EXPERIMENTAL THYROIDISM 
by ( 
R. H. CUNNINGHAM, M. D. 
(From the Department of Physiology of Columbia University at the 
College of Physicians and Surgeons, New York) 
From 
THE JOURNAL OF EXPERIMENTAL MEDICINE 
Vol. Ill, No. 2, 1898 Volume III 
MARCH, 1898 
No. 2 
THE JOURNAL 
OF 
EXPERIMENTAL MEDICINE 
experimental thyroidism* 
By R. H. CUNNINGHAM, M. D. 
{From the Department of Physiology of Columbia University at the College of 
Physicians and Surgeons, New York.) 
Plates XIV-XVIII. 
CONTENTS. 
PAGE 
I. Introduction 148 
II. Retrospect of Previous Observations 151 
III. Objects and Plan of Research 157 
IV. Operative Procedure and Methods 158 
V. Experiments 161 
Part I. The production of thyroidism in normal and in diseased animals. 
A. The subcutaneous injection of thyroid and other extracts 
in normal animals 162 
B. Thyroidism from ingestion of thyroid material 165 
1. Administration of fresh gland to normal animals ... 165 
2. Thyroidism from stale or dried material 169 
C. Thyroidism in diseased man 178 
D. Results and general considerations 181 
Part II. The influence of food on the appearance of the acute cachexia 
thyroidectomica 187 
A. Historical introduction 187 
B. Experiments 191 
* This article was received by the editor in August, 1896, but on account 
of its length and the pressure of other material the publication has been 
delayed until the present time. In consequence of the active interest and 
research relating to the thyroid gland during recent years, this delay is 
much to be regretted. The date of completion of the article should be 
borne in mind by the reader. (Editor.) 148 
Experimental Thyroidism 
CONTENTS.—Continued. 
PAGE 
Part III. Some of the physiological actions of certain extractives 200 
A. The active extractives of the thyroid gland 200 
1. Introduction 200 
2. Methods of extraction 203 
B. The effects of the thyroid extractives on thyroidless dogs. 207 
C. The toxicity' of the thyroid extractives . 210 
Appendix 217 
D. The effect of the thymus extractives on the acute cachexia 
of thyroidless dogs 221 
E. The intravascular injection of the extractives 232 
1. Intravascular injection of boiled thyroid extracts . . 232 
2. Intravascular injection of the thyroid and other ex- 
tractives 234 
VI. Conclusions 239 
Description op Plates 241 
I. INTRODUCTION. 
With, the widespread employment in myxcedema of the thyroid 
gland and its various preparations that followed the reports of Mur- 
ray, Horwitz, Mackenzie, and Fox, concerning the beneficial effects 
of thyroid extract in that disease, numerous other observers have also 
called attention in the past three years to the fact that in the course 
of such treatment certain symptoms are liable to arise. The symp- 
toms consist of headache, dizziness, tachycardia, fever, nausea, vomit- 
ing, severe diarrhoea, fibrillary tremor and agitation, insomnia, urti- 
caria, incomplete paraplegia, loss of consciousness, and finally general 
collapse. They are more or less liable to follow either the subcuta- 
neous injection of the extracts, or the ingestion of large doses either 
of the fluid extracts or of certain commercial desiccated thyroid prepa- 
rations. 
In October, 1893, my attention was personally drawn to this sub- 
ject by the fact that an adult man (Part I, C, Obs. 1, see below), who 
had previously taken large doses of unquestionably fresh, raw thyroid 
gland with absolutely no disagreeable after-effect, promptly developed 
evident symptoms of thyroid intoxication or “ thyreoidismus,” after 
taking daily for three days six five-grain thyroid tablets of Burroughs, 
Wellcome & Co. The difference in the action of the dried product 
when contrasted with the inactivity of the fresh gland was so striking R. H. Cunningham 
149 
in this instance that I determined to investigate fully the cause of this 
difference and, if possible, discover the source of the intoxication. 
From my first observation referred to above I was led to believe that 
the toxic symptoms were probably caused by the action of certain 
toxic substances which had developed in the thyroid glands after their 
removal from the sheep. This single observation did not sufficiently 
demonstrate the correctness of the above opinion, and, in order to de- 
termine this and a number of points closely related to this subject, I 
began at that date the extensive series of experiments that are de- 
scribed in this monograph. 
In a previous paper * dealing with one of the many corollaries of 
this subject I have already referred to the negative results obtained 
from feeding animals upon large amounts of fresh thyroid glands, but 
at that date, owing to the incompleteness of some of the comparative 
intravascular injection experiments and other experiments upon mon- 
keys that are described also in this paper, I refrained from describing 
the special results that are given here. Previously to that date I had 
not only expressed the essential points demonstrated by my results to 
my friend Dr. S. J. Meltzer, but had in conjunction with him per- 
formed one experiment that resulted fully in accordance with my 
previous views upon this subject. 
It must be noted that during the progress of this work Prof. 
Kocher f has intimated that possibly the thyroid intoxication may be 
due to the decomposition of the thyroid material; and later Lanz,:}: 
working in Prof. Kocher’s clinic, has published his experimental in- 
vestigations on this subject. This writer experimenting on himself 
and two friends noticed only an unimportant increase in the pulse 
rate to follow the ingestion of 20 to 30 grammes of fresh, raw thyroid. 
Having contrasted the effects of dried thyroid preparations by Merck, 
Haaf, and Burroughs, Wellcome and Co., upon mice, rabbits, dogs, 
and men, Lanz concludes that thyroidism consists of two components: 
“(a) einer Giftwirkung infolge Verarbeitung zersetzten Driisenmater- 
* Medical Record, New York, June 15, 1895. 
t Kocher, Corr. Bl. f. schweizer Aerzte, 1895, No. 1. 
X Lanz, Deutsche med. Wochenschr., 1895, No. 37. 150 
Experimental Thyroidism 
ials, (b) einer fur die Schilddiiise specifischen Wirkung. Letzterer, 
d. h. der Thyreoidismus im eigentlichen Sinne des Wortes, ovder-besser 
gesagt die Hyperthyreosis, iiussert sich je nach der Provenienz des 
Driisenmaterials und je nack der Art des Versuckstliieres in verschie- 
dener Intensitat ist quantitativ, aber niclit qualitativ verschieden.” 
I do not consider, however, that the experiments which this observer 
relates in his article indisputably warrant the latter of these conclu- 
sions, for a number of objections may be offered to them. Thus he 
found that mice die after the ingestion of either the decomposed dried 
thyroid material or the fresh material, requiring, however, very much 
larger doses of the latter. In these experiments the so-called fresh 
material appears to have been in reality a dried preparation that had 
been prepared as quickly as possible from the recently removed glands 
by drying in vacuo, pulverizing, and administering in the form of 
what Lanz terms “ Totaldrtisenpillen.” It is questionable, therefore, 
whether Lanz really employed the unaltered fresh material, for, before 
such material can be dried by this means, certain chemical alterations 
of the various proteid and other substances may readily occur. In 
fact I shall emphasize later that some of these substances do alter con- 
siderably in drying, and that even during a lengthy process of diges- 
tion, if large lumps of the unquestionably fresh raw gland have been 
ingested, a certain quantity of toxic material may possibly form in the 
central portions of the undigested pieces of thyroid. So exceedingly 
prone to early decomposition is the thyroid or “ neck gland,” that even 
the average slaughter-house butcher is generally acquainted with the 
fact. 
The further consideration of other points dwelt upon by this author 
is deferred to another section. 
On comparing my totally independent results with those of Lanz, 
I find that some of our experiences accord fully; others, however, do 
not, and in this paper I have endeavored, where possible, to explain 
the cause not only of these differences, but also of certain apparent 
clinical discrepancies that tend more or less still to surround this sub- 
ject with some degree of uncertainty. 
The original plan, therefore, upon which the present paper is R. H. Cunningham 
151 
framed is, first, to give a brief historical retrospect of certain previous 
important observations of others that bear more directly upon the 
numerous varieties of experiments performed by myself; second, to 
describe the objects, plan, and mode of research; third, to describe the 
experiments in definite series; and, finally, after comparing my results 
with those of others, to state the conclusions. The object being mani- 
fold, and the material rather extensive, I have determined for the 
purpose of description to divide the subject-matter of my experiments 
into parts, discussing in Part I thyroidism in healthy and diseased 
animals; in Part II the inquiry is made whether the appearance of the 
cachexia thyroidectomica is hastened or otherwise influenced by the 
ingestion of altered animal food stuffs; and in Part III are related cer- 
tain comparative subcutaneous and intravascular injection experiments 
in which were used various organic substances or mixtures of sub- 
stances that had been isolated from the thyroid and the thymus bodies. 
II. RETROSPECT OF PREVIOUS OBSERVATIONS. 
The first to use the thyroid juice for the purpose of investigating its 
physiological effect when injected subcutaneously or intravenously into 
animals seems to have been J. R. Ewald.* This observer removed the 
thyroid glands from a healthy dog, minced them, mixed them with 3 ccm. 
of warm water, and after the expiration of a few minutes pressed out the 
juice, which was filtered in some instances before using. This juice was 
then injected into a vein of another dog. Three hours after, this animal 
fell into a peculiar cataleptic condition which lasted one hour and a half. 
While in this condition the temperature was not increased or scarcely 
perceptibly so. In other experiments the subcutaneous method was 
employed with similar effects in some cases, but in others abscesses and 
non-absorption of the juice occurred. Ewald also states that similar, 
though less intense, effects were produced by extracts of the thyroid 
glands of other varieties of animals. 
Previously to the above experiences of Ewald, Pellacani, f at first alone 
and later in conjunction with Foa,j; had injected extracts from the liver, 
the suprarenal capsule, and the kidney of the calf into dogs, rabbits, 
* J. R. Ewald, Berlin, klin. Woehenschr., 1887, March 14. 
f Pellacani, Arch, per le sc. med., iii, 1874. 
|Foa and Pellacani, ibid, vii, 1884. 152 
Experimental Thyroidism 
guinea-pigs and frogs. After the subcutaneous injection of the ex- 
tracts, agitation, vomiting, dyspnoea, somnolence, and general prostration 
appeared. The next morning the animal was paralyzed and death ensued 
later. When the extract was injected into a vein, dyspnoea, agitation, 
rapid heart action at first, which subsequently diminished in frequency, 
followed. In four hours the temperature had risen, and four hours later 
it fell, the animal dying shortly after. These writers concluded that 
these effects were common to many gland extracts. Mattei * and also 
Alexander f have disputed these observations. Langendorff, \ however, 
repeated Ewald’s experiments and found that the subcutaneous injection 
of thyroid juice produced effects similar to those observed by Ewald. 
Intravascular injection of the fresh juice produced rapid death. Intra- 
vascular clotting of the blood occurred in some of the animals, and in 
others the coagulability of the blood was lessened. Langendorff, in dis- 
cussing his results, very appropriately refers to the practically similar 
effects that Pellacani, Foa, and Wooldridge § had noted as occurring with 
the extracts of other animal glands. 
Alonzo,|| and Horsley,** repeated Ewald’s experiments, but with 
negative results. Horsley emphasizes the complication of these injec- 
tion experiments by the presence of the “ tissue fibrinogens ” of Woold- 
ridge, which are excessively toxic. Halliburton f f and Brodie \\ studied 
the effects of injections of these nucleo-proteid substances and fully con- 
firm the previous statements as to their toxicity. 
In this connection the observations of Wagner, quoted by von Eisels- 
berg,§§ are interesting. Wagner injected mucin from the salivary glands 
of the ox into cats and produced agitation, tremors, and tetanoid spasms 
that more or less resembled those of the cachexia thyroidectomica. The 
great similarity of these symptoms to those produced by Foa and Pella- 
cani by extracts of liver, suprarenal capsule, etc., is striking and suggests 
the possibility that a great number of animal substances exist that will 
produce similar symptoms when injected subcutaneously. 
* Mattei, Arch, per le sc. med., vi, 1883. 
f Alexander, Ziegler’s Beitriige, xi, 1892. 
J Langendorff, Berlin, klin. Wochensch., 1889, p. 786. 
§ Wooldridge, Ludwig’s Festschrift, Leipzig, 1887. 
|| Alonzo and Ughetti, Riforma medica, Oct., 1890, p. 1364. 
If Gley, Comptes rend. d. la soc. d. Mol., 1891, p. 250. 
** Horsley, Virchow’s Festschrift, 1891, and Brit. Med. Journ., Jan. 30 and 
Feb. 6, 1892. 
ft Halliburton, Journ. of Physiol., xviii, 1895. 
ft Halliburton and Brodie, ibid, xvii, 1894-95. 
§§ von Eiselsberg, Sammlung med. Schriften von d. Wien. klin. Wochenschr., 
No. 4, 1890. R. H. Cunningham 
153 
On the other hand, Vassale * states that, after the intravenous injection 
of thyroid juice into thyroidectomized dogs, in three animals the symp- 
toms of the cachexia diminished in intensity and the animals were saved 
for some length of time. Vassale concludes that the juice thus added 
simply sustains the animal until some accessory gland vicariously assumes 
the function of the thyroid. Similarly Gley f and Lanz J found that some 
animals could be thus saved for some time, and the latter of these writers 
states that thyroidectomized dogs can be kept alive for months with 5 to 
10 grm. of thyroid given daily by mouth. When this dose is stopped 
the tetanic attacks recur; and he also has noticed that the severity of these 
recurrent attacks diminishes more and more with the lapse of time after 
the thyroidectomy. 
Historically bearing upon the validity of the conclusions that appear 
to be taught by the experiments of Gley and of Lanz are the well-known 
observations of Piana, Ewald, Wdlfler, Wagner, Carle, Fuhr, Autokratow, 
Gley and others as to the frequent occurrence of accessory thyroid glands 
in the aortic and other regions. Gley, and Edmunds § also state that if 
the parathyroids (Sandstrom) are left in thyroidectomized dogs the ani- 
mals live. I have seen young dogs live for several weeks after the re- 
moval of both lobes of the thyroid and the parathyroids that were par- 
tially embedded in them. In all of these animals either aortic or other 
accessory glands were found; in some were found several small accessory 
aortic glands which often were so minute that even one accustomed to 
the appearance of these bodies might easily overlook them. 
In 1894 Ballet and Enriquez, || endeavoring to produce experimental 
exophthalmic goitre in two dogs by the subcutaneous injection of the 
unboiled thyroid extract, claimed that besides fever, tremor and agitation, 
tachycardia and a swelling of the thyroid gland occurred. This goitre 
disappeared when the injections were discontinued, and reappeared when 
they were begun again. The extract used by these observers was a gly- 
cerine one, macerated for twenty-four hours and filtered through paper. 
They state that no abscesses followed the subcutaneous injection of this 
fluid in more than one hundred injections. The swollen thyroid exhib- 
ited ecchymoses on the surface and weighed 3.75 grm. The intestinal 
hemorrhages they attributed to vasomotor origin from the fact that no 
* Vassale, Centralbl. f. d. med. Wissensch., 1891, p. 14. 
t Gley, loc. cit. 
| Lanz, loc. cit. 
§ Edmunds, Proc. of Physiol. Society, 1895, No. 4. 
|| Ballet and Enriquez, Sem. med., xiv, p. 536, 1894, and Soc. med. d. hop. 
d. Par., 1894, pp. 805 and 941. 154 
Experimental Thyroidism 
ulceration of the intestinal mucous membrane could be discovered. The 
state of the liver and the condition of the blood in the portal vein are not 
referred to in their paper. From similar experiments on dogs and rab- 
bits Lanz * attributes these results to septicaemia following the injection 
of a decomposed preparation, and does not consider them as the symp- 
toms of thyroidism. One of his animals developed an abscess in the 
parotid gland, and he infers from this that possibly a similar occurrence 
had misled Ballet and Enriquez. Furthermore the thyroid glands in 
Lanz’s animals are stated to have become decreased in size to a consider- 
able extent. In the hands of Edmunds f no visible effect was produced 
by the subcutaneous injection of the thyroid extract (mode of prepara- 
tion not described) into normal monkeys. Of thyroidectomized monkeys, 
out of eight treated with injections none recovered. 
Up to the present I have confined my remarks to the negative and 
positive results derived from experiments upon the lower animals, but 
after Murray % in 1891 recommended the subcutaneous injection of a 
macerated glycerine extract of sheep’s thyroids for the treatment of 
myxcedema, many clinical announcements appeared calling attention to 
certain dangerous symptoms that were liable to occur during the treat- 
ment. Thus Murray § and others agree that the injections were fol- 
lowed in some instances by nausea, flushing, pain in the lumbar region, 
loss of consciousness, and symptoms of collapse. Mackenzie || and also 
Fox gave the extract or the raw gland by the mouth in order to avoid 
the dangers consequent to the injections. Mackenzie states in his sum- 
mary that the acceleration of the pulse and the rise of temperature follow- 
ing the administration of thyroid are proportional to the amount in- 
gested. Fox gave both the glycerine extract and the fried minced gland, 
and produced in a myxcedematous patient at the expiration of a fortnight 
profuse perspiration and inability to walk or stand steady. 
Kocher and other observers did not observe such toxic symptoms to 
follow even large doses of the fresh raw gland. Bruns ** gave doses of 5 
and 10 grm. of fresh thyroid from lambs or calves. In one case only did 
headache, nausea, and loss of appetite occur. This patient took 46 grm. 
in 14 days, during which period a loss of 10 kilos in weight occurred. 
* Lanz, loc. cit. 
t Edmunds, loc. cit. 
J Murray, Brit. Med. Jour., 1891, p. 796. 
§ Murray, ibid., 1892, p. 449. 
|| Mackenzie, Brit. Med. Jour., 1892, p. 940. 
Fox, ibid., 1892, p. 941. 
** Bruns, Ueutseh. med. Wochensch., 1894, p. 785 It. H. Cunningham 
155 
In the other cases reported by Bruns no unpleasant disturbances resulted, 
although the amount of raw thyroid taken was greater. Kocher * gave 
10 grm., and often larger doses, of fresh thyroid without evil effects and 
unaccompanied by any diminution in the bodily weight; in fact the 
weight often increased. The only effect of the fresh raw thyroid in 
doses of 20 to 30 grm. that Lanz noticed in himself and in two friends 
was an unimportant increase in the pulse rate. The length of time that 
such doses were continued is not stated nor are the other details of these 
experiments described in Lanz’s paper. 
Sonnenburg’s f experience with the raw gland in a case of cachexia 
thyroidectomica in which a small portion of the gland had been left is 
also very instructive. His patient took 15 grm. of fresh minced calf’s 
thyroid on February 6, 7, 8, 9, 13, 14, 15, 16, 23 and 28, also on March 
2 and 8. During the month of March she took fourteen 15-gramme 
doses of thyroid. The temperature became normal in February and 
remained so. The weight at the beginning of February was 37 kilos; on 
the 19th, 37.75 kilos; and on March 3rd the weight had reached 40.2 
kilos. Sonnenburg’s results differ markedly from the opinions promul- 
gated by numerous later writers regarding the special susceptibility of 
myxcedematous cases to the early occurrence of the symptoms of intoxi- 
cation during the exhibition of various thyroid preparations. 
Beclere J reports the following marked instance of acute thyroidism. 
92 grm. of sheep’s thyroids having been taken in 11 days by a myx- 
oedematous patient, the myxcedema symptoms were replaced by those 
of thyroid intoxication, which consisted of agitation, tachycardia, in- 
somnia, increased temperature and respiration, exophthalmos and in- 
complete paraplegia. In short a rather severe degree of the so-called 
thyroidism was produced. No particulars, however, are given either as 
to the source of the glands or as to their absolute freshness. Nor do the 
majority of clinical reporters of thyroidism from the raw gland particu- 
larize as to the absolute undoubted freshness of the material which had 
been given. In a number of instances the patient has procured the 
glands from the family butcher, who often removes them from carcasses 
that have been hanging in his shop or in his ice-box for one day or more. 
Such thyroid glands are certainly not fresh in the strict sense of the 
term. Probably putrefaction has not occurred, but the rapid and well 
known post-mortem alteration has occurred. In warm weather the dead 
glands will give an acid reaction even within three hours after death, and 
* Kocher, loc. cit. 
f Sonnenburg-, Arch. f. Min. Chir., xlviii, 4, p. 857. 
$ Beclere, Mercredi mcd., 1894, p. 511. 156 
Experimental Thyroidism 
often a perceptible odor is noticeable after six hours in spite of the fact 
that the glands have been kept in an ice-chest. In fact one of the most 
vexatious obstacles that was met with in conducting these experiments 
with the raw gland was the difficulty of procuring large amounts of the 
perfectly fresh glands and utilizing them within a few moments after 
their removal. 
