurred abdominal pains radiating toward the back, 
vomiting, meteorism, jaundice, swelling of the liver and rise of tempera- 
ture. A hard tumor was palpable deep between the navel and the xiphoid 
process. In the urine was found 2.2% of sugar. Cure occurred spontaneously. 
In Ehrmann’s case an extremely severe diabetes (8% of sugar, acetone) devel- 
oped at the time of the outbreak of a syphilitic exanthema. The inunction 
cure was interrupted and an antidiabetic regimen introduced. All symp- 
toms disappeared within eight days. Albu’s case was very chronic. In a 
forty-four-year old man (primary affection fourteen years previous) there 
developed gastric disturbances, emaciation, jaundice, and enlargement of the 
liver; after a longer time, fat stools and glycosuria (0.9%); also a tumor was 
palpable deeply. Under enemas of potassium iodide, and pancreatin, improve- 
ment occurred; and after several months tumor and glycosuria disappeared 
and the case was cured. In general, lues does not play a great role in the 
etiology of diabetes, v. Noorden found syphilis in the history of 1.2% in male 
individuals under twenty years of age, 7.1% in males over twenty, and 2.3% 
of female diabetics of all ages. 
Chronic indurative pancreatitis is a very common disease. It may proceed 
from the vessels (arteriosclerosis, endarteritis obliterans) or from the excre- 
tory ducts. It may be diffuse or circumscribed. In gall-stone affections 
there may sometimes occur isolated sclerosis of the head of the pancreas 
{Riedel). Chronic indurative pancreatitis often occurs simultaneously with 
atrophic cirrhosis of the liver, especially in alcoholics. Weintraud, Bence, 
and others have described such cases, in which as a result of high-grade defic- 
iency of pancreatic function there occurred pronounced disturbances of 
fat absorption. In Bence’s case severe diabetes existed. The section showed 
a marked disappearance of the pancreas and sclerosis; the islands of Langer- 
hans were entirely destroyed, and only remnants of the acinic tissue were 
present. In very severe alcoholism there exists simultaneously sclerosis of 
the liver and pancreas (and suprarenals), sometimes associated with the 
deposition of iron-containing pigment in the liver, pancreas, skin, etc. (cir- 
rhose bronzee or diabete bronzee). Atrophy of the pancreas with sclerosis 
is a common finding in diabetes mellitus. When it occurs the insular apparatus 
is mostly rather severely damaged. We shall come back later to the considera- 
tion of v. Hansemann’s granular atrophy of the pancreas and the interacinic 
sclerosis of Opie, and the sclerosis periacineuse of Lepine, and of Lemoine and 
Launois. In severe damaging of the glandular parenchyma, there may in 
such5cases occur disturbances of absorption. In the case of Keuthe, that had 
previously been described by Glassner and Siegel, there existed a moderate 
disturbance of the fat absorption (the fat in the diet was slight only) and 
several times transitory glycosuria (of 0.3% to 0.7%). The autopsy showed 
marked atrophy of the pancreas, the duct of Wirsung was not to be found, the 
islands of Langerhans were in part retained or were hypertrophied. Some- 
times the marked sclerosis of the pancreas is the result of a lithiasis pancreatitis. 532 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
Lithiasis of the pancreas may occur isolated; but not rarely it is combined 
with cholelithiasis. In certain cases kidney stones were also found. In this 
event, we may speak of a general stone diathesis, that not rarely is familial. 
The pancreas stones are whitish, brittle, crumbly; unlike gall-stones they 
contain no pigment, but on the contrary are rich in lime-salts, so that under 
circumstances they can be demonstrated by the X-rays. Probably they 
usually originate (as do gall-stones) after a chronic catarrh has established in 
the duct system of the pancreas. Often the larger and smaller pancreatic 
passages are plugged up with stones. In other cases there are found one 
or more larger stones, which pass with severe colic, and may temporarily 
or permanently block up the larger ducts of the pancreas, or even the princi- 
pal excretory duct. Behind the place where the stone lodges there often 
occurs a dilatation of the passage in question and an indurative pancreatitis, 
which at the beginning affects the islands but little, but on longer duration 
damages them severely. The pancreatic colics that Minnich first intimately 
described commence with severe girdle-like pains radiating to the back and 
even to the shoulder. In a case that I saw, the girdle-like pains associated 
with symmetrical hyperesthetic zones over the iliac crests led me to think of a 
spinal affection, until on the next day the occurrence of very voluminous stools 
with creatorrhea and steatorrhea made possible the diagnosis of occlusion of 
the duct of Wirsung by a pancreatic stone. The impaction of a pancreatic 
stone can also take place without pains. This was the case in a patient ob- 
served by Gigon and me. Also here there recurred from one day to another all 
the acute absorptive disturbances characteristic of impaction of a pancreatic 
stone, without, however, the existence of colic. At autopsy there was found 
in addition to numerous small stones in the pancreas a stone the size of a cherry 
stone which fully occluded the place of opening of the pancreatic duct into 
the ampulla of Vater. 
The high-grade indurative pancreatitis that so frequently complicates 
stone of the pancreas, especially on the occlusion of the chief excretory duct 
by a stone, makes intelligible the fact that lithiasis of the pancreas is so fre- 
quently associated with disturbances of the sugar metabolism. Oser reports 
that among seventy cases, diabetes or at least temporary glycosuria was 
observed in twenty-four, that is, in more than 34% of the cases. Lazarus 
indeed found it in 45%. Albu mentions an interesting case. The test for 
alimentary glycosuria had previously resulted negative. There existed a 
tumor in the region of the pancreas which distinctly enlarged during a severe 
attack of colic. On test for alimentary glycosuria, 2.9% of sugar was found 
in the urine. In the case of mine previously mentioned a slight diabetes 
existed before the colic. The patient could easily be made sugar-free by a 
strict diet. After the colic and the occurrence of the fat stools, the diabetic 
metabolic disturbances became essentially worse; after about eight days the 
voluminous stools disappeared; after another two weeks the stools were entirely 
normal, even after heavy overloading with fat; simultaneously with this there 
was also observed a retrogression of the diabetic metabolic disturbances, so 
that the patient again became temporarily sugar-free. Apparently as a sequel GROSS ANATOMICAL DISTURBANCES 
533 
of severe inflammatory processes in the ducts, the islands of Langerhans do 
not, in occlusion of the duct of Wirsung by stone, behave so refractory as in 
animal experimentation after ligation of the excretory ducts. It is also of 
importance for the occurrence of disturbances in sugar metabolism, whether 
the second pancreatic duct is obliterated or is likewise closed by a stone, or 
whether numerous intrapancreatic passages are rendered impassable; as the 
intensity and the extensiveness of the sclerotic processes are in part dependent 
on these factors. 
These circumstances are also important for the occurrence of disturbances 
of absorption. It is without other considerations to be expected that these 
only become manifest in a pronounced manner when the flow of pancreatic 
juice into the intestine either is fully interrupted, or at least almost completely 
ceases. I would like to enter here upon the question as to the relationship 
that exists between the disturbances of absorption that occur on cessation 
of the pancreatic juice in man, and the internal secretion of the pancreas. 
At the beginning, when the animal experiments of Abelmann were regarded 
as indicative, the question seemed to have become entirely cleared. We 
referred the occurrence of absorptive disturbances to the absence of the pan- 
creatic juice, the occurrence of glycosuria to insufficiency of the internal 
secretory activity of the pancreas. In more recent times this question has 
encountered confusion in the literature. Naturally there occur disturbances 
of fat and protein absorption when the production of pancreatic juice is normal, 
as in profuse diarrheas of various origin, amyloidosis of the intestine, etc. 
We know further the disturbances of fat absorption in complete cutting off 
of the bile from the intestine and also the fat stools in certain forms of Basedow’s 
disease; as important differential criteria against both the last-mentioned forms 
are, since Friedrich v. Muller’s investigations and the observations of v. Noorden’s 
clinic as to Basedow’s disease, the disturbance in fat decomposition that occurs 
on the cutting-off of the pancreatic juice and again the slight holdings in soaps. 
To this should be added the fact that in typical pancreatic stools, the creator- 
rhea, that is the more prominent occurrence of striped muscular fibers, domi- 
nates the microscopical picture. With this is associated a more distinct loss of 
nitrogen by way of the feces than is observed in other disturbances of absorp- 
tion. Finally there have been worked out a series of methods for demonstrating 
the absence of a proteolytic or amylolytic ferment in the feces obtained after 
purgation. Many authors have raised objections to these diagnostic postu- 
lates, as they have observed cases of disease of the pancreas in which the charac- 
teristic disturbances of absorption were absent, in spite of complete cutting-off 
of the pancreatic juice from the intestine. Thus Deucher, Albu, Ury, Alexander, 
Keuthe and Brugsch saw normal fat-splitting in pancreatic diseases. Also 
creatorrhea is sometimes absent. We might suppose that in these cases the 
other digestive ferments have entirely taken over the role of the pancreatic 
secretion. Brugsch explains that on simple occlusion of the excretory duct 
of the pancreas there occur no, or only temporary, absorptive disturbances, but 
more intense disturbances only when the pancreas is completely degener- 
ated, or the gland tissue is for greater part destroyed through carcinoma or 534 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
abscesses, etc. Then only would loss of fat occur up to 60% and the nitrogen 
loss up to 20%. This hypothesis, which has indeed not been based on the 
examination of a definite case, but has been influenced by the views of Lom- 
broso which we have already criticised, is not decisive. I refer only to the 
previously mentioned case of Gigon, in which the absorptive disturbances set 
in suddenly on occlusion by stone and lasted until death. The pancreas cannot 
degenerate in a day; if, however, it has already been markedy degenerated, we 
cannot readily see how it can have furnished sufficient secretion up to the day 
on which the occlusion occurred. Too, it seems especially inappropriate to 
apply off-hand to human pathology the results of animal experiments, which 
as we have seen are not as yet fully explained. It would indeed be conceivable 
that the other digestive secretions in the dogs render the pancreatic secretion 
less indispensable than in man. In human pathology, the conditions seem to 
me to be clearer and to justify a single standpoint, v. Noorden and Salomon 
have pointed out in this regard that in cases of absence or insufficiency of the 
pancreatic juice, the absorptive disturbances become manifest, if the intestine 
is overloaded with fat; if in this functional test, butter stools occur we may 
take it for granted that there is certainly a disease of the pancreas or absence 
of the pancreatic juice. Also this is true if creatorrhea makes its appearance. 
It should not be forgotten that in many of the cases of pancreatic disease in 
the literature (especially in carcinoma, in which fat stools are absent, on account 
of the increasing cachexia), the intake of diet was very slight at the time of the 
observation. We must here again refer to the anatomical relations of the 
duct system. We must consider that if the second duct of the pancreas is 
not obliterated or occluded, enough pancreatic juice may still reach the intes- 
tine, even if the principal duct be completely occluded, that the disturbance 
does not become manifest even on heavy overloading. As far as the fat-split- 
ting is concerned, Salomon has pointed out that during the tedious procedure 
of drying the stools on the water-bath, always more fatty acids occur. If we 
do not take this into account, we may arrive at entirely false values for fat- 
splitting. We may summarize by saying that markedly lessened or absent 
production of pancreatic juice, or cutting-off of the pancreatic juice from the 
intestine, leads in man to characteristic absorptive disturbances. 
I have entered into detail into these conditions, because we require a 
clear formularization if we wish to enter into the question as to how far the 
internal secretory activity of the pancreas is independent of the external secre- 
tory activity, and whether these disturbances occur isolated in the gross ana- 
tomical diseases of the pancreas. In the acutely onsetting, severe, damagings 
of the organ (suppurative or acute hemorrhagic pancreatitis, necrosis of the 
pancreas or apoplexy of the pancreas) it is intelligible that we do not see much 
of the disturbance of the external or internal secretory activity of the pancreas. 
Often, too, in complete extirpation of the pancreas in animal experimentation, 
the sugar does not occur immediately if septic processes are present at the 
same time. When diet is low or is not ingested at all, of course the absorp- 
tive disturbances do not occur either. If the course is subacute, as a rule 
both disturbances are present. In tumors of the pancreas, the behavior of the GROSS ANATOMICAL DISTURBANCES 
535 
disturbances varies very much. Cysts may leave behind sufficient function- 
ating pancreatic parenchyma and hence may pursue their course without any 
disturbance whatsoever. If the greater part of the pancreas takes part in 
the process sympathetically, a latent insufficiency of both functions may develop 
that may eventually become evident only on overloading; although it is intel- 
ligible that in individual cases on account of especial anatomical relation the 
absorptive disturbances may become more distinct through compression of 
the duct system. In carcinoma of the pancreas it seems that the islands of 
Langerhans hold out longer against the carcinomatous infiltration than do 
the acini. As the carcinoma usually is seated in the head of the pancreas it not 
infrequently happens that there is complete shutting off of secretion through 
compression of the chief duct, and hence a distinct prominence of absorptive 
disturbances. We should consider, of course, that the ingestion of food in such 
a case is very slight on account of the cachexia. 
In carcinoma we not rarely observe, in addition to this that the intensity 
of the glycosuria diminishes with increase in the cachexia, or the sugar entirely 
disappears. This is entirely comprehensible. We see even in the pancreasless 
dog the glycosuria diminish, if with the weakening of the liver processes the 
mobilization of sugar is also less. In slight grades of chronic indurative or more 
atrophic pancreatitis no disturbances in carbohydrate metabolism need neces- 
sarily be present. In advanced cases it may very well be assumed that the 
function of the insular apparatus has often suffered previous damage and has 
thus led to disturbances in the sugar metabolism. We shall see later that this 
form of pancreatitis not rarely forms the pathologico-anatomical stratum for 
the “genuine” diabetes mellitus. In this, as is well known, no absorptive 
disturbances occur, although the antidiabetic diet mostly means a considerable 
and permanent overloading of the fat absorption. In former times this was 
associated with a heavy overloading of the intestines with meat. Thus can 
the production of pancreatic juice be strongly limited without disturbances of 
absorption becoming manifest. These occur only with the higher grades of 
atrophy of the pancreas. The most important are the cases with occlusion by 
stone, and those of consecutive sclerosis. In stoppage of the duct by stone we 
have in addition the suddenly appearing characteristic absorptive disturbances, 
which are fully developed, and most often the latent or manifest disturbances 
in carbohydrate metabolism that had already been present, perhaps because 
the catarrh of the duct system has for a long time led to incrustation of the 
ducts and to indurative pancreatitis. There are, however, cases in which, at 
least at the beginning, there exist fully developed disturbances of absorption, 
but only minimal latent disturbances of carbohydrate metabolism. These 
cases are entirely intelligible, if through impaction of a gall-stone or through 
other factors leaving the pancreas for greater part intact, the supply of pan- 
creatic juice is interrupted. Ehrmann and others, have described such cases. 
As example I submit the following: 
Observation LXVIII.—R. M., thirty-five years. Entrance into the clinic Nov., 1911. 
Until one and one-half years ago the patient was entirely well. Then obstipation that 
often lasted four or five days set in, and also slight headache. For about seven months 536 
DISEASES OE THE INSULAR APPARATUS OF THE PANCREAS 
severe colicky pains in the right hypochondrium, about ten days after this jaundice, that 
has lasted until to-day. Since this time four or five bowel movements daily that were very 
voluminous, “more than he ingested as food.” The stools are clay-colored. In spite 
of this fact the appetite remained very good, the patient fell off rapidly. The patient is 
almost entirely impotent. More severe jaundice, hair on head very much thinned 
out, that in the axillae a’most entirely absent, sparse on the pubis. Colossal hydrops of the gall- 
bladder. In addition, in the middle line, very deep, is a resistance hard to outline. Ascites. 
Rontgen examination: Diffuse aortic extension of a moderate degree. Wassermann 
negative. Increased peristalsis of the stomach, although emptying of the stomach is not 
essentially slowed. Urine deeply jaundiced, no sugar. Chemical examination of the 
stomach contents normal. 
The stools (3-4 daily) are very massive and are acholic; urobilin test constantly nega- 
tive; minimal, quantitatively not estimable amounts of urobilogen {Dr. Charnas). The 
stools are of gray-white color, glittering with fat, of very foul odor, microscopically show 
much neutral fat, soap and fatty acid needles and striated muscle fibers. By loading with 
fat (250 gm. oats, oatmeal, and 300 gm. butter) there occur typical butter stools. The 
test was repeated five times always with positive results. 
The chemical examination of the stools (with the overloading test) showed 38.3% 
unsplit fat and 64.2% fat in the form of fat acids and soaps. The chemical examination 
of the butter-stools showed 71.7% neutral fat. 
The examination of the stool for tryptic ferment according to Gross, and also for dia- 
static ferment according to Wolgemut showed only traces. In one examination, however, 
there was found slight, but distinct tryptic and diastatic action. 
Five tests for alimentary glycosuria (100 gm. of dextrose, fasting) were always negative. 
During the stay at the hospital there often occurred colicky pains in the gall-bladder 
region. 
The ascitic fluid had a specific gravity of 1012, 8% albumin. The protein bodies 
precipitated by acetic acid were present only in traces. 
The Salomon-Saxl’s carcinoma reaction was positive. 
Although the Salomon-SaxVs test as well as the ascites spoke for a new growth, yet the 
possibility of an occlusion of the ductus choledochus by stone could not be excluded; so that 
the patient was operated on. There was found at operation, deep down in the abdominal 
cavity, a tumor whose situation was not quite clear. Cholecystogastrostomy was done. 
Death occurred some weeks afterward. Section showed a scirrhous carcinoma of the 
head of the pancreas, with closure of the pancreatic duct, marked dilatation of the passages 
in the body and tail of the pancreas. The ducts were filled with a milky yellowish fluid. 
The ductus choledochus was occluded about cm. above the papilla of Vater, and there 
was marked dilatation of the bile ducts above it. 
The case described fulfills all the conditions that we could establish at a 
physiological experiment. There are present all symptoms that are characteristic 
for the cutting-off of the pancreatic juice {and the bile), while the carbohydrate 
metabolism was entirely normal even on heavy overloading. Such cases have an 
important significance. They show us that in human beings the internal 
secretory and the external secretory activity of the pancreas are fully independent 
of each other within wide limits. 
B. Genuine Diabetes Mellitus 
It is not my intention here to depict the symptomatology of diabetes 
mellitus in exhaustive fashion. Much more will I limit myself merely to 
sketching the clinical picture, assigning only somewhat more space to the GENUINE DIABETES MELLITUS 
537 
metabolic disturbances in order to discuss later the position of the pancreas 
in the pathogenesis of diabetes mellitus. 
The Carbohydrate Metabolism.—Among the symptoms of diabetes 
mellitus, glycosuria is the most striking for physician and laity. Theoretically 
and also more practically important, certainly, is hyperglycemia, for glycosuria 
is only a result of this. There is in diabetes mellitus an excretion of sugar 
without hyperglycemia, but not rarely there occurs hyperglycemia without 
excretion of sugar. If the diabetes has existed for a long time, the kidneys 
lose their finer sensitiveness for the heightening of the blood-sugar contents, 
they gain in sugar-imperviousness (v. Noorden, Liefmann, and Stern). There 
is also in such cases no proportion between the degree of the hyperglycemia 
and the intensity of the glycosuria. Especially is this true for the diabetes of 
old age. The fact is also very important, as may be expected, that the toler- 
ance only rises when the sugar in the blood has been for a long time normal, 
and that a series of symptoms, that we regard as the sequel of a long-continuing 
hyperglycemia (furunculosis, impotence, diabetic gangrene, rheumatoid pains, 
etc.) only vanish when the hyperglycemia is combated. 
For the assumption of diabetic disturbance of metabolism there is neces- 
sary the demonstration that the sugar excreted in the urine is grape-sugar. 
Further, there must be excluded a series of conditions that according to experi- 
ence are associated with a temporary excretion of sugar, or at least appreciably 
reduce the tolerance for carbohydrates. Of such conditions I mention acute 
febrile diseases, intoxication with carbon monoxide or morphine, and asphyxic 
conditions, etc. 
It should further be considered that after copious ingestion of sugar, 
sometimes slight amounts of sugar are found in the urine of even normal 
human beings. The glycosurias in certain ductless glandular diseases especially 
in Basedow’s disease and in acromegaly are considered in detail in the chapters 
on the subjects. We shall consider later the matter of nervous glycosurias 
(in traumatic neurosis, hysteria, neurasthenia, and in certain nervous diseases, 
such as tabes and [general] paralysis). 
I might here mention the laws that the excretion of sugar follows. In the 
great majority of cases of diabetes we can observe a narrow relation between 
intake of food and excretion of sugar. If we place such a diabetic on a diet 
of a constant composition, the excretion of sugar sets in at a definite level and 
maintains it for a long time. In cases that have not advanced entirely too far, 
it is known that the tolerance may be influenced by a corresponding dietetic 
regime. If the patient on account of the limitation of the sugar-forming 
material becomes sugar-free, and if the amount of sugar in the blood remains 
for a long time normal, a reparation occurs, so that later a diet without gly- 
cosuria may be borne that formerly led to sugar-excretion. On the other 
hand the tolerance is depressed when a high sugar-content of the blood has 
existed for a long time. 
It is known that the individual food-stuffs are not equivalent in their 
action on the glycosuria. Carbohydrates and protein act more positively 
on the glycosuria than fat, while alcohol, for instance, does not influence the 538 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
glycosuria. Also the individual carbohydrate and protein bodies show differ- 
ences in their action. Of the kinds of sugar, maltose, for example, acts more 
glycosuric than glucose, and this again acts more strongly than levulose. 
However, the individual diabetics do not behave the same throughout. For 
example, milk-sugar is borne very well by many, others react to it with a 
severe excretion of sugar. 
Also the individual protein bodies influence the glycosuria in different 
manners. To mention only a few examples, casein and meat-albumin act 
more on the glycosuria than plant-albumin and egg-albumin, the latter acts 
less glycosuric when it is ingested in its native condition. The foundation 
for this lies partly in the fact that the individual protein bodies are drawn into 
decomposition at different rates. In very severe cases of diabetes the differ- 
ences vanish, however. Otherwise the individual diabetics act differently with 
regard to the administration of protein. Especially severe cases often react 
to increase of the ingestion of protein with a sugar elimination relatively 
stronger than on the administration of carbohydrates—“ protein sensitive 
cases.” 
The question whether in human diabetes sugar can be built out of pro- 
tein has been energetically discussed. On the clinical side it has been shown 
that severe cases of diabetes mellitus that have been kept for months on exclu- 
sively meat-fat-diets, constantly excrete so much sugar that it is hardly possible 
to refer this to the slight carbohydrate-content of the diet and to the original 
glycogen-content of the organism. It is further known that in especially 
severe diabetics the excretion of sugar varies simultaneously with the ingestion 
of protein. The question of sugar-formation out of protein can to-day be 
answered with a “yes.” On the contrary the question as to what extent the 
normal or the diabetic organism can build sugar out of protein cannot be safely 
decided with the methods of investigations of metabolism to-day at our dis- 
posal. We cannot in this manner make sure as to the origin, as far as ingested 
food material is concerned, of the sugar eliminated in the urine. It is very 
probable that the sugar appearing in the urine also in slight cases does not only 
depend on the change in carbohydrates, but also on that of the protein. Theo- 
retical considerations that I shall not enter into here, speak for the fact that 
from ioo gm. of protein (about 16% nitrogen) not more than 80 gm. of sugar 
can be formed. From i gm. of N therefore would come about 5 gm. sugar. 
The question is much more complicated by the fact that we have, too, to 
regard fat as a sugar-former. At all events, however, the administration of 
fat does not ordinarily increase the excretion of sugar. On these facts the 
dietetic treatment of diabetes is for most part built. This is readily under- 
stood when we consider, that, as v. Noorden emphasizes, that fat is transmitted 
to the blood and the tissues especially by the lymphatic paths, and from there 
is transported to the liver only in accordance with needs, while carbohydrates 
and protein directly flow to the liver through the portal vein and increase 
the condition of irritability of the liver. The facts that, apart from theoret- 
ical considerations, speak for the formation of sugar from fat: In severe cases 
of diabetes mellitus we sometimes observe a not inappreciable increase of GENUINE DIABETES MELLITUS 
539 
sugar elimination when we administer large quantities of fat during a hunger 
period. In such cases the dextrose to nitrogen quotient sometimes raises to 
io. Further cases are known in which on abundant ingestion of fat the dex- 
trose to nitrogen quotient is found higher than in the period of less fat in- 
gestion. Finally, we have the results of exact metabolism investigations in 
cases of very severe diabetes, which show that for long protracted periods so 
great quantities of sugar eliminated that these cannot be explained by the 
changes in protein and carbohydrates, v. Noorden has therefore mentioned 
that the conclusions drawn from the dextrose to nitrogen quotient as to the 
extent of the formation of sugar out of protein in human diabetes, are faulty, 
as we do not know the source of the sugar. 
In one group of diabetics this regularity, as just described, between the 
sugar-value of the food and sugar eliminations exists in much less well ex- 
pressed manner; indeed it may even happen that this law may be broken down 
by other factors. I shall describe in detail later the nervous glycosurias depend- 
ent on organic foundations. I shall cite here only the psychical factor. Any 
psychical agitation, a fright, a great excitation on account of a case of death 
in the family, or business cares, can suddenly lead to an outbreak of the diabetes. 
The glycosuria may attain a high grade; lassitude, great thirst, polyuria, induce 
the patient to consult the physician, who then finds sugar. [Allen1 has pointed 
out that the functional nervous traumata of the World War produced very 
little diabetes. This does not alter the statement of the author that a trauma 
may be the immediate cause of a diabetes, a latent tendency to which had 
existed previously.—Editor.] 
Often a slight limitation of the diet suffices to bring about a disappearance 
of the sugar, or the sugar disappears spontaneously. In a short time, normal 
tolerance is reestablished. At all events such cases as just mentioned are 
exceptional. Ordinarily, also in this group of cases is the alimentary factor 
plainly to be recognized; but this is small in comparison with the psychical 
factors. In such cases we see not rarely that painful affections of any sort 
at all may serve to increase the excretion of sugar. I naturally will not say, 
concerning the category of cases in which the alimentary factor dominated 
the scene, that also psychical excitements may not temporarily lower the 
tolerance. In the nervous cases, however, the nervous factor predominates. 
[It is customary now to limit fat in the treatment of diabetes, although 
very recent work has shown that in the absence of much protein, fat is not 
especially harmful.—Editor.] 
The Protein Metabolism.-—The question of protein need in diabetes has 
been studied in numerous metabolism investigations. In light and moderately 
severe diabetics the protein need is certainly not increased; and even in severe 
diabetics, as long as they are nourished rationally, we cannot speak of an 
increased need for protein. This has long been shown by the protracted investi- 
gations of Weintraud. In a series of severe cases, I have investigated the 
nitrogen elimination of the “ hunger ” day and found values that do not differ 
from those furnished by normal individuals under like conditions. The 
1 Allen (F. M.). Article “Diabetes” in Nelson Loose-Leaf System of Living Medicine. 540 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
severe diabetic, he who rationally fed, remains constantly on a diet rather 
poor in protein, can indeed enter upon a striking low protein need, and shows, 
when abundant protein is now administered, a striking tendency to reten- 
tion of nitrogen. Only in the severest cases, before the fatal coma, does the 
melting down of protein seem to raise to a high degree. 
Benedict and Joslin calculate the nitrogen elimination per kilogram of 
body weight in their fasting-experiments, and find that the average of all in 
these experiments is higher than in normal individuals; yet much might be 
said in objection to the calculation per kilogram of body weight, as the relation 
between protoplasm and body-mass becomes disarranged in severe diabetics 
on account of the extreme poverty in fat. 
In the severest cases also the high elimination of endogenous uric acid 
indicates a marked melting-down of muscle protein (v. Noorden). 
The qualitative alterations of the protein metabolism are, apart from the 
high ammonia values dependent on the becoming acid, not appreciable. 
We shall here say only a few words about the ketonuria of diabetics. The 
ketone bodies originate from the change in protein and fat substance on 
diminished carbohydrate combustion. The cause of this origination should 
not be otherwise than in a normal man when he has been fasting or has eaten 
meat and fat exclusively. Also in this case they are due to the lack of assimila- 
tion of carbohydrates. That in the diabetic such considerably high degrees 
are attained is comprehensible because in him is absent also the sugar originat- 
ing from the protein, and because they develop so very gradually. If the 
ketonuria lasts longer and attains higher grades, it gives rise to lipoidemia and 
to fattening of the liver. In the most severe grades of lipoidemia the blood 
may assume a light rose-red color and on standing may express a cream-like 
dense layer to the surface. [This ketonuria is associated with changes in the 
acid-base equilibrium, whence acidosis. See addendum.—Editor.] 
The alterations in the salt metabolism to be observed in diabetics are 
associated in part with the formation or the elimination of ketone bodies. 
Through the formation of large amounts of the ketone acids, alkalies are 
withdrawn from the body, and as is known, later the alkalescence of the blood 
sinks and then the calcium equilibrium is minus (Gerhardt and W. Schlesinger). 
The equilibrium of water in diabetics often shows significant variations 
on alterations of the diet. If diabetics who formerly had fed without purpose 
are placed on a diet poor in carbohydrates and protein, they often gain in 
weight in a short time. It is very probable that this depends not so much on 
the filling up of the fat deposits and partly also of the glycogen deposits, but 
much more on the retention of water. In more fully advanced cases the 
water-contents of the tissues is much reduced. Rumpf found the water- 
contents of the tissues of diabetics who had died in coma lower than 
in normal individuals. 
[Patients develop edema because of the retention of sodium chloride. 
“Rare cases of diabetes show edema which resists strictest salt privation and 
here the clinical prognosis is usually bad.”—Allen (.F. M.) Article “Diabetes” 
in Nelson’s Loose-Leaf System of Living Medicine.'—Editor.] GENUINE DIABETES MELLITUS 
541 
The Respiratory Metabolism.—The first experiments as to the caloric 
exchange in diabetics are those of Pettenkofer and Voit. At the beginning, 
these investigators misinterpreted their experiments. They overlooked on 
the one hand the loss in oxygen that the diabetic suffers through the elimina- 
tion of sugar rich in oxygen, and on the other hand they committed the error 
of comparing the change in an emaciated diabetic weighing 54 kg. with 
a healthy individual weighing 71 kg. These objections have been 
set forth especially by Leo; Pettenkofer and Voit later modified their opinion; 
Fr. Voit again discussed the experiments in detail and came to the conclusion 
that in severe diabetics the demand for calories is not increased. This result 
is entirely in agreement of the long-protracted metabolism experiments of 
Wientraud carried out at Naunyn’s clinic. II. Leo, R. Stuve, Nehring and Schmoll 
and Magnus-Levy and Salomon have further instituted experiments with the 
Zuntz-Geppert apparatus. They found that in severe diabetics the oxygen 
requirements were increased. I shall not enter into the question of the experi- 
ments of Livierato and of Robin and Binet, as the methods used are not 
reliable. 
The interest in this question was reawakened through the demonstration 
that there was an increase in the production of calories in the dog without a 
pancreas. Since this is true a series of experiments have been published. Of 
especial interest is a great number of experiments that were carried out in 
Atwater-Benedict’s respiration calorimeter. Finally I mention a series of 
experiments carried out by Eugene DuBois and Borden S. Veeder with Petten- 
kofer's apparatus at Kraus’s clinic, and finally experiments with the Zuntz- 
Geppert apparatus by Leimdorfer. I shall discuss later the experiments last 
mentioned. The experiments of Eugene DuBois and Borden S. Veeder showed 
no increase in heat production. These authors arrived at the same results as 
did Pettenkofer and Voit. 
A more exact exposition is demanded by the first-mentioned experiments 
carried out in the respiration calorimeter. They were begun by Benedict, 
Dr. Joslin, and myself in collaboration, when I had gone to Boston for the study 
of the respiration calorimeter. Our work in common concerned itself with the 
first twelve experiments. I reported briefly concerning these experiments at 
the Congress for Internal Medicine, 1909; and there, on the ground of the 
comparison of the figures obtained with those obtained with a normal subject, 
whom I had especially selected for comparison on account of his low body 
weight, came to the conclusion that the resting-exchange of the three diabetics 
investigated by us, and especially that of one very severe case, was not es- 
sentially raised. Later Benedict and Joslin on the ground of their more numer- 
ous experiments came to another assumption. Since that time I have let 
the matter rest on account of other work. Only now at the preparation of this 
chapter have I reviewed the experiments, and also the large experimental 
material of Benedict and Joslin, and have attained the conviction that I must 
hold fast to my original opinion. As the question is of importance, I shall 
contribute the first twelve experiments, that Prof. Benedict has in praiseworthy 542 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
manner allowed me to publish separately in extenso. There will be found in 
them some details that seem to me to warrant an exact exposition. 
First, a few remarks concerning method. The experiments herewith published were 
carried out in a so-called calorimeter. Therefore in the fasting experiments we were con- 
cerned with estimation of the metabolism in a quiet, comfortable, sitting-position. It is 
to be expected that the values-obtained in the fasting-experiments do not fully represent the 
basal metabolism, but lie somewhat higher. The figures republished by me differ somewhat 
here and there from those in the corresponding experiments of Benedict and Joslin. I 
cannot state the reason for this, the differences are however so slight that they do not influence 
the total result in any way. As concerns the exact details of the arrangement of the experi- 
ments, I refer to the work of Benedict and Joslin. In the tables will be found the heat- 
production as well as the heat-elimination. The values for the heat-elimination were 
estimated, by adding to the value shown by the calorimeter, also the vaporization heat of 
the water produced (amount of produced water 0.568). The calculation of the heat pro- 
duction was based on the behavior of the body-temperature. 
If, for example, the body temperature during an experiment rose, there was added to 
the amount representing the elimination of heat an amount that would be necessary to 
warm the person under experimentation the corresponding tenths of a degree. If the 
temperature fell, the loss of heat had to be subtracted from the figures representing heat 
elimination. Ideal values for the heat production we do not find, however, as the indi- 
vidual organs may possess different temperatures, and, for example, after ingestion of food 
the fall of heat from the liver to the mouth or rectum, where the temperatures are taken, 
ought to be greater than during fasting. Perhaps this is the reason that Benedict and 
Joslin do not give values for heat-production in their experiments. 
Experiment No. I.—Person under Experimentation A 
Date 
Period 
Amount of 
urine 
Dextrose 
N 
D:N 
CO2 
O2 
R.Q. 
h2o 
Pulse 
Tempera- 
ture (F.) 
Heat elimi- 
nation 
Heat pro- 
duction 
Polar- 
iza- 
tion 
Titra- 
tion 
Nov. 4, 1908 
Preceding period 
( 
4 8 
.... 
Fasting 
j 
.... 135.8 
l 
12—2 o’clock 
118.3 
3-2 
3-36 
0.81 
4-is 
38.5 
40 . I 
0.699 
41.4 
81 
137.6 
Sum from 10 
to 
2 o’clock 
288.0 
8.26 
1.85 
77.2 
80.3 
• • • J 273.42 
1 The first period of 8 to io o’clock I have omitted, as the values in comparison with those in the later fasting- 
experiments were non-serial. Probably the patient, who was in the apparatus for the first time, was restless. 
Date 
Period 
Amount of 
urine 
Dex1 
Pola- 
riza- 
tion 
rose 
Titra- 
tion 
N 
D:N 
O 
O 
02 
R.Q. 
H20 
Pulse 
Tempera- 
ture (F.) 
Heat elimi- 
nation 
Heat pro- 
duction 
Nov. 5, 1908 
220 gm. 1 
meat 1 
N = I 
10.22 gm. ( 
Preceding period 
7.24— 9.22 o’clock.. 
8.22-10.28 o’clock.. 
10.28- o’clock.. 
12.28- 2.28 o’clock.. 
303 • 1 
210.1 
328.6 
184.2 
7-9 
6.7 
10.6 
5-2 
8.91 
7.0 
9.78 
5-65 
1.46 
1.1 
1.49 
1.39 
6.1 
6.33 
5.04 
4.04 
42.9 
43 9 
41.0 
44-3 
43 9 
0.721 
0.680 
28.6 
42.4 
35 -1 
84 
82 
81 
145-7 
148.8 
140.9 
Sum (urine fr 
om about 5 hours) .... 
22.5 
22.43 
3.98 
127.8 
Experiment No. II.—Person under Experimentation A GENUINE DIABETES MELLITUS 
543 
O 
Dextrose 
E - 
Date 
Period 
Amoun 
1 urine 
P°ifr- Titra- 
tfon ; 
N 
D:N 
CO2 
O2 
R.Q. 
H2O 
Pulse 
& a) 
Heat eli 
nation 
Heat p 
ductic 
Nov. 18, ’08 
Preceding period 
7 -8.52 o’clock.. 
8.52-10.52 o’clock.. 
102.2 
3.88 
3.87 
3-45 
0.80 
4.84 
4-3i 
97.9 
2.94 
0.80 
38.5 
47-9 
69 
98.1 
138.6 
139 
98.1 
Fasting.... 
10.52-12.52 o’clock.. 
S8.7 
I .29 
1.36 
o.55 
3-00 
37.8 
38.2 
0.721 
36.3 
67 
98.0 
135-9 
134 
12.52— 2.52 o’clock.. 
50.2 
0.60 
0.96 
o.5S 
1-74 
37.9 
40.7 
0.677 
45-8 
65 
97.8 
131 -5 
127 
Sum 
206.8 
4 83 
5-77 
I .90 
II4.2 
406.0 
400 
Experiment No. III.—Person under Experimentation A 
Experiment No. IV.—Person under Experimentation A 
Nov. 19, ’08 
r 
237 gm. 
meat = 
9-91 gm. 
N 
Date 
Preceding period 
7 —8.50 o’clock.. 
8.50-10.50 o’clock.. 
10.50- o’clock.. 
12.50- 2.50 o’clock.. 
n> 
3. 
0 
P. 
O' 
C/l 
tO 
M W tO M 
GJ VO VO M 
4s* GJ **4 "4 
in GJ O 
Amount of 
urine 
w 
O 
O' 
GJ On O GJ 
~4 M O **4 
On VO M 4^ 
=51 
2 e> to 
P 1 h 
D 
X 
c4 
*-t 
O 
CD 
OO 
M 
On O GJ 
to *4 to vO 
Gl O GJ O 
j+.H 
O ct- 
a 
p p 
4- 
00 
GJ 
M M M O 
GJ Gi 00 00 
00 00 ~4 Gl 
2 
GJ 
K) 
4* 
GJ Gi 4* 
0 to Gl 
00 4* -4 VO 
D 
£ 
4* 4^ 
to Gl 4* 
to 00 
O 
O 
G> 
GJ 
00 
4^ 
■4* On GJ 
O Gl GJ 
9 
O 
\o 
OOO 
O' 0 
VO O Gl 
00 VO GJ 
0 
Gl Gl 
Gl GJ O 
-4 GJ 00 
a 
0 
O' O' "4 
O' 00 to 
Pulse 
O • VO • VO • O 
00 . 00 • 00 . 00 
M • On • Gl • GJ 
Tempera- 
ture (F.) 