After the advent of the various commercial desiccated prepartions of 
sheep’s thyroids put upon the market by a great number of firms, the 
occurrence of mild or of severe thyroidism is more frequently noted in 
the clinical reports. Bramwell, Abraham, Kocher, Leichtenstern, Melt- 
zer, Ewald, Lanz, and a host of English, French, German, and American 
observers, all relate experiences more or less similar. Briefly summed up, 
one learns from their reports that the activity, toxic and alleviative, of 
such commercial desiccated preparations is exceedingly variable, but all 
of these writers unite in urging the employment of great care at the be- 
ginning of the administration of such preparations, in order to avoid, if 
possible, the effects of overdosing. 
Lanz, apparently considering a certain dried preparation as equivalent 
to the fresh gland, relates several comparative cases as illustrative of his 
views regarding the causation of at least the greater part of the symp- 
toms of thyroidism by the decomposition products which the various 
other dried commercial preparations are concluded to contain. For in- 
stance, to a case of goitre was given on March 2, two “ Totaldriisen- 
pillen ” (Haaf), each equal to .2 grm., and the dose was increased by one 
pill each day until March 8. From March 9 to March 13 no thyroid was 
given, with the result that the pulse fell from 104 to 84. On March 13 
ten more pills were given, and repeated thereafter with a daily additional 
increase of two pills. On March 16 the pulse was 104-108 and tempera- 
ture 38.1° C. No other symptoms occurred. In another case when the 
progressive dose had reached 10 grm., and this amount had been given 
twice, the patient complained of headache, lassitude and sleepiness. In 
other cases as much as 9 grm. of this preparation per day were required 
to produce the first symptoms of disturbance. With the preparation of 
Burroughs, Wellcome & Co. even 1 grm. per day could not be borne 
longer than one week without causing headache, excitement, loss of 
flesh, etc. 
In his experiments on mice Lanz also employed the “ Totaldriisen- 
pillen ” preparation, ultimately with fatal effect, finding that the English 
preparation in doses of even less than 1 grm. caused death, whereas the 
mice in some instances required total amounts of 50 grm. of the dried 
fresh calf thyroid to produce the same effect. These results demon- R. H. Cunningham 
157 
strated nothing in my opinion but the fact that the toxicity of the var- 
ious dried thyroid preparations varies greatly in degree. 
Even the latest evidence, therefore, does not satisfactorily answer the 
question as to whether the absolutely fresh raw thyroid material is toxic 
or harmless. I submit, therefore, in the following pages the results of 
my own independent investigations on this subject. 
III. OBJECTS AND PLAN OF RESEARCH. 
Bearing in mind the confused evidence that existed in the literature 
up to October, 1893, as to the toxicity of the thyroid material, and 
comparing the experiences of previous clinical workers with the results 
of my first personal observation with the fresh raw gland (page 178), 
I aimed primarily: 
(1) to determine conclusively whether or no the fresh raw thyroid 
material is toxic either to man or to the lower animals; 
(2) to investigate the relationship of the symptoms of induced thy- 
roidism to those of Graves’ disease; 
(3) to observe whether or no the toxic thyroid or other animal 
material influences the appearance of the cachexia in thyroidless 
animals; 
(4) to study the effects of various substances extracted from the 
thyroid, thymus and other glands upon thyroidless animals, with the 
possible result of ultimately isolating the active substance that the 
thyroid body is considered to contain. 
Briefly summarized, I proposed to elucidate the above-mentioned 
objects: 
(a) by producing in various animals acute or chronic thyroidism 
and noting in every instance the character of the thyroid material 
employed; 
(b) by also endeavoring to produce in animals a train of symptoms 
similar to those of thyroidism, employing for the purpose animal 
material other than the thyroid gland; 
(c) by producing the cachexia thyroidectomica and noting the sus- 
ceptibility of these animals to the thyroid and other animal material 
as well as to special substances that had been chemically isolated from 
this material; 158 
Experimental Tliyroidism 
(id) by administering the thyroid material in a certain disease that 
is claimed by many to be due to over-activity of the thyroid gland. 
Lastly, it has been deemed advisable to repeat with some modifica- 
tions certain intravascular injection experiments of Schafer * and 
Oliver, j- My reasons for so doing are given in full in Part III. 
Naturally during the progress of my numerous experiments many 
more or less important and interesting questions in connection with 
the previous thyroid work of others came to light, but their enumera- 
tion is deferred until I have discussed the points upon which they bear 
directly. 
IV. OPERATIVE PROCEDURE AND METHODS. 
In every instance in which thyroidectomy was performed the animals 
were anaesthetized with ether and the strictest aseptic and antiseptic pre- 
cautions observed throughout the operation. In all the intravascular 
injection experiments ether was also employed. In these latter experi- 
ments I frequently administered a large preliminary dose of morphine 
also, and at the end of each experiment the still anaesthetized animal was 
painlessly killed by an overdose of the anaesthetic. 
In order to produce the intoxications I administered the thyroid or 
other animal material either by subcutaneous injection or by mouth. 
My mode of procedure by the latter method was as follows: 
Birds. Small pieces of thyroid, meat, capsules, tablets, etc., were 
placed on the hack of the tongue and the bird was allowed to swallow 
them. Liquid extracts, bouillon and powdered thyroid suspended in 
water were injected into the oesophagus through a rubber tube attached 
to a syringe of large capacity. 
Babbits. Some of these animals would chew the tablets and swallow 
them. Usually it was necessary to powder them, suspend in water, and 
give by the tube. The raw material, after it had been minced very 
fine with a mechanical meat grinder, was mixed with a small quantity 
of distilled water and injected into the stomach with the tube and 
syringe. 
Carnivora. Cats and dogs would readily eat large amounts of the 
fresh material; the dogs often considerable quantities of even putrid thy- 
roid. Sugar-coated tablets and capsules that had been dipped in syrup 
were taken with avidity by the dogs; one of the dogs consuming 300 
* Schafer, Internal Secretion. Brit. Med. Jour., Aug. 10, 1895. 
t Schafer and Oliver, Jour, of Physiol., xvi, 1894; xvii, 1895; xviii, 1895. R. H. Cunningham 
159 
tablets in a few minutes and whining for more. Large quantities of 
powdered material, liquid extracts and defibrinated blood were admin- 
istered through the stomach tube. 
Monkeys. In all instances the tube was necessary and only inserted 
after previously cocainizing the fauces with a momentary spray of 1 or 
2 per cent, solution of cocaine. Owing to the ease with which these ani- 
mals vomit they were kept under close observation for a number of hours 
after the dose, and if vomiting occurred, the fact was specially noted and 
the dose not counted. 
Man. The perfectly fresh raw thyroid material was given always in a 
very finely minced state, after wrapping in gelatine wafer papers. The 
dried commercial preparations were taken in the form of capsules or 
tablets. 
In order to produce the intoxications the following varieties of material 
were used: 
(a) Eaw thyroid, fresh, stale, or putrid, from the sheep, pig, calf, ox, 
and in a few instances from the dog. 
(&) Eaw thymus and suprarenal capsules, fresh, stale, or putrid, from 
the calf and ox. 
(c) Fresh thyroid, rapidly dried in vacuo, from the sheep. 
(d) Dried commercial thyroid from the sheep; a great number of dif- 
ferent batches from five different firms being tested. 
(e) Meat (muscle, etc.), fresh, stale, or putrid, from the ox. 
(f) Aqueous extracts, glycerine extracts, and bouillon from a, b, c, d, 
and e. 
(g) Special substances or mixtures of substances chemically isolated 
from a, b, c, d, e and f. 
(h) Defibrinated blood of thyroidless dogs removed during the acme 
of the cachexia. 
(i) Sundry commercial so-called nuclein preparations and bouillon 
prepared from them. 
Preparation of extracts.—At the outset of the investigation Murray’s 
method was followed;* later I omitted the carbolic acid and the gly- 
cerine, and extracted with water only or with a normal saline solution, in 
* Murray (Brit. Med. Jour., Oct., 1891) prepared the thyroid extract by 
grinding the sliced glands with bits of ordinary glass tubing in a mortar. 
After thorough disintegration a fluid drachm of a mixture of equal parts 
of sterilized glycerine and a five per cent, aqueous solution of carbolic acid 
was then added, and when well triturated the mixture was macerated for 
twenty-four hours. At the expiration of this period it was filtered through 
a double layer of sterilized paper under pressure, and of the nearly clear, 
pale yellow filtrate 15 minims were employed for each injection. 160 
Experimental Thyroidism 
some instances adding a few crystals of thymol as a mild preservative. 
These extracts were exceedingly easy to prepare, but rather too crude for 
aseptic subcutaneous injections. The aseptic fresh extracts were there- 
fore prepared as follows: 
A known weight of finely ground material, absolutely fresh—the ani- 
mal having been slaughtered 10 or 15 minutes previously—was rubbed 
in a mortar for 15 minutes with an equal weight of boiled distilled water. 
This mass was placed in a stout, fine-meshed cloth and the juice ex- 
pressed by a powerful press. This juice was diluted with an equal vol- 
ume of water to facilitate filtration, quickly filtered through coarse paper 
by means of a vacuum pump, and finally filtered through a Chamherland 
candle. By using large quantities of material and employing a number 
of candles I could procure daily sufficient fresh fluid for my purposes. 
2 ccm. of this solution was assumed to be approximately equivalent to 1 
grm. of the raw material. Throughout the investigation it has been 
my aim for the sake of simplicity to maintain the strengths of my ex- 
tracts that were not filtered through the Chamherland candles so that 1 
ccm. of liquid would equal 1 grm. of the raw material. I have thus 
invariably injected or given twice the noted cubic centimetres of the ex- 
tracts that had been filtered through the candles. When it is stated that 
the animal received 15 ccm. of the filtered (Chamherland) extract (1 ccm. 
= .5 grm. of gland), I mean in reality 30 ccm., or the approximate equiv- 
alent of 15 grm. of the raw material. 
In preparing the bouillons the thyroid, thymus and meat were also 
ground as fine as possible, covered with an equal weight of water, and 
boiled for different periods of time, water being added from time to time 
to supply the loss from evaporation. After cooling and skimming off 
the grease the fluid was filtered usually through paper, and the filtrate 
was then ready for use. 
In many instances I found the administration of these bouillons much 
facilitated by previously evaporating them to one-half or one-fourth of 
their original volume. 
Throughout this article I have applied the term “ fresh ” to the mater- 
ial only when I was positively sure that such was the case. Our labora- 
tory attendant having witnessed the slaughtering of the animals, the thy- 
roid or other material was immediately removed and forthwith conveyed 
to the laboratory, where it was prepared for use as rapidly as possible. 
Generally speaking, within twenty to thirty minutes from the time of 
their removal I had ground the glands and given them to the test 
animals. 
In certain experiments in which the effects of the fresh material were R. H. Cunningham 
161 
compared with those produced by the same material after it had been 
kept for different periods of time, I proceeded as follows: 
Each piece of fresh substance was halved and each half placed in a 
separate vessel. After weighing, one portion was ground and imme- 
diately administered. The remaining unground portion was put in the 
ice-box for twelve or more hours, then ground, and finally given to an 
animal as nearly like the preceding one as possible. This method of con- 
trol consequently enabled me to give the animals approximately the same 
material in different states of freshness. 
Kegarding the mode of preparation of the various commercial dried 
preparations * that I have employed, naturally I am in the dark. Judg- 
ing merely from the appearances and odor of the products one would con- 
clude that the different firms employ very different methods. Nearly all 
of them appear, however, to contain large quantities of common salt, a 
circumstance that caused considerable trouble in a number of instances 
with the monkeys. 
The description of the preparation of the special substances from the 
thyroid, thymus and other material is postponed to Part III. 
V. EXPERIMENTS. 
In the following description of my experiments I do not give in 
detail every experiment performed, for this would make this article 
unnecessarily voluminous and filled with wearisome repetition. I 
wish it distinctly understood that the results of the experiments upon 
which my conclusions are based have been repeatedly obtained, and 
when I have made an unrepeated observation the fact is distinctly 
stated. Many of the animals were utilized for a number of different 
experiments, but a week or more was usually allowed to elapse from 
the end of one experiment to the beginning of the next, the animal 
being carefully observed in the interim. Sufficient time was thus 
allowed for the complete elimination of the preceding preparation. 
* In this connection I take occasion heartily to thank Messrs. Fairchild 
Bros. & Foster for the large amounts of their thyroid preparations so 
kindly furnished. Also I am deeply indebted to Mr. Yon Holland, of the 
Eastman’s Supply Company of New York, for kindly supplying the greater 
part of the fresh material that has been used in the course of my experi- 
ments. 162 
Experimental Thyroidism 
PART I. THE PRODUCTION OF THYROIDISM IN NORMAL AND IN DISEASED 
ANIMALS. 
A. The subcutaneous injection of thyroid and other extracts in normal 
animals. 
In spite of the previous observations of Foa, Pellacani, Wooldridge, 
Horsley, Langendorff and others relative to the complications con- 
cerned in such experiments, I wished to satisfy myself fully as to 
whether the absolutely freshly made crude extracts would produce the 
ultimate lethal effects that these authors ascribe to the various extracts 
in general. A few tentative experiments were thus performed on 
rabbits and dogs, but owing to the occasional occurrence of abscesses 
at the points of injection, I abandoned the crude extracts for the 
aseptic varieties, viz. those that had been filtered through a Chamber- 
land candle. 
Though abscesses very rarely followed the injection of these aseptic, 
unboiled, aqueous extracts, the ultimate effect of large doses of the 
various extracts in general was uniformly fatal, some of the rabbits dying 
in less than one hour from 30 ccm. (= 30 grm. of material), others not 
until the following day or the day after. Decreasing the doses I found 
that some of the rabbits died in about six hours from one injection of 
10 ccm. of thyroid extract, others withstood this amount for several days 
and died usually during the night. With doses of 3 to 6 com. death did 
not so frequently occur. Some of the animals withstood these small 
daily amounts for 6 or 10 days, finally dying during the night, or after 
manifesting the usual symptoms on the day preceding death. 
If the injections were discontinued after the onset of mild toxic symp- 
toms several of the rabbits recovered completely, even though consider- 
able paralytic weakness had developed in the legs. 
' When the aseptic thymus extract was used my average results were 
about the same. 
With extracts from material macerated from 12 to 96 hours the rabbits 
succumbed to much smaller doses, the objective symptoms being possibly 
more pronounced. Similar extracts prepared from the sugar-coated thy- 
roid tablets of Burroughs, Wellcome & Co., the only commercial prepara- 
tion procurable at the time the above experiments were made, appeared 
remarkably active, 3 grm. often proving fatal to a rabbit in one or two 
hours. R. II. Cunningham 
163 
When very large doses of the fresh aqueous extracts were injected, 
within 20 minutes in two instances, the animals exhibited fibrillary mus- 
cular twitchings, rapid respiration, accelerated pulse, inability to sit up, 
the animal lying sprawled out on its belly, and marked exophthalmos in 
many instances. If the dose was small some of these animals recovered; 
if the dose was large the animal became apparently paraplegic, the 
paralysis seeming to be due more to muscular weakness than to a cen- 
tral disturbance. Finally, a general paralysis, one or two slight fits, 
coma, and death supervened. The rectal temperature of some of the 
animals was investigated and found in the early stages either normal or 
very slightly increased. If an extract from stale or dried thyroid or 
thymus had been injected the temperature was usually markedly in- 
creased. Frequently in the stage of coma the temperature fell 1° F., 
or even 1.5° F. below the normal. 
When the dose of the extracts was small and given daily, the animal 
in the course of a few days became much depressed and refused food. 
As time elapsed emaciation and great general weakness became promi- 
nent. The temperature rose to 105° F. or even higher. The hind legs 
became very weak and the animal appeared paralyzed, the knee jerks 
often remaining present, however. In two rabbits slight exophthalmos 
was observed. Finally, a slight, or severe, watery haemorrhagic diar- 
rhoea developed and the animals promptly died. 
The results of my experiments with dogs with all of these filtered, un- 
boiled extracts were practically the same, much larger doses naturally 
being required to produce a fatal result. Dogs as a rule withstood the 
injections for longer periods of time, and several of these animals, even 
after becoming paraplegic, fully recovered when the injections were 
stopped. One hardy animal withstood 25 ccm. of fresh filtered thyroid 
extract administered daily, except Sundays, for eighteen days, but finally 
succumbed with the usual symptoms. 
The following experiment will indicate the average result: 
Exp. I. Four yellow mongrel dogs of about the same weight were 
chosen. Dog 1 received daily injections of 20 ccm. of fresh thyroid ex- 
tract and died on the sixth day, having exhibited during life consider- 
able emaciation, great weakness; paralysis of all four extremities, more 
marked, however, in the hind legs; a temperature of 106° F.; pronounced 
thirst, and numerous bloody evacuations. 
Dog 2 received 20 ccm. of a fresh filtered thymus extract daily for 
eight days and succumbed, manifesting symptoms identical with the 
above. On the day preceding the death of the animal a slight exophthal- 
mos and considerable conjunctivitis were noticed. 164 
Experimental Thyroidism 
Dog 3 was injected daily with 10 ccm. of a filtered thyroid extract pre- 
pared from raw material that had been kept twenty-four hours in an ice- 
box. It died after the fifth injection. 
Dog 4 got 10 ccm. (= 10 grammes of raw gland) of a filtered extract 
prepared from some sugar-coated tablets of Burroughs, Wellcome & Co. I 
note by the way that this particular batch of tablets had produced severe 
toxic symptoms in man. Result: died twelve hours after receiving the 
third injection. The symptoms manifested by this dog differed some- 
what from those of the other animals. The emaciation was more marked. 
The fibrillary muscular twitchings were extremely prominent. The hind 
legs were stiff and kept rigidly extended. Voluntary movement ap- 
peared to he completely lost, hut cutaneous sensation was present. Con- 
siderable cyanosis accompanied by very marked exophthalmos finally set 
in and after two slight fits the respiration ceased. 
The lesions found both in rabbits and in dogs differed only in degree 
and were as follows: 
The composition of the blood appeared to have been greatly altered. 
Usually very peculiar friable clots were found in the portal vein and its 
tributaries. Numbers of large or small intestinal ecchymoses were pres- 
ent either in the mucous membrane or beneath the intestinal perito- 
neum. The liver frequently contained haemorrhages and the surface was 
often mottled with small haemorrhagic areas. The kidneys were deeply 
engorged in some animals, but appeared normal in others. Sometimes 
the medulla of the suprarenal bodies was completely disintegrated and 
the seat of a haemorrhage. Abscesses of the salivary glands, such as 
Lanz has noticed, did not occur in any of my animals. The thyroid 
lobes in three dogs were the seat of superficial or interstitial ecchymoses. 
These accumulations of blood would naturally increase the weight of 
these bodies, but a microscopical examination showed that no apparent 
hypertrophy was present such as Clark, Greenfield, Bamberger, Macken- 
zie and others state as occurring in exophthalmic goitre in man. In 
neither rabbits nor dogs did I get the marked diminution in the size of 
these bodies that Lanz observed in his animals, but the further detailed 
discussion of this latter circumstance is included in a later sub-section. 
From the above I was convinced that subcutaueous injection of the 
unboiled, crude thyroid extracts is lethal, provided the dose be large, 
or small and frequently repeated. Having eliminated possible compli- 
cating septic and pysemic effects in the latter instance by using aseptic 
extracts that had been quickly prepared from absolutely fresh material, R. H. Cunningham 
165 
it was concluded that ordinary septicaemia was not a necessary factor 
in the intoxication. 
Comparative experiments with the aseptic extracts of other glands, 
and commercial nucleo-proteid preparations, have shown me that an 
intoxication accompanied by the same symptoms and lesions will like- 
wise occur when these latter substances are injected. The symptoms 
of the so-called thyroidism can thus be produced by the subcutaneous 
injection of extracts of other glands. 
Extracts from material that had been kept for twelve hours or more 
appeared more active. The extract from the above-mentioned thy- 
roid tablets was similarly exceedingly toxic; but after keeping this 
and the other extracts until very marked putrefaction had occurred, 
and refiltering through the candle, the toxicity appeared to become 
considerably lessened. 
Having, therefore, evolved by this means practically no more facts 
than previous observers have noted, the subcutaneous injection of 
these complex mixtures was abandoned and I concluded that I could 
not thus gain definite information either as to the specific toxicity of 
the unaltered thyroid material, or to the relationship of increased 
thyroid secretion, or of disturbed thyroid function (Moebius), to 
Graves’ disease. 
B. Thyroidism from the ingestion of thyroid material. 
1. Administration of fresh glands to normal animals. 
Many clinical observers having established the fact that thyroid 
juice from the sheep, pig, calf, or young ox, is effective in myxoedema, 
material from similar sources was employed in the following observa- 
tions. 
Generally speaking, I began the experiments on Mondays and 
gave daily doses for six consecutive days, skipping the seventh day on 
account of my inability to procure absolutely fresh glands on that day. 