4* 
O' 
4* 
O 
GJ VO 00 
Heat elimi- 
nation 
4^ 
ON 
O 
Gl O' 
O m 0 
Heat pro- 
duction 
1 Average. 
Experiment No. V.—Person under Experimentation A 
g* o, o 
X TO «n ?■ 
►T 3 + *3 >o 
o*g u 
C/l 
O 
00 
Date 
Preceding period 
7 —9.20 o’clock.. 
9.20- .20 o’clock.. 
11.20- 1.20 o’clock.. 
1.20- 3.20 o’clock.. 
TJ 
0 
3. 
0 
PL 
Gl 
to 
o 
00 
M tO 
VO 00 GJ O' 
VO 'O w 00 
Gi Gi 00 4^ 
Amount of 
urine 
GJ 
O 
GJ 
00 
«*4 -£* *4 GJ 
W Gl O' 4^ 
-4 VO W K) 
g.K’g 
§ ? S 
O 
ct> 
X 
O 
<T> 
■*4 
VO 
Gl 00 4^ 
vo 4a- 4a. O 
O 4* Gi GJ 
0 ?V 
t>3 
to 
«*4 
O 
O O m O 
O VO M Gl 
4a. NO GJ VO 
2 
. . • O' 
. . . -O 
D 
00 
o 
GJ GJ 4^ 
-4 00 to 
GJ GJ 4*. 
O 
O 
<» 
GJ GJ 4a. 
•*4 00 M 
M *4 4^ 
O 
o 
-4 
GJ 
to 
OOO 
<1 -4 
GJ K) 4a. 
O O Gl 
p 
4* Gl Gl 
00 to 00 
Gl O 00 
E 
O 
O' O' *4 <1 
4*. 00 to to 
Pulse 
vo • O • vo O 'O 
~4 • ~4 • CO CO 4 
O' • 00 • O O 00 
Tempera- 
ture (F.) 
to 
O' 
W M M 
GJ 4a. Gl 
to W GJ 
M 00 “4 
Heat elimi- 
nation 
4*. 
o 
M M M 
to GJ Gl 
00 *4 4a. 
i Heat pro- 
j duction 544 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
O 
Dextrose 
Tempera- 
ture (F.) 
8 
O rj 
Date 
Period 
Amoun 
urine 
Pola- 
riza- 
tion 
Titra- 
tion 
N 
D:N 
O 
O 
o2 
R.Q. 
H20 
Pulse 
Heat eli 
natio: 
Heat pr 
ductio 
Nov. 24. ’08 
Preceding period 
7 —9.20 o’clock. 
175-6 
5-27 
7.46 
1.23 
6.06 
70 
97 9 
75 gm. 
9.20-1 x .20 o’clock. 
237.6 
16.63 
17-73 
I . II 
39-8 
42.2 
0.687 
58.8 
72 
98.0 
146.1 
147 
roll +25 
gm. dex- 
11.20- r. 20 o’clock. 
214.2 
15.85 
16.32 
I .04 
37.8 
37-3 
0.735 
53-9 
67 
98.05 
135.7 
133 
torse 
97-95 
1.20- 3.20 o’clock. 
108.5 
7.27 
7.92 
0.67 
37-5 
37-5 
0.726 
49-1 
63 
135-5 
132 
97-8 
560.3 
39-75 
41-97 
2.82 
1151 
117 . i 
0.7151 
161.8 
417.3 
412 
Experiment No. VI.—Person under Experimentation A 
Nov. 9. ’08 
Fasting. 
1 
Date 
Preceding period 
7 - 9.02 o’clock. 
9.02-1 r .02 o’clock. 
r r . 02- i.02 o’clock. 
1.02— 3.02 o’clock. 
CD 
2. 
o’ 
o* 
o 
o 
M N) 
O' vO CaJ 4- 
tO M O' M 
O C/l O' CJ 
Amount of 
urine 
VO 
Ui 
n 10 cn o 
CJ *>4 4* m 
>-< 4* O' Cj 
o N o 
3 <f f 
0 
cd 
X 
*-* 
o 
CD 
'C 
tO CJ O' M 
m 00 o 4^ 
4* m to vo 
O S-* 
a *■* 
? 
Co 
■S 
O M M M 
VO O to oo 
O O 4* 
z 
to Co O' 
00 oo m 
Co to CJ CJ 
o 
z 
4^ 
4^ 
4^ 
4>* ca 
Ca ->4 m 
VO C/l O 
o 
o 
4^ 
O' 
O 
Ca 
O' vo C 
O' 4* O 
o 
o 
Cn 
O O O 
*4 O' -*4 
M VO tO 
-4 vo vo 
O 
C/l C/l 4^ 
OJ vo O' 
•O H C/l 
w 
6 
*4 «*4 
~4 -4 ~4 
Pulse 
vO • vo • vo • ’O 
00 • 00 • 00 • VO 
O • • *4 • to 
Tempera- 
ture (F.) 
C/i 
O 
00 
M M M 
O' -4 
O w O' 
M CaJ 
Heat elimi- 
nation 
C/1 
o 
4> 
-4 O' O' 
O -l '4 
Heat pro- 
duction 
Experiment No. VII.—Person under Experimentation B 
1 Average. 
Date 
Period 
Amount of 
urine 
Dextrose 
N 
D:N 
CO2 
02 
R.Q. 
H2O 
Pulse 
Tempera- 
ture (F.) 
Heat elimi- 
nation 
Heat pro- 
duction 
Pola- 
riza- 
tion 
Titra- 
tion 
Nov. 10, ’08 
Preceding period 
8 — 8.54 o’clock. 
214.7 
8.46 
1.03 
8.2 
98.85 
f 
8.54—10.54 o’clock. 
7.42 
I .07 
53-7 
57-3 
41.9 
77 
194 3 
196 
98.9 
10.54-12.54 o’clock. 
268.8 
9-95 
54-2 
57-7 
0.683 
67.2 
77 
190. I 
193 
13 ■ 9 gm. 1 
99 0 
l 
12.54- 2 • 54 o’clock. 
2.14 
3-23 
58.3 
59-3 
0.715 
45-9 
77 
193 6 
169 
98.2 
655.9 
24.38 
5.33 
174-3 
0.6931 
155.0 
578.0 
558 
Experiment No. VIII.—Person under Experimentation B GENUINE DIABETES MELLITUS 
545 
Date 
Period 
Amount of 
urine 
Dextrose 
N 
D:N 
CO2 
O2 
R.Q. 
H2O 
Pulse 
Tempera- 
ture (F.) 
Heat elimi- 
nation 
Heat pro- 
duction 
Pola- 
riza- 
tion 
Titra- 
tion 
Nov. 16, ’08 
f 
Fasting.... j 
Preceding period 
7 — 9.21 o’clock. 
9.21- .21 o’clock. 
11.21— 1.21 o’clock. 
1.21- 3.21 o’clock. 
266.2 
152.6 
105.4 
161.2 
15.17 
7.02 
4.22 
2.10 
14-iS 
7.32 
4-75 
2.53 
2.26 
1 -49 
1.25 
0.85 
6.26 
4.88 
3- 80 
2.98 
82 
80 
79 
80 
46.4 
44.2 
46.4 
99-0 
98.5 
162.0 
159-9 
156.7 
98.3 
98.6 
419.2 
1334 
14.60 
3 59 
137-0 
478.6 
Experiment No. IX.—Person under Experimentation B 
Experiment No. X.—Person under Experimentation B 
O 
Dextrose 
Tempera- 
ture (P.) 
Ir, 
g a 
Date 
Period 
Amoun 
urine 
Pola- 
riza- 
tion 
Titra- 
tion 
N 
D:N 
CO2 
O2 
R.Q. 
H2O 
Pulse 
Heat eli 
natioi 
Heat p 
ductio 
Nov. 17, ’08 
Preceding period 
I 
7 - 8.07 o’clock. 
II 
127.0 
7.11 
7-19 
0.92 
7.82 
8.07- 9.26 o’clock. 
7.26—11.26 o’clock. 
165.4 
275.3 
8.93 
1915 
9-57 
14-37 
90 
83 
I. Chief f 
2.26 
6.36 
52.0 
54-1 
0.699 
60.0 
990 
174-3 
160 
period 
98.5 
meat, < 
16.9 gm. 1 
11.26- 1.26 o’clock. 
215.7 
10.04 
11.04 
2.20 
5 • 0 
52.0 
53-7 
0.705 
58.4 
76 
173-7 
168 
3 • 10 
2.74 
98.3 
N l 
1.26- 3.26 o’clock. 
165.0 
8.13 
8.48 
55-2 
57-6 
0.697 
60.2 
80 
173-8 
177 
98.4 
656.0 
37 32 
33-89 
7.56 
159.2 
165-4 
0.7001 
178.6 
521.8 
505 
1 Average. 
Experiment No. XI.—Person under Experimentation C 
O 
Dextrose 
Tempera- 
ture (F.) 
e - 
g a 
Date 
Period 
Amoun 
I urine 
Pola- 
riza- 
tion 
Titra- 
tion 
N 
D:N 
CO2 
02 
R.Q. 
H2O 
Pulse 
Heat eli 
natior 
P*. O 
4^ 
a w 
Nov. II-I2 
Preceding period 
1908 
7 —8.50 o’clock. 
86.8 
2.34 
I . IQ 
2.23 
1.4 
8.50-10.50 o’clock. 
95-4 
1.72 
1.94 
1.38 
48.9 
46.8 
0.759 
46.8 
82 
98.6 
181.7 
172 
98.2 
Fasting.... 
10.50-12.50 o’clock. 
69.7 
0.56 
0.84 
I .09 
0.76 
47-5 
45-8 
0.753 
43-8 
81 
98.2 
161.7 
162 
12.50- 2.50 o’clock. 
55.2 
0 . II 
0.28 
0.93 
0.29 
47-4 
52.1 
0.661 
52.1 
80 
157.1 
165 
98.5 
220.3 
2.39 
3.06 
3.40 
0.91 
143-8 
144.7 
0.7221 
500.5 
499 546 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
Date 
Period 
Amount of 
urine 
Dextrose 
N 
D:N 
O 
O 
• 02 
R.Q. 
h2o 
Pulse 
Tempera- 
ture (F.) 
Heat elimi- 
nation 
Heat pro- 
duction 
Pola- 
riza- 
tion 
Titra- 
tion 
Nov. 12-13, 
Preceding period 
1908. 
r 
8.58-10.58 o’clock. 
272.5 
10.90 
9.81 
3.11 
316 
59-7 
59-2 
0.734 
42.3 
88 
99-2 
199.9 
184 
Meat 
98.6 
17-39 | 
10.58-12.58 o’clock 
244.0 
9.76 
10.22 
3.58 
2.56 
59.8 
58.4 
0.744 
66.6 
89 
196.5 
207 
gm. N 
99 0 
l 
12.58- 2.58 o’clock. 
157.2 
5.66 
5.81 
307 
1-9 
57-4 
57.8 
0.722 
46.1 
87 
191.8 
176 
98.4 
25.84 
976 
176.9 
588.2 
567 
Experiment No. XII.—Person under Experimentation C 
The Fasting Experiments 
The rest-fasting experiments are summarized in an easily reviewed 
manner in the following table: 
Rest-fasting Experiments 
Person under ex- 
periment 
Date 
Age 
Weight 
Height 
D:N 
C02 
02 
R.Q. 
Calories 
Per 
hr. 
P er 
kg. 
and 
min. 
Per 
kg. 
and 
min. 
Per 
hr. 
Per 
kg. 
and 
hour 
No. I. A 
Nov. 4.. . . 
47 
49.1 
171 
(4 • 77)—4.92 — 4.7i—4 ■ 15 
3-34 
4-76 
0.688 
1-39 
Diabetes mellitus 
No. III. A 
Nov. 18.. . 
47 
52.8 
171 
66.6 
No. VII. B 
173 
(6.131-4.83 — 3.82-2.43 
24.07 
3 -36 
4.76 
84.0 
I .40 
Diabetes mellitus 
4 
No. IX. B 
173 
(6.24)-4.88 — 3.80-2.98 
22.52 
3-4 
4 33 
77.8 
1 .30 
Diabetes mellitus 
No. XI. C 
Nov. 11.. . 
23 
59.2 
176 
(2.23)-! . 40 — 0.76-0.29 
23-93 
340 
4.76 
0.722 
83.17 
1-45 
Diabetes mellitus 
A. W. W. normal 
Mar. 15.. . 
57.0 
3 65 
4.10 
0.840 
76.55 
1.37 
1 Average. 
|l laid these tables before the congress in my communication. It will 
readily be understood why I on the data of these experiments believed that 
there was an essential increase in the production of calories in diabetes mellitus. 
The production of calories per kilogram per hour is on the average in the diabetics, 1.34, in 
the normal person, 1.345; the oxygen consumed is in the diabetic greater throughout. It is 
on the average, 4.59, in the normal person, 4.24. 
I shall speak later as to the cause of the greater oxygen consumption in 
diabetics. 
The carbonic acid production is on the average in diabetics, 3.26, in the normal person, 
3-65- GENUINE DIABETES MELLITUS 
547 
Hence the production of carbonic acid is somewhat less in the diabetics. 
The respiratory quotient is very low throughout in the diabetics, cor- 
responding to the circumstance that all the cases investigated were moder- 
ately severe cases. Also the person C may be counted with the moderately 
severe cases. 
The question that I asked myself at the reworking-up of the experiments 
was the following: Do there exist severe cases of diabetes mellitus that in 
spite of the copious elimination of sugar show no increase in heat production 
during fasting? As there were only a relatively few experiments at my dis- 
posal for the solution of this, conclusions as to the question were merely ten- 
tative. The diet which the persons tested received on the days before 
the experiments were mixed. It contained, however, neither abundant 
carbohydrate or protein. As all experiments began fourteen hours after 
the latest ingestion of food and lasted six hours, so that the experiment lasted 
for the fourteenth to twentieth hours after the latest ingestion of food, the 
quotient D:N observed must be regarded as high. Only in person C did the 
quotient D:N fall almost to o during the period of experimentation. In 
the first persons under experimentation the ammonia value was also raised very 
high. In person A the /3-oxybutyric acid in the urine was also estimated 
and found in not inappreciable quantity. I have not included these figures 
in the tables and refer to the detailed works on Benedict and Joslin. In such 
severe cases, as persons A and B are, one must expect under conditions of 
experimentation that there would have been an appreciable result, if the 
heat production in severe diabetes is really increased. It was not the case, 
however. We have already seen previously that the chemical observations 
allow this result to be anticipated. 
On the study of the extensive and carefully detailed experimental material 
contributed later by Benedict and Joslin I have arrived at the conviction 
than an increase of heat production in diabetes mellitus cannot be inferred 
also from this material. The explanation of the deviating conclusions of 
Benedict and Joslin is to be sought, I think, in the fact that they did not take 
into account the difference in body weights of the normal persons and diabetics 
they investigated. I here quote in descending series the body weights of 
the normal individuals and the diabetics. 
Normal individuals: 83.5-79.7-74.4-67.6-66.5-66.0-59.6-48.5. 
Severe diabetics (weight during the experiment): 67.1-59.0-54.9-52.7- 
51.8-48.8-48.0-40.5. 
A glance at this summary shows the great difference in body weight 
between the normal and the diabetic individuals. 
When we compare with one another the heat production of those cases 
that have the same body weight, we obtain the same result that I found in 
the preceding experiments. This is seen in the following summary: 
Mrs. B. 
Diabetic G 
Weight 
67.0 
Height 
161.0 
178.0 
Calories per kg. per hr 
1.15 (bed calorimeter) 548 
DISEASES OE THE INSULAR APPARATUS OF THE PANCREAS 
L.E.E. 
Diabetic F 
Weight 
59-6 
S9-o 
Height 
i79-o 
176.0 
Calories per kg. per hr 
i-47 
i-39 
Dr. R. 
Diabetic A 
Weight 
48.5 
48.8 
Height 
167.0 
171.0 
Calories per kg. per hr 
i-39 
i-34 
The heights of the persons under experimentation are not entirely alike. 
In the cases of Mrs. B. and diabetic G the difference is indeed appreciable. 
In the other two pairs the difference would not signify much. In addition, 
in one case the difference favors the normal individual, in the other it favors 
the diabetic. We see from this summary that the heat production in cases of 
severe diabetics does not differ essentially from that of the equally heavy normal 
individual. 
Benedict and Joslin themselves made the objection that their material 
is not uniform in respect to body weights. They sought to rule out this 
objection in the following experiment (Case C. S., 227). The first investiga- 
tions were undertaken at a time that the patient weighed 62.4 to 65.4 kg. 
They found at that time a heat production between 1.23 and 1.40 per kilo- 
gram per hour. As the patient had later fallen away to 54.9 kg., the heat pro- 
duction (in one experiment) was 1.26 per kilogram per hour. I can ascribe 
to this one experiment no demonstrative value. It is a known law that in 
normal individuals the metabolism lies higher the smaller and lighter the indi- 
vidual is. This is readily seen from the figures that Benedict and Joslin 
themselves have summarized. 
Investigations with Zuntz Geppart apparatus (p. 168): 
Individuals between 65 and 43.2 kg. 02 requirements per kg. 
per minute ; 4.08 c.c. 
Individuals between 66 and 88.3 kg 3.5 c.c. 
Investigations with the respiration calorimeter, during sleep (p. 168): 
Individuals between 64.1 and 55 kg 4.04 c.c. 
Individuals between 66.1 and 84.7 kg 3.56 c.c. 
There does occur in severe diabetes a circumstance moreover that must 
be considered especially. It is known that in the obese the basal metabolism 
is relatively low, as the obese person possesses little respiring protoplasm 
in relation with body weight. The severe diabetic is, however, always strongly 
drained of water (as is shown in investigation on the water-contents of the 
organs of those dying in coma). Moreover, in severe diabetics almost every 
trace of fat has disappeared from the ordinary sites of fat-deposition, as can 
be seen at almost every autopsy. If now in addition the protein constituent 
suffers severe damage in the later stages, the mass of respiring protoplasm 
in severe diabetes will be still greater in proportion to body weight. I believe, 
therefore, that even if on calculation per kilogram of body weight there is 
found in severe diabetics a slight increase of heat production, this would 
not mean much. GENUINE DIABETES MELLITUS 
549 
Already Lusk has pointed out the dissimilarity of the material compared 
by Benedict and Joslin, and from this has drawn the conclusion that the increase 
of heat production found by Benedict and Joslin is less high than these authors 
suppose. From the calculations and discussions cited I must, however, conclude 
that the demonstrations of an increase of heat production in severe diabetes, 
has with the material at hand, not been supplied.1 
Now as concerns the oxygen requirements, this in severe cases of diabetes 
is undoubtedly increased. This may be seen in my tables. I find that the 
oxygen requirements with otherwise similar heat production average in the 
diabetics 4.59, in the normal individuals 4.24. 
1. This is also to be seen in the figures of Benedict and Joslin:2 That there 
is an increased heat production, however, cannot be inferred from the increased 
demand for oxygen. Already Leimdorfer mentioned that in the severe diabetic 
through the loss of bodies very rich in oxygen, in the urine (sugar, ketone 
bodies), the relation between oxygen consumption and carbonic acid pro- 
duction is disarranged. Direct calorimetry actually shows in the experiments 
made at the Boston Institute, that in diabetics with normal heat production, 
the oxygen consumption is increased. 
2. In the experiments with the administration of meat the specific dynamic 
energy of the protein and the time consumed in the decomposition of this 
in severe diabetes was investigated. The question can, however, scarcely 
be discussed, because the number of experiments is too small. 
3. The experiments with the administration of carbohydrates seem on 
the contrary to be worthy of mention. In these investigations there was 
sought to be determined whether in short periods (two hours) the respira- 
tory quotient did not temporarily rise. The two experiments on this sub- 
ject agree very prettily. In normal individuals, on the administration of 
just as much carbohydrates, we would expect an increase of the respiratory 
quotient to nearly 1.0. In the two experiments on the diabetic the respira- 
tor)r quotient was hardly influenced, however. In the severe diabetic, there- 
fore, the administration of carbohydrates does not suffice to increase the combustion 
of sugar. These experiments agree very prettily with the experiment of 
Falta, Grote, and Staehelin on the dog without a pancreas. Also here the 
respiratory quotient was not increased on the administration of sugar. In 
both experiments on the diabetic the heat production rose somewhat in the 
first two-hour periods. This rise is perhaps to be referred to the increased 
work of digestion. 
The manifestations on the part of the vegetative nervous system in 
diabetics has only recently been made the subject of study. I have already 
1 Remark on Correction.—Also in a second publication that Benedict and Joslin made a short 
time ago concerning this subject (A Study of Metabolism in Severe Diabetics, Carnegie Institu- 
tion of Washington, Publication No. 476, 1912), this is shown in an indubitable manner. Here 
are found statements only as to the carbonic acid production and the oxygen requirements; in the 
severe diabetics there was a CO2 elimination (per kg. per min.) of 3.13 c.c. (according to my calcu- 
lation 3.25); in the normal individual of like weight this was 3.13. 
2 In the second publication, 4.54 O2 per kilogram per minute in the severe diabetics as against 
3.75 in normal individuals of the same weight. 550 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
in the discussion of the experimental physiology mentioned Lowi's reaction. 
Its absence shows an increased excitability of the dilator pupillae (innervated 
by the sympathetic). We have tested this reaction in human diabetes on 
a large amount of material and have found it positive in a number of cases. 
We could not demonstrate that it is connected with the intensity of the glycosuria 
or ketonuria. We sometimes found it positive in cases in an aglycosuric 
condition, and in other severe cases; even in the presence of coma, it was 
negative. The glycosuric action of adrenalin in diabetes has been studied 
by Newburgh, Nobel, and myself. It was found that in cases in the agly- 
cosuric state, adrenalin in almost all cases leads to a distinct increase 
in the elimination of sugar. On the contrary, in a certain number of these 
aglycosuric cases, the action was negative. There were among these cases 
that had to be regarded as severe, cases that only on the complete withdrawal 
of the carbohydrate and strong limitation of the protein would be main- 
tained sugar-free, and that on the administration of slight amounts of 
carbohydrates responded with glycosuria. These investigations show the inde- 
pendence of the nervous and alimentary factors, at least in the aglycosuric 
state. An especially intense action of the adrenalin on the heart and vas- 
cular system in diabetes could not be shown. On the contrary, among the 
cases investigated were a number in which enormous adrenalin-diuresis 
supervened. Among the numerous non-diabetes cases on whom we tested 
the diuretic action of adrenalin, we never saw an action so intense. It is 
especially worthy of remark that among the diabetics who resisted so in- 
tensely, were also cases in an aglycosuric condition. Therefore in many a 
diabetic the vessels of the kidneys are in an abnormally irritable state, [a fact] 
which was not known before. I might take advantage of this opportunity to 
add some remarks concerning the diuresis in diabetes mellitus. Ordinarily we 
find a parallelism between the intensity of the elimination of sugar and the 
amount of the urine. It has been known for a long time that there are excep- 
tions to this rule. There are cases in which a long period of increased gly- 
cosuria precedes the occurrence of diuresis (v. Noorden). There are further 
cases in which, as v. Noorden likewise emphasizes, the polyuria outlasts the 
glycosuria for a long period. Then there are cases in which, in spite of high 
percentage of sugar, the amount of urine is very slight. Naunyn reports, for 
example, a case in which about 8-9% of sugar was excreted, with 2 
liters of urine. In another case there was just as much sugar, and a specific 
gravity of 1040, with urine amounting to only 1200-1400 c.c. We designate 
these cases diabetes decipiens. On the other hand there are cases with con- 
siderable polyuria with relatively little elimination of sugar, especially if 
the diabetes came as a result of head injury. Naunyn reports, indeed, a case 
of pure uncomplicated diabetes who constantly, with a diuresis of 5-6 liters 
eliminated only 1.2-2% of sugar. Hence the elimination of sugar 
is certainly not the only cause of the increased diuresis, and perhaps not 
the principal cause. According to the experiments previously mentioned the 
increased diuresis has its foundation in an especial sensitiveness of the kid- 
ney vessels to an irritant circulating in the blood. We can summarize the GENUINE DIABETES MELLITUS 
551 
observation set forth in the statement that in many cases of diabetes mellitus 
a heightened excitability of certain organs innervated by the sympathetic {dilator 
pupillce, liver, kidney, etc), may eventually also exist in the aglycosuric condition. 
The excitability of the autonomous nerves in diabetes mellitus is not 
diminished throughout. We have even in numerous experiments in the 
advanced stage of diabetes found strikingly intense actions of pilocarpine 
on the secretion of sweat and saliva. Also the miotic action of pilocarpine 
is very distinctly pronounced. That the diabetic glycosuria is not diminished 
by pilocarpine, is here mentioned because the fact again illustrates the inde- 
pendence of the nervous and alimentary factors. In advanced cases there 
are found many kinds of manifestations that perhaps may even point to a 
heightened irritability in many territories of the autonomous nervous system. 
We observed in almost all very severe cases high-grade obstipation, whose 
spastic nature was shown on the palpation of the sigmoid flexure and through 
the appearance of the stools. Up to the present I have not seen similar state- 
ments in the literature. Purgative measures are of service in such cases 
only when they are given in rather large doses, and then defecation is rather 
painful. Such patients prefer enemas to purgatives. The spastic nature 
of this obstipation is demonstrated too by the prompt action of a subcutaneous 
injection of atropine (i mg.). On what ground there occurs the development 
of such a spastic obstipation is difficult to say; it can hardly be due to the 
lack of bread in the diet, as these cases on account of considerable ketonuria 
could not long have been kept on a carbohydrate-free diet, and the diet was 
in addition always very rich in cellulose (vegetables). 
I would further mention here an observation which I have likewise not 
been able to find in the literature. We found in all severe cases of diabetes 
in which the examination was made, a relative or absolute increase in the 
mononuclear cells in the blood. As the total count of the leucocytes was 
always normal, there always existed, then, a relative and absolute diminution 
in the number of neutrophilic cells. It is possible that chemotactic influences 
lie at the basis of this. If we regard this as in connection with the spastic 
obstipation, we could consider it as the expression of a high tonus of the 
autonomous nerves. 
I would not leave the description of the manifestations of the vegetative 
nervous system without mentioning a finding that probably belongs here. 
In investigations carried out together with Newburgh and Nobel, we found on 
the administration of thyroidin to nondiabetic individuals a reduction of the 
fall of blood-pressure from heart to periphery. Investigations on the blood- 
pressure in the brachial artery with Riva-Rocci ’s apparatus showed no change, 
while the investigation at the finger with Gartner’s instrument showed in 
many cases a distinct fall of the blood-pressure. In the diabetics we found, 
however, after the use of thyroidin a distinct, and in many cases, an appreciable 
increase in blood-pressure with both methods; this increase often outlasted 
the thyroidin medication for days. We could also observe this in cases 
in the aglycosuric condition. It is very well likely that this increase of blood- 
pressure is brought about through an enormously increased activity of the 552 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
chromaffin tissue. If this is so, it must be assumed that in diabetes there 
exists an enormously increased excitability of this organ or of the nervous centers 
regulating its activity. 
Also the erethism of the vessels of the skin speaks for an increased excit- 
ability of the vegetative nerves. The red face of the diabetic, lending as 
it does such a characteristic appearance to the advanced case, is well known. 
Also there mostly exists distinct dermographism. On exposure the skin 
often reddens to far over the trunk. It is known that the skin of the severe 
diabetic is often very dry on account of the severe draining of the dry body of 
its water, yet there do not rarely occur sweats, even in cases that show no 
manifestations of a complicating tuberculosis of the lungs. 
Finally I would mention a group of diabetics in whom the conditions 
of hyperexcitability and hyperirritability of the sympathetic nervous system 
are still more prominent. These are for the most part diabetics in middle 
life, who overwork much and who in their occupations are exposed to great 
excitements and cares; moreover, they may have sustained traumas. Psychic 
excitements are here an important factor in the influencing of the glycosuria. 
The blood-pressure is often raised not inappreciably, but in spite of this, 
traces of albumin are found only transitorily, and here and there is seen an 
entirely isolated cast. In such cases, adrenalin acted glycosuric in the agly- 
cosuric state; the Lowi’s reaction was positive. We may perhaps designate 
these cases as hypertonic diabetes. 
As example I cite the following case: 
Observation LXIX.—G. K., forty-eight years old, conductor; entrance into the first 
medical clinic on Sept. 6, 1912. In the year 1904 the patient suffered a train injury. In 
it he was thrown to the floor, and the right thigh was contused. In July, 1910, he fell 
from a wagon, immediately after which he had the sensation as if something internal had 
torn. Since this time, always sensitiveness to pressure in this region, and very nervous. 
In 1911 unquenchable thirst with decrease of the previous appetite. The skin was dry, 
the potentia coeundi fell off very much. On entrance there was found 3.7% sugar and 
a distinctly positive acetone reaction. The sugar-elimination after the ingestion of 75 gm. 
of roll and a third of a liter of cream was about 80 gm. dextrose, the excretion of acetone 
was about 3 gm. On withdrawal of carbohydrates the sugar sank rapidly, the oat-meal 
treatment that was instituted brought about only traces of sugar, the acetone disappeared. 
The tolerance rose very quickly, so that after six weeks the patient bore 60 gm. roll, 30 gm. 
rice, and 60 gm. potato without excretion of sugar. 
The amount of urine during the sugar-free period was also appreciably increased. 
Mostly there were values of 2000. At the beginning also values between 3000 and 
4000. The specific gravity was raised only in the first day. Then it sank quickly to about 
1010, and later showed great variations; it mostly lay low, around or lower than 1010, and 
temporarily would increase to 1020. 
The patient was very excitable, the patellar reflexes were lively, the blood-pressure was 
high, varying according to measurements by the Riva-Rocci apparatus between 130 and 
150. Correspondingly the arteries showed increased tension, but there were no signs of 
arteriosclerosis. The heart dulness was broadened to a slight extent toward the left. In 
the urine was found on repeated examinations at most minimal traces of albumin. No 
casts were found in the centrifugated fluid. Lowi’s reaction was positive. 
In the aglycosuric condition 1 mg. of adrenalin was injected many times. Regularly 
there occurred a not inappreciable elimination of sugar, once to 6 gm., in the hours after 
the injection. One of these experiments took place at the time that the tolerance of the GENUINE DIABETES MELLITUS 
553 
patient was already essentially increased. Further the diuretic action and especially 
the action on the heart and vessels was strongly marked. In the experiment mentioned' 
the blood-pressure rose to 180. 
The investigation of the respiratory gas-exchange {Dr. Bernstein) always showed nor- 
mal CO2 production, and mostly an increased 02 consumption. The gas-exchange after 
an adrenalin injection was investigated twice. Both times the oxygen consumption and 
carbonic-acid production rose strongly, but the respiratory quotient was not influenced. 
I cite the following experiment as an example: 
I C02 
Per kg. per min. \ O2 
Per kg. per min. 
RQ 
Before 
217.6 
| 
• 2.75 317.7 
4.02 
0.685 
20 min. after injection of i 
mg. adrenalin 
250.0 
372.5 
0.671 
In this experiment the injection led to an elimination of 6 gm. of sugar. The action of 
adrenalin was therefore intensive in all respects, only the raising of the respiratory quotient 
was wanting. 
I would here mention quite briefly the complications of diabetes mellitus. 
In diabetes in men, impotence is one of the most frequent complications; 
only very rarely does there occur increased sexual desire. With the former is 
often found an atrophy of the testicles. In the diabetic women, menstruation 
is disturbed only in the severest cases, but on the contrary, conception is 
rare. In men, there is never observed a retrogression of the secondary sexual 
characters. The deleterious influence affects therefore only the generative 
part of the function of the sexual glands. The vulnerability of the tissues, 
the falling out of the teeth, the suppurations, diabetic cataract, furunculosis, 
the xanthelasma, the pruritus, the rheumatoid pains, the diminution of the 
reflexes, and the degenerations of the posterior column are here merely briefly 
indicated. These symptoms are for the most part brought into a relation 
of cause and effect with the constant hyperglycemia, yet this explanation is for 
very many of the cases as yet very uncertain. This is also true for the prema- 
ture arteriosclerosis of the diabetic with its sequel, diabetic gangrene, which 
is perhaps the result of the hypertonic condition we have described. [The 
author here confuses somewhat sexual desire and the condition of the generative 
cells. Does sexual desire depend on the interstitial cells or the generative cells, 
or on both or on neither? As was pointed out in the addendum to the chapter 
on the sexual glands, the function of the interstitial glands is still sub judice, 
and may not be an endocrine function at all. The role of the nervous system 
should not be entirely overlooked here. According to Allen, the lowered resis- 
tance of the diabetic is not due to the glycemia, but to the deficiency of the 
insular function alone.—Editor.] 
Let us survey now the alterations of the metabolism in genuine diabetes! 
First, I would again point out that according to investigations up to the 
present there are demonstrable neither an increase of the protein decom- 
position nor an increase of heat production. Why then does a severe case 
of diabetes become thin? The basis lies apparently in the devaluation of his 
diet through the limitation of sugar and of ketone-bodies. This is especially 554 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
true of the omnivorous, irrationally fed, severe diabetic. Such a person loses 
flesh in spite of the abundant ingestion of the food because a certain part 
of the material ingested leaves the body unused. In such an individual the 
heat production can be raised at most by the increased work of digestion, 
and because he must warm the large amounts of fluids of which he partakes 
to body temperature. The polyuria conditions a slight loss of heat. This 
is, however, an ectogenous raising of the heat production. In the light and the 
moderately severe diabetic, he who can be made sugar-free very early by a 
relatively slight restriction of the ingestion of protein and carbohydrate and 
thus again uses his diet to its full value, there lies no basis for emaciation. 
The severe diabetic can only be made sugar-free through great limitation of 
the proteids and carbohydrates. Also this individual may, as Weintraud 
has already shown, be maintained at body weight for a long time, on this 
just adequate diet, indeed it seems as though through the chronic under- 
feeding he may become established on a lower requirement for calories, as 
we can observe also in chronically underfed nondiabetic individuals. In 
still further advanced stages of the disease, the adequate diet does not serve 
any longer to maintain freedom from sugar in the urine; indeed in very severe 
cases it is no longer possible to limit the glycosuria to a low figure, as now 
on account of the strong formation of ketone bodies, carbohydrates must be 
administered unconditionally. That in such cases the carbohydrates are in a 
position to limit the formation of ketone bodies, at least to some degree, 
indicates that a part of the carbohydrates goes over the glycogen stage, 
although on account of the rapid re-combination this cannot be demonstrated 
with certainty in respiration experiments. The most marked effects are 
in such cases produced by the exclusive administration of carbohydrates, 
especially of oat-meal (v. Noorden), perhaps because other simultaneous 
administration of protein favors the re-combination of the formed glycogen. 
In such cases, too, we then see the body weight rapidly increase, a phenom- 
enon that is certainly not explained by the inhibition of water alone. In 
the very highly advanced cases these carbohydrate treatments are, as is 
known, also of no use. The severe diabetic loses weight and uses up his 
protein constituent, because he can be maintained sugar-free and ketone- 
body-free only on an extremely just adequate diet; as soon, however, as 
the diet becomes more abundant, the elimination of sugar and ketone bodies 
is increased, by which the value of the diet is detracted from. That the 
fattening of severe diabetics presents great difficulties is intelligible as it is 
known that a fattening is only possible when abundant assimilation of 
carbohydrates goes on at the same time. 
To me it seems that very much seems to speak for the fact that the 
metabolic disturbance that is present in genuine diabetes mellitus is made 
up of two different factors. The one factor consists of a disturbance in ana- 
bolism. This disturbance in the building up of glycogen is usually first to appear. 
The alimentary influence is here predominant. In the initial stages a distur- 
bance becomes manifest only on overstraining of the carbohydrate assimilation. 
If we adopt the viewpoint that the disturbance of glycogenesis affects both PATHOLOGICAL ANATOMY OP DIABETES MELLITUS 
555 
liver and muscle and that combustion of the carbohydrates in the muscles is 
only possible after preceding assimilation, we may in this sense speak also of a 
disturbance in sugar-combustion. On account of the lessened formation of 
glycogen, there gradually develops a deficient splitting up of protein and fat, 
and the formation of ketone bodies. 
The other factor consists in a disturbance of catabolism. This is most 
evident, when in spite of the ruling out of alimentary influences sugar is con- 
tinually formed from protein substances and fatty substances and eliminated 
(increased sugar-production). This increase of the catabolism must therefore 
be regarded as endogenous; it leads, if the lack cannot longer be made up 
through ingestion of food, to a melting down of protein substance and fatty 
substance. We can therefore very well speak of an increased metabolism in severe 
diabetics, whether this is due to the devaluation of the food administered in 
excess, or to a melting down of the body substance. This increased transforma- 
tion is expressed in the experiments on respiration only by increased oxygen 
requirements, not by increased carbonic acid production or heat production. 
These two disturbances show a certain independence of each other; in 
the initial stages of diabetes the disturbance in anabolism tends to come to 
the front, as the predominance of the alimentary factor would indicate. There 
do, however, exist cases in which the catabolic factor predominates already at 
the commencement (neurogenic diabetes). In the later stages both factors 
are present at the same time, although they are not always just as strong as 
each other. 
If we review once more the alterations of metabolism that characterize 
the diabetes after extirpation of the pancreas, and compare these with those 
of genuine human diabetes, it is not hard to recognize a distinct difference; 
to both are common the anabolic as well as the catabolic disturbances. They 
differ from each other, however, in the behavior of the protein metabolism and 
the heat production. In the dog with pancreatic diabetes the decomposition 
of protein and the heat-production are much increased; in genuine diabetes 
these are not essentially altered. Before we discuss this fundamental differ- 
ence, I must first tell about the results of pathologico-anatomical research 
in genuine diabetes. 
Pathological Anatomy of Diabetes Mellitus 
Bouchardat first in 1845 expressed the opinion that diabetes came about 
through a disease of the pancreas, at all events Bouchardat was forced to the 
assumption that under circumstances only a functional disturbance may exist, 
since in many cases of diabetes mellitus he found the pancreas normal. 
After Bouchardat, Lapirre, Frerchs, Cantani, Seegan, and Lanceraux 
drew attention to the pancreas in autopsies on diabetics, and found that in 
addition to cases with the most varied alterations of the pancreas there were 
also cases of diabete maigre in which the pancreas was apparently normal. 
In 1891 Lemoine and Launois described the sclerosis of the blood and lymph 
vessels in diabetes. In 1893 Laguesse first expressed the view that in diabetes 556 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
the islands of Langerhans were diseased. In 1894 v. Hansemann described 
a specific atrophy of the glandular parenchyma in diabetes mellitus, 
associated with proliferation of the connective tissue about the acini, which, on 
account of the similarity to granular atrophy of the kidney he designated 
granular atrophy of the pancreas. In a later work v. Hansemann reported on 
investigations in thirty-four cases of diabetes mellitus. In the majority of these 
this granular atrophy was found, in six cases was found hyaline degeneration 
of numerous islands, to which, however, v. Hansemann attributed no great 
significance. Dieckhojf examined the islands especially and among seven cases 
found three times diminution in the number of islands, once disappearance of 
the islands, once the insular tissue qualitatively altered, and twice no altera- 
tions. He also found that the glandular parenchyma for the most part showed 
changes. In 1898 Schlesinger first reported that he found in cases of pancreatic 
disease without diabetes that the islands were remarkably well preserved. In 
several interesting studies, Opie advocated the opinion that the disease of the 
islands of Langerhans was the cause of the diabetes. 
Opie distinguished two types of chronic inflammation of the pancreas; 
an interlobar pancreatitis (twenty-one cases) brought about by occlusion of the 
excretory duct by pancreatic stone or gall-stone, or by compression of the duct 
by tumors, or as the result of an acute inflammation of the pancreas on account 
of infection of it from the intestine, or by generalized tuberculosis, or as an 
accompaniment of atrophic cirrhosis of the liver. Here the islands are only a 
little altered, and indeed only altered if the cirrhosis is of a very high degree. 
On the contrary we find in interacinic pancreatitis the islands markedly affected 
and on marked changes in these also, for the most part, diabetes. Opie de- 
scribes among the cases here observed also one of generalized hyaline degenera- 
tion of the islands of Langerhans. Ssobolew, into a consideration of whose 
experimental studies I have already entered, described alterations of the pan- 
creas without diabetes in which the glandular parenchyma was in part highly 
altered, while the islands seemed to be very much more resistant. In primary 
or metastatic carcinoma of the pancreas the islands are often retained in the 
midst of the tumor tissue; only in one case of primary tuberculosis of the pancreas 
were traces of sugar present, there being present in this case also an extensive 
dense formation. In sixteen cases of diabetes he found, on the contrary, mostly 
disappearance of the islands or diminution of their numbers, or signs of de- 
generation. He comes to the conclusion that in diabetes, the islands seem to be 
the least resistant. As enemies of the insular theory appeared Gutmann, 
KarakaschejJ, Ilerxheimer, and others. Herxheimer found in a majority of 
these cases v. Hansemann’s granular atrophy, and in addition in five cases found 
changes with the strong predominance of the regenerative new formation of 
excretory ducts, and he designates this form cirrhosis of the pancreas on account 
of its similarity to cirrhosis of the liver. He did not regard as significant the 
changes he found in the islands. Also Schmidt maintains a sceptical attitude. 
These authors show that in diabetes mellitus also the glandular parenchyma 
may be very much diseased, and that the islands throughout do not have to be 
the only part diseased; in many cases the islands are remarkably well preserved PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
557 
or show distinct signs of regeneration; and in many cases they appear entirely 
normal. Karakaschef upholds as already mentioned previously, the opinion 
that the islands constitute only reserve material, and under circumstances can 
form new glandular parenchyma, while Gutmann assumes a new formation of 
islands from glandular parenchyma. MacCallum describes a case of juvenile 
diabetes in a child, in which the islands showed a high-grade hypertrophy. 
Before the appearance of a part of the work directed against the insular theory, 
Sauerbeck had treated the subject in a “Referat” [collection of references] and 
in a monograph. He collected one hundred and fifty-seven cases of diabetes 
from the literature. The islands found normal in 40%, of which there were 
twenty-six cases with alterations of the glandular parenchyma. Changes in 
the islands were noted in one hundred and seventeen cases. In these the islands 
were not found at all, or only scars marked their places in seven. In twelve 
more cases the number of the islands was diminished whereby the glandular par- 
enchyma was rendered in part atrophic. In ninety-eight cases the islands were 
altered qualitatively, there occurring hemorrhages, simple atrophy, hyaline 
or fatty or hydropic degeneration, sclerosis, or acute or chronic inflammatory 
alterations. In seventeen of his own cases of diabetes mellitus Sauerbeck 
found mostly that alterations of the glandular parenchyma ran parallel with 
those of the islands, and usually that in severe cases of diabetes mellitus distinct 
alterations of the islands were present. Sauerbeck inclines more to the insular 
theory; he believes that diabetes cannot originate from the parenchyma, as in 
cases of severe alterations of the parenchyma the diabetes may remain absent 
entirely. 
Recent times have brought a series of important studies on this subject. 
v. Ilalasz investigated twenty-nine cases of diabetes mellitus. He found 
90-95% of the islands normal eight times; six times in 60-90% of the islands, 
seven times in 30-40% of the islands, he found alterations that consisted in 
hemorrhages, sclerosis, atrophy, hyaline degeneration and in atheroma of the 
blood-vessels. Signs of regeneration were found only twice. Alteration of the 
parenchyma was found by Ilalasz chiefly in old diabetics, and the weight of 
the pancreas was for the most diminished, often distinctly, v. Ilalasz con- 
cluded that not every diabetes is a pancreatic diabetes. Heiberg investigated 
six cases of diabetes mellitus and found the islands either qualitatively altered 
or the number of them diminished. Heiberg attributes this defect in the islands 
to their destruction by inflammatory processes, in which residues of the inflamma- 
tion were not always necessarily present. In one case the islands showed 
in part the round-cell infiltration described by M. B. Schmidt, Halasz, and 
Cecil Russell. There was found in addition in this case islands with necrotic 
cells, without [round cell] infiltration; Heiberg regards these alterations as 
the later stage of the inflammatory processes. 
In a later publication in which Heiberg reports on investigations of the 
pancreases of two diabetic children, he again mentions that the number of 
the islands must be considered as well as their quality. Saltykow examined 
twenty-one cases with pathologically altered pancreas without diabetes; of 
these four cases show insignificant alterations in the islands, which were other- 558 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
wise well preserved. In many cases, especially in sclerosis and diffuse carcino- 
matous infiltration of the pancreas, the islands were indeed very well preserved. 
In nine cases of diabetes Saltykow found always alterations in the islands. 
Among these was a case of isolated hyaline degeneration of the insular apparatus 
with diabetes, as it had already been described by Opie, Wright and Joslin, and 
others. 
A far-reaching confirmation of Opie’s findings was contributed by Russell L. 
Cecil; he found among ninety cases of diabetes alterations of the pancreas 
in seven, and among these regularly alterations of the islands, such as sclerosis, 
hyaline degeneration, leucocytic infiltration. In seventy-six cases were found 
fibrosis, in twenty-seven hyaline degeneration, etc. In twelve cases the 
alterations affected the islands exclusively; and among the cases without quali- 
tative alteration of the pancreas was found striking smallness of the organs or 
decreased number of islands. 
The question has been studied the most thoroughly by Weichselhaum. 
Weichselbaum had previously reported with Stangl thirty-three cases of dia- 
betes mellitus in which striking alterations in the islands, but not essential 
changes in the parenchyma had been found. The latest communication of 
Weichselhaum is based on one hundred and eighty-three cases of diabetes 
mellitus. The number of control experiments and pancreases of non-diabetics 
is still greater. Microscopically the pancreases of diabetics often showed 
distinct atrophy and decrease in size, and fatty degeneration; often they were 
entirely normal. Microscopically constant alterations in the islands were 
found. In addition to diminution in the number of islands and decrease of 
their extent {Neumann), Weichselbaum described a hydropic degeneration of 
the island cells; in this the protoplasm of the cells loses its structure, becomes 
transparent, shows characteristic granular inclusions and eventually is de- 
creased in size (transition into atrophy). This hydropic degeneration was found 
in 53% of the cases and indeed almost exclusively in younger individuals. 
In 43% of the cases, mostly in persons over fifty years of age, Weichselbaum 
found sclerosis of the islands, proliferation of the connective tissue in and 
about the islands, and mostly interlobar and intralobar proliferation. There 
was found also sclerosis of the arteries. In 28% of the cases there was found 
hyaline degeneration of the island cells together with the sclerosis above 
mentioned. Manifestations of regeneration of the islands were found chiefly 
in the head of the pancreas, and indeed in young individuals. Hypertrophy 
of the islands were found only in some cases of insular sclerosis. While there- 
fore the insular apparatus regularly showed alterations, high-grade degenera- 
tion of the glandular parenchyma was found only in closure of the pancreatic 
duct or in carcinoma of the pancreas. In the control investigations on the 
pancreases of non-diabetic individuals these changes were almost always 
absent, but on the contrary there existed high-grade atrophy of the glandular 
parenchyma, whereby the weight of the pancreas was very much diminished; 
in chronic tuberculosis even to 20 gm. Weichselbaum mentions that in diabetes 
mellitus the relation between regeneration and destruction of the islands must 
be considered; and not only the structure but also the number of islands. PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
559 
On the basis of his investigations Weichselbaum distinguished from the 
pathologico-anatomical standpoint three forms of human diabetes; first a 
youthful form, the proper diabete maigre, in which is found the hydropic 
degeneration of the islands; this is hereditary and would seem to depend on 
congenital weakness or on failure of formation of the insular apparatus. Then 
he distinguished the form dependent on chronic interstitial pancreatitis, that 
occurs in the later years of life and is commonly associated with lipomatosis of 
the pancreas and general adiposis (diabete gras). This form is hence lipogen- 
ous or depends on a chronic catarrh of the excretory ducts and chronic alco- 
holism and is often complicated with cirrhosis of the liver. Finally the third 
form, which, depending on the hyaline degeneration of the islands, occurs in 
the later years of life, apparently is a subvariety of the second form, and is 
usually associated with sclerosis of the arteries. 
I have reproduced rather in detail the numerous labors as to the patho- 
logical anatomy of the pancreas in “genuine diabetes,” and have purposely 
confined myself strictly to the words of the various authors, because it seemed 
to me that an intimate penetration into the development of the question makes 
its solution essentially easier. On reviewing once again the entire material 
detailed, we see that with increasing exactness the microscopical investigation 
and also the findings of the pathologico-anatomical alterations in the islands 
have become essentially commoner, so that the later authors almost all belong 
to the adherents of the insular theory. It is further perfectly clear that 
pathologico-anatomical alterations found in so-called genuine diabetes mellitus 
are not of a uniform nature, a conception that is upheld in the larger and more 
thorough of the works cited. A large group possesses well-defined character- 
istics, although the names given to it by different authors are different. It is 
the form of interacinic pancreatitis occurring in later life, that v. Ilansemann 
calls granular atrophy of the pancreas, Opie, interacinous sclerosis, Lepine, and 
Lemoine and Launois, sclerose periacineuse, and which Weichselbaum regards 
as dependent on interstitial pancreatitis. The causes of it are probably very 
different. In part they are sclerotic changes similar to those of cirrhosis of the 
liver, often occurring in common with hepatic cirrhosis and like it dependent 
on alcoholism. Commonly the cause can be ascribed to high-grade arterio- 
sclerosis of the vessels of the pancreas; in other cases an ascending catarrh of 
the duct system might be the cause. The latter cases go over without sharp 
boundary into that large group of high-grade atrophies of the pancreas, which 
we previously treated under the gross anatomical alterations of the pancreas. 
In all these cases are found in addition to changes in the insular apparatus more 
or less pronounced alterations of the glandular acini, which is true of the cases 
that proceed from catarrhs of the excretory ducts only when the process is 
more advanced. It is comprehensible why these cases do not lead to absorp- 
tive disturbances, for there is still enough functionating parenchyma present, 
and it is to be expected that such disturbances became manifest only on high- 
grade diminution of pancreatic juice production. The decision as to whether 
the alterations in the insular apparatus observed in this form suffice to explain 
the disturbance in carbohydrate metabolism is certainly very difficult, and 560 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
is further complicated by the occurrence, commonly observed, of regenerative 
manifestations in the islands. It is indeed very questionable whether these 
new-formed islands have the same functional integrity. We see, however, in 
many forms of cirrhosis of the liver often strongly developed and widespread 
regeneration of the liver tissue, and yet we find in these cases signs of deficiency 
of liver function. Also the occurrence of individual hypertrophic islands and 
adenomatous proliferations of islands does not furnish a certain conclusion 
as to the function of the entire insular apparatus. Likewise, as Saltykow points 
out, just as little does the finding of partially normal islands speak against the 
island theory; for example, we have in cases of nephritis, large amounts of 
normal renal parenchyma visible microscopically, without casting doubt as 
to the insufficiency of the renal tissue. That also in this group are found cases 
in which the insular apparatus has suffered relatively severe damage need 
cause no astonishment. Weichselbaum emphasizes the fact that the cases with 
isolated hyaline sclerosis of the insular apparatus probably form only a sub- 
division of this group; also here is commonly found a sclerosis of the vessels of 
the organ; it seems to me very likely, however, that in these cases of isolated 
sclerosis of the insular apparatus there is expressed a certain undervaluation 
in the rudiments of the insular apparatus, that becomes manifest only on the 
additional occurrence of further damaging influences. 
For the judgment of the role that the pancreas plays in the pathogenesis 
of diabetes mellitus, no doubt the second group—that which affects youthful 
individuals—is the more significant. Most important for us are those cases 
in which the diabetes commences at an early age, and, ceaselessly progressing, 
leads to fatal coma. It is these cases that up to the present have furnished so 
unsatisfactory pathologico-anatomical findings. The monographs on dia- 
betes by Naunyn and by von Noorden state likewise that in the rich experi- 
ence of these authors numerous cases are met with, in which even the most 
careful microscopical examination of the pathological anatomists did not show 
anything certain. In one of these cases the count of the islands has furnished 
inferences worthy of remark. It is shown in this group that the number of 
islands and also their size is markedly diminished, and indeed there are state- 
ments that the islands are entirely wanting. The supposition of Hei- 
berg that in such cases the defect in islands can be referred to a preceding 
inflammation with the formation of scars has much in its favor. In many 
cases of juvenile severe diabetes, however, the number and size of the islands 
is insignificantly and perhaps not even at all diminished. In these cases 
Weichselbaum constantly found the hydropic degeneration. This statement 
of Weichselbaum’s has up to the present time not been recognized by all 
pathological anatomists. If, however, the hydropic degeneration in such 
cases is found to be constant, we must also ask the question if the alterations 
are not of a secondary nature, brought into existence by the long duration 
of the hyperglycemia and acidosis, and if these relatively slight alterations 
suffice to explain the high-grade functional deficiency. This form of diabetes 
always commences with heavy elimination of sugar. In the majority of 
cases there is found in the later stages an intensity of glycosuria, that comes PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
561 
up to that seen in pancreasless dogs, and in the most of cases even exceeds 
this. On the whole we can hardly be mistaken if we were always to assume a 
participation of the pancreas in such cases. The hereditary element so con- 
spicuous in the pathology of this form of diabetes points to a weakness in 
the “Anlage” of the insular apparatus, as a result of which any toxic or infec- 
tious deleterious influence at all finds a locus resistentiae minoris. In spite 
of all this we cannot reconcile the incongruity of the pathologico-anatomical 
findings and the intensity of the metabolic disturbance and must ask ourselves 
the question whether if in this form of human diabetes, and perhaps in the 
most cases of severe human diabetes, there is not present, in addition to the 
insufficiency of the pancreas, also another disturbance that we have essentially 
to regard as an increase of sugar production dependent on a nervous basis. 
Before we enter into this question, it is necessary to observe more care- 
fully those forms of diabetes in which the clinical observation or the patho- 
logical anatomy points toward a prominent participation of the nervous 
system in the coming about of the diabetic disturbance of metabolism. 
The question as to whether we are justified in recognizing a “nervous 
form "’ of diabetes has been discussed in a lively manner for a long time. The 
discovery of the “piqure” happened before that of diabetes after extirpa- 
tion of the pancreas. Since the time that the discovery of pancreatic dia- 
betes turned the general attention toward the pancreas, the interest in nervous 
diabetes has fallen behind. The greater part of the clinical observations 
of “nervous” diabetes come from earlier times, thus making critical observa- 
tions not less difficult. 
I shall first select from the observations at hand those which seem to me 
the most important, and describe them more exactly. 
Glycosuria occurs not infrequently in brain hemorrhages and encephalo- 
malacias. This was first described by Leudet. They may be associated with 
acute hemorrhages as well as the chronic encephalomalacias. A case of the 
latter sort is described by Naunyn in which the diabetes gradually developed 
during a slowly progressing encephalomalacia. For the most part there 
exists in addition to the glycosuria, polyuria, and also even albuminuria. Cases 
of the first kind are communicated by Dutrait, Frerichs, and others. The 
seat of the hemorrhage or softening in such cases associated with glycosuria 
is mostly the pons or its vicinity. Especially interesting is the case of Rein- 
hold. In a sixty-three and one-half-year-old woman with melancholia, ten 
days before death there developed a marked edema of the feet and strong 
glycosuria. Section showed a hemorrhage on the floor of the fourth ventricle 
(serial sections), slight hydrocephalus, and a strong hyperemia of the liver. 
It should not remain unmentioned that glycosuria is sometimes observed 
in the parts of the brain that lie further off, and that cases occur in which 
there is no glycosuria in spite of hemorrhages in the neighborhood of the 
pons. Such a case is reported by Lemcke. In this case there was an enormous 
lowering of the body temperature to 23°C. There was found neither glycosuria 
nor albuminuria. Section showed a fresh focus of hemorrhage beneath 
the floor of the fourth ventricle. 562 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
It is an interesting fact that II. Strauss in tests for alimentary glycosuria 
in cases with fresh apoplectic attack, several times found them positive immedi- 
ately after the attacks but they were negative later. In this category belong 
too the cases of brain hemorrhage after trauma to the head. The first 
case was described by Claude Bernard (Physiol, experim., Tom. i, 1855). 
Glycosuria disappears at the same time as does the wound. 
Here also belongs the case of Drummond. A seventy-six-year-old man 
suffered a blow on the head. Since that time increasing weakness, thirst, 
and glycosuria. Autopsy showed besides an extreme dilatation of the lateral 
ventricle and the aqueduct of Sylvius, a small blood effusion in the fourth 
ventricle. 
I mention further the case of Kammitz. A seventeen-year-old girl, pre- 
viously well, caught her head in a cutting machine. Loss of consciousness, 
later vomiting, and copious bleeding from the nose, and downflow of blood 
along the posterior wall of the pharynx pointed with certainty to fracture 
of the base of the skull. The temperature at first was 35°C. After two days 
an abducens paralysis became evident. A week after the trauma there devel- 
oped increased thirst, polyuria, and glycosuria (about 1% sugar). The sugar- 
contents gradually rose to 2.3%. There now existed excessive polyuria. About 
three weeks after the trauma the somnolent condition had disappeared, the 
diplopia still existed, and a unilateral hypoglossus paralysis had developed. 
During the next few weeks, the sugar following exclusive meat diet fell to 1% 
but the polyuria had decreased but little. Two months after the trauma traces 
of sugar were still present, one month later the urine in spite of abundant 
ingestion of food was entirely free of sugar, but there still existed a diuresis 
of 4-6 liters, with a specific gravity of 1005. Nothing was noted, unfortunately, 
as to the further course. The supposition of a hemorrhage in the medulla 
oblongata, that became still more marked some time after the trauma, is very 
probable in this case. 
Entirely similar is the case of Plagge. A sixteen-year-old boy suffered 
a head injury, after which amblyopia and strong glycosuria commenced. 
The glycosuria disappeared after two or three weeks, while the polyuria 
remained for two or three months. 
Further I might still mention the case of Loeb. In the first case (pontile 
hemorrhage with rupture into the fourth ventricle and with general arterio- 
sclerosis) sugar and albumin were found in the urine. The urine had been 
examined previously and found to be free of sugar. In the second case there 
occurred after an apoplexy (probably small hemorrhage of the pons) sugar 
and albumin in the urine. All manifestations later vanished leaving not 
a trace behind. Loeb regards the albuminuria as conditioned centrally. 
In addition to the hemorrhages, it is chiefly tumors and abscesses in this 
region that can lead to glycosuria. The case of I wan Michael is much cited. 
In a twenty-five-year-old man there occurred, together with increasing weak- 
ness and tormenting headache, polyuria, polydipsia, and glycosuria. The 
amount of urine reached over 6100 cubic centimeters, the elimination of 
sugar reached to 25 mg. Death in coma followed later. Autopsy showed a PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
563 
cysticercus racemosus of the floor of the fourth ventricle. Steida reports on 
the contrary a case of cysticercus racemosus of the fourth ventricle which, 
in spite of changes in the floor of the ventricle, did not call forth glycosuria. 
Of the other changes in the floor of the fourth ventricle associated with 
glycosuria have been observed tubercle (de Jonge) sclerosis, abscesses and 
tumors (especially gliomata). The changes may also affect the vicinity of 
the cerebellum. The first glioma was reported by Nevrat-Perrotton; other 
cases are described by Reimer, Catola and others. Especially worthy of remark 
is the case of van Ordt. It concerned an eight-and-one-half-year-old girl 
in whom no sugar was found at the beginning of the illness. The test for 
alimentary glycosuria was first positive on the aggravation of the tumor 
symptoms, then 3.2% of sugar occurred in the urine, then on limita- 
tion of the carbohydrates in the diet the sugar disappeared, later to 
reappear also on a strict diet to the extent of 3^2%• The autopsy, in addi- 
tion to showing several miliary tubercles on the floor of the fourth ventricle, 
revealed a tumor in the territory of the posterior corpora quadrigemina, the 
cerebral peduncle, and the tegmentum of the pons, which also involved the floor 
of the fourth ventricle. According to the judgment of van Ordt, this could have 
been present only in the course of the last weeks. The pancreas was found 
to be normal. According to van Ordt’s statistics, glycosuria has been found 
up to the present in 
Cerebral tumors i time 
Cerebellar tumors i time 
Basal ganglionic tumors — 
Thalamic tumors 3 times 
Tumors of the corpora quadrigemina 3 times 
Dorsal pontile tumors 5 times 
Basal pontile tumors 
Tumors of the floor of the fourth ventricle 18 times 
If we take only those cases in which the floor of the fourth ventricle 
was destroyed to a greater or less extent, we find that 70% of all these 
cases are associated with glycosuria. Tests for alimentary glycosuria were 
found positive five times in eleven cases of tumors of the interior of the skull, 
three times in sixteen cases of other diseases of the brain (among them one 
case of lues). It should be mentioned that abscesses of the cerebellum very 
commonly lead to increase of temperature and glycosuria (Hammond). 
I believe that among the cases detailed as well as among numerous 
analogous cases there are those which fulfill all the requisitions of a diabetes 
conditioned nervously. It is true, as Naunyn says, that he has seen many 
cases of apoplexy with glycosuria but that he could not exclude in these the 
possibility that a slight diabetes did not exist beforehand. It must further 
be said that exact examinations of the pancreas especially with reference to 
the insular apparatus are scarcely at hand. We can, however, only with 
difficulty conceive how in individuals with previously perfectly normal sugar- 
metabolism, and especially in the youthful cases, so high grade a damage 
to the pancreas can develop so suddenly. The parallelism in the develop- 564 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
ment of the glycosuria and the brain symptoms points much the more to 
the fact that alterations in the nervous system have a decisive significance. 
According to the experimental experience up to the present only the assumption 
of an irritation of the nervous centers and paths as cause of the “nervous” 
glycosuria is possible. It is therefore intelligible that pathological altera- 
tions in the neighborhood of the floor of the ventricle or the subthalamic 
region do not always necessarily lead to glycosuria. Irritation would the 
sooner follow if tumors or apoplexies gradually encroach upon the corre- 
sponding centers; rapid destruction of these centers on account of hemor- 
rhage or softening would much rather lead to symptoms that are the opposite 
of irritative symptoms. The case of Lemcke with considerable hypothermia 
may be perhaps explained in the above way. I should like to point out one 
point further, namely, the strong hyperemia of the liver in Reinhold's case, 
which is seen regularly too after the piqure. 
The cases of diabetes after trauma here need a more exact analysis. We 
have to consider the following points: 
1. Whether the diabetes began immediately or at least a short time after 
the trauma, or after an interval of several months or years. 
2. Whether the trauma affected the head and whether other brain symp- 
toms existed in addition to the glycosuria, or whether other parts of the body 
were affected by the trauma. 
3. Whether the diabetes healed again, or whether it existed further or 
relapsed; in short, whether a chronic diabetes developed. 
Concerning the frequency of these different factors several statistics are 
at hand. Jodry (cited by Lepine) collected one hundred and forty-five cases 
of diabetes after trauma. The trauma affected the head in seventy-two 
cases—50%; the vertebral column in twenty-seven cases—20%; the abdomen 
in twelve cases—8%; the seat of the trauma was not defined in 1.7%. 
In a third of the cases, the diabetes became manifest during the first 
days after the trauma. 
Lepine analyzed twenty-nine well observed cases from the literature and 
added five cases of his own. The symptoms of diabetes appeared in the 
first three days—ten times; in the first week—five times; in the first three 
months—twelve times; later seven times. 
Asher found among one hundred and twenty-nine cases of diabetes after 
trauma fifty-four cases of injuries of the head; sixty-two cases of injuries 
of other parts of the body; nine cases after injuries of an undefined kind. 
Higgins and Ogden among two hundred and twelve cases of head-injury, 
found sugar in 9.3%. If only the severest cases were considered, the percentage 
rose to 23.4%. 
Among eighty-four cases of simple wound of the scalp, sugar was found 
in 5-95%- 
Among forty-three cases of wounds of the scalp that laid bare [freilegten] 
the bone, in 9.3%. 
Among forty cases of concussion of the brain with loss of consciousness, 
but without fracture, in 2.5%. PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
565 
Among twenty-four cases with fracture of the vault of the skull, in 20.8% 
Among twenty-one cases with fracture of the base of the skull in 23.8%. 
The question as to the connection between trauma and diabetes has been 
discussed in a lively manner. Ebstein and later Kausch collected the cases of 
traumatic diabetes from the literature. While Ebstein inclines to the view 
that also cases of chronic diabetes, eventually diabetes first occurring a long 
time after the trauma may be ascribed to the trauma, Kausch is very scep- 
tical. He would hold as valid only the ephemeral or transitory glycosurias 
occurring immediately after, or only a short time after the trauma, and denies 
the connection between trauma and chronic diabetes, especially when the 
latter first occurs a long time after [the accident]. I believe that we must 
consider Kausch right in many points, even if perhaps he goes too far, in 
the separation of the ephemeral or transitory glycosurias and chronic diabetes. 
It seems to me appropriate to go a little further into the points [just] previously 
sketched. I am not considering the subject as maintained in the law governing 
responsibility for accidents. Naunyn and v. Noorden mention that one must 
not be too narrow-minded, as considering the obscurity of the conditions, 
individuals should not suffer harm on account of theoretical considerations. 
The scientific side of the question, however, demands a much more rigid critique. 
Now as regards what concerns the first point, we can ascribe, with con- 
siderable justification, diabetes after head injury to the injuries of the nervous 
centers regarding sugar-metabolism, when the elimination of sugar occurs 
within the first eight to fourteen days and especially when, too, other symptoms 
are present that indicate an injury to the brain stem and medulla oblongata. 
I have mentioned in brief several such cases on page 553. As further examples 
I would cite both cases of Bouchard. In a seventeen-year-old and twenty- 
one-year-old man respectively there occurred, after fracture of the base of the 
skull glycosuria to 1.5% and 1.75%, and albuminuria and cylin- 
druria. The first case healed entirely, but the second case died after some 
days. If no brain symptoms are otherwise present, we cannot, however, 
deny without anything further the connection with the trauma. Very in- 
teresting is the observation of Honiger that new-born infants whose heads have 
been strongly squeezed by the artificially induced birth, can show glycosuria 
for several days, while the long duration of a spontaneous birth never leads in 
itself to glycosuria. 
If the glycosuria starts in a longer time after the trauma, we can here also 
not deny the connection with trauma in every case without anything further. 
It is conceivable that blood effusions that are undergoing absorption in organi- 
zation, may exercise an irritation in the corresponding centers through shrink- 
age and the action of traction (Rosenberger). Of course this would hold only 
for very few cases. We may regard that of Schaper as such a one. In a duel, 
a dagger thrust penetrated the orbit and went deep into the cranial cavity. 
There developed a right-sided paralysis and gradually a high-grade diabetes. 
Death occurred after three and a half months; it was found that the path of 
the stab reached to the left border of the medulla oblongata and was filled 
with pus and coagulated blood. There should finally still be thought of, in 566 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
such cases of later glycosuria, the spontaneous glycosuria of the traumatic 
neurosis. We shall consider this latter in the discussion of the connection of 
psychoses or psychic excitements with glycosuria. The fact whether there 
is polyuria is important in the solution of the question as to whether the late 
glycosuria is associated in any way with the trauma. In many cases of head 
injury the glycosuria starts in simultaneously with pronounced polyuria. 
Usually both develop at the same time. If the glycosuria later disappears, 
the polyuria often lasts for many months, in other cases the polyuria develops 
first, and the glycosuria accompanies it only after weeks or even months. The 
central origin of such polyuria is very probable. On it is based the hypothe- 
sis of a central origin of the glycosuria. In any case the similarity with the 
sugar and polyuria puncture is worthy of notice. 
The second question concerns itself with whether glycosurias after trauma 
that does not affect the head, but other parts of the body, can be referred to 
the trauma and can be regarded as nervous glycosurias. Kausch himself has 
furnished noteworthy contributions to this subject. He described twelve 
cases of fractures of the pelvis, thigh, leg, patella, or toes, that showed ephe- 
meral glycosuria. This glycosuria continued for at most ten days and under 
circumstances, on the ingestion of grape-sugar, would be increased to 30 gm. 
It is worthy of remark that these cases later did not show any alimentary glyco- 
surias and therefore presented an entirely normal carbohydrate metabolism. 
Before Kausch, Haedke has already pointed out that after traumata of different 
kinds alimentary glycosurias would be obtained in a large percentage. The 
connection of such transitory glycosurias with trauma, in cases that are not 
narcotized, is doubtless. Experimental pathology (glycosuria after injury to 
the sciatic, etc.) gives us an idea as to the kind of connection. Very much 
severer is the significance in a series of cases, of which I shall quote the follow- 
ing cases of Scheuplein more exactly. 
A young soldier who was not hereditarily predisposed to diabetes fell 
about 12 m. from a third-story window. He fell on his buttocks. There 
was found a luxation of the first lumbar vertebra, without there being symp- 
toms that pointed to an injury of the spinal cord. Reposition was successful; 
complete cure resulted, so that later the patient could again ride and carry on 
severe bodily labor as menial servant [in the army]. Fourteen days after the 
fall it occurred that the urine was much thinned and pale, and that the feeling 
of thirst was distinctly increased. The urine contained sugar. Ten days later 
the sugar-content of the urine was very great, and the amount of urine reached 
about 13 liters. The patient was placed on a meat diet. After fourteen days 
the sugar had disappeared, but the polyuria remained for a while longer. 
Two years after the trauma the patient was entirely free of sugar, although his 
diet consisted chiefly of cereals. The body weight, that at the time of the sugar 
elimination had sunk very low, raised again so that in short the patient could 
be regarded as cured in every respect. The significance of this case is indeed 
not easy [to determine]. We could perhaps think of an apoplexy of the pan- 
creas, but against this speaks the simultaneous diabetes insipidus. Against a 
hemorrhage in the medulla oblongata speaks the absence of any other brain PATHOLOGICAL ANATOMY OF DIABETES MELLITUS 
567 
symptoms. Scheuplein discussed the possibility of an injury of the solar 
ganglion. To me the possibility seems in any case to be thought of that on 
account of the great swelling formed by the injured vertebra there followed an 
irritation of the sympathetic paths in their course from the sugar center to the 
suprarenals. By this means can be explained even the polyuria. Scheuplein 
also refers to a case of Braun. In a twelve-year-old boy there existed a spondy- 
litis of the twelfth thoracic and first lumbar vertebrae with an acute-angled 
kyphosis. When the boy was placed in a horizontal position, symptoms of 
collapse, with polyuria and glycosuria, developed. Comfortable lying on roll 
pillows brought about a cessation of all manifestations. Also I must not leave 
unmentioned the case of Schwenkendick. A man sustained a tread of a foot in 
the vicinity of the navel. After some hours great thirst and polyuria started. 
Two days afterward there occurred stormy manifestations, marked pallor of 
the face, coldness of the extremities, distention of the abdomen, frequent 
vomiting. The urine was at first free of albumin and sugar, after two days more 
there was found 4.75% of sugar and abundant acetone. Later the 
patient evacuated black stools that contained blood, and death soon followed 
under manifestations of coma. The author thinks of apoplexy of the pancreas 
or necrosis of the pancreas or of affection of the splanchnic nerves. 
It is possible that in the setting free of this glycosuria, pain plays a con- 
siderable role. For instance, it has been known for a long time that in severe 
neuralgias there exists inclination to alimentary glycosuria. Frerichs reports 
such a case; in a forty-eight-year-old man there occurred, after a cataract 
operation, at the same time as severe neuralgic pains of the right half of the 
face, sugar in the urine up to 2%%. As the pains ameliorated, the 
sugar disappeared and ten years later the man was still sugar-free. It is also 
known that cases of sciatica, especially those with frequent attacks, frequently 
show alimentary glycosuria. H. Strauss found [urines tested for alimentary 
glycosuria] in three cases positive, and then when the painful attacks were 
over, negative in the same patients. Much cited is also the case of Frerichs, 
concerning a short injury of the sciatic nerve with severe attacks of pain, during 
which sugar always appeared in the urine. As the suffering ameliorated the 
sugar disappeared entirely. It might be possible that in such cases the irrita- 
tion passes away along the sympathetic nervous system through irradiation. 
We do not know certainly as yet as to whether longer continuing glycosuria 
may originate through involvement of the splanchnics or the great ganglia of 
the sympathetic as the result of chronic inflammatory processes—impaction 
in hard tissue, hemorrhages, etc. In the cases of long continuing glycosurias 
of high grade known up to the present time, and previously detailed, the associ- 
ated involvement of the pancreas or the centers in the brain stem through the 
violent concussion cannot be excluded entirely. 
I now turn, finally, to the third question, whether in the wake of a trauma 
a chronic or eventually a later recurring diabetes on a nervous foundation, 
is conceivable. It seems to me that the possibility that a scar formation 
exercising irritation on the centers regulating sugar metabolism cannot entirely 
be ruled out, as I have already signified. But at all events severe diabetes of 568 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
year-long duration, that is progressive and eventually ends in a coma, cannot 
be explained by it. If the diabetes after the trauma is chronic, it is indeed 
very probable that a predisposition [Anlage] for diabetes has existed beforehand. 
Although we, in the previously detailed cases of organic alterations of the 
brain, must regard it as extremely unlikely that an acute alteration of the 
pancreas should exist at the same time, this (factor) cannot be excluded in 
those cases of brain syphilis which are also designated “nervous.” The 
cases are so interesting that I would like to discuss them. In i860, Leudet 
first described such a case. It was that of a thirty-two-year-old woman, who 
four years previously had progressed as far as the development of a “saddle 
nose.” In her there developed rather suddenly polyuria and polydipsia, un- 
consciousness, paralysis of the eye-muscles, left-sided anesthesia, etc. In the 
urine was abundance of sugar. On the institution of a potassium iodide treat- 
ment the diabetes insipidus and glycosuria disappeared, and also the brain 
symptoms ameliorated. Later, with a more recent aggravation of the brain 
symptoms, polyuria occurred again, but not sugar. Autopsy showed that 
the choroid plexus was adherent to the left border of the calamus scriptorius, 
and the brain substance of this was “eroded.” In the book by Frerichs are 
reported three cases of lues with brain symptoms and in part associated with 
very severe diabetes, in which diabetes disappeared under antileutic treatment, 
or, as in one case, improved considerably. Very instructive cases are reported 
by Dub and Lemonier. I would like to mention more in detail the case of 
Hemptenmacher. In a forty-two-year-old woman who had been infected with 
syphilis thirteen years previous there developed, at the same time with a 
polydipsia and pollakisuria, a left-sided hemiplegia with severe headache. In 
the urine was found 3.6% of sugar. Under the inunction treatment and 
potassium iodide the glycosuria gradually disappeared without the retention 
of an antidiabetic regime. Also the brain symptoms gradually ameliorated, 
and later complete cure was obtained. 
In this and in other cases there without doubt exists a casual connection 
between lues and diabetes. The occurrence of diabetes simultaneously writh 
tertiary luetic symptoms, the cure of diabetes by antiluetic treatment without 
alteration of the diet alone allows of no other conclusion. On the other hand 
the interpretation of the condition as nervous diabetes is entirely uncertain, 
as a simultaneous alteration of the pancreas is not to be excluded. It is true 
that never was the occurrence of absorptive disturbances mentioned, but the 
fact cannot be excluded that the insular apparatus may alone have been 
damaged in its function; the case of Manchot, moreover, that ran along without 
brain symptoms showed likewise no absorptive disturbances. 
Theoretical Conclusive Considerations 
Before I finally turn to the question as to what signification the internal 
secretion of the pancreas has for the pathogenesis of human diabetes, I should 
like briefly to summarize the most important points that were touched upon 
in the course of the exposition. THEORETICAL CONCLUSIVE CONSIDERATIONS 
569 
1. Embryology, anatomy, experimental pathology, and clinical observa- 
tion point to a certain independence of the insular apparatus. The em- 
bryological investigations showed that the insular apparatus and the acini 
developed separately. The anatomical investigation showed a different struc- 
ture of these two apparatus; a transition of the one tissue-element into the 
other has not up to the present been demonstrated with certainty. The ex- 
perimental pathological investigations showed that after ligation of the excre- 
tory ducts the acini become destroyed, while the insular apparatus for the most 
part behaves refractorily. The pathological-anatomical observation likewise 
showed that on the one hand the insular apparatus ordinarily is more resistant 
to certain destructive processes and that on the other, isolated alterations of 
the insular apparatus occur; finally clinical observations showed that distur- 
bances in the function of the glandular apparatus and the insular apparatus 
occur entirely apart from each other, and that to such isolated disturbances a 
corresponding pathological-anatomical finding can with probability be 
ascribed. 
2. After the complete extirpation of the pancreas always occurs (in the 
dog) a characteristic disturbance of metabolism; there always develops a 
severe diabetes leading to death, in the course of which affection the glyco- 
genesis is to a high degree, but not entirely, prevented in the liver and muscles; 
the disturbances in the assimilation of sugar might lead immediately to a 
disturbance in the combustion of sugar. In addition to this disturbance in 
anabolism exists a severe disturbance in catabolism, that affects not only the 
carbohydrate metabolism (increased sugar production), but also the protein, 
fat, and salt, metabolism. The catabolic disturbance shows, on extirpation 
of the pancreas, great regularity; there further exists regularly a certain hyper- 
excitability of the sympathetic nerves. 