During the following week, and often in the third week, the same, or 
larger amounts even, were continued in order that the test might be 
as fair as possible. This period of time was deemed sufficient for the 
effects of possible cumulative action to appear. The rectal tempera- 166 
Experimental Thyroidism 
ture, the pulse, the respiration, the weight, the condition of the thyroid 
body, and the condition of the eyes, were carefully followed in num- 
bers of animals from day to day. For the purpose of more accurately 
determining the effect of the thyroid feeding upon the normal thyroid 
gland, I quickly and carefully exposed and measured the thyroid lobes 
of several etherized dogs before the administration was begun. On 
exposing these bodies at the end of the experiment, preparatory to their 
removal, measurements were again taken in situ and the two measure- 
ments compared. 
Owing to the fact that animal food-stuffs may undergo purefactive 
alteration in the intestines of rabbits and monkeys as well as in those of 
man, I invariably introduced the fresh material in an exceedingly 
finely divided state, hoping thereby to facilitate the digestion and ab- 
sorption of the entire dose in the shortest possible time. 
Obs. 1. A young cock; weight 2520 grm.; pulse 142; temperature 
108§° F.; was given 50 grm. per day of fresh sheep’s thyroid for sixteen 
days. The total amount received by this bird was 700 grm. At the end 
of the experiment the weight was 2530 grm.; otherwise no effect had 
followed. 
Obs. 2. Two rabbits were given 40 grm. of fresh calf’s thyroid daily, 
except Sunday, for twelve doses. Two more rabbits received 800 grm. 
each of fresh sheep’s thyroid in 18 days, in doses of 50 grm. per day. 
These rabbits decreased from 30 to 75 grm. in weight, but this fact is 
not surprising, for in order that the stomach should be empty at the 
time of the administration the animals were allowed to eat only from 
midday to six o’clock in the afternoon. The effect was negative in other 
respects. Other similar experiments in rabbits yielded results almost 
identical with the above. 
Obs. 3. Having fed for two or more weeks several dogs with daily 
doses of as much as 300 grm. of fresh thyroid, I gave to one of these ani- 
mals nothing in the way of food for six days except a mixture composed 
of chopped thyroids of the ox, calf and sheep. In every instance the 
animals gained in weight, one dog increasing as much as 1 kilo. In no 
animal was the temperature disturbed or diarrhoea produced. The ani- 
mals were all so lively and jumped about so much that often considerable 
difficulty was experienced in getting the pulse rate proper to the state of 
rest. Numbers of careful daily estimations demonstrated conclusively 
that no acceleration or irregularity had been produced. R. II. Cunningham 
167 
Obs. 4. On the normal cat but one feeding experiment was performed. 
This experiment yielded a negative result after eighteen daily doses of 50 
to 60 grm. of mixed sheep and calf thyroids had been given. 
Monkeys. Obs. 1. Java monkey (Macacus cynomolgus) with moderate 
horizontal nystagmus; weight 1357 grm.; pulse rate 106; rectal tempera- 
ture lOlf ° F. 90 grm. of fresh sheep thyroid were given to this animal 
in three days. At the end of this time the temperature was 101° F., 
pulse rate 100, and the weight 1354 grm. On the fourth and fifth days 
the animal received doses of 55 grm. of the fresh raw thyroid, but with- 
out disturbance of its general health. 
To several other Java monkeys, one Bonnet, one Rhesus, and a Capu- 
chin monkey, doses of 30 to 35 grm. of fresh sheep thyroids were given 
daily except Sunday for one to three weeks. In none of these latter 
monkeys did toxic symptoms arise. 
Obs. 2. A large Java monkey; weight 2230 grams; temperature 102£° 
F.; pulse about 160 (animal much frightened); was given 15 grm. of fresh 
young ox thyroid. The next morning the temperature was 102, the 
pulse 150; the animal being still much frightened. It was then given 43 
grm. more, and daily thereafter the following amounts: third day, 55 
grm.; fourth day, 75 grm.; fifth day, 55 grm.; sixth day, 57 grm. (T. 
101f° F.; pulse 110; weight 2265 grm.); eighth day, 65 grm. On this date 
the temperature was 101£° F.; the pulse 110; and the weight after taking 
the above dose 2280 grm. On the ninth day it received 67 grm.; tenth 
day, 75 grm.; eleventh day, 57 grm.; twelfth day, 63 grm.; thirteenth day, 
67 grm. The animal now weighed 2271 grm.; the temperature was 101° 
and the pulse 96. The thyroid administration was then suspended and 
two days later the rectal temperature registered 102° F. The large 
doses ingested by this animal produced therefore not the least manifesta- 
tion of the so-called thyroid intoxication. 
From these experiments it would seem that the temperature of some 
of the monkeys to whom large doses of the fresh gland were given did 
appear to diminish somewhat and remain below the normal during the 
administration. Thus in the monkey quoted in observation 2 the tem- 
perature registered 102£° F. before any thyroid was given. During the 
experiment it seemed to fall progressively, and on the day that the ex- 
periment wyas discontinued had reached 101° F. Two days later it had 
become 102° F., and has apparently remained between this and 102£ for 
some weeks. 
On the other hand I have noticed that the rectal temperature of many 
of the monkeys to whom nothing except their usual food had been given 
would often vary from day to day. The morning temperature of some 168 
Experimental Thyroidism 
of these monkeys would be as low as 99° F., while the afternoon tempera- 
ture would register from 101§° F. to 102§° F. Again, in bringing the 
animals from their house to the laboratory where the daily doses were 
administered and the temperatures taken, an unavoidable though short 
exposure to the open air was necessary. I am unable consequently to 
determine definitely whether the diminution noted resulted from the 
thyroid material or was merely an ordinary variation from natural causes. 
The practical absence of effect on the bodily weight is noteworthy and 
contrasts greatly with that produced in monkeys by much smaller though 
equivalent doses of the dried commercial thyroid. 
Man. Naturally the experiments described below were conducted in 
every instance with due precaution, and daily personal observations were 
made, so that should the least symptoms of the intoxication arise the 
treatment could be discontinued immediately. 
Obs. 1. Adult man, aet. 45 years; weight 205 pounds; pulse 80; axil- 
lary temperature 98£° F. Moderate obesity, but otherwise normal. 
Digestion excellent. Took daily for four days 8 grm. doses of fresh 
sheep’s thyroid, the material being from a lamb that had been slaught- 
ered but a few minutes. No effect was noticeable. From May 22 to 
June 4 daily amounts varying from 40 to 60 grm. were taken, the fresh 
thyroid being always finely minced and rolled in one or more gelatin 
wafer papers, llesult: pulse 80; temperature 98§F.; weight 207 lbs. 
The fresh thyroid was then replaced with the commercial tablets and 
the effect of small doses of these is described below. 
Obs. 2. An adult man, weighing 190 lbs., took daily except Sunday 
eighteen 16-grm. doses of fresh calf’s thyroid. During and at the end of 
this treatment no perceptible alteration either of the pulse rate or the 
temperature could be determined. The man gained one pound in weight, 
however. 
The question may arise as to whether these men really received the 
thyroid gland and not some other gland, such as thymus or salivary 
glands. Starr,* Owen f and others relate such occurrences, and in fact 
such a mistake is rather liable to occur if the choice of the material be 
left entirely to the discretion of the family butcher. The thymus, “ neck 
sweetbread,” or “ throat bread,” is well known to the average butcher, 
but the thyroid or “ throat glands ” are not so generally known, and are 
in fact often regarded by certain butchers as bits of muscle. I am fully 
satisfied that all the men for whom I have prescribed the fresh thyroid 
* Starr, M. A., Med. News, Dec. 15, 1894. 
t Owen, David, Brit. Med. Journ., Feb. 16, 1895. R. H. Cunningham 
169 
did get the correct thing, for the slaughter-house butchers who supplied 
the above men had removed numbers of thyroid glands for my personal 
use and were well acquainted with the two lobes. Moreover, at my 
request, the above men brought me from time to time samples of what 
they were taking. 
From the above observations it appears that normal cocks, rabbits, 
cats, dogs, monkeys and men manifest no toxic symptoms whatsoever 
after the ingestion of large amounts of the finely ground absolutely 
fresh raw thyroid substance. Further, no exophthalmos, tremor, in- 
creased temperature or acceleration of the pulse could be detected, and 
the body weight was diminished, and that immaterially, in rabbits 
only. 
2. Thyroidism from stale or dried material. 
Rabbits, (a) Administration of thyroid. Obs. 1. Several sheep’s thy- 
roids were halved and one of the portions was put in the ice-box for 
twenty-four hours. Of the fresh portion 50 grm. were immediately given 
at 10.30 A. M. to a rabbit. Of the second or stale portion 50 grm. were 
also given to a second rabbit. The first rabbit manifested no ill ef- 
fects, but the second died during the night, evidently having had a 
severe diarrhoea. The experiment was repeated, but 30 grm. only of 
the stale material were given to the second rabbit. In this instance the 
first rabbit showed no visible disturbance; the second, however, died in 
about twenty-four hours, exhibiting diarrhoea, marked weakness of all 
four extremities, dyspnoea and cyanosis, exophthalmos and coma, fol- 
lowed by death. 
Obs. 2. A large rabbit was given 30 cc. of a water and glycerine ex- 
tract from glands twenty-four hours old. The death of the animal fol- 
lowed in six hours, after it had manifested the usual symptoms except 
exophthalmos. A smaller rabbit that had received 50 grm. of the same 
material in the fresh state on the previous day showed nothing. 
A third rabbit was given 20 ccm. of a glycerine extract prepared from 
glands that had been kept a similar length of time, with the result that 
on the following morning the animal was dull, took but little food, had 
an increase of 1.5° F. in temperature, and had lost 20 grm. in weight. 
After another 20 ccm. dose of the same extract it succumbed during the 
night. 
Obs. 3. Exp. 1. Rabbit; weight 1680 grm.; given 1 grm. (11 grains 
= 1 sheep’s thyroid?) of a dried commercial preparation. Two days 170 
Experimental Thyroidism 
later the animal weighed 1540 grin.; it was dull and refused food, and 
the temperature had risen 1° F. 3 grm. of the same preparation were 
administered in the afternoon and the animal died during the night, 
leaving signs of having had a very severe hemorrhagic diarrhoea. The 
weight of the body after death was 1380 grm. 
Exp. 2. Brown rabbit; weight 1705 grm.; temperature 101f° F.; was 
given 6 grm. (6 grains = 1 average thyroid) of a desiccated commercial 
preparation (No. 220005) from another firm. The next day the animal 
was dull and did not take its food; temperature 102§° F. Its weight 
was now 1680 grm. The dose was not repeated and the animal recovered 
in a few days. 
Exp. 3. Babbit; weight 1700 grm.; temperature 102° F.; was given 16 
grm. (2£ grains = 5 grains of sheep’s thyroid) of one of the earlier prep- 
arations of desiccated thyroid from a third firm. As no effect followed 
in twenty-four hours, the dose was repeated with an equally negative 
result. It should be noted that I had given 5 grain doses three times a 
day of this particular sample to man for the treatment of obesity, but 
without producing the desired effect; nor did diarrhoea, headache, py- 
rexia, etc., occur during a two weeks administration of this preparation. 
Exp. 4. Large white rabbit was given 10 sugar-coated tablets of an- 
other unnumbered preparation (each tablet = 5 grains fresh gland) from 
the preceding firm. These tablets were finely pulverized and given as 
usual through the stomach tube. Kesult, death in twelve hours. 
Exp. 5. Babbit given three sugar-coated tablets obtained from a 
fourth firm. Besult, death in four hours, preceded by paralysis of the 
hind extremities, cyanosis, some exophthalmos, rapid respiration, pulse 
about 280 per minute, two very slight general convulsions, just after 
the second of which the respiration ceased. 
To rabbits, therefore, comparatively small amounts of either aque- 
ous, stale thyroid extracts, or of commercial desiccated thyroid usually 
prove very toxic. I write “ usually,” for the toxicity of the different 
trade preparations varies very greatly. Thus the equivalent of 1 
gramme of raw thyroid of a preparation by one firm will in many 
instances cause death in a rabbit, whereas many times that amount of 
another firm’s preparation may produce slight symptoms only, which 
may completely disappear in one or two days. Different lots even 
from the same firm vary very much; some of the lots appearing to be 
but very slightly toxic, while others are excessively so. 17. II. Cunningham 
171 
(b) Administration of thymus. Wishing to see if identically the 
same results could not be produced in these very susceptible animals 
by means of other glands, meats, etc., I made a number of observa- 
tions to determine this question. The following observation will indi- 
cate my results in general from these comparative administrations. 
Obs. 4. A number of absolutely fresh lamb’s thymus bodies—in many 
instances that of the calf was used also—were halved and separated into 
two portions, one of which was put aside for a known number of hours; 
the other was minced or made into bouillon, and fed to a rabbit, but in 
every instance with a negative result. After forty-eight hours or more 
the former portion was similarly prepared and fed to other rabbits. In 
some instances both the raw material or the concentrated bouillon from it 
produced death in from two to six hours, the animals exhibiting symp- 
toms usually identical with those produced by very much smaller amounts 
of the stale thyroid. Usually, however, I found it necessary to keep the 
thymus glands on ice for a few days longer for marked toxicity to de- 
velop. I do not mean to give the impression that these thymus glands 
had become putrefied, in fact such was not the case, and were one to 
judge by their appearance and odor they would be considered still fresh 
enough for human consumption. Indeed, in my experiments with rab- 
bits it has seemed to me that when a great amount of putrefaction has 
occurred in both the thymus and thyroid material, the bouillon, extracts, 
etc., appear to be somewhat less toxic. No doubt putrefactive processes 
alter the chemical structure of the chief toxic substance or substances. 
The effects of administering the desiccated commercial preparations of 
thymus gland were not studied, but on one occasion I administered a 
dose of thirty-two grm. of a commercial nucleo-proteid * preparation 
prepared from thymus and other glands, to a strong healthy rabbit, with- 
out consequent ill effect. 
(c) Administration of meat extracts. Closely related to the results 
obtained in this series of experiments on rabbits to which stale prepara- 
tions of thymus and of thyroid were given, are the observations of Kem- 
merich, f Bogoslowsky \ and others. The former of these writers called at- 
tention to the fact that in addition to the salts, certain organic substances 
* This nucleo-proteid preparation was prepared from various glands, of 
which the thyroid was one. Chemically, the preparation contained a con- 
siderable quantity of iodine, 
f Kemmerich, Pfliiger’s Arch., ii (1869), 49. 
| Bogoslowsky, Centralbl. f. med. Wissensch., 1871, 497. 172 
Experimental Thyroidism 
are present in meat extracts and are the cause of the cardio-excitant ac- 
tion that results from the ingestion of the meat extracts. Bogoslowsky, 
repeating Ivemmerich’s previous experiments, similarly found increase in 
the pulse rate and also a rise of temperature. Both fully agree that such 
extracts are excessively toxic to rabbits, usually producing death within 
a few hours. Kemmerich gave an extract equivalent to 1333 grm. of 
horse-flesh to a rabbit which rapidly began to exhibit the following 
symptoms: dullness; respiration increased from 120 to 180; pulse rose 
from 240 to 400 and became stronger; a stage of depression then super- 
vened and the animal soon lost the power of maintaining the upright 
position, the hind legs appearing paratyzed; later violent dyspnoea and 
convulsions terminated the rabbit’s existence. The pathological changes 
consisted of gastro-enteritis, hyperoemia, and many small gastro-intestinal 
ecchymoses. In other words, Kemmerich’s rabbits all died with a chain 
of symptoms that are practically similar to those that may be produced 
in rabbits, and also in monkeys, by administering the stale or the dried 
thyroid material. The pathological changes found in all of my poisoned 
rabbits fully accord with those described by Kemmerich, but to satisfy 
myself fully of the correctness of the observations of these writers I re- 
peated their experiments, using, however, ox-meat instead of horse-meat. 
Briefly stated, a quantity of absolutely fresh meat was procured from a 
neighboring slaughter-house and the extraction of four or five pounds of 
this finely minced meat begun within a few minutes after the death of 
the ox. As in the case of the raw thyroid material, half of the original 
quantity was put aside on ice for a number of days, then extracted by 
boiling and the bouillon given to rabbits. To sum up, the results in this 
series of experiments were as follows: 
In no instance, after repeated trials, did I succeed in producing any 
toxic symptoms in rabbits by means of the bouillon from the perfectly 
fresh meat, even if the amount of the concentrated bouillon was equiva- 
lent to as much as five pounds of meat. After keeping the meat on ice 
for 10 days or preferably for 14 days, it being still sweet, the bouillon 
from it proved usually very toxic, causing death generally in from two to 
four hours, usually preceded by exophthalmos with or without nystagmus. 
Dyspnoea and slight convulsions also frequently occurred. 
Similar extracts from good soup meat cut from carcasses that had hung 
fourteen days or more proved in some instances toxic, and in others not. 
In one experiment the extract was made from one pound of apparently 
good soup meat purchased at a third-rate butcher-shop and given to a 
rabbit, with the result that the animal died in less than an hour. H. H. Cunningham 
173 
The symptoms exhibited by these animals poisoned by the stale-meat 
bouillons and the lesions found after death were similar to those pre- 
sented by the animals poisoned with the thyroid preparations; but, for 
the meat to develop its full toxicity to rabbits, it was necessary to keep 
it very much longer than the thyroid or the thymus, not long enough, 
however, for a noticeable odor of putrefaction to develop. 
The herbivorous horse and cow, according to Brinton,* may be 
brought to eat fish and flesh, but had the above-mentioned toxic sub- 
stance developed in the flesh in considerable quantities, no doubt these 
animals would present the same degree of susceptibility to the meat 
extracts that is known to exist in the sheep. 
Birds. Having fed a cock with large quantities of fresh thyroid gland, 
later with extract of fresh meat, and finally with extracts of stale meat, 
with absolutely negative results as regards the bodily weight and tempera- 
ture, I administered to this bird large quantities of preparations of com- 
mercial thyroid, one gramme of which had produced fatal results in 
monkeys. 
Obs. 1. Cock; weight 2520 grm.; temperature 108f° F; received daily 
the following preparations: 1st day, six 5-grain thyroid tablets f of Bur- 
roughs, Wellcome & Co.; 2nd day, six similar tablets; 3rd day, twelve 
ditto—weight 2500 grm.; temperature 108f° F. Feathers fall out read- 
ily; 4th day, 10 grm. of Parke, Davis & Co’s desiccated thyroid; 5th day, 
20 grm. ditto; 6th day, 30 grm. ditto; 8th day, 20 B. W. & Co’s tablets 
(another lot); 9th day, 50 ditto; 10th day, 36 grm. of P. D. & Co’s thy- 
roid; 11th day, 32 grm. of Fairchild’s thyroid; 12th day, 180 grm. of raw 
sheep’s thyroids, three days old; 13th day, 60 grm. of putrid ox thyroid. 
Weight 2540 grm., temperature 108§° F. 
The effect was thus negative. I havd noted that the feathers of 
this bird fell out in great numbers, but as it was kept in a room main- 
tained at a high temperature owing to the presence of monkeys, prob- 
ably no special significance should be attached to this occurrence. 
Cats. Owing to the difficulty met with in administering the dried 
preparations to these animals, but one experiment was performed, 
* Brinton, Cyclopedia of Anat. and Physiol., v, 1859, p. 388. 
t Chemical examination of small quantities of all the above commercial 
preparations, some remnants of which I still possess, reveals the presence 
of iodine, and presumably in the form of thyro-iodine of Baumann. 174 
Experimental Tliyroidism 
namely, I gave to a cat 100 B. W. & Co’s thyroid tablets at one dose, 
but without disturbing the general health of the animal in the least. 
Dogs. In none of the numerous experiments upon normal dogs or 
upon previously splenectomized dogs could I succeed in producing 
the slightest sign of the intoxication. Even in the cases in wdiich 
these animals were fed for periods of a week or more on nothing but 
sheep’s thyroids, no alteration of the temperature occurred. Some of 
the animals, although thin and in very poor condition at the begin- 
ning of this diet, gained flesh rapidly and at the end of the experiment 
were in far better general condition than at the commencement. 
Before any thyroid was administered to two of these dogs I exposed 
the thyroid lobes in each and carefully and quickly measured them. 
After the animals had been fed upon large quantities of fresh, stale and 
dried thyroid, and finally for a week upon nothing but stale thyroid, the 
dogs were anaesthetized, the lobes exposed and measured in situ. The 
latter measurements practically coincided with those at the beginning 
of the experiment, and thus no evident alteration in the size of these 
normal glands had followed the ingestion of the large quantities (300 
to 600 grm.) of mixed thyroid. 