3. The investigation of the metabolism in human diabetes shows distur- 
bances in both anabolism and catabolism; the latter, however, confine them- 
selves only to the sugar metabolism, while quantitatively increased breaking 
up of protein and fat are not demonstrated even in the severer cases. On 
the contrary, catabolic disturbances in the sugar metabolism are much more 
severe in the graver cases, as the glycosuria attains a much greater intensity 
than in the dog without a pancreas. 
4. Concerning the nervous manifestations in human diabetes, we can 
distinguish two types, between which we find all possible transitions. In the 
first, rarer, type, to which v. Noorden has lately directed attention, the nervous 
manifestations are strongly in the foreground from the beginning. Before 
everything is the psychic factor, that under circumstances dominates the 
elimination of sugar from the beginning up to even years, or at least influences 
it to a marked degree. Especially accentuated does the nervous factor enter 
into certain psychoses, into traumatic neuroses, into severe attacks of pain, 
etc. But this can be the case in even uncomplicated cases of human diabetes. 
In such cases it would perhaps be possible to demonstrate regularly a hyper- 
excitability of a certain part of the sympathetic system; especially does the 
glycosuric action of adrenalin always seem in such cases to be distinctly present, 570 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
indeed under circumstances the entire complex of adrenalin action (vascular 
and cardiac manifestations, etc.), seems to be very decidedly pronounced. 
There are all the transitions between this and hypertonic diabetes, in which 
in addition to the hyperexcitability of the sympathetic nervous system, there 
also occur conditions of permanent hyperexcitability. 
In the much more frequent second type the alimentary factor is in the 
foreground from the beginning. It governs the intensity of the elimination 
of the sugar, whereas psychical factors have no distinct influence on this. 
Especially are there no manifestations of hyperexcitability of the sympathetic 
system, especially that apparatus which has to do with the regulation of sugar 
metabolism. In the later stages of this type, when it has developed to severe 
diabetes, there occur a series of symptoms that point to a hyperexcitability of 
the sympathetic system. Then adrenalin can make the glycosuria distinctly 
more intense or, if the patient has been rendered sugar-free, may call forth 
glycosuria. Further there then begins an especial sensitiveness of the renal 
vessels, in that adrenalin, or similar agents, like pituitrin, then act diuretically. 
Finally there now shows itself the note-worthy phenomenon that long continued 
administration of thyroidin raises the blood-pressure, without eliciting any 
stronger manifestations of hyperthyroidism than when it is used in non-diabetic 
individuals. This phenomenon seems to indicate an especial lability of the 
sympathetic nervous system. To this is added in severe diabetes the known 
erethism of the vessels, the genesis of which is hard to account for; finally I 
would like to point out a symptom that seems to me to belong at this place; it 
is the extraordinary richness in blood of the liver, which we see, as already Klebs 
mentioned, in the individuals dead from severe diabetes. 
All these manifestations are common to the later stages of both types; 
I would believe that they are more markedly pronounced in the later stages 
of the first type. Yet for the corroboration of this is necessary a greater 
material than has been observed up to the present. 
Let us now investigate how far the pathologico-anatomical findings suffice 
to explain the clinical observations. No doubt there are cases with gross 
anatomical disturbances of the pancreas and especially of the insular appara- 
tus, that without anything else explain a severe disturbance of function of the 
same. Such cases rightly deserve the name pancreatogenic diabetes. There 
are further described in detail cases of alterations of the central nervous sys- 
tem, whose seat makes appear intelligible long continuing irritative mani- 
festations on the part of the sympathetic centers, which have to do with the 
regulation of metabolism, or perhaps on the part of the paths that bind these 
with the chromaffin tissue. It is doubtful whether a permanent diabetes 
may become manifest through such gross anatomical disturbances. In addi- 
tion there exists a great many cases in which nothing certain is found in the 
nervous system and the insular apparatus shows only relatively slight altera- 
tions. If we accept the viewpoint of Weichselbaum, however, it seems to me 
that up to the present there has been in such cases an insufficient agreement 
between the pathologico-anatomical findings and the intensity and acuteness 
of the clinical manifestations. Especially would this hold true for the juvenile THEORETICAL CONCLUSIVE CONSIDERATIONS 
571 
uncontrollably progressive cases of diabetes mellitus. In such cases there lies 
close the thought of a congenital weakness in the rudiment [Anlage] of the 
insular apparatus, whereby the hereditary and familial occurrence may become 
more intelligible. We can also suppose that in such individuals various dele- 
terious influences—infections and intoxications, etc.—find a locus resistentiae 
minoris and damage the insular apparatus; and we can further suppose that 
the same alterations of the insular apparatus may recuperate, especially if 
by reason of a corresponding dietetic treatment or prophylaxis the damaged 
organ is given time and rest for recovery. 
It appears, however, that through these means of consideration alone the 
problem of human diabetes will not become solved. The nervous factor that, 
as clinical observation teaches, often occupies the foreground, assigns to the 
nervous system a much more important role. A disturbance of the regulation 
of sugar metabolism through the central nervous system is especially to be 
thought of in two directions. Either the activity of the insular apparatus 
may be deficient thereby, so that the nervous impulses necessary for a normal 
function are too weak—an insufficiency on a nervous basis, such as we know 
in the glands with an external secretion in achylia gastrica, for instance. It 
appears to me, however, that according to that which I have previously set 
forth concerning the nervous type, this assumption has little a priori to recom- 
mend it. Or, in the metabolism of sugar there may be an increase in catabo- 
lism through an enormous excitation of those centers which regulate the 
activity of the chromaffin tissue. We can designate this type, then, as nervous 
or adrenalinogenic. I would only point out especially that in this type the 
insular apparatus is entirely intact. That such an excitation of the nervous 
centers leads to a continuous and strong glycosuria, brings into relief a cer- 
tain weakness of the insular apparatus. In individuals with completely 
normal pancreas, such excitations as increase the catabolic processes are 
neutralized by the corresponding counter-regulations. The difficult feature 
of the question seems much more to lie in the fact that in the nervous type 
this condition of hyperexcitability seems to occur primarily and that it increases 
the disturbance in metabolism in a manner that is hardly possible through 
failure of the insular apparatus alone, while it accompanies the pure pan- 
creogenic type only secondarily and perhaps in a less intense form. That 
also in the nervous type an increased adrenalin-contents of the blood could 
not up to the present be demonstrated, seems to me to signify nothing against 
this assumption; on the one hand, the biological methods up to the present 
have been insufficient for the demonstration of adrenalin in the serum (I refer 
to the work of 0 ’Connor, Priestly, Fleming, Kahn and myself) and on the other 
hand we can conceive that on insufficient contraregulation even minimal sur- 
plus production of adrenalin produces a significant effect on sugar metabolism. 
[Allen regards as true diabetes only the cases in which the pancreas is 
involved. The question of hypersecretion of adrenalin is questionable. 
Cannon and Rapport believe that they have demonstrated that there is a center 
which governs the production of adrenalin. On the other hand many of the 
circulatory effects formerly ascribed to the adrenalin spontaneously produced 572 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
in the body have been denied by Stewart and by Gley.—See chapter on the 
suprarenal gland.—Editor.] 
As to the cause of such an abnormal excitation in the nervous system we 
know as yet nothing. We have, however, met with similar conceptions in the 
diseases of the other ductless glands. I refer to Basedow’s disease where 
especially in the peracute cases, the increase of function of the thyroid gland is 
ascribed by many authors to a central excitation; and indeed they regard 
many symptoms as coordinate with hyperthyroidism, and conditioned cen- 
trally. We could designate the entire disease picture as hyperthyrosis, and 
the important syndrome conditioned by the hyperfunction of the thyroid 
gland we could designate hyperthroidism. According to this hypothesis we 
could regard these hyperfunctional conditions of the ductless glands as neu- 
roses. So far as this theory of diabetes is concerned, we are unmistakably 
approaching again the view first pronounced by the genial investigator of 
diabetes, Claude Bernard, although in a considerably modified form. 
If we now on the basis of the developed view, finally turn to the question 
as to why the diabetes of dogs without their pancreas deviates in some essen- 
tial points from that of the genuine human diabetic it seems to be that as yet a 
satisfactory explanation has not been possible. The principal difference lies 
in the fact that in the dog without a pancreas the catabolic factor of the car- 
bohydrate metabolism is less strong, that of the fat and protein metabolism 
more strong, while in genuine human diabetes the first in more strongly 
developed, and the latter factors fail almost entirely. Perhaps there may after 
all be elicited some grounds for the explanation of this considerable difference. 
On the one hand it might not be impossible that in the carnivorous dog the 
significance of the inner secretion of the pancreas is not quite the same for the 
metabolism as in the omnivorous human being. 
We must then assume that in the dog the pancreatic hormone exercises 
also a direct inhibiting influence on the splitting up of protein and fat. A 
certain decision of this question if exact observations of sudden and complete 
absence of pancreas [function] in man were at hand, which up to the present 
has not been the case. 
On the other hand the following idea might very well be elicited from what 
has been said: In experimental pancreatic diabetes, only the pancreas is absent, 
all the rest of the manifestations are secondary; in genuine human diabetes there 
exists, however, a disease of the whole apparatus regulating sugar metabolism 
(■nervous centers in the medulla and brain stem, connecting paths, pancreas, and 
chromaffin tissue) with insufficiency, but not complete absence, of one part and 
more or less independent hyper excitability in the other part. 
Through this view, which has been the product of v. Noorden's clinic in 
recent years, the problem of the pathogenesis of diabetes mellitus has been 
broadened, but the solution of it seems only to have been thrust back one 
step further. 
As far as the other glands are concerned in the bringing about of diabetic 
glycosuria, we may off-hand ascribe with certainty an important role in this 
direction to only two other glands, the thyroid and the hypophysis. There THEORETICAL CONCLUSIVE CONSIDERATIONS 
573 
exists, however, but little clearness in which way these ductless glands enter 
into the regulative mechanism of sugar metabolism, and whether they exercise 
this influence chiefly or exclusively by way of the pancreas. In the chapter 
on Basedow’s disease we found that hyperthyroidism was not rarely associated 
with a reduction of the assimilation limits for carbohydrates; indeed, under 
circumstances, it could lead to spontaneous glycosuria. The circumstance 
that the alimentary factor is so prominent in these cases, speaks for 
the fact that through the hyperthyroidism there is called forth an insufficiency 
of the pancreas; further, the circumstance that with the suppression of the 
hyperthyroidism the glycosuria again disappears and eventually there come 
about normal relations, shows that this insufficiency is actually the result 
of hyperthyroidism. It appears therefore as has already been amplified 
in the chapter on Basedow’s disease, that hyperthyroidism seems to signify a 
functional overloading of the pancreas; it is intelligible, from this standpoint, 
that glycosuria sets in only in individuals predisposed to it. As without 
such a functional overloading glycosuria would never occur, we are well 
justified in speaking of a thyrogenic glycosuria in such cases. This also 
is mostly easily delimited from true diabetes complicated with Basedow’s 
disease. 
As far as the diabetic glycosurias that occur so frequently in acromegaly 
and gigantism are concerned, it has already been set forth in the correspond- 
ing chapter that there is present in the great majority of cases an organic 
disease of the insular apparatus. It was mentioned there that in all conditions 
of hyperfunction of the glandular hypophysis a period of an abnormal tend- 
ency to growth is followed by a period of decay, and that the entrance of this 
decline is different in the various organs and especially so in the various duct- 
less glands. The insular apparatus appears to be especially sensitive. Besides 
these true diabetic glycosurias there is present in rare cases of acromegaly 
a similar condition to that observed in true thyrogenic glycosurias; in these 
cases right at the beginning of the disease there develops a glycosuria, which 
later disappears and gives place to a normal assimilative ability. Whether 
this glycosuria is of thyrogenic origin or whether the hypophysis does not 
enter in some other manner directly into the regulatory mechanism of the 
carbohydrate metabolism, I shall not touch upon. 
v. Noorden has portrayed the influence of the ductless glands upon the 
regulation of the carbohydrate metabolism in the following scheme. I have 
modified it in that I have added to it two connecting lines—one between 
the chromaffin tissue and the tissue at the periphery (chiefly the muscular 
system) and one between pancreas and tissue. This lends expression to the 
opinion that pancreas and chromaffin tissue directly regulate the assimila- 
tion and dissimilation of carbohydrates. Let me call attention to the fact 
that the line of connection between thyroid gland and pancreas is meant 
to express only the fact that increased thyroid activity disturbs the equilibrium 
to the disadvantage of the pancreas. Whether this happens through the 
influencing of the activity of the insular apparatus or through influencing 
the ultimate organs affected is still uncertain. 574 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
“The line of dashes represents nerve paths; the solid lines represent blood paths. The 
arrows show the direction of the excitation; the signs + or — behind them mean whether 
the stimulus transmitted by the respective path increases or diminishes the specific activity 
of the organ in question, whether it acts assimilatorily or dissimilatorily.” 
Differential Diagnosis.—A sharp separation of the ephemeral or transi- 
tory glycosurias from true diabetes is not practical. There are fleeting tran- 
sitions between these forms. We would naturally not regard every individual 
who has one time eliminated grape-sugar in his urine as a diabetic; otherwise 
if investigations as to alimentary 
glycosuria (ioo gm. grape-sugar) carried 
out at great intervals result always 
negatively, we could with justification 
speak of the cure of the diabetes. 
We would think in general of a 
pancreatogenic diabetes when the 
alimentary factor comes strongly in 
the foreground; especially if pancre- 
atogenic resorptive disturbances are 
present; further in all those conditions, 
which according to experience favor 
infection of the pancreas; hence in 
cholelithiasis, pancreatic stones, also in 
lues, cirrhosis of liver, and arterioscle- 
rosis, etc. Hirschfeld regards also the behavior of diuresis as a differential 
diagnostic factor. It is not unlikely that in true pancreatic diabetes there 
is at the beginning no polyuria. 
In glycosurias that occur during the course of infectious diseases, there 
is indeed much that speaks for the involvement of the pancreas in the infec- 
tion; there is much for the thought, however, that the violent conditions of 
excitation in the vegetative nervous system may be of significance for the 
genesis of a nervous glycosuria. 
For the assumption of a nervous glycosuria there are brought about 
symptoms that indicate a disease of the pons, cerebellum, and medulla oblongata, 
perhaps also circumstances that can bring about an irritation of the splanchnics 
or the great sympathetic ganglia either directly or by circuitous routes; 
especially, then, severe neuralgias. Further we have to turn our especial 
attention to the behavior of the vegetative nervous system and the influen- 
cing of the glycosuria through the psyche. In many cases we can perhaps 
carry out the test for adrenalin glycosurias (in the aglycosuric condition) 
or Lowi’s reaction; high-grade polyuria as well as simultaneously existing 
hypertonia speak for the nervous form or for a marked associated involvement 
of the nervous system. 
Finally, as to the thyrogenic form, naturally we must take pains to detect 
synchronous systems of hyperthyroidism. I would mention that in all the 
cases of true thyrogenic glycosuria that I have seen, the eye symptoms were 
at most indicated. But tremor, sweats, and mononucleosis of the blood 
Centn 
Nerei- 
\Syst.^s 
TTiuroid- 
ffland 
Tissue 
Liver 
Chromaffin 
tissue 
Intestine 
Pancreas 
Fig. 98. THEORETICAL CONCLUSIVE CONSIDERATIONS 
575 
were always present. A higher degree of glycosuria speaks well against the 
purely thyrogenic origin. Fat stools with strikingly good splitting of the fat 
and abundant soap-contents speak for the thyrogenic glycosuria. The diagnosis 
would be assured, if with the retrogression of the hyperthyroidism (sponta- 
neously or by means of Rontgen illumination, etc.), the glycosuria disappeared 
altogether, and if now strong loading of the carbohydrate metabolism no longer 
led to elimination of sugar. 
To close with some therapeutic points of view. In pancreatogenic dia- 
betes the difficult feature of the treatment up to the present lies in the diet, 
which purposes to avoid [the functionating of] the diseased organ. This 
is brought about by limitation, or even by temporary complete withdrawal 
of the supply of carbohydrates and by simultaneous limitation of the supply 
of proteins. Also in cases with ketonuria, an abundant supply of fat should 
be avoided. The patient should be made free of sugar, and when possible, 
maintained sugar-free. There often occurs in such cases a restoration of 
the insular apparatus; if later than the investigation shows that the assimi- 
latory ability has significantly increased, carbohydrates should again be 
administered at times in order to avoid permanent poverty in glycogen. The 
great significance of v. Noorden’s oat-meal treatment lies in the fact that in 
an individual under-nourished with carbohydrates large quantities of gly- 
cogen are administered as an increment. Thus is often explained the wonder- 
ful action on the ketonuria. The catabolism becomes limited. In the severe 
forms the complete withdrawal of carbohydrates is not possible permanently, 
as the complete absence of glycogen increases the formation of ketone 
bodies entirely too markedly. Here we must try to restrict the glycosuria 
at least as much as possible, and counteract the overloading with acids by 
alkali therapy. 
[The above paragraph is retained as in the previous edition. Allen’s fasting 
treatment seems to have found favor in this country; it is especially well 
adapted for hospital treatment. Joslin1 has worked out the dietaries that 
should follow the initial hospitalization. This is well presented by him in a 
recent article. Since the advent of the Allen form of treatment, V. Noorden’s 
oat-meal treatment has suffered. Falta himself has developed a cereal treatment 
which he regards as a successor to the oat-meal treatment. See addendum. 
Recently the insulin treatment as evolved by Canadian investigations has 
been used, and with success. See footnote, p. 6, and addendum, just 
below.—Editor.\ 
Much indeed speaks for the fact that in the nervous form too vigorous 
dietetic measures act unfavorably, although v. Noorden points out that in 
such cases a weakness of the insular apparatus may always be supposed, which 
tends to come to the fore in the further course, and therefore that a complete 
disregard for prophylactic dietary prescriptions may be disastrous for the 
patients. In the pure thyrogenic form the treatment of the hyperthyrosis 
occupies the foreground, in the pursual of which, however, vigilance in a 
1 Joslin (E. P.). The treatment of diabetes by the general practitioner. Pa. M. J., Vol. XXV, 
No. 6, March, 1922, pp. 373-381. 576 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
dietetic respect is not excluded. The treatment of diabetes in acromegaly 
should coincide with that of genuine diabetes. 
Addendum 
Allen, in his book on “Glycosuria and Diabetes,” draws an essential 
distinction between these two conditions, pointing out that in non-diabetic 
animals the limits of tolerance are apparent, not real, and that in these animals 
there is no real limit to the power of utilization of the sugar except death. Also 
that in the various forms of glycosuria dextrose always produces a limitation 
of the amount of urine, never a diuresis as in diabetes. He divides diabetes 
by pancreatic operation into a diabetes gravis and a diabetes levis, according 
to whether dextrose is or is not excreted on meat diet, and each 
of these into a permanent and a transient form. Permanent diabetes gravis 
and transient diabetes levis are absolute terms; but transient diabetes gravis and 
permanent diabetes levis are relative, the two conditions passing into each 
other. These various types depend on the condition of the pancreatic rem- 
nant. The ways that diabetes could be produced when the pancreas rem- 
nant is of more than ordinary size are by an irritative nervous lesion, such 
as the Bernard puncture, and by circulatory disturbances in the pancreas. 
The fact that the nervous system can influence the pancreatic hormone, as is 
practically also Falta’s conclusion, seems to the editor to speak in favor of 
Crile’s contention that diabetes may be conditioned centrally, the nerve 
cells showing chromatolytic changes. At all events the intermediation of 
the islands of Langerhans of the pancreas remain unquestioned, this bringing 
about a deficiency of what Allen terms “pancreatic amboceptor.” Accord- 
ing to Allen’s experiments there occurs in diabetes not a change in the hepatic 
cells that cause them no longer to fix dextrose, but a change in the physical 
state of dextrose itself. Instead of combining with a colloidal “pancreatic 
amboceptor” to be in a condition to be utilized, it maintains its ordinary 
crystalloidal properties, thus causing diuresis. Whether there is any dis- 
tinction between pancreatic hormone and the pancreatic amboceptor does 
not seem very clear in a cursory review of Allen’s voluminous work. Allen 
seems to call the substance an amboceptor because it acts as an intermediary 
body between the dextrose and various body cells. It has in common with 
hormones, at all events, the fact that it is an internal secretion, dependent 
on the integrity of the insular apparatus of the pancreas. Evidence is brought 
forward that at least one form of diabetes insipidus is associated with cir- 
culatory disturbances of the pancreas but that is not associated, as is diabetes 
mellitus, with any evidence of insular involvement. 
It is probable that the good results of oats on diabetes are due to the fact 
that rest is provided for the pancreas. According to Allen:-—by reason of 
freedom from harmful stimuli from the intestine, also perhaps by reason of a 
diminished labor of external secretion, and possibly by reason of a mild 
beneficial stimulation in a positive sense, the pancreas is able to perform its 
function of internal secretion more efficiently, and the diabetic condition is 
correspondingly benefited. This explanation agrees with facts in the literature. ADDENDUM 
577 
On the strength of his experiments, Allen has advocated and practised with 
good results a method of treatment, which consists in abstinence from food and 
drink, doses of alcohol (not absolutely essential), and the administration of 
sodium bicarbonate. [See below.] This regime is continued for twenty-four 
to forty-eight hours after the absolute disappearance of sugar from the urine 
(which occurs in from one to eight days), when it is replaced with 10-40 gm. 
of carbohydrates in the form of steamed green vegetables (gradually increased), 
together with fats and proteins (which are also increased gradually). As soon 
as sugar reappears in the urine, another fast day is instituted. Stengel, Jonas 
and Austin while advocating Allen's treatment for severe cases of diabetes show- 
ing high ketonuria, have had good results in the milder cases, those in which 
Allen’s treatment is perhaps too severe, by placing the patient on a carbo- 
hydrate-free diet, then adding green vegetables to this diet, and later allowing 
carbohydrates, below the limits of tolerance. The days of the carbohydrate- 
free diet are to be spent in bed, at rest. (Article in Nelson's Loose-Leaf System 
of Living Medicine.) 
As has been stated in the text, Allen regards as true diabetes mellitus 
only that diabetes which is due to pancreatic disease (the islands of Langerhans). 
“Hyperthyroidism may be accompanied by more or less tendency to hyper- 
glycemia and glycosuria and apparent lowering of the sugar tolerance, but the 
‘paradoxical law ’ (assimilation of all but a trivial fraction, no matter how high 
the dosage) still holds. The increased metabolism may well serve to bring out 
any latent diabetic tendency, and true diabetes with hyperthyroidism is rare. 
The increased metabolism may well serve to bring out any latent diabetic 
tendency, but pathologic study will reveal the origin of the latter in pancreatitis. 
The apparently high assimilation of sugar in hypothyroidism and hypopitui- 
tarism is explained by the habitual hypoglycemia. Diabetes is frequent with 
hypophyseal disturbance, but a more interesting and fundamental relationship 
will be discovered if an adequate pathologic study show a corresponding fre- 
quency of pancreatitis. Such diabetes is usually mild, and the remarkable 
variations of apparent tolerance at different stages of acromegaly or gigantism 
may be explained by variations in intestinal absorption, renal activity, and the 
metabolic alterations of cachexia. The pluriglandular doctrine, of sets of 
glands arrayed one against the other, requires mention only as an exploded 
fiction. Defectives of various kinds may suffer from diabetes, sometimes be- 
cause the same injury has affected several organs; but the great majority of 
diabetics are not otherwise defective, and the assumption of a diabetic ‘con- 
stitution’ or ‘diathesis’ is now archaic. Altogether, though any organ of the 
body may conceivably influence any other organ, in diabetes these other factors 
are rare and slight even as modifying influences and the disease is clearly the 
result of a definite disturbance in a single organ, namely the pancreas.” 
Although Allen states that it has recently been possible to reproduce all 
details of clinical diabetes, including lipemia, acidosis, and coma, by suitable 
partial pancreatectomy in animals, in a recent article he states that in dogs and 
cats a certain cachexia might be obtained that is of unknown nature, and 578 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
which possibly bears some relation to the metabolic alterations in states of 
prostration which suppress glycosuria even after total pancreatectomy. 
Mann in a brief though comprehensive review of the subject of diabetes 
mellitus, with some bibliography, states the following: “The obesity which 
precedes glycosuria in a considerable number of cases is explained as the result 
of fat formation from carbohydrate, which the organism is no longer able to 
burn. In some unknown way the 0-oxybutyric acid of fat decomposition 
requires the concomitant burning of sugar, and in diabetes these acid bodies 
accumulate and upset the acid-base equilibrium, causing the serious and 
dangerous group of symptoms known as acidosis. Our tests for this condition 
are the ferric chloride or nitroprusside tests of the urine, and the CO2 of the 
alveolar air, as well as of course the clinical evidence of sweet breath, languor, 
dyspnea, etc.” 
The chemical tests now used in the diagnosis of diabetes mellitus have 
recently been well dealt with by Snowden. They have to do with: “(a) 
examination of the urine for glucose and acids; (b) determination of the glucose 
content of the blood; and (c) blood tests indicating the degree to which acid 
bodies have reduced the alkali reserve of the blood and tissues.” The threshold 
point of the glucose concentration in the blood is placed at between 0.14 % 
and 0.16% A single normal determination by Snowden of this indis- 
pensable blood glucose content test cannot be accepted as normal. Snowden 
quotes Sellards’ test for determining the alkali reserve. He cites it as follows: 
“About 1 cc. of blood is withdrawn from a vein into a small syringe and expelled 
at once into 20-25 cc. of pure 95% alcohol. It is shaken and the precipi- 
tated protein filtered off. A few drops of phenolphthalein are added to the 
clear filtrate and it is then evaporated to dryness over a water bath in a white 
porcelain dish. If the normal quantity of carbonates are present, the filtrate 
turns pink as it approaches dryness, and remains pink; if there is slight reduc- 
tion, there is only a faint pink as it dries and this fades out in a few seconds; 
if there is considerable reduction, no pink color is evident either during or 
after drying, but a pink will develop if one drop of distilled water is put on the 
dried residue; in case of very marked reduction there is no pink even with the 
distilled water. This test is very simple, requires no extra apparatus and is very 
reliable. 
“All cases showing the excretion of acetone bodies in any amount in the 
urine, should be checked up with a test for alkali reserve, in order that the 
condition may be met before it has gone too far.” 
In a discussion on Snowden’s article, O. H. Perry Pepper points out that 
Sellards’s method is admittedly a rough method and that it may be seriously 
interfered with if the alcohol used is not actually pure. 
The use of alkalies to combat this acidosis or lack of alkali reserve has not 
been very successful. Just* why this is so is not clear,1 but Joslin and 
Allen have discarded alkalies in the treatment. Reliance is placed rather 
upon discontinuance of fat first of all, then fasting, drinking freely of liquids, 
According to Jonas (personal oral communication), the alkalies neutralize also natural sub- 
stances that would otherwise oxidize the ketones.—Editor. ADDENDUM 
579 
and, if necessary, giving some carbohydrate for a day or two and again fasting. 
(.Joslin for a time did use sodium citrate, but he does not mention it in his recent 
article in the Pennsylvania M. J. of March, 1922.) 
v. Noorden has recently stated that he still uses sodium bicarbonate in 
diabetes mellitus in spite of the criticism of the American investigators. What 
he considers obnoxious in the use of sodium bicarbonate in diabetes is the 
excessive size of the dose. v. Noorden believes that the treatment of diabetes 
should be adjusted to the individual in which the disease occurs. In other 
words, he treats the individual diabetic. His extensive experience with diabe- 
tics enables him to adjust the finding to each individual case. v. Noorden 
does not believe in limiting fats to the extent that the Americans do. 
Falta himself has recently instituted a “ Mehlfruchtekur” (cereal treatment). 
For details the reader is referred to the original volume. Falta regards the 
“cure” as a development of the oat-meal treatment of v. Noorden. 
The charge of “fanaticism” in the treatment of diabetes has been by 
various German authors against each other and against various special systems 
(Kuren). 
The question of feeding in diabetics is not as yet entirely systemizecT. 
While Falta accomplishes something by his main reliance on cereals and the 
school of Joslin restricts fats, Newburgh and Marsh have pointed out that many 
diabetics do well on a diet low in protein and high in fat. Strouse also has used 
more fat in the treatment of diabetes than the school of Joslin. Williams has 
pointed out the fact that the Allen treatment has undoubtedly added to the 
length of years of the diabetics, and has discussed other good features of the 
method. 
We quote Wilder, Boothby, and Beeler as follows: “The sugar tolerance of 
the diabetic patient is depressed by high calorie, luxus diets, but much more 
depressed by protein than by isocaloric amounts of fat. This protein effect 
is not primarily due to the sugar and ketogenic substances which the ingestion of 
protein throws on the metabolism, but to some other more specific action of pro- 
tein the result of which is to interfere with the mechanism of sugar utilization.” 
Allen and Wishart have determined as result of their work that in diabetes 
light exercise aids health, heavy exercise does harm rather than good. Allen 
has determined (Am. Jr. Med. Sciences, March, 1921) that in diabetes the 
asthenia and the gangrene are due to the specific endocrine deficiency and not to 
simple malnutrition, hyperglycemia, glycosuria, or other causes. 
Insulin (or iletin), the principle of the islands of Langerhans isolated by 
Canadian investigators has to a certain extent been standardized. A unit of 
insulin is that amount required to reduce the blood sugar of a two kilogram 
rabbit to the point of convulsion. The amount of total glucose in the diet util- 
ized in the presence of one unit of the principle has varied from 1.5 grams to 
7 grams in individual patients. 
Insulin is given entirely by hypodermic injections, and its effect probably 
does not last longer than eight or ten hours. Injection is usually given three 
hours before feeding and never more than three or four times a day. At present, 
it is to be used only for severe cases of diabetes, and with the utmost caution.. 580 
DISEASES OF THE INSULAR APPARATUS OF THE PANCREAS 
It demands even more accurate quantitative diets than are used without it. 
The great danger lies in producing coma and convulsions due to hypoglycemia, 
which is readily produced by withholding an adequate amount of food after 
injection of insulin. Much harm may be caused by the use of it, if it is em- 
ployed with inaccurate diets or in the absence of extremely close observation.1 
(See editorial in Boston M. and S. J., Vol. CLXXXVIII, No. 1, Jan. 24, 1923, 
pp. 18 and 19.) 
A study of the hypophysis in diabetes mellitus by Fry has shown that it 
exhibits definite histological changes. It contains adenomatous masses of 
eosinophile cells, and there is colloid invasion of the anterior lobe, together with 
area of cellular degeneration in this part of the gland. The findings of Kraus 
in the hypophysis in diabetes have been mentioned in the addendum to the 
chapter on the pituitary gland. 
Allen (F. M.). Studies concerning glycosuria and diabetes. Boston, 1913, N. M. Leonard. 
Allen (F. M.). Studies concerning diabetes. Jr. Am. M. Ass., Vol. LXIII, No. n, Sept. 12, 
1914, pp. 939-943- 
Allen (F. M.). Art. “Diabetes mellitus” in Nelson's Loose-leaf System of Living Medicine. 
Allen (F. M.). Experimental studies in diabetes, Series II, 4. The internal pancreatic function 
in relation to body, mass and metabolism. Ill, Pancreatic cachexia. Am. Jr. Med. Sci., March, 
1921, pp. 350-364. 
Mann (R. W.). A resume of diabetes mellitus. The Canadian Medical Asso. Jour., Vol. XI, 
No. 4, April, 1921, pp. 243—251* 
Snowden (R. R.). The chemical procedures that are of use in the control of diabetes. [With 
discussion.] Pa. M. J., March, 1922, Vol. XXV, No. 6, pp. 383-389. 
Pepper (O. II. P.). Discussion on above. Same issue of above journal. 
Joslin (E. P.). The treatment of diabetes by the general practitioner. Pa. M. J., March, 1922, 
Vol. XXV, No. 6, pp. 374-381. 
Falta (IE.). Die Mehlfriichtekur bei Diabetes mellitus. Urban, Berlin and Vienna, 1920. 
Falla (IE.). Praktisches und historisches zur Mehlfruchtckur bei Diabetes mellitus. Deutsche 
med. Wochenschrtft, Vol. XXXI, No. 47, Aug. 4, 1921, pp. 889-891. 
Joslin (E. P.). The prevention of diabetes mellitus. J. Am. M. Ass., Vol. LXXVI, No. 2, 
Jan. 8, 1921, pp. 79-84. 
Newburgh (L. II.) and Marsh (P. L.). The use of a high fat diet in the treatment of diabetes 
mellitus. Arch. Int. Med. XXVI, p. 627, 1920, and Arch. Int. Med., XXII, No. 6, June 15, 1921, 
pp. 699-705. 
Strouse (5.). Dietetic therapeutics. M. Clinics of N. America, Vol. V, July, 1921, pp. 229 seq. 
Williams (J. R.). A devaluation of the Allen method of treatment of diabetes mellitus. Am. 
Jr. Med. Sc. Vol. CLVII, No. r, July, 1921, pp. 62-72. 
Wilder (R. M.), Boothby (W. M.), and Beeler (C.). Studies of the metabolism of diabetes. Jr. 
Biol. Chem., Vol. VI, No. 2, April, 1922, pp. 311-357. 
Allen (F. M.) and Wishart (M. B.). Experimental studies in diabetes Series II. The effects of 
exercise. Am. Jour. Med. Sciences, Vol. CLXI, Feb., 1921, pp. 165-193. 
Stengel (A.), Jonas (L.), and Austin (J. H.). The treatment of diabetes mellitus with special 
reference to Allen's method. Pennsylvania Medical Journal, Vol. XIX, No. 4, Jan., 1916, pp. 283-287. 
Fry {II. J. B.). The pituitary gland in diabetes mellitus and disorders of the glands of internal 
secretion. The Quarterly Journal of Medicine, Vol. VIII, No. 32, July, 1915, pp. 277-299. 
Kraus {E. J.). Hypophysis und Diabetes mellitus, Virchow’s Archiv., Vol. CCV, III, 1920, 
pp. 68-134. 
1 Present insulin preparations are protein free. Symptoms after its use can be relieved by 
the administration of food, for instance orange juice with glucose. It is especially useful in 
juvenile diabetics, diabetics who are undergoing surgical operations, diabetics with coincident 
infections, such as tuberculosis, gangrene or syphilis, diabetics otherwise not amenable to treat- 
ment, and diabetic coma (in which it may be characterized as a specific). See special article 
■—The status of insulin, J. Am. M. Ass., Vol. LXXX, No 17, April 28, 1923, pp. 1238-1241, 
where a history of its discovery and preparation is given, with a bibliography. CHAPTER XIV 
THE DIFFERENT FORMS OF OBESITY AND ADIPOSITAS 
DOLOROSA 
We have already spoken of obesity in other chapters. It seems to me 
appropriate, however, to describe the relations of the ductless glands to the 
pathogenesis of obesity, even though I do not tell anything new. Further, 
it would be appropriate to discuss the relations between obesity and lipomato- 
sis, as also the origin of lipomatosis has been brought into relation with 
disturbances of the ductless glandular system. 
A. THE DIFFERENT FORMS OF OBESITY 
Two different principal types of obesity have been distinguished (v. 
Noorden, Lorand), exogenous obesity and endogenous obesity. By exogenous 
obesity Lorand understands the obesity of big eaters that which later becomes 
combined with diabetes; endogenous obesity he refers to a disease of the ductless 
glandular system. Such individuals are for the most part anemic, have an 
“unhealthy fat,” and the combination of the disease condition with diabetes 
belongs to the great rarities. The separation and characterization of both forms 
has been carried on exhaustively by v. Noorden in his monograph on obesity. 
According to v. Noorden exogenous obesity is either an overfeeding obesity 
or a laziness obesity, or the result of both overfeeding and laziness combined. 
Exogenous obesity often occurs familially or hereditarily, although v. Noorden 
points out that in many of these cases there has been much more the hereditary 
transmission of a habit of living than that of a definite constitution. Naturally, 
cases occur that must be regarded as transition forms between exogenous and 
endogenous obesity. A further entrance into the subject of exogenous obesity 
does not lie within the confines of my theme; I shall refer to the exhaustive 
exposition of v. Noorden. 
In endogenous obesity much value has been laid on the demonstration of 
a diminution of the basal metabolism and great pains have been taken in the 
demonstration. While such a diminution may be demonstrated in myxedema 
with certainty and ease, the attempts to demonstrate it in endogenous obesity 
have met with great difficulties. As the fat tissue only takes part in internal 
respiration to a limited degree, the basal metabolism must fall very strongly 
in each fat individual if we wish to calculate it per kilo of body weight. We 
possess however no method of estimating the fat contents of an individual, but 
must rely on coarse, insufficient estimations. The investigations up to the pres- 
ent on the fasting and rest values of corpulent individuals (v. Noorden, Thiele 
and Nehring, Stuve, Magnus-Levy, Rubner, Jacquet and Svenson, Salomon, Reach, 
Staehelin, and v. Bergmann) have been subjected to an analytical criticism 
581 582 
OBESITY AND ADIPOSITAS DOLOROSA 
by,. Noorden; the calculation of the exchange per kilo of body weight, must, as 
already mentioned, be rejected as of no use. The calculation of the quotient 
02 consumption . .......... . . . 
■ b0(ty height— s^ows m corpulent individuals higher values sooner than in 
normal individuals. This is perhaps due to the fact that in heavy accumula- 
tions of fat the work of the heart and of the respiratory muscles is perhaps 
made more difficult, v. Noorden arrived at the result that the estimation of the 
respiratory exchange at rest has up to the present furnished no sure decision in 
this question. This is true apparently of the estimations up to the present of 
the factors influencing the exogenous respiration gaseous exchange. The 
opinion has been held that in the corpulent the ingestion of food should call 
forth a slighter increase of the exchange. Herein lies a tendency to saving. 
The experiments that have been made up to the present, however, do not bear 
strict criticism. Up to the present only the determination of the calorie require- 
ments has led to reliable results in some cases. The supply of heat was esti- 
mated in a very careful manner and for a long period, and it was determined 
that corpulent persons either take on fat or do not lose it under conditions 
under which normal persons either would not become corpulent or would lose 
in body weight. In this method care should be taken that exogenous factors 
are not allowed to take a part. The corpulent individual, to whom every 
movement is attended with exertion and is disagreeable, has often learned to 
get along with the minimum of movement, otherwise he sits and stands as a 
normal individual. To this must be added also the phlegm of such individuals. 
These methods can thus furnish a certain conclusion as to the diminution of the 
basal metabolism, if extremely low values are found. This is actually so in the 
cases reported. Such cases are, however, as v. Noorden has pointed out, quite 
rare. 
We must now consider the question as to whether a diminution in the 
basal metabolism characterizes endogenous obesity, and whether this is neces- 
sary for the assumption of a case as such. In a typical myxedema it is true 
that simultaneously with the reduction in the basal metabolism there occurs 
an increase of the body weight, but this does not always progress to obesity. 
It is much more probable that the increase in weight can depend solely or in 
great part on the accumulation of myxedematous tissue and the water accumu- 
lation. In normal grown individuals the ingestion of food rises or falls with the 
greater or lesser need for it. The body weight, apart from slight variations, 
often remains the same for years at a time. This depends on a flne regulatory 
mechanism that as yet has not been investigated sufficiently. The most 
important element in the same is the appetite, although at times we eat very 
much more than the appetite really craves for, and then follows a period not of 
lessened appetite, but perhaps of increased demand for movement, the cause 
of which is not known. May not, perhaps on the occasion of too great demand 
on the assimilation, substances arise which give occasion to this desire for 
movement? If now the diminution of the basal metabolism increases the body 
weight, that is, the need for food does not keep pace with the exchange, it seems 
to me that a diminution of the basal metabolism is less to blame for this increased PANCREATOGENIC OBESITY 
583 
body weight than a disturbance of the regulatory mechanism; and it is perhaps 
not inconceivable that there are forms of endogenous obesity without diminu- 
tion in the basal metabolism. In exogenous obesity, according to this point 
of view, the regulatory mechanism is disturbed voluntarily or on account of 
bad habits (v. Noorden); in endogenous obesity, involuntarily through an altera- 
tion in the working together of the factors governing assimilation. If now I 
investigate how far such factors depend on the function of the ductless glands, 
it is known to me that I trespass into the territory of speculation, yet I see no 
other way of bringing into association the few certain observations that we 
possess on this question. At first I must again call to mind that the ductless 
glands exert an influence on both the endogenous and the exogenous factors of 
the total metabolism. Upon the endogenous through diminution of the 
vegetative functions, for example; on the exogenous by their influence on the 
temperament, the psyche, the desire for movements, etc. 
i. Pancreatogenic Obesity 
We shall consider in the first place a form of obesity, whose genesis has 
yet not been furnished to us. It is observations from the physiology and 
pathology of metabolism that makes the supposition of such a form possible; 
if this supposition, however, suffices, many other forms of endogenous obesity 
may be made the more readily intelligible from this standpoint. The complete 
extirpation of the pancreas in the dog leads to an appreciable increase in the 
gaseous exchange. High-grade insufficiency of the insular apparatus in man is 
not, however, associated with an essential raising of the heat-production. 
Therefore, if although up to the present there has not been demonstrated by 
gaseous-exchange experiments concordant results as to a quenching of the heat 
production through the function of the insular apparatus, other considerations, 
nevertheless, seem to ascribe to the pancreas an important role in the calorie 
economy. 
v. Noorden first adhered to such an opinion, in that he indicated the possi- 
bility “that fixing of glycogen and sugar-production can be disturbed, while 
fat formation from carbohydrate still functionates. The fat tissue then 
takes up the excessively formed carbohydrate (as fat); there already exists a 
true diabetic disturbance of metabolism, but without glycosuria” (diabetogenic 
obesity). 
I would consider in the following consideration a further possibility: 
It is known that carbohydrates have the ability to save protein to a much 
larger extent than fat, and that an individual can hardly maintain his nutri- 
tion on protein and fat alone. An abundant feeding, especially when there is 
a simultaneous raising of the protein constituent, succeeds only when there 
is abundant carbohydrate in the diet. Hence carbohydrate diminishes the 
decomposition of the protein. As the specific dynamic energy of protein is 
very much higher than that of fat and of carbohydrate the increase of the 
calorie production associated with the more abundant ingestion of nutrition 
is restricted. Now to-day there is not a particle of doubt that the accumulation 584 
OBESITY AND ADIPOSITAS DOLOROSA 
of carbohydrates is under the governing power of the insular apparatus. There 
must also accrue to the pancreas a direct influence on the assimilation of fat, 
not only because on the ingestion of abundant carbohydrates a portion of these 
is converted into fats, but because in severe diabetes the elimination of ketone 
bodies increases enormously on the administration of abundant fat. For fatten- 
ing, therefore, is necessary a functionally intact pancreas. That we so often see 
diabetes supervene in fat people is perhaps due to the fact that the long over- 
strained pancreas becomes insufficient, apart from the circumstance that 
chronic overfeeding is often associated with other factors deleterious to the 
pancreas (alcoholism, continual hyperemia of the abdominal organs, etc.). 
The considerations up to the present are concerned chiefly with exogenous 
obesity. We can conceive, however, that the origin of obesity may receive 
an impetus through a primarily strengthened function of the insular apparatus, 
in that the assimilation of larger amounts of food goes on abnormally easily, 
and hence there does not occur the setting free of the reactions that in normal 
individuals work against an ingestion of food which for a long time supersedes 
the need. 
2. Thyrogenic Obesity 
The idea of thyrogenic obesity was first set forth by von Hertoghe, v. 
Noorden, Lor and, Ewald, and others. Occasion for it was given by observations 
of rather rapidly developing obesity with slight symptoms of hypothyrosis, 
slight puffiness of the feet, apathy, diminution of memory, insomnia, etc. 
To it is often added a slight grade of anemia. Such individuals often bear 
reducing treatment very badly, v. Noorden mentions especially that in such 
cases reducing treatment often leads to conditions of cardiac weakness, while 
a thyroid-gland treatment is often accompanied by rapid results, the manifold 
oppressive symptoms disappear, the individuals become livelier, fresher, and, 
although they eat with appetite and do not essentially restrict the intake of 
food, they now gain in weight rapidly. There appear to be very different etio- 
logical factors that lead to such a slight functional disturbance of the thyroid 
gland. In many cases there had been numerous parturitions following each 
other at short intervals. In others the obesity develops immediately at the 
close of a protracted infectious disease, v. Noorden mentions for instance cases 
in which the obesity developed progressively after an abdominal typhoid, and 
refers to similar examples from the French literature. 
The diagnosis of this form of obesity is often difficult, because the symp- 
toms of hypothyrosis are only suggested. The justification for one’s regarding 
the hypothyroidism as the cause of the obesity can, however, in many such 
cases, indeed not be doubted. It is found in the entire course of the disease 
and in the excellent action of the thyroid treatment, which we may regard as 
a sort of functional test. Of course thyroid gland acts as an agent that reduces 
weight also in the cases of ordinary exogenous obesity. The essential point 
lies, however, as v. Noorden mentions, in the difference between the complete 
action of the -thyroid cure and the intolerance against much withdrawal of 
food, and, as I would attach especial value to, in the high tolerance for thyroid- DYSTROPHIA ADIPOSO-GENITALIS 
585 
gland preparations. From the theoretical standpoint the assumption of such 
a thyrogenic obesity is well founded. We can conceive that just in such slight 
degrees of thyroid-gland insufficiency, the balance between thyroid-gland func- 
tion and the function of the pancreas is disturbed in favor of the latter, and that 
thus is furnished the impulse for the origin of an obesity, while with a severe 
disturbance of the function of the thyroid often all vegetative functions are 
highly diminished, and therewith the ingestion of food and the appetite are 
restricted. The very general observation that in such cases of thyrogenic 
obesity the assimilation limits for carbohydrates lie abnormally high, indicates 
with the greatest probability a preponderance of the pancreatic function. 
3. Dystrophia Adiposo-genitalis 
[In this form, whether it be of primary genital or hypophysial origin, there 
is found a characteristic distribution of fat such as has been described in detail 
in the appropriate chapters. It depends on the withdrawal or the weakening 
of the protective influence of the interstitial glands on body formation.—Editor.] 
The distribution of fat has per se nothing to do with obesity, as it is retained in 
such individuals when they otherwise become very thin on any other basis, 
and for the reason that sure cases of hypophysial dystrophy and also many 
eunuchoids do not come to the development of a pronounced obesity, while the 
abnormal distribution of fat is always present. Also a certain degree of fatty 
infiltration of the muscles may be peculiar to this dystrophy, independently of 
obesity, as well as a weak, velvety texture of the skin, and the behavior of the 
hair. The fact is, however, that in both forms, obesity develops very com- 
monly, even to excessive degree. The factors that give occasion to this are as 
yet not entirely clear. We must consider that eunuchoids have another tem- 
perament than normal individuals; they are less lively, have less energy, the 
muscular tonus is slighter; in hypophysial dystrophy there also happens that 
in the severer cases the vegetative functions seem to course more slowly, and 
the basal metabolism therefore is established at a low level, as experimental 
investigations on animals have shown. Also in these forms the function of the 
insular apparatus seems to have a certain preponderance, at least, as has already 
been set forth in detail, in almost all cases there is a strikingly high tolerance 
for carbohydrates. In the intimate pathological correlations between glandu- 
lar hypophysis and thyroid, also a thyrogenic factor can, in many cases 
of hypophysial dystrophy, very well play a part. Ordinarily this does 
not seem the case, at least the result of a thyroid treatment in such cases is not 
so excellent as in the ordinary obese individuals, and the tolerance for the 
administration of thyroid gland is not essentially higher. There are numerous 
statements in the literature that in such cases of hypophysial dystrophy the 
peroral administration of hypophysis tablets or eventually a combination [of 
these] with sexual gland substance was followed by results. 
4. Epiphysial Obesity 
It is as yet doubtful whether we are justified in recognizing such a form. 
At all events it is remarkable that commonly with the development of pineal 586 
OBESITY AND ADIPOSITAS DOLOROSA 
tumors in adults, obesity also develops. This may attain an excessive degree. 
We may readily conceive that the obesity may be brought about on account of 
limitation of function of the neighboring hypophysis. Actually, in the case of 
Raymond and Claude, the hypophysis was very much flattened. One would 
then expect the other characteristic symptoms of hypophysial dystrophy in all 
cases. From the cases in the literature, which, however, have not been de- 
scribed very exactly, I have not succeeded in eliciting a safe basis for this. 
B. ADIPOSITAS DOLOROSA 
In the years 1882 and 1892 respectively, Dercum described a disease picture 
which is characterized by a peculiar form of fattening and by the painfulness 
of the fat masses. Later Vitaut called attention to two additional cardinal 
symptoms, namely the asthenia and certain psychical alterations. Dercum 
considered the disease as due to an especial form of dysthyroidia; since that time 
numerous pertinent cases have been reported; most authors adhere to the 
ductless glandular pathogenesis of this disease, although others, especially 
French authors, oppose the setting up of this syndrome as a disease sui generis, 
advocating the opinion that from this syndrome there are transitions to the 
different forms of lipomatosis and to the trophic edemas. Lately Lyon is 
even of the opinion that also the different forms of obesity and those of lipoma- 
tosis go over into each other without sharp boundaries. Many authors assume 
a nervous trophic origin for this syndrome. Before I enter into the description 
of the syndrome, I would like to report an appropriate case. 
Observation LXX.—Fr. B., fifty-six years old. Entered the first medical clinic Sept. 3, 
1912. The parents of the patient were both corpulent. Of five brothers three are very 
corpulent, -and of four sisters, two. According to the statement of the son the localization 
of the fat in the corpulent relatives is not just the same as in the patient. The four chil- 
dren are not adipose. There is no diabetes or gout in the family, so far as is known. As 
a child and youth the patient was healthy. The obesity began to develop during his mili- 
tary service, especially later, however, when the patient adopted a sedentary life; he. was 
landlord of an inn and ate and drank very much, consuming 4L2 liters of wine daily and 
smoking very much. The obesity was especially heavy from the thirty-fifth year of life 
on. The fat developed in cushions on the shoulders, on the upper arm, on the thorax, and 
on the pelvic girdle, while forearms and hands and [lower] legs and feet remained thin. 
For about ten years there often occurred oppressions of respiration and vertigo, especially 
on going up stairs and on long marches. Lately he can hardly walk on this account. The 
appetite became slight, and he ingests practically only liquid nutrition. In the spring of 
1912 he weighed as much as 140 kg. Since that time he lost about 30 kg. For a long time 
there has existed pains in the hepatic region; during the last weeks he vomited several 
times daily, independently of the ingestion of food, also belches. For the last year there 
has been entire impotence and failure of libido; this latter had for a long time been developed 
only very moderately. 
The patient now weighs 105 kg. and by Nov. 9 had lost 3 kg. more. The body length is 
170 cm., the span width, 169 cm., the greatest circumference of the abdomen 124 cm. 
There are enormous accumulations of fat on the upper arms and on the outer sides of the 
shoulders, also on the inner side of the upper arm, also a thick cushion of fat over the verte- 
bra prominens (a true fat neck), also on the outer sides of the buttocks and of the thighs; 
the thin forearms and [lower] legs stand in characteristic contrast to the heavy fat accu- 
mulations on the shoulder and pelvic girdle. In consequence of these the patient presents ADIPOSITAS DOLOROSA 
587 
the appearance of an athlete. On closer examination, however, it is noted that the body 
build is slender, and that thorax and pelvic girdle are not abnormally broad. The cir- 
cumference about the shoulders is, in consequence of the enormous cushions of fat, 128 cm. 
The circumference of the abdomen a hand’s breadth under the xiphoid process is 122 cm., 
the greatest circumference of the thorax, 123 cm., the greatest circumference of the upper 
arm on both sides, 40 cm. On the inner side of the forearm may be felt on both sides sev- 
eral symmetrical fat nodules, the size of a nut; the fat has accumulated more abundantly 
on the upper part of the thorax, in the vicinity of the nipples, so that it drapes forward 
Fig. 99.—Case of adipositas dolorosa (Observation LXX) 
in two enormous folds, directed obliquely outward and downward, and drapes backward 
in several oblique and horizontal folds. From the waist on the fat again begins to be enor- 
mous, so that it hangs below like an apron over the symphysis and half conceals the genitalia. 
Laterally over both iliac bones are enormous fat nodules that are bounded below by 
folds. On the outer side of the femur palpation reveals a more diffuse embedding of dense 
nodular fat. On the inner side is found on each side an enormous fat nodule. The distri- 
bution of fat is everywhere strictly symmetrical. At some places are found thick sym- 
metrically disposed fat nodu’es of the size of a hen’s egg to that of an apple. Often the 
nodules are smaller, seeming to the palpating finger like small nodules. Everywhere over 
the fat cushions are to be seen ectatic veins, around which are plainly evident in the whole 
course of the veins fat disposed like bunches of grapes. Here the fat is especially painful. 
The left ’obe of the thyroid gland shows a struma about the size of a goose egg. 
The border of the liver is palpable three finger-breadths below the border of the ribs, 
and is hard. The urine shows urobilin and traces of albumin. 
Test as to alimentary glycosuria (ioo gm. dextrose) negative. 
After injection of 3 cc. pituitrinum glandulare, and later 5 cc., there was no increase 
of temperature. 
The blood sugar-contents is normal. 
Blood count: Leucocytes, 12,000, of which: 
Neutrophiles, 50%; 588 
OBESITY AND ADIPOSITAS DOLOROSA 
Lymphocytes, 42%; 
Large mononuclears, 6%; 
Eosinophiles, 2%; 
X-ray shows that the aorta is 7 cm., the heart 13.5 cm. broad. The genitals show 
nothmg especial. 
The sella turcica is seen (by X-ray) to be of normal size. 
Nerve status: The fundus is normal. The pupils react promptly. Patellar reflexes 
are weak on both sides, superficial abdominal and cremasteric reflexes normal. No Babinski, 
no Romberg. Slight paresis of the right facial nerve. Distinct alcoholic tremor. Gross 
strength of the muscles reduced. Gait somewhat insecure. Sensibility not essentially 
disturbed. 
Fig. ioo.—Inflammatory alteration of the fat tissue in a case of adipositas dolorosa 
(Observation LXX). 
The microscopical examination of an excised piece of fat showed pronounced peri- 
vascular infiltration consisting especially of mononuclear, and partially of polynuclear 
cells. Especially distinct is this infiltration in the interstitial connective tissue between 
the individual fat lobules, although the smallest perivascular infiltrations are found also 
around the capillaries between the fat cells themselves. 
The patient failed very rapidly; soon he was not oriented as to time and space; there 
occurred hallucinations of faces, he spoke confusedly, believed himself to be on a journey, 
whistled and made a noise, especially at night. Apparently there was diplopia on looking 
toward the left. Slight paresis of the left abducens. The ingestion of food became always 
slighter; nutritive enemas were not retained. At times vomiting. The pulse accelerated, 
small, soft cardiac remedies were without effect. At the close there developed an ulcerous 
pharyngitis, later bronchitic murmurs; death occurred with increased cardiac weakness. 
Autopsy (Assistant Dr. Schopper): Hypertrophic cirrhosis of the liver with moderate 
enlargement of the organ and uniformly granulated superficial and cut surface. Marked 
fat infiltration of the heart in the form of nodular fat lobules with penetration of the fat ADIPOSITAS DOLOROSA 
589 
until up to the endocardium. Concretio cardio cum pericardio. Increase of the fat also 
in the pericardium, hypostasis of the lungs, etc. Chronic internal hydrocephalus with 
granular thickening of the ependyma. Slight fatty degeneration of the kidneys and of 
the myocardium. Acute splenic tumor. Ulcerative pharyngitis. Marked atheromatosis 
of the aorta. Slight sclerosis of the peripheral arteries. 
Fig. ioi.—Thyroid in a case of adipositas dolorosa (Observation LXX). 
The distribution of fat corresponds to the clinical description. The fat is of a yellow- 
ish gray color, firm consistence with individual stripes and spots of white-gray color that 
are appreciable even macroscopically. 
The hypophysis is rather small, otherwise macroscopically normal. 
The thyroid gland is macroscopically for greatest part quite normal, in the left lobe is 
found a goose-egg-sized strumous nodule. 
The suprarenals are microscopically normal. 
Also in the sexual glands is found nothing especial. The pancreas is macroscopically 
normal. 
The microscopical examination of the pancreas and the suprarenals showed fully nor- 
mal conditions. The microscopical examination of the thyroid gland showed, as the adjoin- OBESITY AND ADIPOSITAS DOLOROSA 
590 
ing illustration shows, a colloid struma, yet there is still found everywhere abundant thyroid 
glandular tissue of normal consistency (Fig. ioi). 
Also the microscopical examination of the hypophysis showed normal relations, as well 
in the glandular lobe as in the nervous lobe and in the pars intermedia. 
Fig. 102 shows a general view. 
Fig. 103 shows a portion of the glandular part on higher magnification. 
Fig. 102.—Hypophysis in a case of adipositas dolorosa. 
Also another piece of fat tissue was examined microscopically; in this 
section there was a perivascular infiltration, more distinctly developed about 
the large vessels. See Fig. ioi. 
Symptomatology.—Adipositas dolorosa, or adiposis dolorosa, is found more 
commonly in women than in men. It usually begins between the forty-fifth 
and the sixtieth years of life. In women the disease often sets in with the 
menopause. There are, however, individual cases in which the beginning 
occurred at the eleventh year of life. As cardinal symptoms of the disease 
are regarded the fat tumors, the tenderness of the fat to pressure or its pain- 
fulness spontaneously (Dercum), the asthenic and the psychical alterations 
(Vitaut). In addition there have been described, however, a series of ac- 
cessory symptoms, that consist especially in disturbances on the part of the 
motor, sensory, and vegetative nerves. ADIPOSITAS DOLOROSA 
591 
The distribution of the fat tumors may vary. Vitaut first distinguished: 
(a) Nodular, asymmetrical fat tumors, disposed asymmetrically in and 
under the skin—lipomatose nodulaire. 
(.b) Circumscribed, diffuse, not sharply delimitable fat growths, lipo- 
matose diffuse localisee. 
(c) General diffuse fat growths, lipomatose diffuse generate; this is the 
most frequent form, and in it the fat is not uniformly distributed as in ordinary 
adiposity, the skin shows much more an uneven texture. The fat masses feel 
lump-like, like a bundle of worms {Dercum), and at those places especially 
Fig. 103.—Anterior lobe of hypophysis in a case of adipositas dolorosa (Observation LXX) 
where a pressure is exerted, for instance in the waist, or where the garters 
press, they are separated from each other by deep furrows. 
In lipomatose diffuse localisee the accumulations of fat are mostly found 
only on the trunk and on the proximal third of the extremities. In such cases 
the fat deposits may be quite excessive and hang down like an apron, as for 
instance in a case of Dercum and McCarthy's, in which the fat masses hung 
laterally over the hips and backward over the buttocks in thick folds, or in a 
case of Loning and Fuss’s in which the fat masses hung from the abdomen and 
the inguinal region almost to the lower third of the thigh. 
In the nodular form the throat and face, as well as hands and feet, eventu- 
ally also the forearms and [lower] legs are entirely free; the latter are often 
very thin. In a case of Debove’s there was found, especially on the outer side 
of the upper arm, symmetrically disposed masses up to the size of a pigeon’s 
egg. The hands were entirely free. These fat nodules may be arranged in a 
multiple manner, or symmetrically. 592 
OBESITY AND ADIPOSITAS DOLOROSA 
On careful observation of the reported cases we may see that all transitions 
between these three types occur. This was already observed by Weiss; the 
classification has but little value. I refer to the case detailed above, which 
constitutes a combination of lipomatosis nodulaire and lipomatosis diffuse 
localisee. 
The second cardinal symptom consists in the painfulness of the fat. In 
many cases there is a sensation of violent burning “as if a dog were tearing the 
flesh from the body” (Haskovec); in other cases the pains occur in attacks, 
under circumstances before the fat infiltrates become visible. In other cases 
Fig. 104.—Perivascular infiltration in a case of adipositas dolorosa (Observation LXX). 
vesicles appear during the attacks of pain. In other cases spontaneous pains 
are absent, the fat infiltrates are painful only on pressure; in my case the pain- 
fulness of the fat infiltrate was limited chiefly to the vicinity of the dilated 
veins. There are also cases described, otherwise typical, in which the tenderness 
to pressure was but very slight. 
In all cases the asthenia is more or less distinctly pronounced. In the case 
described above, the muscular weakness was so great that the patient could 
scarcely walk. 
Psychical alterations are indeed very common, but not constant. The 
case of Loning and Fuss, a sixty-six-year-old woman in whom the disease had 
existed for about twelve years was mentally entirely normal and active. The 
psychical alterations are very various. In many cases hallucinations and 
conditions of excitement are observed, in others, as for instance Ballet’s case, 
depressive melancholic conditions. Also the accessory symptoms are very ADIPOSITAS DOLOROSA 
593 
diverse and not constant. On the part of the motor nerves are observed 
tremor (alcoholism), slowing of the speech, alterations of the reflexes, espe- 
cially reduction. On the part of the sensory nerves there are hyperesthe- 
sias and paresthesias, disturbances of the sensibility, etc., on the part of the 
vegetative nerves often vasomotor symptoms such as dermographism, tachy- 
cardia, dyspnea, anidrosis, and hyperidrosis. There occurs in addition, 
trophic disturbances, such as premature turning gray of the hair, and on the 
part of the vascular system hemorrhages, inclination to nose-bleed, purpura, 
etc. As may be seen, very diverse symptoms are collected together in this 
group. As we are mostly dealing with elderly people with fatty heart and 
severe alcoholism, many of these symptoms are readily intelligible without 
anything further. 
Investigations as to the metabolism are as yet very sparse. Schwenck- 
enbecher observed two cases in which the body weight only began to fall when 
the administration of calories was as low as 19 calories per kilogram. In 
many cases polydipsia is asserted, in others reduction of the body temperature. 
Pathological Anatomy.—There are already a series of autopsies, into a 
consideration of which I shall enter somewhat exactly, as it is necessary for 
the discussion of the pathogenesis. 
Dercum described two cases, in which were found macroscopically enlarge- 
ment and calcareous infiltration of the thyroid gland. In a case of Dercum’s 
was found uniform atrophy of the thyroid gland, and widespread intersti- 
tial neuritis of the peripheral nerves in the depositions of fat. In a case 
of Burr's was found degenerative alterations in many lobules of the thy- 
roid gland, also a glioma of the hypophysis, and in addition interstitial neuritis, 
sclerosis of the liver, and atrophy of the ovaries. In a case of Dercum and 
McCarthy's the thyroid gland was normal, there was found an adenocarcinoma 
of the hypophysis, enlargement of the right suprarenal, hemolymph glands 
in the fat tissue, interstitial neuritis, hypoplasia of the testicles, and acute 
parenchymatous nephritis. In a case of Guillain and Alquier’s the thyroid 
gland was found to be enlarged and the connective tissue in it increased. 
The hypophysis was likewise enlarged, the connective tissue in the glandular 
portion was increased, in association with which the eosinophilic and baso- 
philic cells were increased, alterations that reminded both these authors 
of an alveolar carcinoma. In a case of Price’s there were found inflamma- 
tory alterations in the thyroid gland as well as in the hypophysis (alveolar 
or glandular carcinoma?) and interstitial neuritis. In a second case there 
was found in the thyroid gland much interstitial tissue, the acini were dilated, 
the hypophysis showed similar but not essential alterations. In the fat tissue 
no especial alterations were found. In a case of Loning and Fuss’s the thyroid 
gland was dense, changed into a whitish-yellow callous tissue; microscopically 
was found smallness of the gland cells and round-cell infiltrate, the hypophysis 
was small, soft, unaltered. Finally, in my case there were no essential alterations 
in the ductless glands. We can hardly ascribe any especial significance to the 
colloid struma, there were found perivascular infiltrates in the fat tissue, 
and cirrhosis of the liver. 594 
OBESITY AND ADIPOSITAS DOLOROSA 
Summing up the autopsy findings we find the following: Among eleven 
cases, there were found nine times alterations of the thyroid gland, especially 
of a chronic inflammatory nature. The hypophysis was examined micro- 
scopically in seven cases. Among these were found alterations five times, and 
these indeed of a very diverse nature (round-cell infiltration, sclerosis, adeno- 
carcinoma, glioma). Also in the sexual glands was sometimes found sclerosis, 
in addition to which was found ovarian cysts, and once hypoplasia of the 
testicles. Liver and spleen often show cirrhotic changes, the kidneys some- 
times interstitial changes. The microscopical examination of the fat often 
showed, as well in the diffusely distributed fat as in the encapsulated lipomata, 
abundant connective tissue; and in some cases newly formed hemolymph 
nodules or perivascular inflammatory infiltration. In other cases there were 
found no inflammatory alterations. Very frequently, there was found inter- 
stitial neuritis (six times among seven cases investigated), as well in the fine 
nerve trunks in the fat tissue itself, as in the nerves of the muscles. In one case 
there was degeneration of Goll’s column. 
Pathogenesis.—The views of the authors as to the pathogenesis of adi- 
positas dolorosa are very different. Dercum considered the cause of the 
affection as a sort of dysthyroidia, through which came about a reduction 
of fat combustion and inflammatory alterations of the nerves. Vitaut expresses 
himself similarly. Most of the authors assume a chronic intoxication, the 
cause of which they see in a disturbance of the function of the ductless glands 
{Price, Ballet, Miquel); but they are not agreed as to which ductless gland 
is at fault. For example, Price believes that in addition to the thyroid, the 
hypophysis plays an especial part, Ballet regards the involvement of the 
thyroid gland as unlikely and thinks of disturbances of the other ductless 
glands, etc. Debove places the nervous system as the central figure of the 
pathogenesis. Strubing and Thimm regard the disease as a trophoneurosis, 
Haskovec as a central trophoneurosis. Sicard and Roussky think of an 
involvement of the ovary, as they saw the disease develop after ovariotomy 
in two relatively youthful cases. Schwenkenbecher believes in an endogenous 
obesity, with a pressure of the fat growth on the small vessels and nerves, 
causing circumscribed circulatory disturbances and paresthesias. We thus see 
that the views as to the pathogenesis of this disease diverge greatly. 
Before I discuss the significance of the ductless glandular system for this 
disease, I would like to say a few words concerning the relationship of these 
to lipomatosis. The view has been adopted by French and German authors 
that adiposis dolorosa is no disease sui generis, but only a syndrome that 
belongs to the great group of lipomatoses and of trophedema. To my knowl- 
edge, Kottnitz was the first to point out that in the symmetrical lipomata 
there frequently occur constitutional symptoms, such as nervous symptoms, 
rheumatoid pains, etc. He describes a case, in which the menopause set in 
prematurely, and at the time of the failing menses, symmetrical lipomata 
several times developed, the eruption of which was attended with pain in 
the part of the body in question. Kottnitz regards adipositas dolorosa as 
a trophoneurosis and believes that all transitions to the painful symmetrical ADIPOSITAS DOLOROSA 
595 
lipomata occur. Also Cheinisse and Fulconis maintain the identity of the two 
diseases. After Potain and Mathieu had assumed transitions from neuropathic 
edemas to pseudolipomata and even to true lipomata, especially Strubing, and 
after him Thimm, advocated the view that neuropathic edema (oedeme blanc 
and bleu), multiple lipomatoses, symmetrical diffuse lipomata, and finally the 
painful lipomata all belonged to a great group of diseases that “had at their 
foundation the same basic process.” Also Miquel sought to establish in detail 
that the oedeme neuropathique of Mathieu, the oedeme segmentaire of Debove, 
the chronic trophedema of Meige and the pseudooedeme catatonique of Dide 
formed with adipositas dolorosa a great group, the cause of which was to be 
sought in alterations of the nervous system and of the ductless glands. Lately 
Lyon after a careful compilation of the literature and the addition of new 
material, has advocated a similar view. 
The view that fleeting transitions exist between painful symmetrical lipo- 
mata and adiposis dolorosa has received much support from the works of the 
last years. Among the circumscribed lipomata that are often distributed in 
great number over the entire body are those, as Launois and Bensaude point 
out, that are painful to pressure and are associated with spontaneous neuralgi- 
form pains. In the symmetrical lipomata the constitutional factor mostly 
comes still more strongly into the foreground. Here are frequently found 
manifestations of asthenia, also vasomotor disturbances, especially bluish-red 
coloration of the skin over the nodes, paresthesias, even psychic distur- 
bances. Also in such cases the hereditary and familial element is often well 
pronounced. As an example I cite a case of Lyon's (case 2). In two sisters 
painful symmetrical lipomata set in at the time of puberty and attained their 
full development at maturity. They were associated with rheumatoid pains, 
dysmenorrhea, and psychic impairment. According to Lyon there may be also 
found in such lipomata lymph nodules similar to those which are found in 
adipositas dolorosa. That in adipositas dolorosa the distribution of fat may be 
rigidly symmetrical is shown by the case quoted in detail above. A quite 
similar distribution of fat was found in a case of Dercum and McCarthy's. 
In my case, there were, in addition, lipomata up to the size of a goose egg, 
with a rigidly symmetrical distribution. This type of fat distribution was 
also present in a case of Bochroch's. 
I will not venture to pass judgment on the question whether there are 
also transitions between lipomatosis and trophedema. I shall only register 
some important findings. In a case of trophedema, Strubing found on micro- 
scopical examination, no edema at all, but only fat with strikingly large fat 
cells. Haskovec describes a case in which there set in at the menopause pains 
in the back and in the limbs, attacks of weakness, and then edema, which, 
recurring constantly, closed with attacks of violent pains. At the site of 
the edema there then gradually developed a painful hyperplasia of the subcu- 
taneous fat tissue. Haskovec regards this case as a transition of a vasomotor 
neurosis or an acute edema to a trophoneurosis. We must remember, how- 
ever, that the acute edema usually shows quite another localization from 
that of the symmetrical lipomata. Also combination of adiposis dolorosa 596 
OBESITY AND ADIPOSITAS DOLOROSA 
with other diseases that are regarded as trophoneuroses, for example, xanthe- 
lasma, are known. Debove has described such a case. 
Finally, as far as the ductless glands are concerned in the pathogenesis 
of adiposis dolorosa, this seems to me very doubtful. The pathologico- 
anatomical alterations in the ductless glands are very diverse. As we have 
previously seen, there have been found rather frequently degenerative changes 
and especially chronic inflammatory changes in some of the ductless glands, 
especially in the thyroid gland and in the hypophysis. (The findings of 
adenocarcinoma or glioma of the hypophysis might very well be an accidental 
coincidence.) 
These chronic inflammatory alterations seem to me throughout not 
remarkable, as in this disease we find them otherwise in many organs. Cir- 
rhotic alterations in the liver and spleen, chronic inflammations in the nerves, 
etc., belong to the commonest findings, and may in part be explained by the 
alcoholism that is present. Thyrogenic obesity, a mild form of myxedema, 
is widely distinguished in its clinical behavior from the picture of adiposis 
dolorosa. Simultaneous sclerosis of the thyroid gland and of the hypophysis 
leads to a combination of myxedema and cachexia, a disease picture that 
has nothing to do with adipositas dolorosa. There does not appear to me 
to be any grounds for assuming the involvement of any of the other ductless 
glands. The assumption of Lyon that all forms of obesity and of lipomatosis 
have their origin in a disturbance of correlation of the ductless glands, I can- 
not subscribe to. Here too many things are thrown together. The sup- 
position of the disturbance of correlation of the ductless glands as the cause 
of a disease is, without corresponding pathologico-anatomical correlate, a 
vague idea, which only obstructs a deeper penetration into the pathogenesis 
of such a disease. So that there remains only the supposition of a tropho- 
neurosis, although I cannot conceal the fact that not much has been gained 
by this assumption. 
There have been described still other trophic disturbances of the fat tissue 
of which I shall here briefly refer to one only, although probably it has less 
to do with the ductless glandular system than adipositas dolorosa. Pic and 
Garde,re first pointed out a trophic disturbance which Simons has lately desig- 
nated lipodystrophia progressiva. It is concerned with disappearance of 
the fat on the face and arms, simultaneously with a gradually increasing 
adiposity in the region of the buttocks and on the thigh. Sensory and vaso- 
motor disturbances are absent. The investigation of the basal metabolism 
in Simon's case showed normal relations. 
In the differential diagnosis of adipositas dolorosa from myxedema we 
should consider that in the latter the swellings are especially in the face; 
from trophedema that this mostly sets in at an early age, that the edema 
is mostly unilateral and that hands, feet, forearms and [lower] legs are usually 
involved; from neurofibromatosis of Recklinghausen that the nodules in this 
affection are much harder and also smaller, that they are more confluent, 
that they do not avoid hands and feet, and that the psychic disturbances 
are more pronounced, also that there are often marked pigmentations of the ADDENDUM 
597 
skin (Debove). The differential diagnosis from alcoholic polyneuritis in the 
obese, concerning which diagnosis Umber and Schwenkenbecker have written, 
is often very difficult, if the characteristic distribution of fat is absent. 
In the treatment of adipositas dolorosa a great role is played by thyroidin 
[perhaps also by thyroxin.—Editor]. In many cases the results are indeed 
undoubted, but this does not furnish evidence for the thyrogenic nature of the 
disease. It has been stated that cases have been cured by thyroidin medication 
{Price). Also the psychic disturbances have retrogressed, v. Noorden has seen 
good results from systematic bath-treatments. X-ray irradiation and iodine 
have been recommended. 
Addendum 
The type of obesity described by Anders under the name adiposis tuberosa 
simplex is apparently nothing more than a transitional stage between simple 
diffuse obesity and adipositas dolorosa [adiposis dolorosa]. Anders has recently 
reported three more cases of this condition. Its identity as a disease picture is 
insisted on by him. In this condition, the small fat masses yield to the usual 
treatment of obesity. He accepts the opinion of Price that the condition 
represents a connecting link between simple obesity and nodular circumscribed 
lipomata without general symptoms.—Editor. It is doubtful whether even 
the adiposis dolorosa will long maintain its position as a disease sui generis 
It is probable that many of the cases described under it could very well be 
classed under the other varieties of obesity. In adiposis dolorosa we have the 
additional factor of pain, which may very well be explained as a neuritis of the 
small nerve filaments. In many of the histories there is quite enough to account 
for the existence of such a neuritis and also the mental changes; nor is the 
asthenia of sufficient importance to delimit this condition as a pathogenic 
entity, although for clinical purposes adiposis dolorosa does constitute one 
of the recognizable types of obesity. 
This being the case, the question as to which ductless glands are at fault 
in adiposis dolorosa seems to me entirely misplaced. We may very well con- 
ceive that certain of the cases might (just as ordinary obesity) show no changes 
in the ductless glands at all, and that others might show changes in individual 
glands or in several, as in the varying types of obesity in general. In no case, 
or perhaps only very rarely, is the condition to be regarded as pluriglandular 
in the author’s conception of the term, but rather as a result of a patho- 
logical or a physiological correlation. 
Price has contributed a case that suggests to him the possibility that, 
in addition to the thyroid condition, there were some disturbances in func- 
tion of the parathyroids—the woman showed alternating, long periods of 
apparent hypothyroidism and hyperthyroidism (without exophthalmus) 
and in addition, during or just before the periods of hyperthyroidism flexor 
cramps of the extremities, especially of the hands and the feet. Whether 
in this case these cramps would be considered a sign of hyperexcitability 
of the nerves such as would presage tetany, or constitute an attack of tetany, 
cannot be decided from the case report alone. 598 
OBESITY AND ADIPOSITAS DOLOROSA 
In the treatment mention should be made of the various “degrassators” 
that bring about a reduction of the fat by electrical means, also of hot steam 
or electrical light baths. It is needless to state that these measures should 
be employed in those weakened and debilitated individuals affected with 
adiposis dolorosa only with extreme caution, if at all. 
McCarthy and Karsner have reported a case of adenocarcinoma 
of the thyroid, with metastases to the cervical glands and pituitary, which 
they regard as linking together three of the groups of pathological fat—adi- 
posis cerebralis, symmetrical adenolipomatosis (a predominence cervicale) 
of Launois and Bensaude, and adiposis dolorosa. McCarthy regards another 
case reported by him with Dercum as an intermediate type between adipo- 
sis dolorosa and adenolipomatose symmetrique a predominance cervicale. 
A third case mentioned by McCarthy in the report was evidently a case of 
eunuchoidism. 
Lipodystrophia progressiva may be mentioned only to state that its 
etiology is obscure and that there is apparently, according to Reuben and 
Zamkin, no relation to ductless glandular disease (although Weber has stated 
that there might be). It is characterized by disappearance of the subcuta- 
neous fat at first from the face and then downwards, affecting the thorax 
before the abdomen. Weber states that it is not always progressive. It 
has its onset in childhood. Weber has given a thorough description of it. 
He states that in some cases the fat atrophy in the upper parts was preceded 
by increase of fat in the buttocks or legs. A bibliography will be found 
appended to the recent article by Reuben and Zamkin. 
Several cases of adiposis dolorosa have been reported recently in the 
literature. Dercum himself has recently shown a case at a clinic. In spite 
of the fact that these cases have been reported, the etiology of the condition 
remains obscure. 
The relationship of ordinary obesity and its concomitants—nephritis and 
especially diabetes—to overeating has been fairly well stressed in the recent 
literature. 
Mooser reports a remarkable case of obesity with marked osteoporosis. 
The author ascribes the condition to defect of the secretions of the thyroid 
and parathyroid glands. The case appears to be unique. 
Obesity after epidemic encephalitis has been reported by French observers. 
It seems to the editor that this is somewhat striking in some of these cases. 
Anders (II. S.). Adiposis tuberosa simplex. Am. J. M. Sc., 1908, CXXXV, 325-333. 
Anders (J. M.). Adiposis tuberosa simplex. Medical Record, Vol. XCIII, No. 23, May 18, 
1918, pp. 888-889. 