This non-diminution in the size of the thyroids in these two dogs does 
not correspond to the results that Lanz * got by injecting rabbits and 
dogs with the thyroid juice. This observer states that owing to the 
extraordinarily inconstant relative size of the thyroid in rabbits he ex- 
posed and measured them before beginning the injections, and also dur- 
ing the period of their administration. Considering that possibly this 
repeated exposure of the glands may have given rise to errors, owing to 
the fact that the normal thyroid might, like the goitrous thyroid, dimin- 
ish in size on exposure to the atmosphere, Lanz devised the following 
procedure to meet this objection: Two rabbits of the same litter were 
chosen and one was injected, but without previously exposing and measur- 
ing the thyroids of either animal. After a certain number of injections 
had been made both the rabbits were killed and their thyroids compared. 
The thyroid of the injected rabbit proved to be one-third smaller than 
that of the uninjected control animal. 
It appears to me, however, that from this inconstant relative size of 
the thyroid, judging from my personal experience in both rabbits and 
dogs, the latter method is certainly open to greater objections than the 
* Loc. cit. It. II. Cunningham 
175 
former, provided the one initial aseptic operation is rapidly performed, 
care being taken to disturb the blood-vessels and lymphatics of the bodies 
as little as possible. When a number of exposures are made one can 
readily imagine that damage, either directly to the gland or to its blood 
supply, would be far more likely to occur, and result in some degree of 
atrophy of the gland. 
Monkeys. Obs. 1. Bonnet monkey; weight 1260 grm.; temperature 
101$°; pulse 110. Given 8 grm. of sheep’s thyroid that had been kept 
in the ice-box for twenty-four hours. It should be noted that on the 
previous day 35 grm. of this same lot had been given to another monkey 
without effect. 
Result: The next morning, considerable depression; refused food, 
moderate diarrhoea, thirst; rapid and irregular heart’s action, about 200 
per minute; temperature 104° F. The dose was not repeated and the 
animal recovered in a few days, during which considerable emaciation 
occurred. 
Obs. 2. Exp. 1. To a Java monkey, weighing 1358 grm., tempera- 
ture 101£ F., pulse about 96, that had been fed two weeks before on 
fresh gland with a negative result, was given 3 grm. of an unnumbered 
desiccated thyroid preparation from a certain firm. As this produced no 
effect by the next morning the animal was given 10 grm. more, and finally 
12 grm. of the same preparation on the third morning. Having ex- 
hausted my supply of this particular preparation the experiment was 
discontinued and the animal observed for ten days. No ill effects re- 
sulted. 
Exp. 2. To the same monkey six 5-grain tablets (each tablet = 5 
grains of raw thyroid) of another firm were given. The next morning 
the temperature was 103° F., the pulse 124, and the animal not so lively 
as usual. It was then given six more tablets. On the following day the 
temperature was 103f° F., the pulse 180; great thirst, considerable agita- 
tion, slight diarrhoea, emaciation, some exophthalmos, and marked ny- 
stagmus. No more tablets were given. 4th day, animal very ill, severe 
diarrhoea, great weakness, crouches all the time and seems unable to sup- 
port itself in the upright position. Temperature 99° F. and pulse 140. 
6th day, bloody diarrhoeic stools, great weakness, and the hind legs ap- 
parently paralyzed. Temperature 98° F.; pulse about 260; respiration 
68. The animal lived throughout the day and night in a partially 
comatose condition and died early on the following morning. 
Autopsy. Marked gastro-enteritis accompanied by numerous small 
and large submucous and subperitoneal ecchymoses. Mesenteric glands 
swollen and much congested. Acute nephritis. Liver very friable and 176 
Experimental Thyroidism 
seat of many ecchymoses. Blood in portal vein clotted, while that in 
the inferior vena cava and cavities of the heart was still fluid. The thy- 
roid gland was not enlarged and appeared unaltered microscopically. 
Exp. 3. Java monkey; very lively and somewhat frightened. Weight 
1995 grm., temperature 102£° F., pulse 180. Given 1 gramme of a 
thyroid powder from a third firm. On the next morning the animal 
was dejected, scarcely noticed its food, but was excessively thirsty, and 
had a very moderate diarrhoea. Temperature 105§° F.; pulse about 240. 
The dose was not repeated. On the third day this monkey was slightly 
better and took its food with some persuasion. The temperature was 
105° F., and the pulse 160. The diarrhoea had disappeared. On the 
morning of the fourth day it was found lying on its side markedly agi- 
tated and squealing. Voluntary motion in the hind legs seemed to be 
lost and moderate exophthalmos and nystagmus were present. Shortly 
after several slight fits occurred and death ensued. 
Autopsy (four hours after death). Weight of body 1725 grammes. 
Stomach, small intestines and mesentery the seat of a number of ecchy- 
moses. Many minute haemorrhages in the liver. Blood in the portal 
vein clotted; that in the heart and inferior vena cava still fluid. Thy- 
roid body normal. 
Exp. 4. A previous monkey, to which 3 grm. of this same prepara- 
tion were given, exhibited within two hours considerable fibrillary muscu- 
lar twitchings; slight exophthalmos; paralysis of the hind legs, appar- 
ently spastic in character, the knee jerks as well as sensation to slight 
pin pricks persisting; excessively irregular and rapid cardiac action; rapid 
and shallow respiration; rectal temperature 102g° F. (101§° F. normal 
for this animal). Several slight fits occurred, in one of which there was 
slight momentary opisthotonos, with considerable rigidity of the extended 
hind legs. Throughout, the animal seemed to be perfectly conscious, and 
when small pieces of bread were placed in its mouth tried to chew and 
swallow them but was unable to do so. In thirty minutes collapse, coma 
and death occurred. 
Autopsy (five minutes after death). The usual haemorrhagic areas in 
the intestines and liver, none in the stomach. The cerebral pia mater 
was deeply congested and also that of the cord. A peculiar tuhe-like 
thrombus about half an inch in length was present in the portal vein, 
hut the blood in the other large veins and heart appeared abnormally 
fluid and of a laky tint. 
Experiments were made in which a number of different lots from 
numerous firms gave practically similar results. I was unable to deter- 
mine which firm’s preparations were most toxic, for the toxicity of dif- R. H. Cunningham 
177 
ferent lots from the same firm varied much, one lot proving excessively 
toxic, while another would produce toxic symptoms only after fairly large 
daily doses had been given for a period of several days. 
All these toxic dried preparations produced pretty much the same 
pathological changes, but the symptoms induced by some of them in 
several monkeys differed in a few instances, one of which has been de- 
scribed in experiment 4. 
Man. My experiences as to the effects of glycerine extracts and 
dried commercial thyroid upon man are essentially similar to those of 
other observers. Very severe intoxication has not been observed by 
me, probably because the effect of the thyroid was always carefully 
followed and the preparations stopped or decreased as soon as the ear- 
lier toxic symptoms appeared. 
In many instances I gave portions of the preparations that had pro- 
duced these toxic symptoms to monkeys, rabbits, and other animals, 
with the result that the monkeys and rabbits invariably exhibited 
severe signs of this intoxication. 
Loss in weight, pyrexia and acceleration of the pulse occurred in 
man only when the dried preparations were given, never with the 
finely minced fresh raw thyroid material. 
In man, as in the lower animals, it was also found that the toxic ac- 
tivity of all these dried preparations varied considerably. The sus- 
ceptibility of the healthy individual seems to vary also, but not very 
markedly. 
Obs. 1. An obese individual took two 5-grain B. W. & Co’s tablets 
three times a day for three days with only an immaterial increase in the 
pulse rate. After four days had elapsed another lot from the same firm 
was given, and one of these tablets taken three times a day produced in 
four days severe headache, dizziness, a temperature of 102° F., pulse 96, 
insomnia for one night, and a moderate diarrhoea. Having completely 
recovered from the above by the end of a week, 4 grains (11 grains = 1 
whole sheep’s thyroid) of Parke, Davis & Co’s dried thyroid were given 
three times a day for a period of three weeks. From this preparation the 
pulse increased to 88 in the first week, but fell to 80 in the second. One 
or two slight diarrhoeic attacks occurred at the end of the first week, but 
none in the second. The temperature was not apparently affected. In 178 
Experimental Thyroidism 
the third week, on increasing the amount to 6 grains three times a day, 
the pulse rose to 90, the temperature to 101° F., and the occasional 
attacks of diarrhoea returned. 5-grain doses were then given and con- 
tinued for three weeks longer. At the end of this time 16 pounds had 
been lost. 
Other preparations of thyroid from this firm have not, however, been 
always so well borne, even one-grain doses three times a day giving rise to 
disagreeable symptoms in some people. 
From Armour’s thyroid in doses of three grains three times a day I 
have seen distinct toxic symptoms arise by the following morning in a 
fleshy female who had taken larger doses of a preparation by Fairchild 
without the occurrence of any ill effects. My average experience with 
this preparation is indicated by the following observation. 
Obs. 2. A man weighing 191 pounds, who had previously taken 
eighteen 16-gramme doses of fresh raw thyroid without effect, was given 
3 grains three times a day of Armour’s thyroid. On the sixth day the 
pulse had risen from 78 to 94 and the temperature to 99° F. The above 
quantity was continued and at the end of the second week the pulse was 
100, the temperature 101° F. Nausea, moderate headache and slight 
diarrhoea were complained of. The dose was reduced to 1 grain per day 
and the above symptoms disappeared. In three weeks the weight was 
lessened by twelve pounds. 
Further observations in healthy men with these impure and complex 
substances would be merely repetitions of the above and are consequently 
omitted, for nothing would be emphasized by them except the general 
variability of the toxic properties of all of these dried preparations of 
thyroid. 
C. Thyroidism in diseased man. 
So far my observations as to the production of “ tliyroidism ” by 
the thyroid material have included experiences only upon healthy men 
and other healthy animals. In reality, however, observation 1 of the 
following series first drew my personal attention to this subject. The 
remaining experiences that are described here are still more apropos. 
Obs. 1. Adult man, 55 years of age, with paralysis agitans, took daily 
except Sundays about 8 grm. of finely minced fresh sheep’s thyroid for a 
period of three weeks. The effect was absolutely negative. After one 
week had elapsed two 5-grain sugar-coated thyroid tablets of B. W. & 
Co. were given three times a day. On the morning of the third day the R. II. Cunningham 
179 
following symptoms of intoxication had developed: Excessive restless- 
ness during the preceding night; severe dizziness and a sensation of ten- 
sion over the forehead; severe dyspnoea; strong but irregular cardiac ac- 
tion, pulse 120 per minute, and temperature 103£° F. The thirst was 
insatiable, the general prostration considerable, and the face and neck 
were covered with a very prominent fiery red erythematous rash. In the 
afternoon of the same day a slight diarrhoea developed. The tablets hav- 
ing been discontinued, all these symptoms disappeared in the course of a 
few days and the patient rapidly gained in flesh and strength. 
Obs. 2. A girl aged 18 years, with exophthalmic goitre. Pulse 125; 
temperature 99° F. Circumference of neck inches. Left lobe of 
thyroid larger than right, and right eye more prominent than left. 
Tremor, insomnia, and numerous other symptoms including cramps and 
occasional attacks of tetany. Took for the first six days 6 grm. of fresh 
sheep’s thyroid slightly cooked. Result, pulse 120, temperature 99°. 
Circumference of neck 13 inches (I had been previously informed by 
the patient that the struma often varied in size). 10 grm. of the finely 
minced raw gland were then given daily for twelve doses, after which the 
pulse was 110, the temperature 98£° F., and the measurement of the 
neck 12 inches. The weight of the patient had increased one pound. 
Previously to taking the fresh raw material this girl had been given one 
tablet (same lot as in Obs. 1) twice a day for three days, with the result 
that the tremor, cardiac symptoms, and general weakness decidedly in- 
creased. The left eye became more prominent and the habitual diar- 
rhoeic movements that usually occurred in the afternoon appeared in the 
morning also. 
Obs. 3. Exophthalmic goitre, but with no evident enlargement of the 
thyroid gland. Pulse 136, temperature 98§°, weight 125 pounds. Took 
for one week except Sunday 10 grm. per day of fresh sheep’s thyroid. 
Result, pulse 120, temperature 98£° F., weight 126 pounds. This man 
had been troubled with almost daily sudden attacks of diarrhoea pre- 
viously to the beginning of the course of thyroid, and, therefore, for the 
first few days capsules of pepsin and subgallate of bismuth were given 
after each meal, the thyroid dose being taken three hours after breakfast. 
Under this treatment the diarrhoea quickly disappeared and did not re- 
appear during the remainder of the time that the fresh gland was taken. 
Obs. 4. Exophthalmic goitre; female, aged 28 years. Previously to 
coming under my charge she had taken fresh pigs’ thyroid for a number 
of weeks in daily doses (amount unknown). After eight or ten weeks of 
this treatment in combination with baths and careful dieting she had 
gained several pounds in weight. The goitre had diminished somewhat 180 
Experimental Thyroidism 
at first, but later enlarged to its former size on stopping the treatment; 
no increase in the pulse rate or palpitation had been noticed. Some 
months later she had been given capsules of one of the dried American 
thyroid preparations. From the use of this preparation such a consider- 
able loss in flesh, severe diarrhoea, marked increase in the general weak- 
ness, and severe tachycardia occurred that the preparation had to be 
discontinued. 
This patient was given the perfectly fresh raw thymus (about 4 
ounces) daily for a number of months with the result that the pulse rate 
decreased from 100 per minute to 84. The enlarged and firm thyroid 
became much softer, and diminished greatly (2 in.) in size. The absent 
menses returned. After a few doses of the pepsin and subgallate of 
bismuth the troublesome diarrhoea permanently disappeared; the exoph- 
thalmos was greatly lessened and von Graefe’s sign entirely gone. The 
weight increased from 105 lbs. to 125 lbs. under this nutritious diet, and 
the strength is now such that the patient can walk four or five miles per 
day without fatigue. 
Obs. 5. A man aged 20 years, with mild Graves’ disease, had been 
taking twelve 5-grain thymus tablets of B. W. & Co. daily for two weeks. 
Without my knowledge he concluded to double the dose, and in three 
days, in addition to great thirst, dizziness, great restlessness, unsteadiness 
in gait, considerable dyspnoea and precordial oppression were developed. 
Accompanying the above were nausea, vomiting, diarrhoea and very 
severe general prostration. The face, arms and neck were covered with 
large urticarial wheals. The temperature rose to 102° F., the pulse to 
150. The tablets were immediately stopped and most of the above dis- 
agreeable symptoms disappeared by the following morning, although the 
general depression and diarrhoea continued for several days. With very 
much larger doses of the fresh thymus no such symptoms reappeared in 
this case. 
In one other instance I have seen the above symptoms occur during 
the administration of these thymus tablets even in doses of eighteen per 
day. 
Obs. 6. Finally, I have had the opportunity of carefully examining 
and questioning an intelligent patient with myxcedema who took for 
about two months small doses of a certain commercial dried preparation 
without the least benefit; in fact, according to her statement, the various 
symptoms of the disease became more marked. The preparation in 
question produced in this case frequent attacks of severe diarrhoea, con- 
siderable acceleration of the pulse rate, headache, and much prostration. 
Another commercial preparation was substituted, and in consequence the R. H. Cunningham 
181 
myxoedematous symptoms rapidly improved, while the diarrhoea, head- 
ache, etc., disappeared and did not reappear unless large doses of this 
latter preparation were taken daily for several days. It should be noted 
that the doses of the respective preparations were the same, in this in- 
stance each tablet being equivalent to 5 grains of the raw gland. 
About 30 grammes of the former preparation being in my possession, 
ten tablets were given daily to a thyroidless dog before the cachexia had 
developed. The appearance of the latter was certainly not delayed, on 
the contrary the dyspnoea and fits presented themselves earlier than usual 
(about 38 hours). On injecting an extract of these tablets into another 
thyroidless dog the cachexia appeared in 30 hours, and none of the symp- 
toms lessened in severity from even repeated injections of this extract. 
The preparation undoubtedly contained very toxic substances, but 
whether any of the supposed active curative thyroid principle was pres- 
ent cannot be definitely stated, owing to the fact that the failure to re- 
lieve the symptoms in the above tests is not conclusive proof of its total 
absence. The important objections to these tests will be discussed more 
fully in Part III. 
D. Results and general considerations. 
The results of the foregoing observations conclusively demonstrate 
the two following main facts: 
First, that the ingestion of very large amounts of finely minced 
fresh thyroid material gives rise to no intoxication whatever in man, 
monkeys, dogs, cats, rabbits and birds, provided the digestive pro- 
cesses in the said animals be performed with the usual normal rapidity. 
Second, that the stale material or the preparations that have been 
made from the thyroid according to the methods usually in vogue may 
or may not produce in certain animals the symptoms of an intoxication. 
In many instances the symptoms may follow even comparatively small 
doses. 
In normal men, monkeys, dogs, cats, rabbits and birds I have never 
been able to produce by means of the fresh thyroid material a rise of 
temperature, acceleration of the pulse either shortly after the ingestion 
of the dose or on the following day, loss in weight except in rabbits (?), 
agitation, general prostration, or exophthalmos. Further, none of the 
above normal individuals exhibited any perceptible enlargement of the 
thyroid gland, nor did accurate comparative measurements of the lobes 182 
Experimental Thyroidism 
before and after the ingestion of the thyroid indicate that any dis- 
cernible diminution in size had occurred. 
Carnivorous animals (dogs and cats) and birds (cocks) appear to be 
insusceptible to the action of the toxic preparations even in enormous 
doses; but man, monkeys, and especially rabbits, speedily manifest the 
various symptoms in greater or less prominence. This marked differ- 
ence was not surprising in the least, for many previous investigators of 
poisonous meat, sausage, cheese, and other ptomaine-containing food- 
stuffs, note the frequent immunity of carnivorous animals from these 
poisons. The natural propensity of cats, and of dogs in particular, for 
all kinds of carrion and sundry bits of putrefied food is also well known 
and needs no comment further than the remark that no ill effects 
follow numerous meals of this character. Boehm * reports that a 
dog was given a large bowl full of poisonous cheese, all of which he 
ate, but no toxic symptoms followed. Chickens and sparrows, ac- 
cording to Gaertner,f are also insusceptible to toxic meat, and other 
observers have reached a similar conclusion. In dogs, however, as has 
been stated elsewhere, Lanz noticed some acceleration of the pulse 
rate, but Edmunds produced no effect by feeding dogs on sheep’s 
thyroids. 
All the dogs and other animals to which I gave the dried commer- 
cial thyroid preparations exhibited great thirst, but as these prepara- 
tions are often one-half chloride of sodium, considerable thirst is what 
one should expect. Great thirst consequently indicates nothing that 
could be definitely attributed to the special action of the toxins. As 
regards the emaciation noticed by Lanz I may add that at the begin- 
ning of the experiment the majority of my dogs were very thin and 
poorly nourished, but while taking large quantities of all kinds of 
thyroid material and receiving excellent food, they rapidly fattened 
and continued to do so while under observation. If these animals 
had been kept housed for a number of months and fed on thyroid they 
naturally would have ultimately fallen into a poor condition; and so 
would other dogs if deprived of out-door exercise and air, no matter 
* Boehm, Ziemssen’s Handbuch, Bd. xv, p. 249. 
t Gaertner quoted by Oestertag, Fleischbeschau. Stuttgart, 1892. 
J Edmunds, loc. cit. R. H. Cunningham 
183 
how well fed the animals may be. Normal carnivorous animals, in 
fact, are not at all suitable subjects for such experiments if one lias to 
keep them in confinement for a long time. Most of the toxic thyroid 
preparations do cause considerable loss in weight in rabbits, monkeys, 
and in man. It is conceivable that the fresh material may do this 
also if gastro-intestinal fermentation occur and the altered thyroid 
products become absorbed. This latter circumstance, I think, very 
probably explains many of the experiences in which clinicians have 
observed mild or severe toxic symptoms to follow the ingestion of 
fresh raw material. This marked katabolic effect of the substances 
contained in these toxic preparations is not, however, specific for the 
thyroid only. Preparations of other ductless glands are liable to pro- 
duce a very similar intoxication accompanied by emaciation. Many 
tox-albumoses, toxic proteids and ptomaines from poisonous meat and 
sausage, fish, cheese and other food-stuffs, usually produce a similar 
marked emaciation, as is clearly shown in the well-known works of 
Bollinger, Brieger, Backlisch, Muller, Panum, Marino-Zucco, and 
many other observers. 
Generally speaking the intoxications produced by all of these poi- 
sons from altered food-stuffs resemble one another in some respects, 
that is, certain symptoms appear to be more or less common to them 
all, while other symptoms are often essentially different. My experi- 
ences with the toxic thyroid material teach that this statement is valid 
for the clinical picture of this variety of intoxication also. Neither in 
the acute nor in the chronic forms of “ thyroidism ” are the various 
individual symptoms always uniform as a whole. Thus one commer- 
cial preparation seems to affect the gastro-intestinal canal chiefly; an- 
other preparation, even from the same firm, appears to suddenly over- 
whelm the muscles; others act upon the central nervous system of 
monkeys and of man also, so that either a spastic or a flaccid form of 
motor paresis or of paralysis may occur. Sometimes exophthalmos is 
prominent; at others no such condition is visible. All of these toxic 
substances seem to profoundly alter the blood. 
In monkeys the majority of thyroid preparations produce a rise of 
temperature; on the other hand some of them in concentrated doses 184 
Experimental Thyroidism 
produce just the opposite effect, a fall of 4° F. below the normal hav- 
ing been witnessed by me. In some cases dyspnoeic symptoms are 
marked; with other preparations the respiratory rhythm may from the 
beginning become progressively slower and finally cease, the exces- 
sively rapid heart-beat continuing for a short time afterward. In 
some of my monkeys no tremor or restlessness was noticeable; several 
others, however, exhibited this agitation very prominently. Acceler- 
ation of the pulse appeared to be produced by all the toxic thyroid 
preparations that were tested by me. 
An analysis of these contradictory physiological effects appears to 
indicate that very probably these toxic preparations contain frequently 
different toxins or at times a combination of toxic substances. In cer- 
tain preparations one variety of toxin or toxins predominates, in others 
a toxin of a slightly different nature may occur and superadd its 
effects to those produced by the other toxins which possibly enter into 
the composition of the preparations in question. 
From Observation 6 under C, and from practically similar ones of 
other clinical observers, I am warranted also in stating that the toxic 
action of some of these dried thyroid preparations exceeds their palli- 
ative action in myxcedema; in fact certain symptoms of the latter 
disease may be made worse thereby, and no palliation at all as regards 
certain others may follow. This fact does not, however, necessarily 
prove that none of the supposed thyroid principle, which most ob- 
servers, as far as I am aware, concede to be present in the thyroid 
gland, is contained in the preparation; for until this principle is ob- 
tained in a pure state, the above clinical test of the complex crude 
product only demonstrates that either the susceptibility of the indi- 
vidual is very great or that the toxins are particularly active, or both. 
If a certain toxin be present in considerable amount, this very toxin 
may possibly nullify or partly counteract any effect resulting from the 
beneficial thyroid principle or principles. 
In reality many of the symptoms produced by these toxins from the 
thyroid material and from other toxic animal material also, show a 
remarkable and suggestive similarity to those composing the clinical 
picture of the experimental acute cachexia thyreopriva. Many of R. H. Cunningham 
185 
the symptoms that are exhibited by intoxicated men, monkeys and 
rabbits on the one hand, and by thyroidless carnivora in the early 
stages of the acute cachexia on the other, bear also a striking similarity 
to some of the most prominent symptoms and complications of exoph- 
thalmic goitre. Thus in all three conditions the central nervous sys- 
tem manifests its over-activity by fibrillary muscular tremor or twitch- 
ing, tetany, etc. The contractions of individual muscles or groups of 
muscles so common in the intoxications and in the cachexia, frequently 
occur also in exophthalmic goitre. Rigidity, contracture, and a var- 
iety of spastic paralysis (Marie, Charcot) are also symptoms which may 
be included in the symptomatology of each. The rapid emaciation, 
the prostration and the weakness occurring with the intoxications, 
with the acute cachexia, and usually with Graves’ disease, need no 
comment. A rise of temperature is frequent in exophthalmic goitre, 
is usual in the intoxications; and on the first few days following the 
thyroidectomy, during the acme of the muscular twitchings in the 
cachexia, the temperature often rises 4° or 5° above the normal (Hert- 
zen, Ughetti, Alonzo, Rogowitsch, Horsley). Considerable accelera- 
tion of the pulse is also invariable, I find, in the early stages of the 
acute cachexia in dogs and monkeys. Slight exophthalmos * in the 
experimental cachexia is rarer, but does occur under circumstances 
which I shall describe in the following division of this paper. Some 
of the toxins from stale meat, thymus, thyroid, etc., frequently produce 
this symptom to a marked degree in rabbits and in monkeys, although 
in normal dogs I have utterly failed to produce this effect when the 
toxic substances were given by the stomach. 
In exophthalmic goitre my own rather limited experiences and the 
very numerous clinical reports of others clearly indicate that certain 
symptoms are very materially increased by these toxin-containing 
thyroid preparations, whereas the absolutely fresh raw material pro- 
duces, according to my experience, no such result. 
The advocates of the theory that a too active thyroid produces 
Graves’ disease, while admitting that possibly some of the symptoms 
* Edmunds has also noticed the occurrence of exophthalmos after removal 
of the thyroid. 186 
Experimental Thyroidism 
following the ingestion of the toxic thyroid preparations may be due 
to chance ptomaines, may raise the objection that the supposed thyroid 
principle is of the nature of an enzyme (White and Davies, Notkine), 
and that the thyroid gland contains immediately after its removal the 
zymogen only of this enzyme. This state of affairs is well known to 
exist in the case of the pancreas, which after removal develops diges- 
tive properties only after a certain period of time has elapsed. The 
nature of this generally conceded thyroid principle is, however, very 
obscure, but were this enzyme the active principle, toxic in character, 
one might reasonably suppose that it would under varying circum- 
stances preserve its toxicity, that is to say, if this special substance be 
obtained in a pure form it should continue to be toxic as before, 
though possibly the toxic symptoms that it produces might differ some- 
what from those produced by the crude toxic material. I have conse- 
quently endeavored (Part III) to isolate from the various preparations 
of thyroid sundry substances in a pure state which have been given 
to normal and also to totally thyroidless or partially thyroidless ani- 
mals. It is needless to say that the results in this direction do not in 
the least disagree with those obtained in the present part of this paper. 
I reiterate that the fresh raw thyroid material shows not the least 
tendency to produce intoxication; that I have not found that the 
symptoms of exophthalmic goitre are increased by its ingestion, pro- 
viding of course that no toxins develop in it during gastro-intestinal 
digestion; that a certain toxic substance or group of substances may or 
may not be present in the stale thyroid material and other animal 
material, which substances may produce in certain animals symptoms 
somewhat analogous to many of those usually met with in exophthal- 
mic goitre. Though both experimental and clinical evidence demon- 
strates the fact that these analogous symptoms are produced by the 
toxic thyroid preparations, this fact cannot be logically or justly 
brought forward even as auxiliary proof to support the theory of those 
(Moebius and others) claiming that an over-active thyroid is respon- 
sible for the various symptoms manifested in Graves’ disease. R. H. Cunningham 
187 
PART II. THE INFLUENCE OF FOOD UPON THE APPEARANCE OF THE ACUTE 
CACHEXIA THYROIDECTOMICA. 
A. Historical introduction. 
Munk * having observed that a diet composed of lumps of meat has- 
tened the death of thyroidless dogs, Breisacher,f a pupil of Munk, inves- 
tigated this relationship and found that a certain number of thyroidless 
or partially thyroid less animals could be kept alive if fed with milk 
or with milk and eggs only. If raw meat or soup were given to 
these apparently normal animals the characteristic symptoms of the 
cachexia quickly developed. Meat carefully extracted by long boiling 
did not produce this effect. In animals in whom £ or of the thyroid 
had been left the bouillon was well borne, but as soon as the remaining 
portion of the gland was removed the symptoms of the cachexia quickly 
appeared, providing the raw meat or bouillon were given. If the meat 
salts were mixed with the milk the action was occasionally similar to that 
of the bouillon. In certain thyroidless dogs, although the tonic and 
clonic muscular contractions and dyspnoeic attacks had appeared, these 
symptoms disappeared if the milk diet was continued. De Quervain,J 
and later Rosenblatt,§ also conclude that the progress of the cachexia is 
milder if the animals are fed on milk only. Masoin, || on the other 
hand, claims that this pretended influence of milk diet upon the cachexia 
does not exist and that the duty of the thyroid gland is to nullify various 
toxins that are produced by the organism, which toxins accumulate in the 
blood and give rise to the convulsions, etc. The antitoxic function of 
the thyroid, previously emphasized by Colzi, Rogowitsch, Fano and 
Zanda, Schiff, Gley, and many others, is insisted upon by Masoin, and 
the intoxication is thus classed with the auto-intoxications. 
The experimental evidence as to the influence of different food-stuffs, 
consequently, is by no means clear, and, as Ewald has remarked apropos of 
Breisacher’s results, it is by no means definitely settled whether it is the 
disturbance of the metabolic processes in the tissues of thyroidless animals 
which directly produces the cachexia, or whether it is'the components of 
various food-stuffs which are directly toxic. The mere administration 
of various kinds of food does- not, as Ewald states, definitely settle this 
question, but from such experiments one can gain a fairly definite knowl- 
* Munk, Bari. klin. Wochenschr., 1889. 
t Breisacher, Arch. f. Anat. u. Physiol., Physiol. Abtheil., 1890, 509. 
t de Quervain, Virchow’s Archiv, cxxx (1893), 504. 
§ Rosenblatt, Arch. d. scien. biolog., St. Petersburg, iii, No. 1, 1894. 
|| Masoin, Paul, Arch, de phys. norm, et path., 5 ser. vi (1894), 291. 188 
Experimental Thyroidism 
edge of the relative susceptibility of certain animals before and after thy- 
roidectomy to the constituents of certain foods, provided certain factors, 
which if present are liable to give rise to very erroneous conclusions, be 
duly taken into consideration. 
Briefly summed up, these factors which so seriously complicate the 
study of this problem are nothing more than the entire series of those 
“ conditioning circumstances ” (Horsley) upon which, as Horsley and 
others point out, the effects of thyroidectomy depend. Thus of all classes 
of animals the thyroidectomized carnivora, dogs, cats and foxes, exhibit 
the severest and most rapidly developed cachexia, death usually occurring 
between the third and fourth day in a comatose state (Wagner). Accord- 
ing to Horsley the average duration of the neurotic, or first stage of the 
cachexia, is from one to two weeks in dogs; from one to three weeks in 
monkeys; young dogs and young monkeys alike dying in this stage. 
Elderly dogs merely exhibit symptoms of indolence and incapacity, indi- 
cating that the activity of the gland appears to be most active when 
tissue metabolism is most active. Under “ other conditioning circum- 
stances ” Horsley * further dwells upon the important influence of a state 
of low nutrition before thyroidectomy, and upon the influence of the sur- 
rounding temperature upon thyroidless animals. 
Possible residual thyroid tissue and the existence of accessory glands 
(Piana, Wagner, Fuhr, Ewald, Carle, Autokratow, Gley and Phisalix) and 
para-thyroids (Sandstroem, Baber, Gley, Kohn, Edmunds), may exert so 
great an influence that either the cachexia may not appear at all in dogs, 
or after a few very mild symptoms have been exhibited all signs of it may 
entirely disappear. 
The operation of removing the thyroid lobes of the dog is an exceed- 
ingly simple one, but if the lobes be shelled from their capsules, as is 
usually done, one or other of the small para-thyroid bodies may be, as 
Gley has pointed out, unintentionally left behind. Should two or more 
be left, very slight or even none of the symptoms of the cachexia may 
sometimes occur, a personal experience which agrees with that of Gley. 
In certain young dogs both thyroid lobes, the para-thyroid bodies and 
any neighboring discernible accessory glands may be removed, neverthe- 
less the results may be the same, or after the expiration of from five to 
ten days the severer nervous accompaniments of cachexia may develop, 
frequently with astonishing rapidity. In the first convulsive attack the 
dog may die, or several attacks of dyspnoea, convulsions, etc., which 
progressively increase in severity, may succeed one another during the 
* Horsley, loc. cit. R. H. Cunningham 
189 
next few days, the dogs ultimately dying often during a severe convulsive 
attack. Other dogs and also cats may exhibit only moderate fibrillary 
twitchings and stiffness of the hind legs for numbers of weeks or even 
months, becoming to all appearances myxoedematous, and finally die 
in that condition. In a few others, after slight symptoms have existed 
for a number of weeks, they apparently subside completely and the dogs 
seem normal. The two latter courses, it is almost needless to remark, 
are generally exceptional. 
According to my experience the vast majority of young dogs in good 
condition will, when they are fed on ordinary raw meat both before and 
after the operation, begin to manifest the symptoms of an impending 
dyspnceic attack within 52 to 54 hours after the total excision of the 
thyroid, and usually die in convulsions very shor{ly after the dyspnceic 
attacks have begun. In such dogs I consider that it may he justly as- 
sumed that for all practical purposes a total thyroidectomy had been per- 
formed. Very evidently none of the accessory glands that possibly re- 
mained were sufficiently active for the performance of much of the func- 
tion of the thyroid. Nevertheless a careful dissection of the hyoid and 
aortic regions of some of the apparently thyroidless dogs, and of a large 
number of normal dogs also, frequently resulted in my finding one or 
more tiny, pale reddish globules from 5 to 1 mm. in diameter, which 
under the microscope presented a structure identical with that of the 
para-thyroid body, or parts of a continuous section appeared similar to 
that body (Plate XV, Fig. 2), while other fields of the same section had 
the appearance of the true thyroid structure. In all my young dogs and 
also in two cats, in which the cachexia developed mildly and not until 
four or five days after the operation, these tiny accessory bodies were 
invariably found. In some of the dogs additional accessory bodies of 
greater dimensions (2 to 8 mm.), such as Fuhr, Piana and others describe, 
occasionally accompanied the smaller ones. Two dogs that survived for 
sixteen days possessed each three small aortic bodies only about 1 mm. 
each in diameter, and in both dogs I found on the right side of the root 
of the neck just above the sternum a small round accessory body about 
1.5 mm. in diameter, similar in structure in every way to the normal 
thyroid body. 
The minuter aortic accessory bodies, often embedded in fat, are exceed- 
ingly to find, and during a careful dissection by even the most 
experienced are very liable to he passed aside as bits of fat. Small bodies, 
apparently thymus remains, will also be met with and macroscopically 
may easily mislead. My own plan was to trust only to the microscope 
and examine everything that appeared to be the least suspicious. In 190 
Experimental Thyroidism 
numbers of instances where this latter plan has been neglected by ob- 
servers and judgment pronounced as to the absolute absence of those 
accessory bodies, I feel very confident that many erroneous statements 
have been made.* Too much stress, therefore, cannot in my opinion be 
laid on the importance of this factor in influencing both the rapidity of 
the appearance and the degree of the cachexia in dogs and cats. 
It is easily seen that in consequence of this latter complicating condi- 
tioning circumstance, numerous experiments, many careful and tedious 
dissections, and much laborious microscopic examination of suspected 
bits of tissue had to be performed before I could obtain a really definite 
idea as to the average number of hours which usually elapsed between the 
operation and the beginning of the dyspnceic attack in the totally thy- 
roidless dog. The average that was given above was obtained from 
fifteen young dogs of about six months to one year in age, and the animals 
were fed both before and after the thyroidectomy on raw meat. 
In studying this problem naturally the contents of the intestine at the 
time of the operation had to be regarded as a possible source of origin 
for sundry ptomaines, etc., whose additional action might complicate the 
results. Every operation was thus performed not earlier than twenty- 
four hours after the last meal, and in addition precautions were taken 
with a number of animals to feed them on bread and water for at least 
two days before performing the thyroidectomy. This latter precaution, 
I may add, did not, however, appear to influence the average time of 
development one way or the other. But if the dogs were fed on bread 
and water alone for several weeks before the operation the general condi- 
tion of the dogs was liable to become so poor that the cachexia frequently 
developed rather more rapidly. A preliminary diet containing a greater 
amount of albuminous food is thus to be preferred. 
My experience with totally thyroidless monkeys has not been large, 
but within twenty-four hours after the operation I have noticed, even in 
partially thyroidectomized monkeys, moderate fibrillary muscular twitcli- 
ings, sluggishness, and a very marked increase in the susceptibility to 
cold; the animals constantly keeping on the day after the operation close 
to the steam heating pipes, while before the operation no proclivity for 
the hot pipes had been exhibited by the monkeys, which were kept in a 
room always carefully maintained at a uniform temperature. 
* In herbivorous animals also (calf and lamb) a number of these small 
bodies are usually present, and possibly their presence accounts in a great 
measure for the long period of time required by these animals to fully 
develop the symptoms of the cachexia. R. H. Cunningham 
191 
My general mode of procedure was essentially the same as has been 
pursued by Breisacher and others and needs no further comment. 
Comparative observations were thus made in which perfectly fresh raw 
meat, extracted meat and special extracts from fresh and from stale meat 
were used. Fresh and also dried toxic thyroid material were given to 
certain animals and the resultant effects noted. Comparative experi- 
ments with undoubted fresh milk were naturally out of the question in 
a large city to which the milk is brought often from a distance of many 
miles. 
B. Experiments. 
1. Dogs. In the following table (p. 192) I have tabulated certain of 
my trustworthy experiments on the dog in the form of series. In each 
series I report with three exceptions only those animals in which not the 
slightest trace of residual thyroid, para-thyroid, or accessory thyroid 
tissues could be found after a most careful dissection and a microscopic 
examination of all tiny bits of possibly suspicious tissue. In series XIII, 
Dog 3, I was inclined at first to question the actual absence of one or 
more of the minuter accessory bodies, but later experiments in which 
certain thymus extractives were injected lead me to attribute the short 
delay of the dyspnoea to the effects of the thymus diet. 
Necessarily from the nature of the experiments the figures are but 
approximate, indicating in a general way the average number of hours 
that elapse after total thyroidectomy before the average young dog in an 
average condition begins to manifest the dyspnoeic attack. 
Numerous necessary exclusions have unfortunately caused the number 
of trustworthy observations in some of the series to diminish consider- 
ably, and in consequence it may be objected that some of the averages 
include too small a number of definite uncomplicated observations, espec- 
ially as the averages differ not by days but by hours only. Granting the 
validity of this objection and also the possibility that the actual figures of 
some of the averages of the series might be slightly different had not so 
many of my dogs (60 per cent.) been provided with accessory bodies, I 
nevertheless offer these results for what they are worth. 192 
Experimental Thyroidism 
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2 
50 
49 
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lent quality. 
Spleen removed 23 days previously. 
XVII. 
2 
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96 
125 
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2 
53 
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oid, boiled 
58 
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2 
58 
53 
56 
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temperature, and emaciation occurred 
( meat. 
in all these dogs. The wounds re- 
mained aseptic. 
INFLUENCE OF FOOD UPON THYROIDECTOMIZED DOGS. R. II. Cunningham 
193 
Disregarding the diet of the animals previous to the operation and 
averaging the various series, one finds that the influence of the after-diet 
appears to be as follows: raw meat, 53 hours; fresh raw meat, 63 hours 30 
minutes; bread and soup, 52 hours; ordinary meat extracted by boiling, 
56 hours; city milk (fair quality), 52 hours; wheat bread, 65 hours; meat 
stew and fresh raw thyroid, 56 hours; fresh thymus, 75 hours; toxic thy- 
roid material, 45 hours 30 minutes; fresh thyroid, 76 hours. 
These averages would appear at first sight to indicate that both the 
kind and the quality of the diet do to a very slight degree influence 
the average time of appearance of the dyspnceic attacks in totally thy- 
roidless dogs, but the differences are entirely too small in my estima- 
tion for one to positively assert the absolute correctness of the indica- 
tion. The differences are certainly not as great as the observations of 
Breisacher would lead one to expect, practically no difference between 
the effect of ordinary raw meat and that of milk appearing to exist in 
the totally thyroidless dogs. In fact no matter what the diet may be, 
the totally thyroidless young dog very quickly develops one or more 
of the symptoms of the cachexia and dies usually within a few days 
/ 
after the performance of the thyroidectomy. Even if large amounts 
of fresh thyroid material be included in the diet the appearance of the 
cachexia is evidently but slightly delayed, although some of the symp- 
toms are frequently modified remarkably in severity. Nevertheless I 
have not been able by this means to prolong the lives of totally thy- 
roidless young dogs longer than 97 hours after the thyroidectomy. 
Possibly this period might have been extended had the minced thyroid 
been successfully introduced into the stomachs of the dogs by artificial 
means, for I have noticed that generally by the second or the third 
day food of all kinds is usually left untouched, water alone being vol- 
untarily swallowed in small quantities. On attempting to feed the 
dogs through the stomach tube, even after cocainizing the fauces, it 
was found that, although very small amounts of milk and thyroid had 
been injected, practically the whole amount was almost immediately 
vomited. Under these circumstances and with the rapidly progressive 
emaciation and general weakness, death of course quickly followed. 
If the totally thyroidless dogs were fed with large quantities of fresh Experimental Thyroidism 
thymus gland or with concentrated bouillon from the fresh gland, a 
somewhat similar though less marked effect both upon the time of ap- 
pearance of the dyspnoea and upon the severity of the symptoms in 
general appeared to occur. In an earlier series of experiments, to 
which I have referred elsewhere,* I did not notice this favorable in- 
fluence of the thymus when fed to the thyroidless dogs; but on repeat- 
ing the earlier experiments and using much larger quantities of either 
the fresh thymus or of the concentrated thymus bouillon, I got the 
very appreciable beneficial effects to which I now call attention. 