Dercum. (F. X.). Medical Clinics of North America, Jan., 1921, pp. 1141, seq. 
Price (G. E.). Clinical types of adiposis and lipomatosis. Report of a case of adiposis dolorosa 
presenting unusual symptoms. N. York M. J., Vol. C, No. 8, Aug. 22, 1914, pp. 355-357. 
McCarthy (D. J.) and Karsner (H. T.). Adenocarcinoma of the thyroid with metastasis to the 
cervical glands and pituitary, a contribution to the pathology of abnormal fat formation. Am. J. 
M. Sc., 1912, CXLIV, 834-847- 
Dercum (F. X.) and McCarthy (D. J.). Autopsy in a case of adiposis dolorosa. Am. J. M. 
Sc., 124, 994, 1902. ADDENDUM 
599 
Reuben (M. S.) and Zamkin (H. 0.). Cases of lipodystrophia progressiva. Archives of Pediat- 
rics, Vol. XXXIX, No. 2, Feb., 1922, pp. 112-116. 
Weber (F. P.). Lipodystrophia progressiva. The British Journal of Children’s Diseases, Vol. 
XIV, Nos. 160-162, April-June, 1917, pp. 81-93. 
Mooser (H.). Ein Fall von endogener Fettsucht mit hochgradiger Osteoporose. Ein Beitrag 
zur Pathologie der inneren Sekretion-Virchow’s Archiv fiir path., Anat. und Physiol., etc., Vol. 
CCXXIX, pp. 247-271. 
Livet (L.). Obesity after epidemic encephalitis. Bull, de la Soc. Med. des Hop. de Paris, Vol. 
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Roger (H.) and Aymes (G.). Transient obesity after epidemic encephalitis, ibid., Vol. XLV, No. 
27, July 29, 1921; Abst. in J. Am. M. Ass., Vol. LXXVII, No. 22, p. 1770. LITERATURE 
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Falta and Rudinger, Studien iiber Tetanie. Kongr. f. innere Med., 1909. 
Farner, E., Beitrage zur pathologischen Anatomie des Morbus Basedowi, etc. V. Arch. f. path. 
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Hofmeister, Experimentelle Untersuchungen liber die Folgen des Schilddriisenverlustes. Beitr. z. 
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Honnicke, Discussion on Kocher’s lecture. Kongr. f. inn. Med., 1906, 108. 
Holmgren, J., Uber das Langenwachstum bei Hyperthyreose. Med. Klin., 1910. Uber den Einfluss 
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—The relation of iodin to the thyroid gland. J. Am. M. Ass., 1907. 
—The probable demonstration of thyroid secretion in the blood in exophthalmic goiter. Ibidem, 
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Hunt, Reid, and Atherton Siedell, Studies of thyroid. Hyg. laborat. Bull. 47, 1908, Treasury 
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Jaboulay, Resection bilaterale du sympathique cervical dans le goitre exophthalmique. Bull. Acad, 
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Jones, Exophthalmic goiter and rheumatoid arthritis. Lancet, 16, Jan., 1909. 
Jonescu, cited in Jahresb. f. Fortschr. a. d. Geb. d. Chir., 1901, p. 454. 
Kahler, 0., Uber den Leitungswiderstand der Haut bei Morbus Basedowi. Prag. Ztschr. f. Heilk., 
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Kappis, M., Uber Hirnnervenlahmungen bei der Basedowschen Krankheit. Mitt. a. d. Grenzgeb. d. 
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Kappis, Uber Lymphocytose des Blutes bei Basedow und Struma. Mitt. a. d. Grenzgeb. d. Med. u. 
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Kashiwamura, Die Schilddriise bei Infektionskrankheiten. Arch. f. path. Anat. [etc.], Berl., 166, 
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Kassowitz, Infantiles Mxyodem, Mongolismus und Mikromelie. Wien. med. Wchenschr., Nr. 22 
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Kaufmann, E., Untersuchungen liber die sog. fotale Rachitis. Berlin, 1892. 
Kirk, Notes on cases of myxodema. Lancet, 2, 743, 1893. 
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Kleinwdchter, Wie ist der Genitalbefund bei Morbus Basedowii? Ztschr. f. Geburtsh. u. Gynaek., 
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—Das Verhalten des Genitales bei Morbus Basedowi. Centralbl. f. Gynak., 1889, Nr. 10, 181. 
Klemm, Die operative Therapie des Morbus Basedowi. Arch. f. klin. Chir., 86. 
Knopfelmacher, Alimentare Glykosurie und Myxoedem. Wien. klin. Wchenschrift., 224, 1904. 
—Wien. klin. Wchenschr., Nr. 28, 712, 1902. 
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Kocher, A., Uber Jodbasedow. Arch. f. klin. Chir., 92, Heft. 5. 
—Uber Morbus Basedowi. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 9, 1902. THYROID GLAND 
609 
—Blutuntersuchungen bei Morbus Basedowi, etc. Arch. f. klin. Chir., 87, 1908. 
-—Die Behandlung der Basedowschen Krankheit. Miinchen. med. Wchenschr., 677, 1910. 
Kocher, Th., Surgical Congress. Berlin, 1912. 
—Die Pathologie der Schilddruse. Kongr. f. inn. Med., 1906. 
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—liber Kropfexstirpation und ihre Folgen. Arch. f. klin. Chir., 29, 1883. 
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Kocher-Langhans, Deutsche Ztschr. f. Chir., 34, 1892, and Arch. f. Path. Anat. [etc.], Berk, 128, 318. 
Kohler, R., Myxodem auf Syphilis beruhend. Berl. klin. Wchenschr., 743, 1892, and 41, 1894. 
v. Korczynski, Einige Bemerkungen uber das Myxodem. Wien. med. Presse, 1898, Nr. 36-37. 
Kostlivy, Uber chronische Thyreotoxikosen. Mitt. a. d. Grenzgeb. d. Med. u. Chir., 21, 1910. 
Kottmann, A., and Lidsky, Beitr. zur Physiologie und Pathologie der Schilddruse. Ztschr. f. klin. 
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1906, 
Kraus, Fr., and Friedenthal, Uber die Wirkung der Schilddriisenstoffe. Berk klin. Wchenschr., 
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Krehl, Miinchen. med. Wchenschr., 1910, Nr. 47. 
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Langhans, liber Veranderungen in den peripheren Nerven bei Cachexia thyreopriva des Menschen 
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Lanz, Uber Schilddriisenfieber und Schilddriisenintoxikation. Mitt. a. d. Grenzgebiet d. Med. u. 
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Lebert, cited by Brener. 
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Leischner und Marburg, Zur Frage der chirugischen Behandlung des Morbus Basedowi. Mitt. 
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Lepine, Lyon Med., 101, 1903. 
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Lewin, Zur Kasuistik des Morbus Basedowi. Inaug.-Diss. Berlin, 1888. 
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Lorand, Uber das Altera, Verb v. Klinkhardt., 1910, 3, Aufk 
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MacCallum and Fabyan, On the anatomy of a myxedematous idiot. Johns Hopkins Hosp. Bulk, 
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Macfie Campbell, cited by Bonchan. 
Macllwaine, Myxedema in mother and child. Brit. M. J., 1261, May 24, 1902. 
Mackenzie, II., A lecture on Graves’ disease. Brit. M. J., 1077, 1905. 
Macpherson, Thyreoid grafting in myxedema. Edinb. M. J., May, 1892. 
Magnus-Levy, A., Untersuchungen zur Schilddrusenfrage. Zschr. f. klin. Med., 33 u. 60, 1897. 
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Maresch, Kongenitaler Defekt der Schilddriise bei einem n jahrigen Madchen, etc. Ztschr. f. 
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Marie, Pierre, Contribution a l’etude et au diagnostic des formes frustes de la maladie de Basedow. 
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Mayo, A consideration on the mortality in one thousand operations for goiter, etc. Surg., Gynec. 
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McCarisson, Lancet 2, p. 1570, 1906. 
Meltzer, tiber Myxodem. New Yorker med. Monatschr., April, 1894. 
Mendel, Zur pathologischen Anatomie des Morbus Basedowi. Deutsche med. Wchenschr., 5, 1892, 
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Meunacher, Blutbefund beim Myxodem. Monatschr. f. Kinderheilk., 6, 666, 1907. 
v. Mikulicz, Die Thymusfiitterung bei Kropf, etc. Berl. klin. Wchenschr., 16, 1895. 
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Minnich, W., Das Kropfherz, etc. Leipzig u. Wien, 1904, Fr. Deuticke. 
Mobius, P. J., Schmidt’s Jahrb., 210, 237, 1886. 
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Moszkowicz, Protokoll der k. k. Gesellsch. der Artze in Wien, 1908. Wien. klin. Wchenschr., 
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Muratov, Zur Pathologie des Myxodems. Neurol. Centralbl., 20, 1898. 
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Mygind, Thyreoiditis acuta simplex. J. Laryngol., 181, 1895. 
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Novak, J., Die Erkrankungen des weiblichen Genitales in ihrer Bedeutung fur den Gesamtorganismus 
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Blutdriisen, Suppl. to Nothnagel’s Pathol, u. Therap. A. Holder, Wien u. Leipzig, 1912. THYROID GLAND 
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Ortner, Vorlesungen fiber spezialle Therapie innere Krankheiten, etc. 
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Reinbach, Uber das Verhalten der Temperatur nach Kropfoperationen. Mitt. a. d. Grenzgeb. d. 
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Reinhold, Zur Pathologie der Basedowschen Krankheit. Miinchen. med. Wchenschr., 1894, Nr. 23. 
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Rocaz and Cruchet, Myxoedeme congenitale. Arch, de med. d. enf., 6, 97, 1905. 
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Rothschild and Lewi, Etude sur la physiopathologie du corps thyreo'ide, etc. Paris, 1908. 
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Salomon, H., Gaswechseluntersuchungen bei Morbus Basedowi. Berl. klin. Wchenschr., 1904, Nr. 
24. 
Salomon and Amalgia, Uber Durchfalle bei Morbus Basedowi. Wien. klin. Wchenschr., 870, 1908 . 
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Saltier, Die Basedowsche Krankheit. Leipzig, 1909 u. 1910, Engelmann. 
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Schkarine, Ref erence in Rev. neurol., 20, 1908 (Russian). 
Schlesinger, H., Meine Erfahrungen fiber den akuten Morbus Basedowii. Therapie der Gegenwart, 
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Schmidt, Adolf, Discussion on the lecture on “Fettstiihle” by //. Salomon. 20 Kongr. f. innere Med., 
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624 HYPOPHYSIS 
625 
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LITERATURE 
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Frdnkel, Stadelmann, and Benda, Klinische und anatomische Beitrage zur Lehre von der Akromegalie. 
Deutsche med. Wchenschr., 513, 1901. 
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Gajkiewicz, cited by Sternberg. 
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Marburg, 1855. HYPOPHYSIS 
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13, Nov., 1899. Arch. f. Psychiat., 34, 303, 1901. 628 
LITERATURE 
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Rosenhaupt, Beitr. zur Klinik der Tumoren, etc. Berl. klin. Wchenschr., 1903. 
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EPIPHYSIS 
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629 CHAPTER VIII 
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630 631 
SUPRARENALS 
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f. exper. Path. u. Pharmakol., 64, 274, 1911. 632 
LITERATURE 
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633 
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Ziiltzer, G., Zur Frage des Nebennierendiabetes. Berl. klin. Wchenschr., 28, 1901. CHAPTER IX 
STATUS LYMPHATICUS AND STATUS HYPOPLASTICUS 
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636 CHAPTER X 
SEXUAL GLANDS 
Achard and Demanche, Un cas d’atrophie testiculaire. Soc. hop. med. de Paris, 21 Dec., 1906. 
Adler, L., Versuche mit Mamminum Miinchen. med. Wchenschr., 13, 1912. 
Alterthum, Die Folgezustande Kastration und die sekundaren Geschlectscharaktere. Beitr. z. 
Geburtsh. u. Gynsek., 1899. 
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biol. Nancy, 10 Nov., 1903. Compt. rend. soc. biol., 1397, 1903, ibidem, 1683. 
Apert, E., Obesite, etat eunuchoide, etc. Bull. soc. pediat., Paris, 3, 108, 1901. 
Babonneix and Paisseau, see chapter on hypophysis. 
Becker, Uber das Knochensystem eines Kastraten. Arch. f. Anat. u. Physiol. Anat. Abt., 1899. 
Belfield, A case of retrograde puberty impotence and diabetes insipidus relieved by suprarenal cortex. 
J. Am. M. Ass., 55, 215, July 10, 1910. 
Bellinzona and Tritondani, Ref. Jahresb. Ophthalmol., 406, 1904. 
Bernhardt, Demonstration in der Berk Gesellsch. f. Psych. Sitz. 5, n, Marz, 1901. Arch. f. Psychiat., 
36, 914. 
Bertelli, Falta, and Schweeger, tiber Chemotaxis. Ztschr. f. klin. Med., 71. 
Biedl, Innere Sekretion. Ueban and Schwarzenberg, 1910. 
Biedl and Konigstein, Untersuchungen tiber das Brustdriisenhormon in der Graviditat. Ztschr. f. 
exp. Path., 8, 358, 1910. 
Bihler, Uber das Verhalten des Blutdruckes bei Chlorotischen. Arch. f. klin. Med., 52, 281, 1894. 
Birch-IIirschfeld, Kongr. f. innere Med., 28, 1892. 
Blumenthal, Ergebnis der Blutuntersuchung in der Geburtschilfe und Gynakologie. Beitr. z. 
Geburtsh. u. Gynsek., 11, 3, 414, 1907. 
Bondi, S., Osteomalacie mit Struma und latenter Tetanie. Sitzungsbr. d. Gesellsch. f., innere. Med. 
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Brener, R., and v. Settler, R., Uber den Einfluss der Kastration auf den Blutbefund weiblicher Tiere. 
Arch. f. exper. Path. u. Pharmakol., 50, 1903. ~~ 
Breus and Kolisko, Die pathologischen Bechenformen. Wien., 1900. 
Brown-Sequard, Expose des effets produits chez l’homme par les injections sous-cutanees. Paris. 
Masson, 1890. Arch, de physiol, norm., 1889, 1890, 1891. 
Bucura, Uber die Bedeutung der Eierstocke. Volkmann’s Vortr. Neue Folge 513/514. 
Bunge, Lehrbuch d. physiol, u. pathol. Chemie., Leipzig, 85, 1889. 
Byrom Bramwell, Chlorosis in a male. Clinical study, April 5, 1907. 
Capellani, Ann. di ostetr. et Ginecol. 2, Nr. 8. 
Charcot, Semaine med., Mars, 1891. 
Charrin, cited by v. Noorden and v. Jagic. 
Chatin, Du chloro-brightisme. Paris, 1894. Bailliere et fils. 
Chrobak, Uber Einverleibung von Eierstockgeweben. ’Centralbl. f. Gynak., 20, 1896. 
Claude and Gougerot, Insuftisance pluriglandulaire endocrinienne. J. Physiol, et path, gen., 1908, 
469 et 505. 
Coffin and Lereboullet, Atrophie testiculaire consecutive a une orchite surlienne. Gaz. hebd. de med.. 
1877. 
Comte, Contribution a. l’etude de l’hypophyse humaine, etc. These de Lausanne, 1898. Beitr. z. 
path. Anat. u. Physiol., 23, 1898. 
Cordier and Francillon, Un case d’infantilisme de type reversif avec syndromes pluriglandulaires. 
Lyon med., 1 Janv., 1911. 
Cordier and Rebattu, L’infantilisme regressif ou tardif n. inconogr. de la. Salpetriere, 1911, 405. 
Cramer, Ovarium und Osteomalacie. Miinchen. med. Wochenschr., 1909, 758 und Zur Physio 
logie der Milchsekretion, ibidem, 1521. 
637 638 
LITERATURE 
Cristofoletti, Zur Pathogenese der Osteomalazie. Gynak. Rundschau, 5, 1911. 
Dalche, Dystrophie orchidienne Bull, et mem. med. hop. de Par., 7 Juin, 1901, 23 Mai, 1902. 
Davis, cited by Schlichter. Wien. klin. Wchenschr., 979, 1889. 
Delbet, cited by Halban. 
Doderlein, Uber Rontgentherapie. Mtinchen. med. Wochenschr, 17, 929, 1911. 
Dubnikoffi, Klinische Untersuchung uber Eisenwirkung und larvierte Chlorose. Dissertation, Bern, 
1908. 
Duckworth, W. L. H., Notes on the anatomy of an eunuchoid man, etc. J. Anat. and Physiol., 41, 
Oct., 1906, 30-34. 
Dupre, These de Paris, 1904-05. 
Duval, R., De la secretion de la mammaire nonpuerperale. Thtise de Paris, 1881. 
Englander, B., Adrenalin bei Knochenerweichung. Centralbl. f. Gynak., 1909, Nr. 13. 
Eppinger, Sella turcica bei Hypoplasie der Genitalien. Ges. f. inn. Med. Wien. Sitz., 27 Jan., 19x0. 
Erdheim, Uber Epithelkorperchenbefunde bei Osteomalazie. Stizungsb. d. k. Akad. d. Wissensch. 
Wien., 116, 311. 1907, Abt., 3. 
Flrdheim and Stumme, Schwangerschaftsveriinderung der Hypophyse. Mtinchen. med. Wchenschr., 
1908, 1202 u. Beitr. z. path. Anat. Physiol., 46, 1909. 
Etienne, Jeandelz and Richon, Malformations organiques multiples chez un castr at naturel. Compt. 
rend. soc. de biol., 62, 1907. 
Falk and Hesky, Uber Ammoniak-Ammonisauren- und Peptidstickstoff im Harn Gravider. Ztschr. 
f. klin. Med., 71, 261, 1910. 
Falta, W., Spateunuchoidismus, etc. Berl. klin. Wchenschr., No. 30 u. 31,1912 und Die Krankheiten 
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Falta and Freund, Uber die Behandlung innerer Krankheiten mit Radiumemanation. Mtinchen. 
med. Wchenschr., 1912, Nr. 14. 
Fehling, Verhandl. d. deutsch. Gesellsch. f. Gynak, Halle, 1888. Freiburg, 1889, interner Kongr., 
1890. 
—Die Form des Beckens beim Fotus und Neugeborenen. Arch. f. Gynaek., 10. 
—Uber Wesen und Behandlung der Osteomalazie. Arch. f. Gnyaek., 28, 1890 u. 29, 1891. 
Ferrari, Sulla clorosi masc. della puberta. Giorn. intern, di sc. med., 263, 1908. 
Fichera, Sur l’hypertrophie de la glande pituitaire consecutive a la castration. Arch. ital. de Biol., 
43, 405, i9°5- 
Fod, C., Su fattori che determinano la funzione della ghiandola mammaria. Arch, di Fisiol., 5, 1909. 
Foges, Zur Hodentransplantation bei Hahnen. Centralbl. f. Physiol., 1898. 
Formanolli, Sur la chlorose masc. Gazz. med. ital., Torino, 1905. 
Frankel, Berl. klin. Wchenschr., Nr. 2, 1911. 
Freund, H., Die Beziehung der weiblichen Geschlechtsorgane, etc. Ergebn. d. Path. Lubarsch- 
Ostertag, 3, 1896. 
Gall, cited by Mobius. 
Gaillard, citation in Cordier et Rebattu. 
Gallavardin and Rebattu, Lyon, med., 30 Janv., 1910. 
Gandy, Soc. med. d. hdp. de Par., 7, Dec., 1906, 17, 1226. Mai, 1907, et Juin, 1911. 
Gauthier, Ein Fall von Milchsekretion aus den Briisten an Stelle der Menstruation bei einem jungen 
Madchen. Reference in Centralbl. f. Gynak., 127, 1904. 
Geinitz, citation in Kussmaul. 
Giudiceandrea, Traitement de la chlorose, etc. Semaine med., 1901, Nr. 3. 
Giudiceandrea, Archangeli, and Bastianelli, Uber die Veranderungen der Schilddriisen bei Chlorosis. 
Reference in Folia haematol., 2, 581. 
Gldvecke, Korperliche und geistige Veranderungen im weiblichen Korper nach kiinstlichem Verlust 
der Ovarien und des Uterus. Arch. f. Gynak., 35. 
Glynn, see suprarenals. 
Godard, Egypte et Palestine. Paris, 1867. Citation in Pelikan. 
Goodman, The cyclical theory of menstruation. Am. J. Obst., 9, 1878. 
Gougerot, Brisseaud, and Gy, Insuffisance endocrinienne thyroi'do-testiculaire. Revue neurol. 2, 
1908. N. iconogr. de la Saltpetriere, 24, 449, 1911. 
Grawitz, Klinische Pathologie des Blutes. IV. Aufl., 1911, Verb Thieme, Leipzig. 
Griffith, The condition of testes and prostate gland in eunuchoid persons. J. Anat., 28, 1894. 
Grigoriu, M. Christea, Beitrag zur Milchsekretion. Gynsek. Rudschau., 4. Jahrg., Nr. 20, 740. 
Groag, P., Untersuchungen iiber Chlorose. Mtinchen med. Wchenschr., 1910, Nr. 30. 
Guggenheimer, Uber Eunuchoide, etc. Deutsches, Arch. f. klin. Med., 107, 518, 1912. SEXUAL GLANDS 
639 
Guiyesse, see suprarenals. 
Haberer, v., and Stoerk, see suprarenals. 
Halban, J., Die Entstehung der Geschlechtscharaktere. Arch. f. Gynaek, 70, 205, 1903. 
—Uber den Einfluss des Ovariums auf die Entwicklung des Genitales. Monatschr. f. Geburtsh. u. 
Gynaek., 12, 498, 1900. 
—Protokoll d. Gesellsch. d. Aerzte. Wien. klin. Wchenschr., 21, 1910. 
—Die innere Sekretion von Ovarium und Plazenta und ihre Bedeutung fur die Funktion der Milch- 
driise. Arch. f. Gynaek., 75, 1905. 
—Zur Lehre von der Menstruation, etc. Centralbl. f. Gynak., 35, 46, 1911. 
Haller, A. v., Elementa physiologica, 8, 116, 1766. 
Halliday, Crom, Ueber einen Fall von Uberpflanzung des Ovariums mit nachfolgender Schwanger- 
schaft und Geburt eines lebenden Kindes. Frage: Wer ist die Mutter? Edinburgh obstetr. 
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Hammond, Am. J. Neurol, and Psychiat., 1882. 
Hanau, Uber Knochenveranderungen in der Schwangerschaft. Fortschr. d. Med., 7, 1892. 
Handmann, Schilddriisenveranderungen und Hamoglobingehalt des Blutes bei Chlorose. Munchen. 
med. Wchenschr., 1911, Nr. 22. 
Hastings, Gilford, see pluriglandular disease. 
Hayem, A propos du traitement de la chlorose. Semaine emd., 179, 1895. 
—De la mort subite au cours de la chlorose. Semaine med., 116, 1896. 
Hegar, Die Kastration der Frauen. Volkmann’s Samml., Nr. 136-138, 1878. Der Geschlechtstrieb, 
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—Korrelation der Keimdriissen und Geschlechtsbestimmung. Ibidem 7, 201, 1903. 
Heidenhain, Hermann’s Handb. d. Physiol., 5, 1883. 
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Howitz, citation in Pick. 
Hudovernig, Un cas de Gigantisme precoce, Etude complementaire, 1906. N. icong. de la 
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Hudovernig and Popovicz, Gigantisme precoce abec developpement precoce des organes genitaux. N. 
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Huntinel, Pseudochlorose der Sauglinge. Allg. Wien. med. Ztg., 1908, 408 u. 418. Translated from 
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Immermann, Krankheiten des Blutes. v. Ziemssen’s Handb. d. spez. Path. u. Therap., 13, Abt., II, 
275-349, 1879. 
Jacobi, M., The question of rest for women during menstruation. The Boylsten Prize Essay of 
Harvard Univ. for 1876, London, 1897. 
Jacobs, Eierstocktherapie. Policlinique, 1896. 
Jentzer und Beuttner, Experimentelle Untersuchunge'n zur Frage der Kastrationsatrophie. Ztschr. 
f. Geburtsh. u. Gynaek., 42, 1900. 
Josef son and Lundquist, Abnormes Langenwachstum, etc. Deutsche Ztschr. f. Nervenh., 39, 1910. 
Kehrer, F. A., Uber gewisse synchrone Nervenerscheniungen und zyklische Vorgange in den Genitalien 
und anderen Organen. Beitr. z. Geburtsh. u. Gynaek., 4, 228, 1901. 
Kisch, Uber Feminismus mannlicher lipomatoser Individuen. Wien. med. Wchenschr., 366, 1905. 
Klein, Ein Fall von Pubertas praecox. Deutsche med. Wchenschr., 47, 1899. 
Kleinhans and Schenk, Experimentelles zur Frage nach der Funktion des Corpus luteum. Ztschr. 
f. Geburtsh. u. Gynaek., 66, 283. 
Krauer, Die Ovarientransplantation. Arch. f. Gynaek., 60, 322, 1900. 
Koppen, citation in Recklinghausen. 
Kolisko, citation in Tandler and Grosz. 
Kon, Jutaka, Hypophysenstudien. Beitr. z. path. Anat. u. Physiol., 44, 1908. 
Kottmann, Ueber innere Sekretion und Autolyse mit spezieller Beriicksichtigung der Eiweiss-Autolyse 
und klinische Fragen fiber Basedow, Myxodem, Chlorose, etc. Cor.-Bl. d. schweiz. Aerzte. 
1910, Nr. 34. 
Krafft-Ebing, Psychosis menstrualis. Enke, Stuttgart, 1902. 
Kussmaul, Uber geschlechtliche Friihreife. Wiirzb. med. Ztschr., 3, 1862. 
Laache, Die Anamie. Christiania, 785, 1883. 640 
LITERATURE 
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Larrey, Mem. de chir. mil. et camp., 2, 1812. 
Launois and Moulon, Les cellules cyanophiles de Phypophyse chez la femme encente. Compt. rend, 
soc. de. biol., Paris, 448, 1903. 
Launois and Roy, Des relations qui existent entre l’etat des glades genitales males et le developpe- 
ment du squelette. Arch. gen. de med., 186, 1903. 
Latzko, Gesellsch. d. Aerzte Wien. Ref. Wien. klin. Wchenschr., 1893, Nr. 17. 
—Wein. klin. Wchenschr., 1894, Nr. 28 u. 29, 1907, Nr. 8. 
Leer sum, van, Uber die Ausscheidung von Aminosauren wahrend der Schvvangerschaft und nach der 
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Lemos Magelhaes, Infantilisme et degener. psych. N. iconogr. de la Salpetriere, 19, 50, 1906. 
Leopold and Mironow, Beitrag zur Lehre von der Menstruation und Ovulation. Arch. f. Gynaek., 
45, 506, 1894. 
Lohlein, Erfahrungen liber den Wert der Kastration bei Osteomalazie. Ztschr. f. Geburtsh. u. 
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Lowy and Richter, Zur Frage nach dem Einfluss der Kastration auf den Stoffwechsel. Centralbl. f 
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Lordet, Allongement des membres inf. chez un eunuque. Arch, d’anthrop. crim. Lyon., Par., 
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Liithje, Uber Kastration und ihre Folgen. Arch. f. exper. Path. u. Pharmak., 48, 184, 1902. 
Maimer, Die doppelseitige Ovariotomie bei Schwangeren. Miinchen. med. Wchenschr., 1117, 1895. 
Mandl and Burger, Die biologische Bedeutung der Eierstocke nach Entfernung der Gebarmutter. 
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Marie, A., Eunuchisme et erotisme. N. iconogr. de la Saltpetriere, 19, 472, 1906. 
Martin, Gaz. hebd., 1877. 
Matthes, Uber die Einwirkung des Oophorins auf den Stoffwechsel. Monatschr. f. Geburtsh. u. 
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Meige, Henry, L’infantilisme, le feminisme et les hermaphrodites antiques. Antropologie, 1895. 
Merletti and Angela, Die Nebennierentherapie der puerperalen Osteomalazie. Klin.-therap., Wchen- 
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Mdbius, cited by Bab. Volkmann’s Samml. klin. Vortr. N. F., Nr. 538. 
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Monari, La clorosi. Modena, 1900. 
Morawitz, Untersuchungen liber Chlorose. Miinchen med. Wchenschr., 1910, Nr. 27. 
Miiller, Fr. v., 24. Kongr. f. innere Med., 1906. Discussion. 
Naegeli, Blutrankheiten und Blutdiagnostik. Leipzig, 230-251, 1908. 
Neu, Med. Klin., 1910, Nr. 46, 1813 u. Miinchen. med. Wchenschr., 1910, Nr. 48, 2533. 
Neubauer and Novak, Zur Frage der Adrenalinamie und des Blutzuckers in der Schwangerschaft. 
Deutsche med. Wchenschr., 49, 1911. 
Neugebauer, Hermaphroditismus beim Menschen. Leipzig, 1908. 
Neumann and Herrmann, Biologische Studien liber die weibliche Keimdriise. Wien. klin. Wchen- 
schr., 1911, Nr. 12. 
Neumann and Vass, Uber den Einfluss der Ovariumpraparate auf den Stoffwechsel. Monatschr. f. 
Geburtsh. u. Gynaek., 15. 
Neurath, Vorzeitige Geschlechtsentwicklung (Menstruatio prsecox). Wien. med. Wchenschr., 1909. 
—Die vorzeitige Geschlechtsentwicklung. Ergebn. d. inneren Med. u. Kinderheilk., 4, 1909. 
—Uber Fettkinder, etc. Wien. klin. Wchenschr., 1911, Nr. 2. 
Neusser, v., Klinisch-hamatologische Mitteilungen. Wien. klin. Wchenschr., 1892, Nr. 3 u. 4. 
-—Zur Diagnose des Status thymico-lymphaticus. Wien., 1911. 
Noorden, v., Die Fettsucht. Holder, Wien. u. Leipzig, 1910. 
Noorden, v., and v. Jagic, Die Bleichsucht. Holder, Wien u. Leipzig, 1912. 
Novak, Die Bedeutung des weiblichen Genitales fiir den Gesamtorganismus, etc. Nothnagel. 
Suppl.-Bd., 1912. 
Novak and Jetter, Beitrag zur Kenntnis der puerperalen Bradykardie. Monatschr. f. Geburts. u. 
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Oerum, Quantitative Blutuntersuchungen. Deutsches Arch. f. klin. Med., 92, 356, 1908. 
Oft, Gesetz der Periodizitat physiologischer Funktionen im weiblichen Organismus Centralbl. f. 
Gynak., 1890, Beil. S., 31. SEXUAL GLANDS 
641 
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Pankow, Die Ursachen der Uterusblutungen. Miinchen. med. Wchenschr., 52, 1909. 
Parhon and Mihailesco, Sur un cas d’infantilisme dysth. et dysorch. J. de Neurol., 14, 210, 1908. 
Pelikan, Gerichtlich-medizinische Untersuchungen liber das Skopzentum in Russland. Translated 
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Pettizzi, G. B., La sindrome epifisaria “macrogenitosomia precoce,” Riv., ital. di neuropat. [etc.], 3, 
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Peritz, tiber Eunuchoide. Neurol. Centralbl., 1286, 1910. 
Pfister, Die Wirkung der Kastration. Arch. f. Gynaek., 56, 583, 1898. 
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Pick, tiber Neubildungen am Genitale bie Zwittern. Arch. f. Gynaek., 76, 191, 1905. 
Piersche, De l’influence de la castration sur le developpement du squelette, Paris, 1902. 
Pittard, La castration chez l’homme. Compt. rend. Acad. d. sc., 1903. 
Plesch, Hamodynamische Studien. Berlin, Hirschwald, 1909. 
Ploss, see Neurath. 
Pommer, G., Untersuchungen tiber Osteomalazie und Rachitis, etc. F. C. W. Vogel, Leipzig, 1885. 
Porges and Novak, tiber die Ursache der Azetonurie bie Schwangeren. Berl. klin. Wchenschr., 1911, 
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Fortschr. d. Theirchemie, 1, 291, 1871. 
Ravano, tiber die Frage nach der Tatigkeit des Eierstocks in der Schwangerschaft. Arch. f. Gynaek., 
83, 587, i9°7- 
Rebaudi, Atti soc. ital. d’obstetr. e gin., 15. Cited by Holfbauer, Arch. f. Gynaek., 93, 405. 
Reck'inghausen, v., Untersuchungen tiber Rachitis und Osteomalazie, Jena, 1910. 
Recklinghausen, v., Festschrift f. Virchow, 1891. 
Regis, cited by Novak. 
Reinl, Die Wellenbewegung der Lebensprozesse des Weibes. Volkmann’s Samml., 243, 1900. 
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Reuss, v., Sehnervenleiden infolge von Graviditat. Wien. klin. Wchenschr., 1908, Nr. 31, 1116. 
Redlich, Ein Fall von Gigantismus inf. Wien. klin. Rundschau, 1896. 
Reinhardt, Adrenalin und Osteomalazie. Centralbl. f. Gynak., 1907, Nr. 52. 
Rethers, Th., Beitrage zur Pathologie der Chlorose. Dissertation, Berlin, 8, 1891. 
Ribbert, Uber Veranderungen transplantierten Gewebes Arch. f. Entwickelngsmechn. d Organ, 6, 
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—tiber Transplantation von Ovarien, Hoden und Mamma, 7, ibidem, 1898. 
Riedel, Menstruatio praecox und Ovarialsarkom. Wien. klin. W’ochenschr., 942, 1904. 
Rieder, cited by v. Noorden und v. Jagic. 
Reidinger, J., tiber Folgen des Verlustes beider Hoden am Ende der Wachstumsperiode. Ztschr. 
f. orthop. Chir., 25. 
Rieger, C., Die Kastration. Gust. Fischer, Jena, 1900. 
Rist and Guillemont, De l’oligosideremie des jeunes enfants et de ses rapports avec la chlorose des 
jeunes filles. Semaine med., 547, 1906. 
Roberts, citation in Bischoff, Beweis der von der Begattung unabhangigen periodischen Reifung und 
Loslosung der Eier, etc. Giessen, 40, 1844. 
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Romberg, Bemerkungen tiber Chlorose und ihre Behandlung. Berl. klin. Wchenschr., 1897, Nr. 25. 
Sacchi, E., Di un case di gigantismo infantile, etc. Riv. sper. di freniat., 21, 1895. 
Sainton, Paul, Un cas d’eunuchoidisme familial. N. iconog. de la Salpetriere 15, 1902. 
Sainton and Dupre, Les characteres cliniques de l’insuffisance testiculaire. These de Paris, 1904-05. 
Salen, E., Ein Fall von Hermaphroditismus verus unilateralis. Verhandl. d. deutsch. path. Gesell- 
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Salomon and Saxl, Beitrage zur Karzinomforschung, 1910, Heft 2. 
Scanzoni, Schmidt's Jahrb., 39, 1853. 
Schauta, Die Pygopagenschwestern Blazek. Gynaek. Rundschau, 437, 1910. 642 
LITERATURE 
Schmidt, B., Referat iiber Rachitis und Osteomalazie. Verhandl. d. deutsch. path. Gesellsch., 1909, 
15-17, April. 
Seiler, F., Uber larvierte Chlorose. Cor.-Bl. f. Schweiz. Aerzte, 1909, Nr. T7. 
Seitz, Die Follikelatresie wahrend der Schwangerschaft, insbesondere die Hypertrophie und Hyper- 
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Gynaek., 77, 203, 1905. 
Sellheim, Kastration und Knochenwachstum. Beitr. z. Geburtsh. u. Gynak., Leip., 2, 1899. 
•—Kastration und sekundare Geschlechtscharaktere. Beitr. z. Geburtsh. u. Gynak., Leip., 5, 409, 
i9or. 
Siegert, Die Atiologie der Rachitis auf Grund neuerer Untersuchungen. Miinchen. med. Wchenschr., 
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Simon, Hermaphroditismus verus. Arch. f. path. Anat. [etc.], Berk, 172, 1903. 
Simonds, Uber die Einwirkung von Rontgenstrahlen auf die Hoden. Fortschr. a. d. Geb. d. Ront- 
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Slocum, citation in llalban. Wien. klin. Wchenschr., 1906, Nr. 1. 
Smith, A discussion on the blood in disease. Tr. Path. Soc., London, 2, 311, 1900. 
Starling and Lane Claypon, Hormon der Brustdruse. Proc. Roy. Soc. London, 77, 1905. 
— Citation in Bayliss und Starling, Ergebn. d. Physiol., 5, 664, 1906. 
Steinach, Willkurliche Umwandlung von Saugetiermannchen in Tiere mit ausgepragtem weiblichem 
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752, 1891. 
Gulecke, N., Uber die experimentelle Pankreasnekrose, etc. Arch. f. klin. Chir., 85. 
Guttmann, Beitrage zur Histologie des Pankreas. Arch. f. path. i\nat. [etc.], Berl., 177, Spplbd., 
128, 1904; Beitrage zur Pathologie des Pankreas bei Diabetes mellitus. Arch. f. path. Anat. 
[etc.], Berl., 172, 493, 1903. 
Haedke, Metatraumatische alimentare Glykosurie. Deutsch. med. Wchenschr., 501, 1900. 
v. Halasz, Uber Veranderungen des Pankreas bei Zuckerkranken unter Beriicksichtigung Atiologischer 
Momente und des klinischen Verlaufs. Wien. klin. Wchenschr., 1909, Nr. 43. 
Hammond, cited by Migazzini, Pathologie und Symptomatologie der Kleinhirnerkrankungen. 
Ergebn. d. Neurol., 1, 1912. 
Ilansemann, Uber die Struktur, das Wesen der Gefassinseln. Verhandl. d. path. Gesellsch., 187, 
1901. 
Hedon, E., Greffe sous-cutan6e du pancreas. Arch, de physiol, norm, et path., 617, 1892. 
Heiberg, K. A., Studien uber die pathologisch-anatomische Grundlage des Diabetes mellitus. Arch, 
f. path. Anat. [etc.], Berl., 204, 175, 1911. Uber Diabetes bei Kindern. Arch. f. Kinderh., 
56, 1911- 
Hemptenmacher, Uber einen Fall von Diabetes mellitus syphiliticus. Mitt. a. d. Hamb., Staats- 
krankenanst., 616, 1901. 
Herxheimer, Pankreas und Diabetes mellitus. Deutsche med. Wchenschr., 829, 1906. Zur Frage 
tiber das Verhalten der Langerhansschen Inseln bei Diabetes mellitus. Festschr. f. Orth, 
Berlin, 1903. Uber Pankreaszirrhose. Arch. f. path. Anat. [etc.], Berl., 183, 228, 1906. 
Hess, Experimentelle Beitrage zur Anatomie und Pathologie des Pankreas. Med.-naturw. Arch., 1, 
1907. 
Higgins and Ogden, Monatschr. f. Unfallheik, 3, Nr. 1. 
Hirschfeld, Uber infektiose Entstehung der chronischen Pankreatitis und des Diabetes. Berl. klin. 
Wchenschr., 1908, Nr. 11. 
—Weitere Beitrage zur Atiologie des Diabetes mellitus. Berl. klin. Wchenschr., 198, 1912. 
Hofmeister, F., Nothnagelvorlesung. Wien., Dec., 1912. 650 
LITERATURE 
Honiger, tiber die ephemare traumatische Glykosurie bei Neugeborenen. Deutsche med. Wchen- 
schr., 500, 1911. 
Kahn, R. H., Zuckerstich und Nebennieren. Arch. f. d. ges. Physiol., 140, 209, 1911. 
Kamnitz, Uber einen Fall von Kopfverletzung mit darauffolgendem Diabetes. Arch. d. Heilk., 
447) 1873. 
v. Karakascheff, K. J., tiber das Verhalten der Langerhansschen Inseln bei Diabetes mellitus. 
Deutsches Arch. f. klin. Med., 82, 1904; 87, 1906. 
Katz and Winkler, Experimentelle Studien iiber Fettgewebsnekrose des Pankreas. Arch. f. Vedau- 
ungskr., 4, 289, 1898. 
Kausch, Trauma und Diabetes. Ztschr. f. klin. Med., Festbd. f. Naunyn, T904. 
Keuthe, W., Ein Fall von Pankreasatrophie. Berl. klin. Wchenschr., 47, 1909. 
Knouthon and Starling, tiber den Zuckerverbrauch im normalen und im diabetischen Herzen. Cen- 
tralbl. f. Physiol., 26, Nr. 4, 169, 1912.—See also On the nature of pancreatic diabetes. Pre- 
liminary communication, Lancet, Sept. 21, 812, 1912. 
Korte, Chirurgie des Pankreas. Handb. d. prakt. Chir., 3. AufL, 1907. 
Kiihne and Lea, tiber die Absonderung des Pankreas. Untersuchungen a. d. physiol. Institut Heidel- 
berg, 2, Heft 4, 1882. 
Kyrle, tiber die Degenerationsvorgange im tierischen Pankreas. Arch. f. mikr. Anat. u. Entwck- 
lugsgesch., 72, 141, 1908. 
Laguesse, G., Sur la formation des dots de Langerhans du pancreas. Compt. rend. soc. de Biol., 44, 
1893 u. 65, 1908; J. de l’anat. et physiol, [etc.], 30, 31, 32, 95, 96, 1894. 
Lanceraux, Notes et reflexions a propos de 2 cas du Diabete sucre avec alterations du pancreas. 
Bull. Acad, de m6d.: 3. Serie, 7, 12-15, 1877. 
•—Nouveaux faits de Diabete sucre avec alterations du pancreas. Ibidem, 1888. 
Langerhans, P., Beitrage zur mikroskopischen Anatomie der Bauchspeicheldrtise. Inaug.-Diss., 
Berlin, 1869. 
Lazarus, Beitrage zur Pathologie und Therapie der Pankreaserkrankungen. Ztschrift. f. klin. Med., 
51 u. 52, 1904. 
Leimdorfer, A., tiber den respiratorischen Stoffwechsel des Diabetikers bei verschiedener Kostform. 
Biochem. Ztschr., 40, 326, 1912. 
Lemcke, Ein Fall von sehr defer Erniedrigung der Korpertemperatur nach primarer Hamorrhagie in 
der Medulla oblongata, etc. Deutsches Arch. f. klin. Med., 34, 84. 
Lemoine and Launois, Lesions du pancreas dans le diabete. Arch, de med. exper. et d’anat. path., 3, 
189T. 
Lemonier, Diabete syphilitique. Ann. de dermat. et de Syph., 9, 398, 1888. 
Leo, tiber den respiratorischen Stoffwechsel bei Diabetes mellitus. Ztschr. f. klin. Med., 19, Suppl.- 
Bd., 101, 1891. 
Lepine, R., Die Beziehungen des Diabetes zu Pankreaserkrankungen. Wien. med. Presse, 108, 1892. 
—Le diabete sucrG Paris, 1909, Felix Algan. 
Leudet, Moniteur de science, i860. 
Levene, T. A., and G. Meyer, On the combined action of muscle plasma and pancreas extract, etc. 
J. of biol. chem., 9, 97, 1911. 
Liefmann and Stern, tiber Glykamie und Glykosurie. Biochem. Ztschr., 299, 1906. 
Levierato, tiber die Schwankungen der vom Diabetiker ausgeschiedene Kohlensaure bei wechselnder 
Diat und medikamentoser Behandlung. Arch. f. exper. Path. u. Pharmakol, 15, 161, 1889. 
Loeh, tiber Glykosurie und Albuminurie nach Gehirnapoplexien. Deutsche med. Ztg., 1057, 1899. 
Lombroso, U., Kann das nicht in den Darm sezernierende Pankreas auf die Nahrstoffe einwirken? 
Arch. f. Path. u. Pharmakol, 60, 99, 1908. 
—Die Gewebselemente, welche die innere Funktion des Pankreas besorgen. Lubarsch-Ostertag, 
dutto del Ergebn. d. Path., 9, 1909. 
Lombroso and Sacerdotte, SuIIe modificazioni istologiche del pancreas dei Conigli dopo la ligatura del 
Wirsung. Rend. R. Acad. diLincei., Roma, 1908. 
Lowi, O., Eine neue Funktion des Pankreas und ihre Beziehung zum Diabetes mellitus. Arch. f. 
exper. Path. u. Pharmakol, 50, 1908. 
Lusk, The influence of cold and mechanical exercise on the sugar excretion in phloridzin glykosuria. 
Am. J. Physiol., June, 1908. 
—Science, N. S., 33> Nr. 846, 433, 1911. 
Liithje, H., 1st die Zerstorung des Zuckers nach Pankreasexstirpation vollstandig aufgehoben? 
Miinchen med. Wchenschr., 1537, 1903. 
Mac Callum, Hypertrophy of islands of Langerhans in diabetes mellitus. Am. J. M. Sc., 432, 1907. PANCREAS 
651 
Magnus-Levy, Der Einfluss von Krankheiten auf den Energiehaushalt im Ruhezustand. Ztschr. f. 
klin. Med., 60, 1906. 
—Respirationsversuche an diabetischen Menschen. Ztschr. f. klin. Med., 56, 1905. 
Manchot, Uber die Beziehungen der Glykosurie und des Diabetes mellitus zur Syphilis. Monatsh. 
f. prakt. Derm., 27, 221, 295, 1898. 
Mayo Robson, Die Beziehungen der Anatomie zu den Krankheiten des Pankreas. Berl. klin. Wchen- 
schr., Nr. 4 u. 7, 1908. 
Mering and Minkowski, Diabetes nach Pankreasexstirpation. Arch. f. exper. Path. u. Pharmakol., 
26, 371, 1889. 
Michael, Zur Atiologie des Diabetes mellitus. Arch. f. klin. Med., 44, 1889. 
Minkowski, Untersuchungen fiber den Diabetes mellitus nach Exstirpation des Pankreas. Leipzig, 
1893. 
Minnich, Fall von Pankreaskolik. Berl. klin. Wchenschr., 1894, Nr. 6. 
Mironescu, Uber die Entwicklung der Langerhansschen Inseln bei Embryonen. Arch. f. Anat. u. 
Entwicklungsgesch, 76, 1910-11. 
Mohr, L., Ztschr. f. exper. Path. u. Therap., 4, 910, 1908. 
v. Muller, Fr., Untersuchungen iiber Ikterus. Ztschr. f. klin. Med., 12. 
Naunyn, B., Der Diabetes mellitus. Wien., 1906, A. Holder. 
Nehring and Schmoll, Uber den Einfluss der Kohlehydrate auf den Gaswechsel des Diabetikers. 
Ztschr. f. klin. Med., 31, 59, 1897. 
Neubauer, E., Uber die Wirkung antiglykosurischer Mittel und iiber Leberglykosurie. Biochem. 
Ztschr., 43, 335, 1912. 
Nevrat-Perrotton, These de Paris, 1859. 
Nishi, Uber den Mechanismus der Blutzuckerregulation. Arch. f. exper. Path. u. Pharmakol, 61, 
186, 1909. 
v. Noorden, Die Zuckerkrankheit. V. Aufl., 1910. VI. Aufl., 1912. Berlin, Hirschwald. 
—New aspects of diabetes. New York, 1912, Treat & Co. 
—Uber Diabetestherapie. Med. klin. 1909, Nr. 35. 
—Uber Theorie und Therapie des Diabetes mellitus. Ibidem, 1911, Nr. 1. 
—Uber neurogenen Diabetes. Ibidem, 19x2, Nr. 1. 
O'Connor, Uber Adrenalinbestimmung im Blute. Miinchen med. Wchenschr., 1439, 1911. 
Opie, On the histology of the islands of Langerhans of the pancreas. Johns Hopkins Hosp. Bull., 206, 
1900. 
Opie, E. L., Pathology changes affecting the islands of Langerhans of the pancreas. J. Exper. M., 
5, 397, u. 527, 1900-01. 
Van Ordt, Beitrage zur Symptomatologie der Geschwiilste des Mittelhirns und der Briickenhaube. 
Deutsche Zeitschr. f. Nervenh., 18, 126, 1900. 
Oser, Erkrankungen des Pankreas. NothnageVs Handb., 1898. 
Pearce, Am. J. Anat., 2, 1903. 
Pettenkojer and Voit, Uber den Stoffwechsel bei Zuckerharnruhr. Ztschr. f. Biol., 3, 380, 1867. 
Pfliiger, Das Glykogen und siene Beziehungen zur Zuckerkrankheit. II. Aufl. Bonn, 1905. 
Plagge, Traumatischer Diabetes. Arch. f. path. Anat. [etc.], Berl., 13, 93. 
Porges and Salomon, Uber den respiratorischen Quotienten pankreas-diabetischre Hunde nach 
Ausschaltung der Abdominalorgane. Biochem. Ztschr., 27, 143, 1910. 
Reimer, Lehrb. f. Kinderh., 10, 306, 1876. 
Reinhold, Beitrag zur Kenntnis der Lage des vasomotorischen Zentrums in der Medulla oblongata 
des Menschen. Deutsche Ztschr. f. Nervenh., 10, 67, 1896. 
Renaut, Sur les organs lymphoglandularies et le pancreas des vertebre. Compt. rend. Acad, de sc. 
Par., 89, 247, 1879. 
Rennie, Quart. J. of Micr.. Sc., 48, 1904. 
Robin et Binet, Les echanges respi'ratoires dans le diabete glycosurique. Arch, gen., 9, 283, 1898. 
Rosenberger, Fr., Die Ursachen der Glykosurie. Miinchen, 1911. 
Rumpf, Untersuchungen iiber den Diabetes mellitus. Ztschr. f. klin. Med., 45, 1902. 
Saltykow, Uber Pankreasdiabetes. Cor.-Bl. f. schweiz. Aerzte, 18, 625, 1909. 
Sandmeyer, Uber die Folgen der partiellen Pankreasexstirpation beim Hunde. Ztschr. f. Biol., 31. 
Sauerbeck, Langerhanssche Inseln und Pankreasdiabetes. Arch. d. allg. Path. u. Anat., 538, 1902. 
—Die Langerhansschen Inseln im normalen und im kranken Pankreas des Menschen. Arch. f. path. 
Anat. [etc.], Berl., 177, Spplbd. 1904. 
Scheuplein, C., Verletzung der Wirbelsaule, Diabetes mellitus acutus, vollstandige Heilung. Arch, 
f. klin. Chir., 29, 365, 1883. 652 
LITERATURE 
Schlesinger, Die Erkrankung des Pankreas bei hereditarer Lues. Arch. f. Path. Anat. fete.], Berl., 
154, 1898. 
Schmidt, M. B., Uber die Beziehungen der Langerhansschen Inseln zum Diabetes mellitus. Miinchen 
med. Wochenschr., 52, 1902. 
Schulze, WDie Bedeutung der Langerhansschen Inseln im Pankreas. Arch. f. mikr. Anat., 56, 491, 
1900. 
Schwenkendick, Ein Fall von traumatischem Diabetes mellitus. Allg. med. Centr.-Ztg., 76, 1, 1907. 
Seegen, Diabetes mellitus, 1893. 
v. Seo, Ueber den Einfluss der Muskelarbeit auf die Zuckerausscheidung beim pankreasdiabetischen 
Hund. Arch. f. exper. Path. u. Pharmakol., 59, 341, 1908. 
Sinn, Der Einfluss experimenteller Pankreasgangunterbindung auf die Nahrungsresorption. Inaug.- 
Diss., Marburg, 1907. 
Ssobolew, Zur normalen und pathologischen Morphologie der inneren Sekretion der Bauchspeichel- 
driise. Arch. f. path. Anat. [etc.], Berk, 168, 91, 1902. 
—Uber die Struma der Langerhansschen Inselnder Bauchspeicheldriise. Arch. f. path. Anat. 
[etc.], Berk, 177, Supplbd., 123, 1904. 
—Beitrage zur Pankreaspathologie. Beitr. z. path. Anat. u. Physiol., 47, 1910. 
Strauss, H., Alimentare spontane und diabetische Glykosurien. Ztschr. f. klin. Med., 39. 
—Glykosurie und Geisteskrankheiten. Ibidem, 39. 
—Neurogene und thyreogene Glykosurie. Deutsche med. Wchenschr., 19, 19 u. 20, 1897. 
Stiive, Arbeiten aus dem stadtischen Krankenhaus. Frankfurt a. M. 44 (Festschr)., 1896. 
Swale Vincent and Thompson, Int. Montaschr. f. Anat. u. Physiol., 24, 1908. 
Thiroloix, Diabete pancreatique. Bulk Soc. anat. de Par., 62, 1891, et Gaz. d. hop. Par., 1894. 
Tiberti, N., Intorno all modo di comportarsi dell’ isola del Langerhans, etc. Arch. ital. de bioh, 
51, 1908; Arch, de Fisiol., 5, 1908; Sperimentale 62, 1908. 
Tscheboksarof, Sur les nerfs secreteurs des surrenales. Russki Wratsch, 8, 873, 27 Juin, 1909. Ref. 
J. de physiol, et path, gen., 11, 962. 
Tuckett, J. L., On the production of glykosuria in relation to the activity of the pancreas. J. Physiol., 
41, 1910. 
Visentini, A., Uber das Verhalten des Pankreas nach Unterbindung und Durchschneidung seiner 
Ausfiihrungsgange. Arch. f. Anat. u. Physiol., Physiol Abt., Supplbd., 1908. 
Voit, C., Physiologie des Stoffwechsels. 228, 1881. 
Voit, Fr., Uber den Stoffwechsel bei Diabetes mellitus. Ztschr. f. Biol., 141, 1892. 
Watermann and Smit, Nebenniere und Sympathikus. Arch. f. d. ges. Physiol., 124, 198, 1908. 
Weichselbaum, A., Uber Veranderungen des Pankreas bei Diabetes mellitus. Sitzungsb. d. k. 
Akad. d. Wissensch. Math.-naturw. Cl. Wien. Abt., 3, 119, 1910. 
—Uber veranderungen des Pankreas bei Diabetes mellitus. Wien. klin. Wchenschrift, 1911, Nr. 5. 
Weichselbaum and Kyrle, Uber das Verhalten der Langerhansschen Inseln des menschlichen Pankreas. 
Arch. f. mik. Anat., 74, 1909. 
Weichselbaum and Stangl. Zur Kenntnis der feineren Veranderungen des Pankreas bei Diabetes 
mellitus. Wien. klin. Wchenschr., 968, 1901. 
■—Weitere histologische Untersuchungen, etc. Ibidem, 969, 1902. 
Weintraub, Die Heilkunde. 1898. 
—Untersuchungen iiber den Stoffwechsel bei Diabetes mellitus und zur diatetischen Therapie der 
Krankheit. Bibliotheka medica, Abt. D., 1, Heft, 1893. 
De Younghe, Tumor der Medulla oblongata; Diabetes mellitus. Arch. f. Psychiat., 13, 658, 1882. 
Ziilzer, Untersuchungen uber den experimentellen Diabetes. 24. Kongr. f. innere. Med., 1907. 
Zither, G. G., Dohrn and Mayer, A., Neuere Untersuchungen iiber den experimentellen Diabetes. 
Deutsche med. Wchenschr., 1380, 1908. 
Zuntz and Mayer, Sur les effets de la ligature des canaux pancreatiques chez les chiens. Bulk Soc. 
roy. d med. pub. de. Belg. Brux., 19, 409, 1905. CHAPTER XIV 
OBESITY 
Ballet, G., L’adipose douloureuse (maladie de Dercum). Presse med., i, 285, 1903. 
v. Bergmami, Der Stoff- und Energieumsatz beim infantilen Myxodem und bei Adiposis universalis. 
Ztschr. f. exper. Path. u. Therap., 5, 640, 1909. 
Bochroch, A case of adiposis dolorosa. Am. J. M. Sc., 124, 569, 1902. 
Burr, C. W., and Riesman, David, Report of a case of tumor of the hypophysis without acromegaly. 
J. Nerv. and Ment. Dis., 26, 20. 
Cheinisse, L’identite de la lipomatose symmetrique douloureus avec la maladie de Dercum. Semaine 
med., 23, 221, 1903. 
Cegard and Roussy, Deux cas d’adipose douloureus suite d’ovariotomie. Presse med., n, 740, 1903. 
Debove, Lipomatose douloureuse. Gaz. d. hop., Nr. no, 1069, 27 Sept., 1904. 
Dercum, A subcutaneous connective-tissue dystrophy of the arms and back, etc. Univ. M. Mag., 
Dec., 1888, and Three cases of a hitherto unclassified affection, etc. Am. J. M. Sc., 114, 521, 
1892. 
Dercum and McCarthy, Autopsy in a case of adiposis dolorosa. Am. J. M. Sc., 124, 994, 1902. 
Ewald, Organtherapeutisches. Therapie der Gegenwart, 1899. 
Fulconis, Maladie de Dercum et lipomatose douloureuse symmetrique. These de Lyon, 1904. 
Guillain and Alquier, Etude anatomique et pathologique d’un cas de maladie de Dercum. Arch, de 
med. exper. et d’anat. path., 18, 680, 1906. 
Haskovec, Lud., Adipose douloureuse ou maladie de Dercum. Rev. neurol., Nr. 23, 15 Dec., 1906. 
Hertoghe, Elypothyreoidie benigne chronique. N. inconogr. de la Salpetriere, 1899, Nr. 4. 
Jaquet and Sevenson, Zur Kenntnis des Stoffwechsels fettsuchtiger Individuen. Ztschr. f. klin Med., 
4i, 375, I9°°- 
Koettnitz, Uber symmetrisches Auftreten von Lipomen. Deutsche Ztschr. f. Chir., 38, 75, 1893. 
Launois and Bensaude, De l’adenolipomatose symmetrique a predominance cerv. N. inconogr. de 
la Salpetriere, 13, 41, 184, 243, 1900. 
Loning and Fuss, Schilddriisenveranderungen bei Adiposis dolorosa. Kongr. f. innere. Med., 222, 
1906. 
Lorand, Uber die Entstehung der Fettsucht, mit Riicksicht auf Veranderungen gewisser Blutgefass- 
driisen. Med. klin., 387, 1905. 
Lyon, J. P., Adiposis and lipomatosis considered in reference to their constitutional relations and 
symptomatology. Arch. Int. Med., 6, 28, 1910. 
Magnus-Levy, Untersuchungen zur Schilddrtisenfrage. Ztschr. f. klin. Med., 33, 1897; ibid., 6o, 177, 
1906. 
Miquel, De la valeur nosologique de la maladie de Dercum. These de Paris, 1904. 
v. Noorden, Die Fettsucht. Nothnagels Path. u. Therap. x. Aufl., 1900 und 2. Aufl., 1910. Wien, 
und Leipzig, Holder. 
—Pathologie des Stoffwechsels, 448, 1893. 
v. Noorden, Uber verschiedene Formen der Fettsucht. Med. Klin., Nr. 1. 
—Uber Fettsucht. Med. Klin., Nr. 1. 
—Uber Fettsucht. Intern, med. Kongr., Budapest, 1909. 
Reach, Stoffwechselversuch an einem fettleibigen Knaben. Festschr. f. Salkowski., 319, 1904. 
Berlin. 
Pic and Gardere, Un cas d’atrophie generalisee de la face. Lyon med., 2, 61, 1909. 
Price, G. E., Adiposis dolorosa. Am. J. M. Sc., 137, 705, 1909. 
Raymond and Claude, see chapter on epiphysis. 
Rubner, M., Beitrag zur Ernahrung im Knabenalter mit besonderer Beriicksichtigung der Fettsucht, 
Berlin, 1902. 
Salomon, H., Uber Drustkuren, besonders bei der Fettleibigkeit. V. Noorden’s Samml, med. Ab- 
handl. Berlin, 1905, Heft 6. 
Schwenckenbecher, Uber die Adiposis dolorosa. Arch. f. klin. Med., 324, 1904. 
653 654 
LITERATURE 
-—Uber die Ausscheidung des Wassers durch die Haut. Deutsches. Arch. f. klin. Med., 79, 29, 1904. 
Simons, A., Eine seltene Trophoneurose “Lipodystrophia progressiva.” Ztschr. f. Neurol, u. 
Psychiat., 5, 1911. 
Staehelin, R., Der respiratorische Stoffwechsel eines Fettsiichtigen im nuchternen Zustand und nach 
Nahrungsaufnahme. Ztschr. f. klin. Med., 65, 425, 1908. 
Striibing, Uber “Adiposis dolorosa” (Dercum) und das “oedeme blanc and bleu.” {Charcot.) Arch, 
f. Dermat. u. Syph., 59, 171, 1902. 
Thiele, O., und 0. Nehring, Untersuchungen des respiratorischen Gaswechsels unter dem Einfluss 
von Thyreoideapraparaten, etc. Ztschr. f. klin. Med., 30, 41, 1896. 
Thimm, Adiposis dolorosa und schmerzende Lipome. Monatschr. f. pakt. Dermat., 30, 282, 1903. 
Umber, Uber einen Fall von Neurolipomatosis dolorosa. Hamburger arztl. Verein, 9. Febr., 
1909. 
Vitaut, Maladie de Dercum (Adiposis dolorosa). These de Lyon, 1901. 
Weiss, A., Adiposis dolorosa. Sammelref. Zntralbl. f. Grenzgeb. d. Med. u. Chir. 7, Nr. 1, 1904. 
White, A case of adiposis dolorosa. Brit. M. J., 11, 1533, 1899. INDEX 
Abderhalden reaction, 56, 151, 449 
Abscesses in the floor of the ventricle, 563 
Absorptive disturbances in Basedow’s disease, 
78, 79 
after extirpation of the pancreas, 521 
“Abwehr” theories, 56 
Achondroplasia, see chondrodystrophy 
Acromegaly, 250 
action of adrenalin in, 278 
blood picture, 274 
definition, 250 
diabetes in, 277, 288 
differential diagnosis, 293 
ductless glandular system, 273, 274 
early acromegaly, 290 
eye changes in, 255, 280, 311 
genital disturbances in, 263, 264 
genitalia in, 263, 266 
and gigantism, 464 
hairiness in, 257, 261 
heart, vascular system, 273 
hyperplasia of suprarenals in, 372 
hypophysial enlargement, symptoms in, 
279 
hypophysis, 279 
joints in, 279 
mental disturbances in, 279 
metabolism, 275, 276 
muscles in, 255 
myxedema and, 270 
nerves and nervous system, 278, 280 
occurrence, 250 
operation in, 295 
osseous system, 251, 252 
pancreas, 274 
pathogenesis, 282 
pathological anatomy, 280 
pilocarpine injection, 278 
polyuria in, 278, 288 
and pregnancy, 267 
skin in, 255 
splanchnomegaly in, 273 
status lymphaticus, 274 
suprarenals, 372 
symptomatology, 250 
teeth in, 251 
thymus gland, 274 
thyroid gland in, 267, 273 
treatment, 294 
vascular system, 273 
Acromegaliform syndrome, 292 
Acroparesthesia differentiation from tetany, 224 
Actinomycosis of the thyroid gland, 117 
Addison’s disease, 349 
adynamia in, 349 
blood picture in, 349 
course of, 351 
definition, 349 
differential diagnosis of, 359 
gastrointestinal disturbances in, 349 
hyperplasia of the thymus in, 350 
metabolism of, 350 
occurrence of, 349 
pathogenesis of, 358 
pathological anatomy of, 352 
physiology, 354 
pigmentations in, 350, 358 
prognosis of, 360 
status lymphaticus in, 350 
suprarenal implantation in, 361 
symptomatology, 349 
thrombosis of the suprarenals, 353 
treatment of, 360 
Adenocarcinoma of the hypophysis, 280, 281 
of the thyroid gland, 63 
Adenomata of the hypophysis, 280, 281, 323 
of the suprarenals, 367 
of the thyroid gland, 63 
Adiposis tuberosa simplex, 597 
Adipositas dolorosa, 467, 586 
differential diagnosis, 596 
forms, 591 
mental symptoms, 592 
and myxedema, 586 
pathogenesis, 594 
pathological anatomy, 593 
symptomatology, 590 
treatment, 597, 598 
Adiposity, see obesity. 
Adrenalin, arteriosclerosis through injection 
of, 366 
biological methods for demonstration of, 366 
chemical methods for demonstration of, 355 
contents of the suprarenal in hypertonia, 365 
in diabetes, 550 
diuresis in diabetes, 550 
general action, 31, 33 
glycosuria after castration, 407 
in diabetes, 56 
after extirpation of the pancreas, 517 
in myxedema, 116 
in osteomalacia, 362, 442 
in pregnancy, 389 
in the premenstrual period, 387 
intoxication in tumors of the suprarenals, 
364 
655 656 
INDEX 
Adrenalin, physiologic action, 355 
relation to iron-free pigment, 359 
therapy in Addison’s disease, 360 
in Basedow’s disease, 155 
in esophageal carcinoma, 350 
in gastric ulcer, 349 
in gynecology, 362 
Adrenalinemia in Basedow’s disease, 80 
Adynamia in Addison’s disease, 349 
Aged, ductless glands, system in, 55, 109 
Allen’s treatment of diabetes, 577 
Agenitalism, 401 
Alcoholism in infantilism, 482 
differential diagnosis from Basedow’s disease, 
106 
Alkalosis, 230 
Amino-acid elimination in gigantism, 472 
in tetany, 203 
Ammonia elimination in endemic cretinism, 162 
in gigantism, 472 
in pregnancy, 389 
in tetany, 203 
Anencephaly, suprarenal aplasia in, 362 
Angina, Basedow’s after, ior 
myxedema after, 125 
thyroiditis after, 64 
Anoci-association, 152 
Antithyroidin in Basedow’s disease, 109 
Aparathyrosis, 187 
Apinealism, 343 
Apituitarism, see also hypophysial dystrophy. 
Aplasia of the sexual glands, 396 
Apoplexia cerebri in diabetes, 561 
Arsenic in thyroidin treatment, 148 
Arteriosclerosis, in myxedema, ir6 
premature in diabetes, 553 
in suprarenal hyperplasia, 366 
in tumors of the sympathetic, 366 
Articular rheumatism, myxedema after, 124 
thyroiditis after, 64 
Asthenia, Stiller’s, 52 
Asthma thymicum, 17 
Atheromatosis, see arteriosclerosis. 
Athyroidism, 22, in 
Atropine in Basedow’s disease, 90 
general actions, 3T 
Autolysis, 90 
Autonomous nervous system, 30 
Balancement in pancreatic tissue, 503 
Basal metabolism, 23, 26 
in acromegaly, 275 
in Basedow’s, 85 
in cretinism, 141, 172 
in eunuchoidism, 4t8 
in hypophysial dystrophy, in extirpation 
of the pancreas, 517 
in obesity, s8r 
after pituitrin injection, 286 
regulation by ductless glands, 23 
Basal metabolism, in tetany, 194 
in various diseases, 161 
Basedow’s disease, 105 
adolescent, 105 
blood picture, 80, 84, 153 
cardiovascular system in, 67, 162 
in chlorosis, 437 
complications, 98 
contrasted with myxedema, 96 
course of, 105 
in diabetes, 565 
diabetes in, 87, 88 
diagnosis, 106 
diarrheas in, 76, 77 
definition, 65 
dysfunction in, 93, 150 
emaciation in, 84 
etiology, ior 
eye-symptoms, 69 
fat stools in, 77, 79 
formes frustes, 78, 79, 160 
forms of, 102 
gastrointestinal tract, 76 
genitalia, 92 
glycosuria in, 87, 88 
heart and vascular system in, 66, 68 
heat, regulation in, 90 
iodine contents of the thyroid gland, 99 
mental symptoms in, 75 
metabolism in, 85 
muscles in, 75 
and myxedema, 96 
nervous system in, 74 
occurrence, 66 
osseous system in, 92 
pathogenesis of, 93 
pathology, 153 
pigmentation in, 91 
prognosis, 106 
psyche and psychoses, 75 
relations with epilepsy, 145, 155 
respiratory organs in, 73 
scleroderma and, 92 
skin, 91 
sympathicotonic, 103 
symptomatology, 66 
tachycardia in, 68 
temperature in, 90 
thymus gland in, 151, 155, 158, 160 
after thyroiditis, 63 
treatment, 106, 154 
tremor in, 74 
vagotonic, T03 
Basedowoid, 103, 160 
Bladder disturbances in hypophysial dystrophy, 
3°S 
Bladder disturbances in tetany, 200 
Blood coagulability after castration, 407 
distribution after injection of adrenalin, 356 INDEX 
657 
Blood picture in acromegaly, 274 
in Addison’s disease, 349 
after injections of adrenalin, 356 
in Basedow’s disease, 80, 84, 153 
after castration, 407 
in chlorosis, 436 
in diabetes, 551 
in endemic cretinism and goiter, 147, 
174,182 
in hypophysial dystrophy, 310 
in infantilism, 481 
in menstrual cycle, 387 
in multiple ductless glandular sclerosis, 
457 
in myxedema, 115, 118 
in osteomalacia, 444 
in the premenstrual period, 386 
in pregnancy, 389 
in the puerperium, 394 
in sporadic cretinism, 140 
in status lymphaticus, 378, 379 
in tetany, 196 
in thymus gland hyperplasia, 237, 247 
after extirpation of the thymus gland, 234 
pressure, after injection of adrenalin, 354, 
355 
in Addison’s disease, 349 
in Basedow’s disease, 68 
in chlorosis, 436 
in hyperplasia of the chromaffin tissue, 
357 
in multiple ductless glandular sclerosis, 
457 
in the premenstrual period, 386 
after use of pituitrinum glandulare, 
286 
of pituitrinum infundibulare, 284 
regulation of, by the ductless glands, 40 
in status lymphaticus, 378 
after sugar puncture, 227 
after thyroid feeding, 68 
in diabetes, 551 
sugar after adrenalin injection, 356 
after cervical cord transection, 38 
in diabetes mellitus, 537 
in hypertonia, 366 
after injections of pituitrinum glandulare, 
286 
of pituitrinum infundibulare, 286 
after pancreas extirpation, 515, 525 
in birds, 523 
in phosphorus poisoning, 362 
sugar after peroral administration of 
adrenalin, 360 
regulation of, through the chromaffin 
tissue, 358 
after suprarenal extirpation, 354 
in tetany, 229 
Brain tumors and diabetes, 562 
Bryson’s symptom in Basedow’s disease, 74 
Cachexia, 52, 127, 596 
Cachexia thyreopriva, 111 
Calcium metabolism in endemic cretinism, 
172 
after castration, 406 
in neurasthenia, 43 
in osteomalacia, 443 
in tabes, 44 
in tetany, 204 
therapy in Basedow’s disease, no 
in tetany, 204, 226 
Caloric production in diabetes, 537 
see metabolism. 
Calzine in Basedow’s disease, no 
in tetany, 227 
Carbohydrate metabolism, 22 
in Basedow’s disease, 87 
in brain diseases, 44 
in chlorosis, 436 
chromaffin tissue and, 357 
in diabetes mellitus, 537 
after extirpation of the pancreas, 515 
after injection of pituitrin, 286 
in hypophysial dystrophy, 303 
after ligation of the pancreatic duct, 516, 522 
in myxedema, 122 
regulation through the ductless glands, 574 
in tetany, 202 
Carcinoma of the epiphysis, 342 
of the hypophysis, 281, 323 
of the pancreas, 536 
of the suprarenal cortex, 367 
of the thyroid gland, 63 
of the thymus gland, 238 
Carpopedal spasm, 190 
Castration, blood picture, 407 
loss of pigment, 406 
oophorin action, 406 
in osteomalacia, 435 
respiratory metabolism, 406 
see also eunuchs. 
Cataract formation in tetany, 205, 206 
Catatonia, metabolism, 43 
Chagas’s disease, 182 
Chemotactic actions of the hormones, 33, 40 
Chlorosis, 435 
blood in, 436 
cardiovascular symptoms, 436 
digestive symptoms, 436 
and eunuchoidism, 436, 438, 439 
generative glands in, 438 
genitalia in, 438 
infantile, 436 
pathogenesis, 439 
symptomatology, 436 
tardive, 436 
Chlorotoid, 436 
Choked disc in acromegaly, 280 
in epiphysial tumors, 342 
in tetany, 192 658 
INDEX 
Cholelithiasis and pancreatitis, 530 
Cholin, general action, 31 
in the suprarenal cortex, 3, 357 
systeme cholingene, 357 
Chondrodystrophy, 492 
definition, 492 
differential diagnosis, 500 
etiology, 500 
familial occurrence, 497 
forms, 496 
occurrence, 497 
partial, 495 
symptomatology, 492 
unilateral, 495 
Chondroma of the hypophysis, 323 
Chromaffin tissue in chlorosis, 440 
in diabetes mellitus, 566 
in Grawitz tumors, 368 
in hypertonia, 366 
in osteomalacia, 437 
in phosphorus poisoning, 362 
physiology of, 357 
in status lymphaticus, 378 
in sugar puncture, 527 
in tetany, 208 
in thymus-gland hyperplasia, 237 
tumors of, 364 
Chvostek’s symptom in diabetes, mellitus, 189 
in tetany, 188 
in the tuberculous, 189 
Circular psychoses, 43 
Cirrhose bronzee, 74, 359, 531 
Cirrhosis, see sclerosis. 
of the liver in infantilism, 483 
Climacteric, 395 
Conarium, see epiphysis. 
Colloid in the hypophysis, 123 
in the thyroid gland, 64, 166 
Conjunctivitis in endemic cretinism, 159 
in tetany, 194 
Constitution and ductless glands, 17, 52, 55 
Constitutional inferiority, 236, 243, 509 
Correlation, see reciprocal action. 
Corpus luteum, 446, 448 
Cranium progeneum, 293 
Creatinin elimination in Basedow’s disease, 90 
in endemic cretinism, 172 
in tetany, 194 
Creatorrhea, in diseases of the pancreas, 533 
Cretinic degeneration, geographical distribution 
of, 164 
Cretinism, endemic, 168 
blood picture, 174 
brain, 170 
dentition, 174 
differential diagnosis, 180 
epiphysial junctures, 173 
genitalia, 173 
growth disturbances, 174 
habitus, 168 
Cretinism, hearing disturbances, 171 
hypophysis, 173 
intellectual disturbances, 172 
metabolism, 172 
mutism in, 171 
nervous systems, 170, 172 
parathyroid glands, 175 
pathogenesis, 178 
pathological anatomy, 160 
respiratory metabolism in, 172 
skeleton, 173 
skin, 168 
speech development. 172 
symptomatology. 168 
teeth in, 174 
thyroid gland, 175 
treatment, 175 
marine, 179 
sporadic, 128 
basal metabolism, 141 
blood picture, 140 
breathing, 140 
definition, 128 
dentition, 139 
differential diagnosis, 144 
enlargement of the liver, 139 
epiphysial junctures, 138 
etiology, 128 
genitalia, 140 
growth disturbances, 138 
hearing disturbances, 143, 148 
hypophysis, 142 
hypothermia, 142 
liver, 140 
metabolism, 141 
mouth and nose, 139 
nervous system, 142 
pathology, 128, 129 
skin, 139 
symptomatology, 130 
thymus gland, 142 
thyroid gland, 128 
treatment, 144 
umbilical hernia, 139 
Crile, see kinetic theory and anoci-association 
Cryptorchidism, 382 
in partial gigantism, 472 
Cyst goiters, 166 
Cysts of the epiphysis, 342 
of the hypophysis, 281, 323 
of the pancreas, 529 
of the suprarenal cortex, 357, 367 
Cysticerci of the floor of the ventricle, 563 
Definition of ductless glandular secretion, 7 
of internal secretion, 7 
Degeneratio genito-sclerodermica, 450 
Delirium tremens, 43 
Dementia precox, 60 
Dentition in endemic cretinism, 174 INDEX 
659 
Dentition in myxedema, 114 
in premature development, 434 
in sporadic cretinism, 139 
in tetany, 206 
Dercum’s disease, see also adiposis dolorosa, 
586 
question of pluriglandular disturbance, 48 
Dermatographism in diabetes mellitus, 542 
in tetany, 193 
Detoxication theory, 8, 9, 18, 93 
Detoxication theory of Basedow’s disease, 93 
Diabete bronzee, 14 
Diabetes insipidus, idiopathic in brain diseases, 
306 
in diseases of the hypophysis, 306, 333 
mellitus, 511 
in acromegaly, 277, 573, 576 
adrenalin diuresis, 550 
glycosuria, 550 
production, 355 
adrenalinogenic, 571 
after adrenalin injection, 527 
alimentary factor, 532-535, 570 
in Basedow’s disease, 87, 88 
blood picture, 551 
blood pressure increase through thyroidin 
in, 55i 
in brain tumors, 562 
carbohydrate metabolism, 537 
in cerebral hemorrhage, 561 
lues, 568 
tumors, 562 
clinical aspect of, 528 
complications of, 553 
decipiens, 550 
dermatographism, 552 
diet in, 5 77-5 79 
differential diagnosis, 574 
in diseases of the hypophysis, 573 
diuresis, 550 
in eunuchoidism, 418 
experimental nervous, 526 
after extirpation of the pancreas, 2x2, 223 
from fat, 539 
genuine, 537 
granular atrophy of the pancreas in, 556 
after head injury, 566 
hypertonic, 35, 44, 552 
hydropic insular degeneration, 559 
insular theory, 556 
ketonuria, 540 
metabolism (summary), 553 
in myxedema, 122 
nervous factor of the glycosuria, 539 
obstipation in, 551 
pancreas hormone, 518, 522; see insulin. 
extirpation of the pancreas, 518 
pathological anatomy of, 555 
after pituitrinum glandulare injection, 
527, 528 
Diabetes mellitus, premature arteriosclerosis, 
553 
protein metabolism, 539 
question of disturbance of glycogenesis, 
of the disturbance of sugar combus- 
tion, and of sugar production, 524 
of the formation of sugar from protein, 
538 
quotient D:N, 516,523 
respiratory metabolism, 541 
salt metabolism, 540 
Sandmeyer’s, 516 
skin in, 552 
Allen’s treatment of, 577 
theory, 568, 572 
thyrogenic, 573 
after trauma, 565 
treatment, 575, 577, see also insulin, 
vegetative nervous system, 551 
water economy, 540 
Diaphragm spasm in tetany, 191 
Diarrheas in Basedow’s disease, 77 
Diathesis, 56 
exudative, 378 
hypertonic, 365 
spasmophilic, 220 
Diet in diabetes mellitus, 575, 577 
Diphtheria, adrenalin treatment of, 361 
suprarenals in, 354 
toxin, suprarenals in injection of, 354 
Diplopia in tetany, 191 
Dissociation of the hormone actions, 16 
Diuresis in diabetes, 550 
in hypophysial tumors, 306 
Ductless glands in adipositas dolorosa, 594, 
595 
autonomy, 39 
degeneration in gigantism, 471, 472 
grouping of, 27 
in hypergenitalism, 433 
hypoplasia of, 459 
influence of, on hairiness, 401 
on the sexual characters, 399, 400 
in pregnancy, 389 
in progeria, 462 
regulation of the metabolism, 21 
sugar metabolism, 574 
glandular diseases, etiology and patho- 
genesis, 41 
sclerosis, multiple, 452 
blood picture, 457 
case histories, 453 
definition, 452 
differential diagnosis, 463 
etiology, 459 
late eunuchoidism in, 457 
secondary, 862 
symptomatology, 456 
treatment, 463 
Ductus thyreoglossus, 62 660 
INDEX 
Dyspituitarism, 338 
Dwarfism, in cretinism, 138, 174 
hypophysial, 313, 314 
hypoplastic, 477, 488 
Paltauf’s type, 485, 489 
primordial, 488 
rachitic, 491 
in suprarenal tuberculosis, 363 
true, 487 
Dysfunction, 16, 19 
in Basedow’s disease, 93 
in marine cretinism, 179 
Dysostosis cleido-cranialis, 507 
Dysthyrosis, 93 
Dystrophia adiposo-genitalis, 585 
eunuchoid, see eunuchs and eunuchoidism, 
and late eunuchoidism in epiphysial 
tumors, 342 
Dystrophy, hypophysial, 295 
in acromegaly, 291 
adrenalin action, 305 
bladder disturbances, 305 
blood picture, 310 
definition, 296 
eyes in, 322, 338, 339 
differential diagnosis, 335 
genitalia, 301, 302 
growth disturbances, 312, 331 
heat regulation, 309 
infantilism, 485 
metabolism, 297, 302 
obesity in 296, 297, 330 
pathogenesis, 326 
pathological anatomy, 323 
pilocarpine action, 305 
polydipsia, 306 
polyuria, 306, 332 
psyche, 322 
skeleton, 321 
skin, 297 
symptomatology, 296 
thermoreaction, 298, 310 
treatment, 336 
tumor symptoms in, 322, 325 
vegetative nervous system, 305 
Early acromegaly, 290 
Eclampsia, 213, 215 
Edema, 125 
in Basedow’s disease, 91 
Edeme neuropathique Mathieu, 595 
segmentaire Debove, 575 
Electrical hyperexcitability in tetany, 187 
Eleodona moschata, 211 
Embryology of the ductless glandular system, 
26, 27 
of the sexual glands, 382, 386 
Enamel, defects of the enamel in tetany, 207 
Encephalomalacia in diabetes, 561 
Endocrines, 17; see ductless glands. 