The dried commercial thyroid preparations and dried thyroid pre- 
pared by myself did not appear to delay the cachexia in the least, even 
though the doses of the dried thyroid were increased to 30 grammes 
(equivalent to about 100 grammes of the raw thyroid) per day. Judg- 
ing from the average of the figures obtained in the eight dogs men- 
tioned in the table, the ingestion of these preparations seemed on the 
contrary to hasten slightly the severer symptoms of the cachexia. It 
should be stated, however, that small portions of all of the dried prepa- 
rations used in this series of dogs had been given to normal rabbits or 
monkeys and all had proved very toxic to both the latter animals. Two 
of the preparations contained the active palliative thyroid substance 
also, for by chemical means the substances that appeared to be toxic 
when taken by the mouth were removed, and the active palliative sub- 
stances were injected subcutaneously into totally thyroidless dogs with 
very favorable results. 
According to my experience, the cachexia so quickly overwhelms the 
completely thyroidless young dog, whether fed on milk, bread, or even 
fresh thyroid, that the comparative effects of different foods cannot he 
accurately tested upon the same dog, and the plan pursued by Breisacher 
of partial thyroidectomy would appear to he the one to he followed if the 
dog is to he the animal chosen for the experiment. Although it is open 
to many serious objections, this method was employed in eight dogs, but I 
got nothing that could be called an unquestionably positive result. The 
method was as follows: In seven young anaesthetized dogs the whole of 
the right thyroid along with its capsule was removed. On the left side 
* Med. Record, New York, June 15, 1895. R. II. Cunningham 
195 
about the upper fourth or fifth was left, none of the large superior ves- 
sels being interfered with. In the eighth dog the left lower fourth only 
of the thyroid body was left, precautions being taken to disturb its vascu- 
lar supply as little as possible. 
Four of these partially thyroidless dogs did not appear to differ in the 
least from normal dogs, and from the second day after the operation were 
fed on raw meat for three to four weeks. During this period no symp- 
toms of the cachexia were manifested. Of the remaining four, the three 
in which about the upper fifth of the left lobe had been left presented 
evident though slight tremor in the rear extremities by the second day, 
and in running about appeared to use the hind legs somewhat clumsily. 
On the third morning these symptoms could not be detected and two of 
these dogs were put upon a diet of stale but good meat. As no further 
symptoms occurred, after two weeks of this diet, the two dogs were used 
for other experiments. To the third dog were given, besides his bread 
and water diet, 20 grm. of a dried commercial thyroid preparation, 1 grm. 
of which had proved fatal to a rabbit. On the next morning the tem- 
perature of this dog had risen 1° F. and the pulse rate had increased by 
thirty beats. In the hind legs the tremors had reappeared and a slight 
degree of stiffness and awkwardness in gait was apparent. Having but 
10 grm. left of this thyroid preparation, this amount was administered 
and the dog carefully examined on the following morning. The tem- 
perature and the pulse were the same as on the previous day and the 
tremor and tetany were also still prominent. The bread diet was changed 
to raw meat and the dog observed for three weeks. On the seventh day 
the temperature and pulse were the same as before the operation, and 
during the rest of the time the animal did not appear to differ from a 
normal dog. 
The dog in which the lower fourth of the left thyroid lobe was left 
presented by the third day considerable tremor, tetany and emaciation. 
On the fifth day the dog appeared better, took a little bread and a small 
amount of thoroughly boiled milk. On the ninth day (afternoon) the 
wound was found perfectly healed, and but for a just perceptible occa- 
sional fibrillary twitching in some of the muscles of the hind extremities 
the animal did not seem to differ from a normal one. On the tenth 
morning it was found in a fit from which it recovered in a few minutes, 
exhibiting, however, the rapid respiration and dyspnoea. After three 
similar fits during the day and probably more during the night the ani- 
mal died on the eleventh day, in spite of several large subcutaneous doses 
of a commercial thyroid elixir. On dissecting out the remnant of resi- 
dual gland it was found to have undergone almost complete atrophy, due 196 
Experimental Thyroidism 
doubtless to insufficient blood supply. The residual thyroid in the pre- 
ceding seven dogs had on the contrary become considerably hypertro- 
phied, the blood supply apparently not having been interfered with. 
In four of the dogs, therefore, not enough of the thyroid had been 
removed to even temporarily disturb the physiological equilibrium. In 
two of the remaining dogs it was evident that though some disturbance 
had followed the partial excision of the gland, the vulnerability of the 
two animals was not sufficiently diminished to show the possible effects 
resulting from stale meat diet. A slight susceptibility to the toxic sub- 
stances contained in the dry thyroid preparation would appear to have 
been produced in the seventh dog, but one cannot positively assert that 
the slight temporary return of the symptoms was not simply a coinci- 
dence dependent upon a temporary disturbance of the activity of the resi- 
dual thyroid tissue. At any rate it was evident that the functional activ- 
ity of the residual thyroid had been sufficiently recovered by the seventh 
day for the metabolism of this dog to proceed in a practically normal 
manner. 
In the eighth dog, though the progress of the cachexia was slower, the 
final effect was the same as that following total thyroidectomy. Thus, 
in spite of the bread and milk diet the fits occurred and the cachexia 
progressed just as one frequently sees it in dogs in which both thyroid 
lobes have been removed, but in which a certain amount of accessory 
thyroid tissue has been unavoidably left. 
It is well known that it is extremely common for dogs in which a small 
amount of residual or accessory thyroid tissue has been left, to have sun- 
dry dyspnoeic and convulsive attacks, between which the dogs may seem 
normal. Consequently, if the milk diet is changed to one of raw meat, 
and the dogs, like those of Breisacher, have an attack after one or two 
days, it is absolutely impossible to decide whether the ingested con- 
stituents of the meat really induced the attack or not, for it is readily 
conceivable that the dogs might have exhibited the symptoms had no 
meat at all been given. One very definite fact obtained, however, is that 
the cachexia develops in the totally thyroidless dog just as readily with 
the milk diet as with the meat diet. 
2. Monkeys. In monkeys the results appeared to be slightly more 
definite, for shortly after the partial thyroidectomy these animals ap- 
peared to become more sensitive to moderate doses of certain commer- 
cial meat extracts, as the following experiment indicates. 
A large normal Java monkey was given 35 grm. of a commercial meat R. H. Cunningham 
197 
extract. This produced a moderate diarrhoea which disappeared in 
twenty-four hours, hut no other disturbance could be detected. On the 
sixth day 20 grin, of the same boiled meat extract were given, but on this 
occasion no diarrhoea resulted. After the expiration of two days the 
dose of 20 grm. was repeated and was again well borne by the monkey. 
Partial thyroidectomy was then performed, approximately the upper 
fourth of the left thyroid lobe being left, and the monkey confined to a 
diet of bread, fruit and water. On the morning after the operation 
occasional fibrillary twitchings were distinctly present in many muscles, 
the temperature had risen from lOlf ° F. to 103° F., and the heart-beat 
from 100 to 156. On the second day the monkey appeared to be chilly 
and continually kept close to the steam heating apparatus and could not 
be enticed away from it even by a banana, of which the monkey was very 
fond. Pulse 186; temp. 104° F. The aseptic dressing was removed and, 
after the small wound had been found to be in perfect condition, was 
replaced. 
By the fifth day the appearance of chilliness had disappeared, the tem- 
perature had become 102° F. and the pulse 112. On the ninth day the 
wound was re-examined and found to be completely healed. The tem- 
perature was 99§° F., the pulse 96, and the monkey seemed as lively as 
before the operation. On the tenth morning 15 grm. of a meat extract 
concentrated from perfectly fresh ox muscle was given to this monkey, 
hut without affecting the animal in the least. 
Two days later at 11.30 A. M. 10 grm. of commercial meat extract, the 
same kind that had been given to the monkey before the partial thy- 
roidectomy, which had been sterilized by boiling and kept in a sealed tube 
from the day on which the original package was opened, was administered 
by means of the stomach tube and the following effects resulted: After 
the expiration of about one hour the monkey became quite restless and 
had one large watery movement. In about two hours and a half the 
animal exhibited still greater restlessness, and the temperature had risen 
from 99§° F. to 101° F., and the heart-beat to 140 per minute. At this 
time a slight though easily discernible degree of exophthalmos accompa- 
nied by horizontal nystagmus was apparent. By six o’clock in the after- 
noon a considerable degree of fibrillary tremor was present, but the trans- 
ient exophthalmos and nystagmus had almost disappeared. On the fol- 
lowing morning the temperature was 103° F., the pulse 180 per minute; 
the fibrillary tremor still marked, but the exophthalmos and nystagmus 
had entirely disappeared. The animal appeared to be again chilly, and 
when removed from the neighborhood of the steam pipes it immediately 
returned, exhibiting considerable awkwardness and stiffness in its move- 198 
Experimental Thyroidism 
merits. Throughout the day the thirst was very pronounced, although the 
diarrhoea had practically disappeared. On the afternoon of the second day 
the pulse was 100, the temperature 100§°, and all the symptoms of chilli- 
ness and the fibrillary twitching had disappeared. On the fourth day 
after the animal had apparently recovered from the effects of the above 
dose, a similar amount of the same meat extract was given and the above- 
mentioned symptoms promptly returned, hut were not quite so pro- 
nounced, and no nystagmus could be detected. On the third attempt to 
reproduce the preceding symptoms in this monkey, in spite of the fact 
that 15 grm. of the meat extract were given, the exophthalmos did not 
recur; the pulse and the temperature, however, increased slightly, and 
the appearance of chilliness, although prominent on the morning after 
the dose had been given, disappeared during the afternoon of that day. 
Five weeks after the operation another 15 grm. dose of the meat ex- 
tract was given to this monkey, which had apparently become perfectly 
normal again, and except for a temporary increase of twenty beats in the 
pulse-rate and a little transient diarrhoea, no effect followed. At this 
date the residual portion of the thyroid gland could he distinctly felt 
and was evidently much increased in bulk, and judging from the exper- 
iences of Wagner, Horsley, von Eiselsberg, Halsted and Breisacher, I 
conclude that a true hypertrophy of its glandular elements had probably 
occurred.* 
Thus, as had been previously anticipated, when sufficient functional 
activity of the residual thyroid had been regained, the increased suscepti- 
bility of the monkey to relatively small doses of the harmful substances 
that were contained in that particular sample of commercial meat extract 
became less and less, until finally with the restoration of normal meta- 
bolism the normal degree of susceptibility was reached. 
Although partially thyroidless monkeys, and probably thyroidless 
dogs, and even men with disturbance of the activity of the thyroid 
gland, appear to be less capable of resisting the action of certain sub- 
stances that are prone to arise in food-stuffs derived from the flesh of 
animals, further evidence is certainly desirable before it can be defi- 
* This hypertrophied residuum of the left lobe was removed after a period 
of 20 months. Although the animal possessed a well differentiated aortic 
body, 2.5 mm. in diameter, and was given fresh thyroid, iodothyrine (Beyer), 
and thyrocolloid prepared according to Hutchison’s method, by mouth 
and by injection, after it had become myxcedematous, it did not survive 
longer than five weeks. R. H. Cunningham 
199 
nitely asserted that the intoxication which follows the ingestion of 
those substances is in reality entirely identical with that variety of 
intoxication of which the cachexia consists. It is true that the experi- 
ments of Bogoslowsky and of Kemmerich, as well as the other experi- 
ments which have been related in Part I of this paper, point to the 
fact that an intoxication, with some of its symptoms usually very simi- 
lar to some of those manifested during the cachexia, can be pro- 
duced in normal rabbits, and even in monkeys, by means of large 
doses of meat extracts prepared from meat that has been kept for a 
variable length of time; but as my experiments in this chapter show, 
the symptoms of the cachexia will develop in the totally thyroidless dog 
or monkey when only cereals compose the diet Roth before and after 
the performance of the thyroidectomy. It is obvious, therefore, that 
although certain toxic substances which a meat diet may or may not 
contain, may still further poison the thyroidless animal, other factors 
probably arising within the organism, as Ewald has pointed out, must 
evidently be considered as playing a far more important part in directly 
producing the cachexia. As regards the experiments in the partly 
thyroidless monkey, it is evident that the most justifiable deduction 
from the results is that, owing to the disturbed general metabolic con- 
dition that temporarily results from the partial loss of the thyroid 
glands, the natural resistance of the animal to a certain toxin-contain- 
ing food was greatly lessened, and in consequence the susceptibility of 
the monkey to such poisons became for the time being more prominent. 
3. Birds. In Part I I found that I was not able to produce any signs 
of an intoxication in a normal cock by the administration of very large 
doses of various decomposed animal tissues, consequently it was deter- 
mined to perform as complete a thyroidectomy as possible and observe if 
any of the symptoms of an intoxication or of the cachexia could he pro- 
duced in this bird by a meat diet, for it is stated that an apparently total 
bilateral extirpation of the thyroid and accessory thyroid bodies does not 
produce the symptoms of the cachexia in chickens (Allara *) and pigeons 
(Ewald and Rockwell f). 
* Allara, Lo Sperimentale, 1885, p. 281. 
t Ewald and Rockwell, Pfliig-er’s Archiv, xlvii (1890), 160. 200 
Experimental Thyroidism 
It is questionable, however, whether the preceding statement is to be 
accepted as final, for, as Horsley remarks, duration of life after the oper- 
ation may play in thyroidless birds the important part it does in some 
other orders. Also the importance of bits of accessory and of embryonal 
thyroid tissue situated in unsuspected locations must not be forgotten, 
for, thanks to Gley, the importance of these apparently insignificant and 
easily overlooked bodies has been clearly demonstrated in rabbits and, 
thanks to Christiani, in rats. 
After extirpating the thyroid and all of the adjacent accessory bodies 
that I could discover in a cock, it was fed for a number of weeks on meat, 
fresh, stale, and even slightly putrid, but no signs of an intoxication or of 
the cachexia could be detected. Wishing next to determine if the thy- 
roidless bird had become susceptible to the substances contained in many 
of the dried thyroid preparations, it was given daily for three weeks large 
amounts (15 to 20 grm.) of the most toxic thyroid preparations that I had 
on hand. Lastly, I gave it by means of the tube the concentrated bouil- 
lon from 800 grammes of very stale sheep’s thyroid, but none of these 
substances produced the least effect and the bird is still under observation. 
Until, however, a careful dissection and a microscopical examination 
of possible residual accessory thyroid tissue is made, I refrain from draw- 
ing any conclusion from the above negative results.* 
PART III. SOME OF THE PHYSIOLOGICAL ACTIONS OF CERTAIN ANIMAL 
EXTRACTIVES. 
A. The thyroid extractives and their influence upon the acute cachexia. 
1. Historical introduction. 
In Part I it was stated that although the results of my experiences 
fully warrant the cbnclusion that the ingestion of even large amounts 
of the finely minced, absolutely fresh, raw thyroid gland for a con- 
siderable period of time is not followed by any signs of an intoxica- 
tion, or by any symptoms that resemble in the least those of exoph- 
* Since the above was written the bird has been killed, more than six 
months after the thyroidectomy. It must be admitted that the above 
experiment merely verifies the previous statement that normal cocks seem 
to be insusceptible to decomposed animal foods, for several small bits of 
tissue were found in the region of the right thyroid body that proved under 
the microscope to be accessory thyroid tissue. Probably these small bodies 
had hypertrophied from very minute embryonal accessory thyroid bodies, 
else I should not have failed to notice them at the time of the operation. R. II. Cunningham 
201 
thalmic goitre, a certain amount of time might be necessary for the 
active principle or principles to develop in the freshly removed gland, 
exactly as is usually the case with an enzyme. In fact, a number of 
observers (White and Davies,* Greenfield,f Notkine,:}: and others) 
hold that the active substance of the thyroid gland is probably an 
enzyme in character. In consequence of the preceding possibility it 
was found necessary to isolate the various components of the raw or 
of the dried complex thyroid material, and determine which of them 
is the active principle, and also if this active principle will induce an 
intoxication if given by the mouth in large doses to monkeys and other 
lower animals. 
In conjunction with the experiments with the substances obtained 
from the thyroid gland, comparative experiments were also made with 
substances derived by similar methods from other animal glands and 
from muscle, and as some of the results that were obtained in the 
latter experiments have not been, as far as I know, hitherto described, 
a brief account of them is also included. 
Evidently from the recent publications of Fraenkel, Baumann and 
Drechsel, a number of independent seekers after the active principle sup- 
posed to be contained in the thyroid gland have been at work at the same 
time as myself, and the preliminary results of one of these observers, 
Drechsel,§ agree in many respects with my own independent observa- 
tions, although the chemical process advocated by Drechsel differs some- 
what from one of those employed by me. 
S. Fraenkel || states in a preliminary report, read before the Society 
of Physicians of Vienna, November 22, 1895, that he prepared cold or 
warm extracts of known quantities of dried sheep’s thyroid, and after 
precipitating the albumins by acetic acid, he found the filtrate active, 
reaching this conclusion from the fact that after drinking the neutralized 
filtrate daily for six days he lost 300 grm. per day during that period. 
By the process very analogous to that frequently used for the extraction 
of creatin—a process also used by me in general for extracting the fresh 
* White and Davies, Brit. Med. Journ., 1892, ii, 966. 
t Greenfield, ibid., 1893. 
J Notkine, Sent. tried., 1895, p. 138. 
§ E. Drechsel, Centralbl. f. Physiol., ix (1896), No. 24. 
|| S. Fraenkel, Med. Record, Jan. 11, 1896. 202 
Experimental Thyroidism 
raw thyroid and thymus glands, muscles, etc.—he obtained, after remov- 
ing the lead by sulphureted hydrogen, a syrup which was dissolved in 
alcohol and precipitated by means of ether or of acetone. This precipi- 
tate crystallized after cleaning. The crystals * were very hygroscopic, 
and permanent only in the “ dried part.” They were soluble in water 
and in alcohol, but insoluble in ether. By decomposition of the precipi- 
tates produced either by phospho-tungstic acid or by phospho-molybdic 
acid, with barium hydrate, a free base was obtained in the form of a 
markedly hygroscopic syrup. The results of the elementary analysis of 
the acetic salt led to the empirical formula To the pure 
substance he applied the term “ thyreoantitoxin.” The physiological tests 
of this substance are also described by him, and will be referred to in de- 
tail later on by me. 
Baumann f was the first to discover that iodine, probably in combina- 
tion, exists in the thyroid gland, and concluded from Roos’ \ results in 
the reduction of goitres by the iodine compound that this compound, or 
“ thyreo-iodine,” is probably the active principle of the thyroid gland. 
The method of isolating the thyreo-iodine is not described in Baumann’s 
article. § 
Drechsel, after trying numerous undescribed methods, chose the fol- 
lowing one which led to crystalline products: 
The fresh pig’s thyroids were minced, and repeatedly extracted with 
water at 35° C. The aqueous extract after acidifying was boiled, filtered 
and evaporated to a syrup, which was filtered after standing. The fil- 
trate was precipitated with phospho-tungstic acid, and this precipitate, 
after being washed free from chlorine, was repeatedly boiled in water 
until no more would dissolve, the insoluble part being finally dissolved 
in an ammoniacal solution. Both solutions were then decomposed with 
baryta water, the ammoniacal being previously treated with CO„ and 
then warmed until all ammonia had been driven off. The filtrates were 
then exactly neutralized with H2S04. The residue of both solutions 
crystallized. According to Drechsel both of these crystalline products 
proved active when fed to thyroidectomized dogs, although not very 
markedly so. Fraenkel’s base this author considers as identical with one 
of the two he describes, although Drechsel does not specifically state 
* S. Fraenkel (Wiener med. BldU., 1895, 13-15) considers these crystals as 
the acetic salt of the base thyreo-antitoxin. 
t Baumann, Zcitschr. f. physiol. Chem., xxi (1895), 319. 
$ Boos, ibid., xxi (1895), 19. 
§ Baumann and Roos, ibid., xxi (1895), 481. See appendix for method, 
etc., p. 217. R. H. Cunningham 
203 
that he has obtained the two crystalline substances in a state of absolute 
purity. The comparative action of these substances on the blood pres- 
sure is also not referred to in that preliminary communication. 
As the above-mentioned observers point out, the only way that one 
can possibly determine which is the true active substance or substances 
of the thyroid is to try to isolate the various substances and try them, 
preferably first on the lower animals after removal of the thyroid gland, 
and later on myxoedematous men. The former I have done, but owing to 
lack of human myxmdematous material I have not had an opportunity 
to test their action in that disease. The various substances were fed in 
several experiments to totally thyroidless dogs, but as these animals very 
early in the cachexia refuse food of any description and later swallow 
fluids either with great difficulty or not at all, the results, even when 
the minced raw gland was given, were so discouraging that I concluded 
to inject the solutions of the various extractives from which the albumin 
and nucleo-proteids had been removed. Naturally, as a control to these 
experiments, equal or considerably larger amounts of the extractives were 
also injected into normal animals and the effects carefully noted; for, 
judging from the previous experiments of Chamberland and Roux,* who 
noted toxic symptoms to follow subcutaneous injections of an alcoholic 
extract of spleen, and of Charrin and Ruffer f with bouillon, I consid- 
ered that very probably all animal tissues would yield extractives which, 
if given subcutaneously in very large doses, would prove to be poisonous 
to many of the lower animals. From my investigations on this subject, 
so far as I have pursued them, I have no reason to alter that opinion. 
2. Methods of extraction. 
Of the various processes used by me in extracting the thyroid, 
thymus, various other glands and muscles, the following three ap- 
peared to yield the best results. One of these processes, namely, 
that frequently employed for the extraction of creatin, is almost iden- 
tical with that described by S. Fraenkel, but the active mixture that 
I have gotten from the fresh raw thyroid by that method does not 
appear entirely to correspond to the alcohol-soluble crystalline sub- 
stance that he describes. Furthermore, the physiological action upon 
the blood pressure appears to differ markedly from that obtained hv him 
with the thyreo-antitoxin. The third process, although yielding a con- 
siderable amount of a gummy, resinous extract, which apparently also 
* Chamberland and Roux, Annales de VInstitut Pasteur, 1888. 
t Charrin and Ruffer, Soc. de Biologie, Jan. 26, 1889. 204 
Experimental Thyroidism 
contains that thyroid principle or principles (Drechsel) which are bene- 
ficial to thyroidless dogs, is open to the objection that probably a certain 
percentage of the active material is lost from the employment of alcohol 
in the method, for, according to my experience, the more nearly absolute 
the alcohol the smaller is the amount of the thyroid substance that 
remains in solution. Briefly, the three methods most frequently em- 
ployed by me for the extraction of the thyroid were as follows: 
(a) The absolutely fresh raw thyroids (sheep, ox, calf) after mincing 
were mixed with about two volumes of cold distilled water and stirred 
briskly for twenty minutes. The mixture being continually stirred, was 
extracted for about twenty minutes at a temperature of 38° C. and then 
boiled for ten minutes. This hot bouillon was filtered through a fine 
linen cloth and the solid residue thoroughly .expressed by means of a 
powerful press. After the grease had been skimmed off, the cool filtrate 
was acidified with acetic acid, boiled for ten minutes, filtered through 
fine paper and the cooled filtrate refiltered through paper. After evap- 
orating this filtrate to a syrup and filtering again, the latter, after the 
acetic acid had been driven off by heat, was dissolved in a saturated solu- 
tion of ammonium sulphate, and additional crystals of this substance 
were added to insure complete saturation of the whole mixture, which 
after standing was filtered through paper. The filtrate was decom- 
posed with baryta water, C02 passed through the filtrate and all ammo- 
nium carbonate driven off by gentle heat. After repeated filtrations 
and evaporations a final brownish, waxy, hygroscopic residue was yielded. 
As the result of comparative tests of the various precipitates and fil- 
trates, it was concluded that this residual waxy mass contained some of 
that part of the thyroid material which considerably influenced both the 
severity of the symptoms and the course of the cachexia in totally thy- 
roidless dogs. 
(&) The well boiled acidified thyroid bouillon, prepared as in the 
preceding method, was precipitated by lead acetate, filtered and excess of 
lead removed by means of sulphureted hydrogen. After testing the 
filtrate for lead it was evaporated on a water bath and, when it had 
reached the consistency of a thick syrup, it was carefully refiltered while 
hot. The syrup was further evaporated, ultimately yielding a dark 
brown wax-like mass, similar in appearance to that which had resulted 
by method a. 
(c) To the filtered acidified thyroid bouillon, after it had been evapo- 
rated at 100° C. to about one-fourth of its original volume and allowed 
to become cold, one-half volume of ether was added and the whole well 
shaken in a stoppered vessel for about twenty minutes. After standing, R. H. Cunningham 
205 
the supernatant ether was decanted and the aqueous remainder filtered, 
all ether being finally driven from the filtrate by means of gentle heat. 
Three volumes of 95 per cent, alcohol were then added to the filtrate 
and the whole allowed to stand for twenty-four hours, the ensuing pre- 
cipitate being then carefully filtered off. The filtrate was finally evap- 
orated at 100° C., being repeatedly filtered during this process until the 
whole had become as dry as possible. This residue was dissolved in 
distilled water by means of heat, and after filtering the filtrate was evap- 
orated at 100° C. until the reaction of the resulting brown gummy wax 
had become neutral or faintly alkaline. This wax appeared to contain 
most of the active substance, although the alcoholic precipitate appeared 
to be slightly active also, due to the fact, as I found out by other methods, 
that the waxy mass is hut extremely slightly soluble in strong alcohol. 
Although it was evident that these waxy hygroscopic masses which ap- 
peared to be very nearly similar, though obtained by three different meth- 
ods, assuredly contained some of the thyroid principle—for subcutaneous 
injections of a 2 per cent, aqueous solution of any of the three consider- 
ably prolonged the existence of totally thyroidless young dogs—it was 
probable that the waxy mass also contained a number of other extractives. 
Consequently a number of methods were employed to subdivide the waxy 
masses and obtain the desired substance in a purer form, possibly in a 
crystalline condition. An aqueous solution of this wax was then pre- 
cipitated, either by phospho-molybdic acid or by phospho-tungstic acid, 
and after carefully washing the precipitates with a 10 per cent, solution 
of the respective acids they were boiled in distilled water, the solutions 
allowed to become cold, filtered, and the filtrates decomposed with 
baryta water, neutralized with sulphuric acid and evaporated to a very 
thick syrup, which, on being set aside, deposited crystals of various 
kinds (5 to 8 varieties). The portion of the precipitate that was insolu- 
ble in boiling distilled water was dissolved as in Drechsel’s method, in 
water rendered slightly alkaline with ammonia; the ammonia removed by 
OOo and heating the filtrate until all ammonia had been driven off. 
This residual solution was finally decomposed with baryta, neutralized 
with H2S04, evaporated on a water bath and set aside to crystallize. 
But few crystals appeared when phospho-molybdic acid was used, the 
chief residual yield appearing to be an oily base-like substance. When 
phospho-tungstic acid was used the proportion of the various crystals was 
larger. These ultimate mixtures, containing 5 to 8 varieties of crystals 
in their oily mother liquor, were injected into totally thyroidless dogs, 
and each found to be active and capable of prolonging the lives of totally 
thyroid less dogs equally as well as injections of the mixed waxy extra c- 206 
Experimental Thyroidism 
tives, and even better, according to my experience, than injections of 
unboiled aqueous or glycerine extracts of fresh raw thyroid glands. 
Various attempts were made to separate the oily mother liquid from 
the various crystals and obtain the various crystals and the mother 
liquor in a state of absolute purity, but these efforts have been up to the 
present unsuccessful, consequently I cannot positively assert whether it 
is the oily or the crystalline substances that are active. From two of 
these ultimate extracts, one by the phospho-molybdic acid method, and 
the other by the phospho-tungstic acid method, I succeeded by using 
amyl alcohol in removing some of the mother liquid, leaving most of the 
crystals undissolved, but neither the activity of the oily mother liquor 
nor that of the remaining crystals appeared to have been diminished, as 
well as could be judged from a test upon two totally thyroidless dogs. 
Thus it cannot be inferred that only the oily substances are probably the 
active parts of these two ultimate extracts. Whether one of these oily 
substances is the same as the base isolated by Fraenkel I cannot say, for, 
though ether precipitates it from an aqueous alcoholic solution, anhy- 
drous alcohol dissolves scarcely a trace of it, and none at all after this 
trace has been several times precipitated by anhydrous ether and the 
supernatant alcohol and ether decanted. FraenkeFs active base appears 
from his account to be so soluble in alcohol that the alcohol-ether method 
is employed in extracting it in a pure form from the crude syrupy mix- 
ture. Further, both of the substances that I get give rise to very marked, 
though transient, alteration of the blood pressure when they are injected, 
singly or combined, directly into a vein, but Fraenkel states that no fall 
of the blood pressure follows the intravascular injection of his base, al- 
though acceleration of the pulse occurs. 
The two active though impure products that I get from the wax ex- 
tracted from the fresh thyroid probably correspond to those described 
by Drechsel, although it must be admitted that I have not been able to 
assure myself that the activity of the two products depends upon the 
presence of two different chemical bodies, for, as has been intimated 
above, I have isolated neither principle in a chemically pure state. It 
is possible that the two active products that are yielded by the waxy 
mass which contains various thyroid extractives owe their activities to 
an imperfectly performed chemical separation at the point when the phos- 
pho-tungstic or phospho-molybdic precipitates were partially dissolved 
in boiling water. I inferred this possibility from the fact that after dis- 
solving one of the crystallized products in dilute alcohol and precipitating 
with ether, recrystallizing and removing as much of the mother liquor 
as possible with amyl alcohol and recrystallizing the undissolved crystals, R. H. Cunningham 
207 
the majority of the latter changed in form and crystallized exactly in the 
stellate form assumed by the majority of crystals yielded by the other 
crystallized thyroid product. An ultimate analysis of these crystals 
isolated in a pure form would have settled the question, but this, how- 
ever, has not been attempted with my present chemical appliances. 
It is noticeable that Drechsel does not specifically state in his prelimi- 
nary communication that he has isolated the two principles in an abso- 
lutely pure form, nor does he state which of the crystalline substances 
occurring in the active residues are the true active principles. Drech- 
sel’s method, however, is evidently a more direct and simpler way of 
obtaining these substances than any of those mentioned above, and I 
have lately endeavored to isolate by that method the two active thyroid 
bases of Drechsel in pure form. Up to the present my several attempts 
have met with no better success in the case of these partially crystalline 
residues, which the method appears to yield, than they previously did 
when I attempted in the summer of 1895 to do the same thing with the 
residues obtained by one or other of the three methods which I have 
described above. The investigations on this subject, nevertheless, are 
still in progress. 
B. The effects of the thyroid extractives on thyroidless dogs. 
In the preceding section it was stated that the daily subcutaneous 
injection of even comparatively small doses of a 2 per cent, solution 
of the gummy, waxy mixture of the thyroid extractives before being 
treated with phospho-molybdic or phospho-tungstic acid, etc., into to- 
tally thyroidless dogs appears to exert a most decided effect upon both 
the course of the cachexia and upon the severity of its symptoms, con- 
sequently it was concluded that the active palliative thyroid substance 
was present in these extractives. I do not intend to convey the idea 
that I succeeded in keeping the totally thyroidless young dogs alive by 
this means for any great period of time, for I have never been able to 
do this either by the injection of fresh aqueous thyroid extracts or by 
feeding large amounts of fresh thyroid glands to the dogs, because all 
of my totally thyroidless dogs died in spite of the injection of the ex- 
tractives in from ten to eighteen days after the operation. When the 
fresh aqueous unboiled thyroid extracts were injected eight to twelve 
days proved to be the greatest length of time that the lives of the 
thyroidectomized young dogs could be prolonged, provided the dogs 208 
Experimental Thyroidism 
had no tiny aortic or other accessory thyroid bodies. When compared 
with the results by the feeding methods which have been described in 
Part II, these results are very striking, for not only was the duration 
of life after the thyroidectomy further increased, but the intensity of 
many of the symptoms of the cachexia was very much lessened. 
Briefly, the effects upon the cachexia of the subcutaneous injection of 
the fresh crude aqueous thyroid extracts were somewhat analogous to 
those of Grley and were as follows: 
If the injections of the thyroid extract were begun on the day of the 
operation in daily doses of from 2 to 10 ccm. (each ccm. = about 1 grm. 
of raw gland), the dose varying with the weight of the dog at the outset, 
all of the dogs at times had mild convulsions, constant fibrillary muscu- 
lar twitching and unsteadiness of gait, while occasional attacks of tetany 
were also prominent. When signs of an approaching dyspnceic attack 
were observed the injection was repeated. As a result the dyspnoea gen- 
erally disappeared in the course of forty-five minutes or one hour. 
From the third or the fourth day the emaciation appeared to become 
more rapidly progressive, and steadily continued until the death of the 
animal. By the fifth or sixth day all food was refused and milk had to 
he given by the stomach tube. Even the milk was usually vomited in 
spite of previous cocainization of the fauces. Finally death occurred 
about the tenth or twelfth day, unless the dogs happened to have a suf- 
ficiency of small aortic or other accessory bodies. In the latter case the 
symptoms progressed more slowly, the tremor and restlessness frequently 
disappearing for several days at a time. In one dog with a large acces- 
sory aortic body all the symptoms disappeared after the lapse of ten 
days. When no injections of the fresh aqueous thyroid extract were 
given to the totally thyroidless dogs until convulsions had appeared, the 
only noticeable effect was a temporary moderation of the fits, the tetany 
and dyspnceic respiration being also considerably lessened, but the bet- 
terment was merely transient. In spite of frequent repetitions of the 
injections the fits recurred after one or two hours and continued to 
occur at intervals until the animals died, usually five or six hours after 
the attack had begun. 
When enough of a sterilized 4 or 6 per cent, aqueous neutral solution 
of the extracted waxy substance was daily injected into the thyroidless 
dogs before any fits or dyspnoea had developed, the effect upon the symp- 
toms of the cachexia was clearly more pronounced than that from the 
crude aqueous extract of the raw gland, and the prolongation of life was R. H. Cunningham 
209 
greater, the dogs not dying until the fourteenth or eighteenth day. In 
these dogs also the pronounced emaciation steadily progressed from the 
second day after the thyroidectomy until the end, although artificial 
feeding with milk was tried. 
When about 30 minims of the 4 per cent, solution was tried as a be- 
ginning daily dose for a dog weighing 5500 grm. the quantity was evi- 
dently too small, for on the morning of the fourth day the dog was 
found in a comatose condition, breathing stertorously and having num- 
erous fits. 100 minims were injected and one hour afterward the dog 
was able to stand up, although considerable stiffness remained in the 
hind legs. Two hours after, as the respiration of the animal had become 
very rapid and panting, and the cramps more pronounced, 75 minims 
were injected. On the next morning only moderate fibrillary muscular 
twitching and a slight degree of restlessness were present, the conjunc- 
tivitis, coryza and tetany having completely disappeared. From this 
date until the day of the animal’s death 100 to 150 minims were injected 
daily, but as the dog would eat nothing and could not be induced to 
retain food artificially introduced into the stomach, death finally occurred 
on the fourteenth day. 
When the fits were allowed to begin before any injections of the ex- 
tractions were given I succeeded in causing the symptoms to subside 
only in those dogs that were injected very shortly after the beginning of 
the fits. If the dogs had been allowed to remain in the rigid, comatose 
condition and have numerous fits, although very large doses appeared to 
slightly lessen their intensity and to diminish the rapidity of the respira- 
tion, the totally thyroidless dogs did not recover from the attack, but 
died in from four to eight hours after it had begun. 
After separating the gummy mixture of extractives into the two par- 
tially crystallized residual portions by treating it with phospho-tungstic 
acid, phospho-molybdic acid, etc., and injecting the residual portions 
separately or in combination into various totally thyroidless dogs, the 
resultant average prolongation of the animals’ lives was practically about 
the same as if an equivalent quantity of the 4 per cent, watery solution of 
the unseparated waxy mixture of extractives had been used. When com- 
paratively large quantities of either one of these two partially crystallized 
residual substances were injected, each of which appeared to be composed 
of crystalline products mixed with more or less oily mother liquor, the 
palliative effects upon the cachexia apparently differed in no way from 
those produced by injections of both combined in smaller amounts. All 
of these dogs died about the fourteenth or sixteenth day in spite of the 
palliative substance that had been introduced under the skin. 210 
Experimental Thyroidism 
As the results of a number of further experiments with the thyroid 
extractives derived either by Fraenkel’s or by Drechsel’s methods have 
been invariably about the same as the above—not even as good when the 
fresh uncooked watery extract of the raw gland has been given—I am 
firmly convinced that it is impossible to prolong for any great length of 
time the life of a young dog that has been deprived of absolutely all thy- 
roid and accessory thyroid tissue, by feeding the raw gland to the dog, 
or by injecting the water-glycerine extracts of the fresh raw gland or 
the concentrated, highly purified extractives isolated from the raw gland 
—an extended conclusion which has apparently been already indicated 
by the well-known experiments of Vassale, Gley, Hofmeister, Hertzen, 
Schwartz, Godart, Edmunds and others, with the crude aqueous or gly- 
cerine thyroid extracts. 
C. The toxicity of the thyroid extractives. 
It is evident, as I have remarked, that some of the active palliative 
thyroid substance is assuredly contained in the gummy extracted mass, 
and as absolutely fresh raw thyroid gland has been used for the 
preparation of this waxy mass, it is also evident that this active sub- 
stance does not exist in the fresh raw gland, for an interval of only 
about twenty minutes occurred between the slaughtering of the ani- 
mals from which the material was taken and the beginning of the 
extraction. Furthermore, from the manner of its extraction it is 
certainly not an enzyme, for boiling does not appear to affect its 
activity in the least. 
Having obtained the active substance in this more purified concen- 
trated form, it was necessary to give large doses of it to susceptible 
animals before I could pronounce upon its toxicity. Finally, from 
the indications of my previous results with the dried or the stale thy- 
roid preparations, it was desirable to make comparative tests with ex- 
tractives derived from the preparations which had proved to be very 
toxic to rabbits and monkeys when administered by the mouth. 
Briefly summed up, I find that after giving the mixed extractives 
from the fresh gland to rabbits by the mouth in doses of 4 grm. 
(= about 220 grm. fresh thyroid) per kilo of rabbit, and continuing 
the same for even five or six days, the rabbits do not appear to manifest 
any symptoms at all, nor does the temperature rise above the normal. R. H. Cunningham 
211 
To monkeys also were given as much as 4 grm. per kilo of body weight, 
but with entirely negative results. With the extractives from an 
average dried commercial thyroid preparation the results were totally 
different and deserve to be more fully described. 
The extraction of the commercial dried thyroid gland was made by 
the acetate of lead method, the same method being also used for the 
fresh raw control material, and 0.25 grm. of the residual gummy mass, 
which the dried thyroid also yields, was given to a rabbit by the mouth. 
At the end of fifteen minutes the respirations of the rabbit had become 
about 225 per minute and were very shallow; the heart-beat was so feeble 
and rapid that it could not be counted. Considerable weakness in the 
hind legs was also present. In twenty minutes it lay sprawled out on its 
belly, with marked exophthalmos, and occasionally a slight muscular 
twitch would occur in one or other of the legs. Pronounced horizontal 
nystagmus next developed and continued for about ten minutes. To- 
wards the end the respiration became slower and shallower and finally 
ceased, about forty-five minutes after the introduction of the dose. It 
was evident, therefore, that the toxic properties of the dried material 
had not been wholly, or apparently even partially removed by the chemi- 
cal processes employed to obtain the gummy mass of extractives, which 
in this case were Contaminated with a considerable number of crystals 
of chloride of sodium. Having treated the gummy mass, liquefied by 
heat, several times with 90 per cent, alcohol, I found that the undis- 
solved portion still preserved its activity as far as its palliative influence 
upon the cachexia was concerned; also that this active residue had 
apparently been deprived of those constituents which were toxic to mon- 
keys and to rabbits. Thus large doses of this active residue could be 
given to these animals by the mouth without producing any of the 
symptoms that the dried powdered gland had produced. 
With the portion dissolved by washing the mass several times with the 
90 per cent, alcohol, precipitating with anhydrous ether and dissolving 
the cleaned precipitate in water, the resultant toxic effects were ex- 
tremely marked. As an average illustration of the effects of small doses 
to rabbits, the photograph reproduced in Plate XIY is appended. This 
rabbit was given 0.1 grm. by the' mouth and the photograph was taken 
about twenty-five minutes after this dose had been ingested. The char- 
acteristic exophthalmos is fairly well seen, as well as the sprawled out 
position due to paresis of all four legs. Shortly after this picture was 
taken a marked, though temporary, horizontal nystagmus developed. 
The number of heart beats increased from 192 to about 286 per minute; 212 
Experimental Thyroidism 
the temperature from 103£° F. to 105§° F., and the respirations from 
60 to 80. At the end of four hours the rabbit was beginning to recover 
and by the next morning the above symptoms had to all appearances 
entirely disappeared. The rabbit now weighed 105 grm. less than it 
did on the previous day, hut this loss was regained in the course of sev- 
eral days. When larger doses (1 grm.) were given to rabbits by the 
mouth the above symptoms rapidly developed, hut were of very short 
duration. All the animals died within from 30 to 45 minutes, and two 
of the four so treated exhibited shortly before death an occasional spas- 
modic twitch in one or other of the extremities. 