Endothelioma of the dura mater, 336 
of the suprarenal cortex, 367 
Eosinophiles in acromegaly, 274 
after injection of adrenalin, 356 
in cretinism, 174 
in ductless glandular sclerosis, 457 
in osteomalacia, 444 
postpartum, 394 
in status lymphaticus, 328 
Epilepsy, 43 
in Basedow’s disease, 153 
in ductless glandular sclerosis, 449 
in tetany, 192, 213, 214, 215, 216, 225 
Epiphysial junctures in Basedow’s disease, 92 
in chlorosis, 438 
in chondrodystrophy, 494 
in cretinism, 138, 178 
in dwarfism, 490 
in early acromegaly, 291 
in eunuchoidism, 416 
in eunuchs, 403 
in hypophysial dystrophy, 321 
in late eunuchoidism, 428 
in progeria, 462 
in rachitis, 491 
in sporadic cretinism, 138 
Epiphysis, 341 
anatomy, 341 
diagnosis and treatment, 344 
pathological anatomy, 341 
symptomatology, 341 
tumors, 342 
Epithelial bodies; see parathyroids. 
Erb’s symptom in tetany, 187 
Ergotin, 31 
poisoning, 218, 219 
Eunuchoidism, 407, 445 
in acromegaly, 445 
blood findings, 419 
case reports, 408, 423 
definition, 407, 423 
with diabetes, 418 
differential diagnosis, 420, 431 
from hypophysial dystrophy, 426 
from infantilism, 420 
genitalia, 417 
hair in, 417 
historical, 422 
late, 422 
mentality in, 419 
metabolism, 418 
obesity, 417 
pathogenesis, 419 
prognosis, 421 
skeleton, 416 
skin, 417 
suprarenal hypoplasia in. 363 
symptomatology, 416, 426 
treatment, 421, 431 
Eunuchs, 401 INDEX 
661 
Eunuchs, occurrence, 401 
skeleton in, 403 
skin in, 403 
symptomatology, 402 
Exophthalmus in acromegaly, 251, 311 
in Basedow’s, 70 
Extirpation experiments, 8, 9, 11 
Eye-grounds in pituitary disease, 338, 339 
Fat stools in Basedow’s, 79 
in pancreatic disease, 523 
Ferment production in Basedow’s, 77 
Fetalism, 487 
Fibrillary contractions, see muscles. 
Fibroma of the hypophysis, 323 
Freundian hypothesis, 56, 60, 151 
Function, pharmaceutical testing of, 31 
Galactogenous substances in the hypophysis, 285 
Galactorrhea in acromegaly, 263 
Galactosuria in visceral neuroses, 344 
Gartner’s duct, 382 
Gas metabolism, see respiratory metabolism. 
Gastric tetany, 222 
treatment of, 227 
Gastrointestinal disturbances in Addison’s 
disease, 336 
in Basedow’s disease, 76 
in chlorosis, 436 
Gelatinous struma of the thyroid gland, 64 
Generative apparatus, 386 
Genitalia in acromegaly, 263, 266 
in Basedow’s disease, 92 
in chlorosis, 438 
in chondrodystrophy, 496 
in endemic cretinism, 173 
in eunuchoids, 417 
in extirpation of the hypophysis, 326, 327, 
328 
in gigantism, 470, 471 
in hypophysial dystrophy, 289, 328 
in infantilism, 477, 481 
in late castrates, 404 
in late eunuchoidism, 422 
in marine cretinism, 179 
in Mongolism, 502 
in myxedema, 123 
in sexual glandular tumors, 433 
in sporadic cretinism, 140 
in suprarenal tumors, 369 
in thymus tumors, 238 
under thyroidin treatment, 421, 430 
in tumors of the epiphysis, 342 
Genotype, 59 
Genu valgum in eunuchoidism, 4x6 
Gigantism, 464 
and acromegaly, 263, 290, 464, 465 
in chlorosis, 440 
hypophysis in, 471 
late eunuchoidism in, 470 
Gigantism, partial, 472 
pathogenesis, 470 
pathology, 471 
transient in suprarenal cortical tumors, 373 
types, 464 
Glioma of the epiphysis, 342 
of the floor of the ventricle, 563 
of the suprarenals, 364 
Glycogen, loss after suprarenal extirpation, 342, 
354 
mobilization through adrenalin, 355 
Glycosuria in acromegaly, 277 
through adrenalin, 355 
after castration, 407 
in cerebral hemorrhage, 561 
syphilis, 568 
tumors, 562 
in chlorosis, 436 
in diabetes mellitus (laws), 537 
in eunuchoidism, 418 
in extirpation of the hypophysis, 326 
after head injury, 566 
in hypophysial dystrophy, 303 
after injection of pituitrinum glandulare, 
288 
of pituitrinum infundibulare, 286 
in myxedema, 122 
nervous, 539 
in pain, 567 
in sugar puncture, 356 
after trauma, 564 
Goiter, 62, 166 
blood picture, 182 
exophthalmic, see Basedow’s disease, 
heart, 166 
differential diagnosis from Basedow’s 
disease, 106 
incidence of, 181 
iodine treatment, 165 
noxus, 165 
prophylaxis, 182 
in tetany, 219 
Gonads, see sexual glands. 
Gonorrheal orchitis in late eunuchoidism, 424 
Grade’s symptom in Basedow’s, 71 
Granular atrophy of the pancreas, 556 
Grawitz tumors, 368 
Growth, regulation of, on the part of the duct- 
less glandular system, 19-21 
disturbance, 19 
in cretins, 138, 174 
in epiphysial tumors, 342 
in eunuchs and eunuchoids, 403, 416 
after extirpation of the thymus gland, 234 
in hypophysial dystrophy, 310, 313, 331 
in idiots (Mongolian), 502 
influencing of, through thyroidin, 149, 
176 
in late eunuchoidism, 429 
in suprarenal diseases, 362, 369 662 
INDEX 
Growth, in tetany, 20 
see also osseous system and epiphysial 
junctures. 
Guanidine, 230 
Hair growth, see hairiness. 
Hairiness in acromegaly, 257, 261 
in epiphysial tumors, 342 
in eunuchoids, 418 
in eunuchs, 403 
in hypergenitalism, 434 
in infantilism, 481 
in late eunuchoidism, 427 
in pregnancy, 389 
in suprarenal tumors, 370, 371 
Hearing disturbances in myxedema, 112 
in sporadic cretinism, 143 
thyroidin treatment in, 148 
Heart disturbances in chlorosis, 436 
in tetany, 194 
see also vascular system. 
Heat regulation, 25 
especially through the chromaffin tissue, 
35°, 356 
in Basedow’s disease, 90 
in brain diseases, 44 
through the ductless glands, 25 
in hypophysial dystrophy, 309 
in myxedema, 123 
in neuroses, 44 
in the premenstrual period, 386 
in tetany, 202 
Hematopoietic apparatus, 39-41 
see also blood picture. 
Hemichromatopsia, bitemporal, 338 
Hemochromatosis, 460 
Hemorrhages, in the parathyroids, 216, 220 
Hemosiderosis, 14 
Hermaphroditism, 397, 445 
Historical development of ductless glandular 
diseases, 1-10 
Hoffman’s symptom in tetany, 188 
Hormones, 7, 28, 31, 36, 38 
Hydrocephalus in aplasia of the suprarenal 
medulla, 352 
in endemic cretinism, 169 
in hypophysial dystrophy, 326 
Hydrochloric acid treatment in Addison’s 
disease, 361 
Hydrotherapy in Basedow’s, 102 
Hyperacidity in Basedow’s, 76 
in chlorosis, 436 
in tetany, 198 
Hyperfunction, 10, 11 
Hypergenitalism, 432 
in tumors of the epiphysis, 342 
in suprarenal tumors, 369 
Hyperglobulia through injection of adrenalin, 
356 
in tetany, 195 
Hyperglycemia, 515 
in injection of adrenalin, 356 
see also blood-sugar. 
Hypernephroma, 368, 374 
in Addison’s disease, 353 
Hyperparathyroidism, 228 
Hyperpinealism, 342 
Hyperpituitarism; see also acromegaly and 
early acromegaly. 
Hyperthermia after injection of adrenalin, 356 
in Basedow’s disease, 90 
in brain diseases and neuroses, 44 
in tetany, 202 
Hyperthymization, 235 
Hyperthyroidism, see Basedow’s disease. 
Hypertonia, see blood-pressure. 
Hypertrichosis, 399 
in suprarenal tumors, 370, 371 
Hypertrophy, vicarious, of suprarenals, 353 
Hypofunction, 9, n 
Hypoparathyrosis, 187 
Hypophysis, 245 
anatomy, 245 
in adiposis dolorosa, 594 
basal metabolism after extirpation of, 
33 7 
and diabetes insipidus, 306 
in ductless glandular sclerosis, 457 
in endemic cretinism, 173 
in hibernation, 248 
in gigantism, 471 
effect on growth, 20 
extracts, 34 
in hypophysial dystrophy (see dystrophy), 
3i3 
in marine cretinism, 180 
in myxedema, 123 
in obesity, 585 
in osteomalacia, 444 
pathological anatomy, 280 
physiology and pathology, 283 
in pregnancy, 391 
relation to the thyroid gland, 334 
in sporadic cretinism, 122, 142 
tablets, treatment with, 337 
Hypopinealism, 343 
Hypopituitarism, see dystrophy, hypophysial. 
Hypoplasia of the parathyroid, 222 
Hypothermia in brain diseases, 44 
in hypophysial dystrophy, 309 
in myxedema, 123 
in sporadic cretinism, 142 
Hypothyroidism, see myxedema and sporadic 
cretinism. 
Hypothyrosis, in 
Hysteria, 43, 56 
differential diagnosis from tetany, 225 
Idiots, 130; see also Mongolism. 
Iletin, see insulin. INDEX 
663 
Imidoazolylethylamin, 2x9 
Implantation of the thyroid gland, 145 
Incretion, 7 
Indicanuria in cerebral diseases, 43 
Infantilism, 52, 474 
blood picture in, 481 
classification, 476 
definition, 476 
differential diagnosis, 483 
from eunuchoidism, 484 
etiology, 482 
forms, 482 
genitalia in, 477, 481 
intestinal, 509 
muscular, 510 
in osteomalacia, 437 
pancreaticus, 486 
pathogenesis, 486 
prognosis, 487 
renal, 510 
symptomatology, 481 
transitional forms, 485, 487 
treatment, 487 
Influenza, thyroiditis after, 64 
Insufhsance pluriglandulare, 452 
Insular apparatus of the pancreas, 512 
Insulin, 6 (foot-note), 579 
Interstitial glands, 382 
see also sexual glands. 
Intestinal colics in Addison’s disease, 349 
disturbances, see gastrointestinal distur- 
bances. 
Intoxication theory, 18 
Iodine Basedow’s disease, 101 
in the pathology of the thyroid gland, 100 
treatment in goiter, 165 
Iodism, 100 
Iodothyrin, 146 
Iron therapy in chlorosis, 442 
Juvenilism, 487 
Kaizine in Basedow’s disease, no 
in tetany, 227 
Ketonuria in diabetes, 540 
after extirpation of the pancreas, 516 
in pregnancy, 389 
Kidney, 215, 366 
Kinetic theory, 56 
Lachrymation in tetany, 194 
Langerhans’s islands in diabetes mellitus, 556 
Laryngospasm in tetany, 191 
Larynx in acromegaly, 251 
and eunuchoids, 407, 417 
in eunuchs, 403 
Late castrates, 406 
eunuchoidism, 422 
Lead poisoning, differential diagnosis from 
Basedow’s disease, 106 
in tetany patients, 2x7 
Leucorrhea, cyclical, 388 
Levulose in diabetes, mellitus, 538 
Levulosuria in the vasomotor neuroses, 43 
Lipodystrophia progressiva, 596, 598 
Lipoidemia in pregnancy, 377, 389 
Lipomatoses, 581, 594 
Lowi’s reaction, 11, 35, 36, 517 
in diabetes, 550 
Lymphatism, 378, 379, 380 
in ductless glandular diseases, 379 
in sporadic cretinism, 141 
Lues, see syphilis. 
Luetin tablets, 431 
Macrosomia, 293, 472 
Malaria, thyroiditis after, 64 
Malformations of the sexual glands, 396 
Magnesium sulphate treatment of tetany, 231 
Mammary glands in hypergenitalism, 434 
in pregnancy, 393 
Meningitis differentiation from tetany, 224 
Melancholia, 44 
in Basedow’s, 75 
in myxedema, 117 
Melanoma of the suprarenals, 365 
Menstrual cycle, 387 
Menstruation, relation to ovulation, 387 
precocious, 434 
Metabolism, in acromegaly, 275, 276 
in Addison’s disease, 350 
in adipositas dolorosa, 593 
after adrenalin injection, 355, 356 
in Basedow’s disease, 85 
after castration, 406 
in chlorosis, 437, 441 
in cretinism, 141 
in diabetes mellitus, 553 
in hypophysial dystrophy, 302 
after extirpation of the hypophysis, 337 
gigantism, in infantilism, 481 
in myxedema, 120 
in pregnancy, 389 
regulation through the ductless glandular 
system, 21-26 
in tetany, 230 
see also basal metabolism, carbohydrate 
metabolism, protein metabolism, salt 
metabolism, and purin metabolism, 
under treatment with thyroidin, 147 
Methyl cyanide, 93 
Migraine, 339 
Mikulicz’s syndrome, 49 
Mobius’s symptom in Basedow’s, 172 
Molimina menstrualia, 388 
Mongolism, 500 
Mononucleosis, see blood picture. 
Mors thymica, 236, 240 
Mucin in the tissues in myxedema, 112, 113 
Muller’s duct, 382 664 
INDEX 
Multiple ductless glandular sclerosis, see duct- 
less glandular sclerosis multiple. 
Multiple sclerosis, 47 
Muscarine, 31 
Muscular atrophy, progressive, 479 
system in acromegaly, 241, 252 
in eunuchoids, 4x7 
in eunuchs, 403 
mechanical hyperexcitability, 190 
in tetany, 190, 193, 194 
Musset’s sign, 67 
Mutism, 171 
Myasthenia, 46 
and tetany, 228 
Myoma. 126 
uteri, relation to goiter, 166 
Myoneural junction, 356 
Myotonia, 46 
in tetany, 190, 192, 214, 225 
Myxedema, 111 
in acromegaly, 255 
in Basedow’s disease, 97 
blood picture, 115, 119, 153 
capillaries in, 125 
cardiovascular system in, 114 
constipation in, 117 
contrasted with Basedow’s disease, 96 
course, 124 
definition, in 
and diabetes, 122 
differential diagnosis, 125 
ductless glandular sclerosis, 456 
etiology, 124 
eye in,119 
formes frustes, 122, 124, 126 
genitalia, 122, 123 
glycosuria in, 122, 123 
hair in, 113 
hearing disturbances, 112, 1x8 
heat regulation, 123 
hypophysis, 123 
in hypophyseal dystrophy, 297 
hysterical, 111 
infantile, 128 
in infantilism, 484 
mental symptoms in, 117 
metabolism, 120 
metabolism under thyroid treatment, 147 
incomplete forms, hypothyroidism, 126 
in Mongolism, 502, 503 
nervous system, 113, 116, 118 
obesity in, 127 
occurrence, 111 
osseous system, 119 
pathology, 124 
psyche, 117 
in scleroderma, 125 126 
skin, 112, 117, 119, 125 
symptomatology, 112 
after thyroiditis, 125 
Myxedema, vascular system, 114, 125 
Myxinfantilism, see infantile myxedema and 
sporadic cretinism. 
Nanisme type senile, 363 
Narcosis death in thymus hyperplasia, 236 
Nephritis, 366 
Nervous diseases and ductless glandular system, 
43 
system, somatic and vegetative in Addison’s 
disease, 349 
in acromegaly, 278, 280 
in adrenalin injection, 356 
in Basedow’s disease, 74 
in the climacteric, 395 
in cretinism, 142, 170, 172 
in diabetes, 551 
in eunuchoidism, 419 
hypophysial dystrophy, 305 
in infantilism, 481 
in myxedema, 115-118 
in neurofibromatosis, 364 
in osteomalacia, 445 
after extirpation of the parathyroids, 210 
after extirpation of the pancreas, 517 
in rachitis, 491 
relations to the ductless glandular system, 
29, 43 
sexual glands, 395 
after sugar puncture, 526-528 
in tetany, 177, 184, 211 
after extirpation of the thymus gland, 235 
Neurasthenia, 43, 161 
Neurofibroma, 364 
Neuroses, 43, 50 
Nicotine, 31 
in infantilism, 482 
Nicotinism, differential diagnosis from Basedow’s 
disease, 106 
Oats treatment in diabetes, 575, 576 
Obesity, in Addison’s disease, 350 
basal metabolism, 581 
in Basedow’s disease, 84 
in epiphysial tumors, 343, 585 
in eunuchoidism, 330 
in eunuchs, 403 
forms (exogenous, endogenous), 581 
in hydrocephalus, 297 
in hypophysial tumors, 296, 328, 330, 585 
in late castrates, 428 
in late eunuchoids, 427 
pancreatogenic, 583 
in suprarenal cortical tumors, 370 
thyrogenic, 127, 584 
Oophorin tablets, 431 
metabolism on the use of, 406 
Operation in Basedow’s, 101, 157-160 
Opotherapie associee, 49, 57, 59, 463 
Optic atrophy, hereditary, 340 665 
INDEX 
Orchitis, gonorrheal, 426 
after mumps, 426 
syphilitic, 426 
Osseous system in acromegaly, 251, 252 
in Basedow’s disease, 92 
in chondrodystrophy, 494 
in cretinism, 130, 173 
in eunuchoids, 416 
in eunuchs, 403 
in idiots, 181 
in myxedema, 119 
in tetany, 207 
see also epiphysial junctures. 
Osteitis, Paget’s, 293 
Osteoarthropathie hypertrophiante, 293 
Osteomalacia, 442, 449 
in tetany, 208, 221 
treatment, 444 
Osteophyte formation in pregnancy, 390 
Osteoporosis congenita, 500 
Ovaraden, 431 
Ovarian, 431 
Ovarian tablets, 431 
Ovaries, see sexual glands. 
Ovotestis, 397 
Ovulation, 387 
Oxyproteinic acid elimination in pregnancy, 389 
Pachyderma, 125 
Pancreas, absorption disturbances, 520, 521 
in acromegaly, 214, 276 
anatomy, 513 
colics, 521, 532 
embryology, 513 
extirpation, 515 
Pancreas, hormone, see insulin. 
Pancreas, hormone of Ziilzer, 519 
ligation of excretory duct of, 520 
lithiasis, 531 
pathological anatomy, 529 
physiology, 515, 526 
r61e of, in fattening, 583 
sclerosis, 531 
Pancreatitis, 529 
Paraganglia, 348, 365 
Paragangliomata, 365 
Paralysis agitans, 46, 228 
Paralysis, progressive, 42, 47 
Parathyroantitoxin, 226 
Parathyroids, anatomy, 184 
in adipositas dolorosa, 597 
detoxication theory, 210 
embryology, 185 
in endemic cretinism, 175 
function, 209, 210 
hyperfunction of, 228 
importance for life, 210 
nervous system, 211, 212, 213 
in osteomalacia, 437 
in pregnancy, 392 
Parathyroids, in thyroaplasia, 129 
see also tetany. 
Parathyroid tablets, 226 
Pedatrophy, 460 
Pellagra in infantilism, 482 
pigmentation in, 360 
Pentosuria in neurosis, 44 
Peptid nitrogen elimination in pregnancy, 389 
in tetany, 203 
Peremeschko’s medullary layer, 247 
Phaenotype, 59 
Placenta internal secretion of, 394 
Pharmacological tests of function, 31, 58 
Plasma contents of the blood regulation through 
the chromaffin tissue, 33 
Phosphorus poisoning, 362 
Physostigmine, 31, 34 
Pigment, loss of, after castration, 403 
Pigmentation in Addison’s disease, 350 
in animals deprived of suprarenals, 359 
in Basedow’s disease, 91 
in chlorosis, 436 
in cirrhosis bronzee, 359 
in ductless glandular sclerosis, 456 
in Grawitz tumors, 368 
in leucemia of the suprarenals, 359 
in myxedema, 114 
in osteomalacia, 444 
in pellagra, 359 
in pregnancy, 389 
in suprarenal cortical tumors, 368 
in tetany, 205 
in the tuberculous, 359 
Pilocarpine, action in acromegaly, 278 
in cretinism, 140 
diabetes, 551 
general action, 31 
in hypophysial dystrophy, 305 
in myxedema, 117 
in tetany, 193 
Pineal gland, see epiphysis. 
Pituitary gland, see hypophysis. 
Pituitrinum glandulare, 31, 286, 337 
in osteomalacia, 337 
therapeutic use, 443 
thermoreaction, 310 
infundibulare, 31, 37, 84, 337 
in acromegaly, 278 
in osteomalacia, 443 
in obstetrics, 362 
in sexual glandular insufficiency, 431 
therapeutic use, 337, 362 
Pluriglandular diseases, 48, 451 
Polyuria in bitemporal hemianopsia, 307 
in cerebral syphilis, 307 
in diabetes, 516 
in ductless glandular sclerosis, 457 
after extirpation of the pancreas, 515 
in hypophysial dystrophy, 294, 332, 333 
in tumors of the epiphysis, 331, 343 666 
INDEX 
Postbranchial bodies, 62, 129 
Pregnancy, 388 
blood in, 389 
cells, 136, 379 
hypertrophy of the suprarenal cortex, 373, 
389, 39i 
hypophysis in, 390, 391 
mammary glands in, 392 
metabolism, 389 
parathyroids in, 392 
placenta, 394 
reactions of fetus, 394 
tetany, in, 221 
thyroid gland, 392 
Premature development, 30 
in tumors of the epiphysis, 343 
Progeria, 363 
Prostate, 382 
in eunuchoidism, 417 
in eunuchs, 402 
in late eunuchoidism, 427 
in new-born boys, 394 
Protein metabolism, 22 
in Basedow’s disease, 85 
in catatonia, 43 
in diabetes, 539 
in myxedema, 120 
in extirpation of the pancreas, 517 
in psychoses, 43 
in tetany, 203 
Protrusio bulbi in Basedow’s, 70 
Psammoma of the epiphysis, 342 
Pseudochlorosis, 438 
Pseudohermaphroditismus, 397 
in tumors of the suprarenals, 372 
Pseudoodeme catatonique Dide, 595 
Pseudotetany, 225 
Psyche in Basedow’s, 75, 76 
in chondrodystrophy, 493 
in eunuchoidism, 419 
in hypophysial dystrophy, 322 
in infantilism, 481 
influence of the sexual glands, 395 
in myxedema, 1x7 
in sexual glandular tumors, 433 
in tumors of the epiphysis, 342 
Psychoses, ductless glands in, 43, 44, 60 
in Basedow’s, 75, 76 
in hypophysial dystrophy, 322 
in myxedema, 117 
Puberty, precocious, 375 
Purin metabolism, 23 
in acromegaly, 277 
in brain diseases, 43 
in eitnuchoidism, 419 
in hypophysial dystrophy, 304 
regulation through the ductless glands, 
23 
Pylorospasm in tetany, 199 
Quinine in Basedow’s disease, 155, 156 
in thyroiditis, 65 
Quotient (D: N) in diabetes mellitus, 547 
after extirpation of the pancreas, 516, 523, 
524, 539 
respiratory, see respiratory quotient. 
Rachitis, 491 
with tetany, 208 
Radium treatment in acromegaly, 295 
in eunuchoidism, 422 
in hypergenitalism, 434 
in thyroid disease, 157 
Rathke’s cysts, 247, 248 
Raynaud’s disease, 44 
Reciprocal action of the ductless glands, 10-16 
Rehn’s sign, 238 
Reichmann’s disease in tetany, 195, 227 
Rejuvenation, 55, 541 
Respiration calorimeter, 541 
organs in Basedow’s disease, 73 
quotient after adrenalin injection, 356 
in Basedow’s, 95 
in diabetes, 547 
after exclusion of the subdiaphragmatic 
circulation, 525 
Respiratory exchange, see basal metabolism. 
Respiratory metabolism, see basal metabolism. 
Respiratory quotient after extirpation of the 
pancreas, 517 
after injection of pituitrin, 286 
Retinitis in acromegaly, 280 
in tetany, 192 
Riesman’s eye-sign, 73 
Rodagen, no 
Rontgen, examination, etc., see X-ray. 
Salt metabolism, 22 
in acromegaly, 276 
after extirpation of the pancreas, 517 
Sarcoma of the epiphysis, 342 
of the hypophysis, 323 
of the sexual glands, 434 
of the suprarenal cortex, 367 
of the thymus gland, 238 
of the thyroid gland, 63 
Schlesinger’s symptom, 190 
Scleroderma, 126, 360 
in Addison’s disease, 360 
ductless glands in, 45, 92 
with myxedema, 125 
pigmentations, 358 
thyroidin treatment, 150 
Sclerose tubereuse du cerveau, 367 
Sclerosis, multiple, 47 
of the pancreas, 531 
of the parathyroids, 217 
premature, of the cerebral arteries in 
tetany, 224 
of the thyroid gland, 65 INDEX 
667 
Sella turcica in acromegaly, 294, 336 
after castration, 403 
in eunuchoids, 416 
in eunuchs, 403 
in hypophysial dystrophy, 322 
in myxedema, 123 
in sporadic cretinism, 142 
. in thyroidless animals, 123 
Senility, 55 
Sensorium in tetany, 192 
Sertoli’s cells, 386 
Sexual characters in chlorosis, 431 
classification, 384 
in eunuchs, 13, 403 
in premature development, 434 
relation to the sexual glands, 398 
in suprarenal cortical tumors, 369 
Sexual glands, 381 
see also interstitial glands, genitals, genera- 
tive apparatus, 
in Addison’s disease, 350 
in adipositas dolorosa, 594 
aplasia, 396 
in chlorosis, 438 
in chondrodystrophy, 496 
in climacteric, 395 
in diabetes, 553 
in ductless glandular sclerosis, 457 
in eunuchoids, 19, 418 
in eunuchs, 403 
in gigantism, 470 
in hermaphroditism, 397 
in infantilism, 481, 483 
in late castrates, 405 
malformations, 396 
in Mongolism, 504 
in myxedema, 123 
in obesity, 585 
in osteomalacia, 444 
physiology, 381 
in pregnancy, 390 
pseudohermaphroditism, 397 
sarcoma of, 
transplantation of, 381, 399, 432, 447 
X-ray irradiation of, 436 
glandular insufficiency, treatment of, 480 
Skeleton, see osseous system. 
Skopzen, 401 
Sodium phosphate in Basedow’s disease, 
102 
Spasmophilia, 204 
Spasmophilic diathesis, 220 
Speech development in cretinism, 172 
Spermin, Poehl, 396, 430 
Squamous-celled epithelial carcinoma of the 
hypophysis, 331 
Status lymphaticus, 34, 377 
in acromegaly, 275 
in Addison’s disease, 350 
in Basedow’s, 84 
Status lymphaticus, hypoplasticus, 379 
in thymus hyperplasia, 236 
Steatoma of the hypophysis, 323 
Stomach tetany, 222 
treatment of, 227 
Strabismus in tetany, 191 
Struma, see goiter. 
hyperplastica parenchymatosa teleangi- 
ectodes, 67 
of the hypophysis, 279, 323 
Sugar puncture, 529 
in animals without suprarenals, 356 
without thyroids, 576 
Suker’s sign, 73 
Suppuration of the suprarenals, 353 
Suprarenal cortex, in acromegaly, 260, 372 
in Addison’s disease, 354 
aplasia, 362 
in ductless glandular sclerosis, 457 
in gigantism, 471 
hyperplasia, 362 
hypoplasia, 353, 363 
in nanisme type senile, 363 
physiology, 354 
in pregnancy, 390 
in the premenstrual period, 387 
in pseudohermaphroditism, 372 
scleroses, 363 
tumors of, 367 
hairiness in, 400 
veins, thrombosis of, 353 
Suprarenals, 347 
in acromegaly, 274, 372 
anatomy, 347 
aplasia, 352 
blood picture, 349 
blood sugar, 350 
conditions of hyperfunction, 364 
detoxication theory, 358 
embryology, 347 
in hemicephaly, 352 
hyperplasia in atheromatosis, 366 
in hypertonia, 365 
implantation of, 361 
importance for life, 394 
in infections, 354 
leukemia, 360 
loss of glycogen after extirpation, 361 
in multiple ductless glandular sclerosis, 458 
pathological anatomy, 352 
physiology, 354 
in progeria, 462 
in sugar puncture, 527 
tumors of cortex and medulla, 374 
see also chromaffin tissue. 
Sympatheticus in Addison’s disease, 371 
see nervous system, 
tumors of, 364 
Sympathicotony, 37 
in Basedow’s disease, 103 668 
INDEX 
Syphilis of the brain and diabetes, 568 
in ductless glandular sclerosis, 459 
in infantilism, 482 
of the pancreas, 530 
of the suprarenal glands, 353 
of the thyroid gland, 64 
Syringomyelia, differential diagnosis from acro- 
megaly, 293 
Tabes, 43, 47 
Tachycardia in Basedow’s, 67 
Teeth in acromegaly, 251 
in myxedema, 114 
see also dentition. 
Teratomata of the epiphysis, 330, 342 
of the hypophysis, 323 
Testicular extract, 430 
Tetanoid, 217 
Tetany, 187 
action of adrenalin, 191 
in adipositas dolorosa, 597 
bladder symptoms, 200 
blood picture, 196 
breathing in, 194 
calcium metabolism, 204 
cardiovascular apparatus, 194 
cataract, 205 
child tetany, 219 
choked disc in, 192 
conjunctivitis in, 207 
definition, 187 
dentition, 206 
differential diagnosis, 224 
in ductless glandular sclerosis, 457 
eclampsia, 213 
enamel, defects of, 206 
endocrine system, 208 
epilepsy, 192, 213 
etiology, 219, 220 
forms, 215 
gastric, treatment of, 227 
in gastrointestinal diseases, 222 
gastrointestinal disturbances, 197 
growth disturbances in, 207 
hair in, 205 
heat regulation, 202 
idiopathic, 218 
in infectious diseases and intoxications, 217 
lachrymation, 194 
magnesium sulphate treatment of, 231 
maternity tetany, 221 
mental symptoms, 192 
metabolism, 202, 230 
myotony, 192, 213 
nervous system, 187, 192 
neuroretinitis, 192 
occupation tetany, 218 
osteomalacia, 208, 221 
parathyroprivic, 215 
pathogenesis, 209 
Tetany, pathological anatomy, 222 
pigmentations, 205-208 
pilocarpine action, 193 
prognosis, 225 
puerile, 220 
pylorospasm, 199 
rickets, relation of, to, 208 
sensorium, 192 
skin, 205 
spasm in, 190 
symptomatology, 187 
teeth in, 206 
thermoreaction, 202 
thyroid gland in, 208 
in thyroid glandular diseases, 219 
traumatic, 216, 233 
treatment of, 221, 231 
trophic disturbances, 205 
vascular system, 194 
Tetanus, differential diagnosis from tetany, 224 
aponicus, 191 
Tethelin, 5 
Thermo reaction, 310, 321 
Thorium treatment, 435 
Toxic adenoma of the thyroid gland, 160 
Thymus gland, 233 
in acromegaly, 274 
anatomy, 233 
aplasia, 235 
asthma thymicum, 236 
blood picture, 237, 242 
chromaffin tissue, 237 
clinical aspect of, 235 
in cretinism, 142 
diseases of, 233 
in eunuchoidism, 419 
experimental physiology, 234, 235, 236 
extirpation 234, 235, 236 
function, 241 
mors thymica, 237, 240, 242 
status lymphaticus, 237 
tumors, 238 
hyperplasia, 236 
in acromegaly, 260, 274 
in Addison’s disease, 337, 350 
in Basedow’s, 84, 99, 159 
pathology, 235 
physiology, 234 
treatment in Basedow’s, no 
Thyraden, 146 
Thyradin, 100, 147 
Thyreoidinum siccatum, 146 
Thyroaplasia, 128 
Thyroid elixir, 147 
Thyroid gland in acromegaly, 273 
in adipositas dolorosa, 594 
adrenalin action after extirpation, 356 
anatomy, 62 
in Basedow’s, 67 
in chlorosis, 437, 438 INDEX 
669 
Thyroid gland, in chondrodystrophy, 504 
dysfunction, 150 
in ductless glandular sclerosis, 457 
embryology of, 62 
effect on growth, 19 
in eunuchoidism, 417 
and hypophysis, 334 
inflammation, 64 
iodine contents, 100 
metabolism, 84 
in obesity, 584 
after pancreas extirpation, 518 
pathology, 153 
in the premenstrual period, 387 
in pregnancy, 381, 392 
in tetany, 208, 217 
tumors, 63 
Thyroidin action on blood, 40 
nervous system, 33 
treatment in adipositas dolorosa, 597 
in athyrosis, 148 
combination with arsenic, 148 
in cretinism, 49 
in eunuchoidism, 422 
in hypophysial dystrophy, 326 
in sexual glandular insufficiency, 430 
in thyrogenic obesity, 584 
Thyroidism, 94 
Thyroiditis, 64, 150 
Thyroprivic equivalents, 218 
Thyroxin, 3, 4, 100, 147, 285 
Timme’s syndrome, 49, 240, 242, 508 
Tongue goiter, 55, 129 
Transplantation of generative glands, 447 
Trauma in diabetes, 565 
in late eunuchoidism, 423 
Tremor in Basedow’s, 74 
Trophedema, 595 
Trophoneurosis, 49 
Trousseau’s symptom, 189 
Tryptophan as mother-substance of pigmenta 
tions in Addison’s disease, 359 
Tubercles in floor of ventricles, 563 
Tuberculin injection in tetany, 191 
Tuberculosis in Addison’s disease, 349 
of the body of the sphenoid bone, 336 
in ductless glandular sclerosis, 459 
of the hypophysis, 323 
Tuberculosis, in infantilism, 482 
of the parathyroids, 217 
of the suprarenals, 353 
of the thyroid gland, 64 
Typhus abdominalis, infantilism after, 482 
late eunuchoidism after, 426 
thyroiditis after, 64 
Umbilical hernia in cretinism, 139 
Vagal neurosis, 44, 378 
Vagotony, 37, 376 
in Basedow’s disease, 103 
in status lymphaticus, 376 
in thymus hyperplasia, 237 
Variola, thyroiditis after, 64 
Vas, ligation of, 446 
Vascular system in acromegaly, 273 
in Basedow’s disease, 62, 162 
in infantilism, 481 
in myxedema, 114 
Vegetative disturbances, 473 
nervous system, 30 
see also nervous system. 
Voice in acromegaly, 251 
in eunuchoids, 417 
in late eunuchoidism, 428 
Water economy, 2s, 44 
in chlorosis, 437 
in diabetes mellitus, 540 
Wave movement in women, 386 
Xanthalasma, 46 
Xanthin bases, elimination in endemic cretinism, 
172 
X-ray examination in acromegaly, 252 
in hypophysial dystrophy, 322 
X-ray examination, see also epiphysial junctures, 
and osseous system, and growth 
disturbances, 
in chlorosis, 441 
in dysmenorrhea, 441 
in hypergenitalism, 434 
irradiation of the sexual glands, 434 
X-ray treatment in acromegaly, 295 
in Basedow’s disease, 109, 157, 160