As this toxic and evidently impure ether-precipitate had been extracted 
from the gummy mass by means of dilute alcohol, I naturally supposed 
that at least a small part of the apparently harmless but active thyroid 
principle had also been dissolved by the dilute alcohol, and this un- 
doubtedly was the case, although the palliative effect of this mixture 
was much less pronounced than its toxic effect. By washing the pre- 
cipitate, produced by adding ether to the alcoholic solution, several times 
with boiling absolute alcohol, decanting the supernatant alcohol and 
injecting an aqueous solution of the oily remainder, which was insoluble 
in the absolute alcohol, into a totally thyroidless dog, the course of the 
cachexia appeared to be modified equally as if the mixed active extrac- 
tives from the fresh raw gland had been used. The decanted alcoholic 
portion, when evaporated and dissolved in water, did not seem to possess 
this power, for the thyroidless dogs that were injected with small quanti- 
ties of the solution promptly died between 50 and 60 hours after the 
thyroidectomy. If large doses of this solution of toxic substances were 
injected into thyroidless dogs when they exhibited a considerable degree 
of tetany and pronounced prodromal signs of an attack of dyspnoea, the 
effect appeared to be that the symptoms of the cachexia became entirely 
altered and gradually gave place to those produced by the toxic sub- 
stances. As some of the latter symptoms were to a certain extent the 
diametrical opposites of the former, the condition of tetany rapidly dis- 
appeared and all four legs soon became weaker, more flaccid, and finally 
completely paralyzed, so that the dogs lay sprawled out upon their bel- 
lies. Slight exophthalmos replaced the enophthalmos and, except for an 
occasional muscular twitch in the legs, no general convulsions, as far as 
I know, occurred. But as all these dogs were found dead on the morn- 
ing following the afternoon on which the injections had been made, con- 
vulsions may have occurred during the night. Although it cannot be 
said that the lives of these dogs were prolonged by the toxin-containing 
mixture which the alcohol extracted from the waxy mass of extractives R. H. Cunningham 
213 
made from the dried thyroid material, the temporary and usually rapid 
effects following its injection in doses capable of producing the intoxica- 
tion with its accompanying paralysis, etc., might, it is conceivable, lead 
one to believe that a large dose of the proper palliative thyroid substance 
had been injected, especially if the dogs were observed only during the 
transitional period between the subsidence of the tetany and the onset 
of the paralysis. Such a conclusion would certainly be erroneous, for, 
though the thyroidless dogs possibly got in this instance a very small 
amount of the proper palliative thyroid substance which the strong alco- 
hol had dissolved, I have been able to produce identically the same effects 
by injecting thyroidless dogs with solutions of poisonous extractives ob- 
tained from various commercial meat extracts which also produced the 
above-described variety of intoxication in normal rabbits. 
In the waxy mass of thyroid extractives prepared from the dried glands 
there appear to be at least two substances with entirely different physio- 
logical actions. These are: 
(a) The principle or principles (Drechsel) that act beneficially upon 
the experimental acute cachexia thyreopriva. 
(b) The principle or principles that are capable of producing an in- 
toxication in certain animals when given by the mouth or by subcuta- 
neous injection. 
The first (a) is evidently the same as that which can be extracted from 
the fresh raw gland, and is apparently innocuous when given by the 
mouth to rabbits and to monkeys in extremely large doses. The second, 
or the toxic principles, does not prolong the lives of the totally thyroid- 
less animals and, moreover, does not appear among the extractives when 
the perfectly fresh thyroid gland is employed. From their chemical be- 
havior it cannot be said that they are enzymes. Nor can it be said that 
the intoxications that they produce are specific for the thyroid only, for 
substances capable of producing intoxications similar in every respect to 
those produced by the thyroid toxins appear to exist in the extractives 
from other stale animal tissues, muscles, spleen, thymus, etc. It is evi- 
dent, therefore, that the thyroid substances which prove toxic by way of 
the stomach to normal rabbits, monkeys and probably also to men, arise 
during the post-mortem chemical alterations which the constituents of 
various animal tissues, and especially those of the thyroid gland, are 
more or less prone to undergo. 
Are the mixed extractives of the fresh thyroid gland poisonous to 
animals when large doses are injected beneath the skin? Most certainly, 
according to my experience, but not more so, or even frequently not as 
much so, as some of the extractives derived by similar chemical methods 214 
Experimental Thyroidism 
from the fresh suprarenal capsules, the spleen, the liver, the muscles, the 
salivary or the lymphatic glands, the spinal cord and the blood (dog). 
But because all the above dead animal tissues will yield extractives that 
are poisonous when injected in rather large doses under the skin of an 
animal, one is not, however, justified in concluding forthwith that these 
poisonous extractives normally enter the blood in this form from the 
living tissues of the body. Consequently I do not think that the sub- 
cutaneous injection of the mixed extractives obtained from a supposedly 
internal secreting ductless gland by the above chemical methods, which 
very probably bring about extensive molecular changes in the original 
living constituents of the glandular tissue, truly indicates whether the 
supposed normal internal secretion, as it exists in the living body, can 
he toxic or not if it is produced in too great a quantity. 
The only reliable method of testing whether or no the impure active 
thyroid principles are capable of producing an intoxication is to give 
large doses by the stomach, for both chemical and experimental evidence 
clearly demonstrate that their palliative activity on the cachexia is not 
lessened when they are absorbed from the alimentary canal. 
Clinical and experimental tests have also clearly shown that when cer- 
tain thyroid preparations are taken into the stomach by healthy or by 
diseased individuals they are capable of producing an intoxication with 
symptoms resembling in some respects those of Graves’ disease. The 
digestive juices, therefore, destroy neither the active palliative thyroid 
principles nor the toxic principles. The raw fresh gland does not ap- 
pear to contain the latter, but does contain the former, an apparently 
harmless substance even when ingested in enormous amounts; therefore, 
if the negative results of the tests by the stomach be considered valid, it 
is extremely probable that in exophthalmic goitre it is not the supposed 
increase of the normal active palliative thyroid principle which is respon- 
sible for the symptoms of that disease. 
Are the toxins which one only finds in thyroid material that has been 
kept for a number of hours after the death of the animal, in reality iden- 
tical with those toxic substances which the adherents of the hyper- 
thyroidation theory of exophthalmic goitre claim the enlarged, or even 
the unenlarged thyroid gland is contributing to the blood? Judging 
from the extremely small amounts, frequently but 15 grains, of many of 
the dried thyroid preparations that will produce death in a strong, 
healthy monkey, I should say that the substances are not the same. The 
toxicity appears proportionately too great, for should a considerable 
quantity of such substances continuously enter the blood. I judge from 
my results in monkeys that rapid death would occur. R. H. Cunningham 
215 
When but fifteen grains of a normal sheep’s thyroid gland contain 
enough of these toxins to kill a monkey or a rabbit, it is legitimate to 
think that the enormously increased secretion of the supposedly over- 
active and often extremely enlarged thyroid in exophthalmic goitre 
would contain many times the quantity of toxins that are contained in 
fifteen grains of a normal gland. Did the internal secretion of the 
living goitre contain proportionate amounts of toxins identical with those 
of the dried normal gland, either a considerable degree of tolerance of 
rather large amounts of the toxins would probably follow, as the active 
secreting glandular elements of the thyroid gradually increased in 
amount, or if such tolerance were not established, very rapid death would 
occur, just as it does in an animal poisoned with the dried juice, or as it 
frequently does in man just after the partial excision of the struma. 
The result in the latter instance is due, according to the majority of 
surgeons (Kocher and others), to the inundation of the system by the 
thyroid juice unavoidably squeezed into the lymphatics during the man- 
ipulations of the operation, or to absorption of some of the poisonous 
juice which, according to Jaboulay, flows in enormous quantities from 
the gland after the performance of exothyropexie. When the enlarged 
living gland is continually adding such enormous amounts of a juice 
which ought, therefore, to contain an enormous amount of extremely 
toxic products, the degree of toxicity being judged by that which can be 
present in such small quantities of the dried normal sheep’s thyroid, it is 
extremely probable that a certain degree of tolerance would occur, else 
the average case of exophthalmic goitre would not be liable to progress 
in the usual chronic manner. If the system of a patient with exoph- 
thalmic goitre become partially accustomed to the large continued inflow 
of the toxin-containing thyroid secretion, and were the poisons of that 
secretion identical with those that one usually finds in the poisonous thy- 
roid preparations, one would hardly expect that the ingestion of the 
additional quantities of the supposedly similar toxins that are contained 
in one five-grain thyroid tablet per day for only one day would be fol- 
lowed by any very rapid and pronounced aggravation of the symptoms of 
the disease, especially as a considerable degree of tolerance of the thy- 
roid toxins can be produced in some of the lower animals, and the same 
thing has been observed by clinicians to occur in man. Thus from a 
series of experiments on rabbits and monkeys I found that by very gradu- 
ally increasing the daily dose of a poisonous thyroid preparation until 
relatively large amounts of the preparation could be ingested without 
producing any very pronounced symptoms, a fair degree of tolerance of 
the toxins that were contained in that variety of thyroid preparation 216 
Experimental Thyroidism 
could be produced. For example, a monkey that had been accustomed in 
this manner to 3 grm. doses of a preparation, took that quantity daily for 
five days and showed but very slight symptoms, whereas, when another 
monkey of the same species, that had previously received no thyroid, was 
given 20 grains of the same preparation, the monkey died in five hours. 
Even a slight degree of tolerance of the poisonous thyroid prepara- 
tions does not, however, appear to be present in exophthalmic goitre, a 
fact fully substantiated by the reports of Auld, Dreyfus-Brisac, Beclere, 
Ewald, Ingalls, Nasse, Stabel, Starr, and numerous others besides myself. 
According to my experience some of the symptoms of the several cases 
of exophthalmic goitre, to which I very cautiously prescribed small doses 
of commercial thyroid tablets that were subsequently found by experi- 
ment to contain a considerable proportion of toxic products, became ap- 
parently aggravated as early as the morning of the second day of the 
treatment, although but two 5-grain tablets had been taken in some 
instances. But the finely minced, absolutely fresh raw sheep’s thyroid 
did not produce, as I have previously pointed out, this exacerbation of 
the symptoms; in fact, the patients with Graves’ disease seemed to bear 
both the fresh gland and the extractives of the fresh gland very well. 
Further, although the urine of individuals with Graves’ disease has 
been demonstrated by Chevalier, Boinet and Silbert, Albu and others, to 
contain a larger percentage of toxins than that of normal individuals, 
none of those writers has demonstrated that the toxins excreted in the 
poisonous urine of those patients were identical chemically with those 
met with in the poisonous thyroid preparations. 
I may furthermore add that the various poisonous thyroid preparations 
do not invariably produce symptoms that resemble those of exophthalmic 
goitre. Some of the symptoms may resemble those of the latter disease, 
but frequently marked differences are met with in the experimental in- 
toxication, and furthermore I reiterate that toxic substances that produce 
identically the same symptoms as those resulting from the ingestion of 
the poisonous thyroid material may develop in other animal tissues. 
The latter poisons vary also in quantity and quality just as the thyroid 
poisons do. , 
From the above evidence it cannot be said that it is by any means con- 
clusively indicated that the toxic substances which may or may not be 
found in certain thyroid preparations are identical with those that 
many observers suppose are being contributed to the blood by the en- 
larged thyroid in Graves’ disease. R. II. Cunningham 
217 
APPENDIX. 
As practically the whole of this paper was already written before the 
publication of the second contribution of Baumann and Boos,* in which 
is described the method of preparing the principle “ thyro-iodine,” which 
they consider to he the active substance of the thyroid gland, my experi- 
ence with that body must be related briefly in this appendix. 
Baumann’s method is as follows: The thyroid glands are boiled in a 
10 per cent, solution of sulphuric acid until a nearly complete solution 
of the glands occurs. The active substance is for the most part contained 
in the fine, flocculent precipitate which also contains fat, fatty acids and 
other substances. The precipitate is repeatedly boiled in 90 per cent, 
alcohol with the result that the “ thyro-iodine ” gradually goes into solu- 
tion in the alcohol. The alcoholic solution is evaporated and the resid- 
uum triturated with milk-sugar. After extracting the triturate with 
ether and benzin, it is dissolved in a cold dilute solution of caustic soda. 
On acidifying this solution the thyro-iodine is precipitated. Having re- 
dissolved it in caustic soda solution and reprecipitated it with HC1 or 
with H2S04, the coloring matters are separated and the thyro-iodine is 
obtained, after drying, in the form of a brownish powder that is insoluble 
in water but soluble in caustic alkalies. By this process 25-30 per cent, 
of the original iodine combination is lost. The greater portion of the 
thyro-iodine is united in the thyroid gland to two proteid bodies, “thyro- 
iodo-globulin ” and “ thyro-iodo-albumin,” and only a small portion of 
the thyro-iodine is present as such in the thyroid gland. 
Boos f has lately investigated the toxicity of thyro-iodine—a prepara- 
tion that had been manufactured by F. Bayer & Co. according to Bau- 
mann’s process—and in reference to Lanz’s conclusions that the symp- 
toms of the thyroid intoxication are due partly to the action of the thy- 
roid material, and partly to the action of decomposition products, writes, 
“ Fine Ansicht, die durch die Versuche mit dem Thyroiodin, wohei von 
irgend welchen Verunreinigungen durch Bacterien oder Zersetzungspro- 
ducte keine Bede sein kann, ihre Bestatigung erhalten hat.” Incident- 
ally, I must add in this connection that, judging merely from the odor 
of some of the bottles of thyro-iodine or rather “ Iodo-thyrine ” that were 
procured from that firm, one would be inclined to believe that a certain 
amount of decomposition had occurred in the original raw thyroid mater- 
ial, probably during the time consumed in collecting a large number of 
glands at the slaughter-house and forwarding them to the manufactory, 
* Baumann and Roos, Zeitschr. f. physiolog. Chem., xxi (1896), 481. 
t Roos, Zeitschr. f. physiol. Chem., xxii (1896), 18. 218 
Experimental Thyroidism 
where further time is consumed in carefully selecting the healthy glands. 
Be this as it may, however, Roos obtained (Exp. 2) from three doses 
(altogether equal to 18 grm. of raw gland) of this thyro-iodine prepara- 
tion, headache, tremor, diarrhoea, palpitation and accelerated heart’s ac- 
tion (108) with a temperature of 36.8° C. From larger doses (the 
equivalent of 18 grm. of raw gland given in two days) practically the 
same symptoms occurred, hut the induced condition was never serious 
and the symptoms ceased after discontinuing the preparation. The ex- 
periences of Grawitz * and of Hennig f with this commercial thyro- 
iodine preparation also confirm those of Roos. 
On the other hand Ewald,\ discussing the effects of thyro-iodine on 
man, remarks as follows: “ Voriibergehende Anwendung des Thyro- 
jodins selbst bis zu 4 grm. pro die, hat keinen erheblichen Einfluss auf 
den Puls. Yon Jodintoxication kann nicht die Rede sein, weil die Menge 
von Jod in der Druse und ihren Praparaten sehr gering ist. Dagegen, 
werden Intoxicationen iiberhaupt heschriehen, wie Steigerung der Res- 
pirationsfrequenz, Kopf- und Gliederschmerzen, Speichelfluss, Urticaria, 
Herzklopfen, Zittern, u. s. w. Oft genug tritt aher trotz Anwendung 
grosser Quantitaten sicher wirksamer Priiparate keine Reaction ein.” 
According to Schuster § even the ten- or twenty-fold dose of thyro- 
iodine causes no disturbance of the pulse in man, nor does the intra- 
venous injection of thyro-iodine cause disturbance of the blood pressure 
or of the pulse (animals?). Nevertheless, Baumann || states, “ Schild- 
driisenpraparate mit welchen man jene Vergiftungserscheinungen uber- 
haupt nicht hervorrufen kann, werden iiberhaupt wenig wirksam sein.” 
Further, Baumann calls attention to the more rapid action of thyro- 
iodine as compared to that of the raw gland or thyroid tablets, and ex- 
plains the occurrence on the ground that the thyro-iodine must first he 
separated from the constituents of the thyroid material by the process of 
digestion—a statement which, in conjunction with the fact that thyro- 
iodine is insoluble in water and exists in very small amount as such in 
the raw gland, is, to say the least, very irreconcilable with the previous 
observations of others as regards the activity of crude aqueous extracts 
in myxoedema. 
As the preceding evidence concerning the toxic nature of thyro-iodine 
* Grawitz, Munch, med. Wochenschr., 1896, No. 14. 
t Hennig1, ibid., 1896, No. 14. 
| Ewald, XIV. Congress f. inn. Med., Wiesbaden, April 11, 1896. Wiener 
med. Wochenschr., 1896. No. 10, 376. 
§ Schuster, Wiener med. Wochenschr., 1896, No. 10, 379. 
|| Baumann, Miinchener med. Wochenschr., 1896, No. 14. R. H. Cunningham 
219 
derived from supposedly fresh thyroid material still leaves the subject in 
doubt, especially as all those observers who note the occurrence of toxic 
symptoms from the administration of thyro-iodine appear to have em- 
ployed commercial thyro-iodine preparations which were obtained from 
the same firm, my own results with evidently active thyro-iodine prepa- 
rations, prepared by myself and carefully tested for iodine, are appended. 
After preparing a large amount of thyro-iodine according to Bau- 
mann’s method and testing it for the presence of iodine, 2 grm. of the 
dried powder (unmixed with milk-sugar) were suspended in warm water, 
the acid solution was neutralized and given to a rabbit by means of the 
stomach tube. No immediate or remote effects on the heart-beat, the 
temperature or the eyes could be detected. No diminution in weight 
resulted. 
A Java monkey was given 8 grm. of this preparation and two days 
later 10 grm. were given. As with the rabbit the result was negative. 
To a patient with an enlarged thyroid gland daily doses of 1 grain of 
this thyro-iodine triturated with a little milk-sugar were given for a 
week. At the beginning of the treatment the circumference of the 
neck was 13£ inches; on the ninth day the neck measured inches. 
No disagreeable symptoms appeared and, as this particular preparation 
was exhausted, the patient was put on 1 grm. doses of the commercial 
“ iodo-thyrine ” (1 grm. = 1 grm. of gland or about 3 milligrammes of 
purified thyro-iodine). After a week’s administration of the latter prep- 
aration the neck measured but 12 inches. So far no disagreeable symp- 
toms have occurred in this patient from doses of the above amount, nor 
has the patient diminished in weight. Possibly were larger doses to be 
given to this patient this preparation might give rise to toxic symptoms 
similar to those that Roos has observed with preparations from the same 
source. 
Owing to lack of opportunity the thyro-iodine preparation made by 
myself was not administered to a patient with myxoedema. I am, there- 
fore, unable to pronounce upon its activity in palliating that disease, but, 
judging from the diminution of the goitre which occurred during its 
administration, I am of the opinion that the preparation could be prop- 
erly considered an active one. The toxic properties of commercial thyro- 
iodine have not been investigated by me in animals, but the experiments 
of Ewald indicate that the toxicity of the various lots probably varies like 
that of the various commercial thyroid powders and compressed tablets. 
According to Baumann * the thyro-iodine is the only active thyroid 
* Baumann, Munch, med. Wochenschr., 1896, No. 20. 220 
Experimental Thyroidism 
principle, and from experiments on two dogs, he and Goldmann con- 
clude that small doses of thyro-iodine are fully capable of completely 
replacing the thyroid function in animals (dogs) that have been deprived 
of that function through removal of the thyroid gland. Gottlieb’s * re- 
sults with thyro-iodine in thyroidless dogs do not, however, agree with 
those of Baumann and Goldmann, and my own results in totally thyroid- 
less dogs with concentrated extracts obtained from thyroid glands by 
means of salt solution, which, according to Baumann and Roos, extracts 
all of the iodine combination from the minced gland, lead to the belief 
that the conclusion of Gottlieb that thyro-iodine is not capable of keep- 
ing the thyroidless dogs indefinitely alive is perfectly correct. Moreover, 
other experiments with purified thyro-iodine yield results that fully con- 
firm the above conclusion of Gottlieb. 
From the clinical results of Ewald and others with commercial thyro- 
iodine in the treatment of myxcedema, it is evident that the thyro-iodine 
prepared by the method of Baumann does contain something that in- 
fluences the symptoms of that disease. Wishing to find out whether or 
no che iodine-containing product which Baumann’s method yields would 
furnish further residual products if it was treated according to Drechsel’s 
method of extracting the thyroid gland, four grammes of the powdered 
iodine-containing thyroid product were boiled in distilled water, the de- 
coction being neutralized by a small quantity of caustic soda solution. 
After this solution had cooled it was filtered and the filtrate precipitated 
■with phospho-tungstic acid. This precipitate was treated as Drechsel 
describes and ultimately yielded a small quantity of gummy residue that 
contained no iodine, but which after being dissolved in water appeared 
to possess physiological properties similar to those of the residue result- 
ing from the ammoniacal solution of the phospho-tungstic thyroid pre- 
cipitate in Drechsel’s process. The chemical nature and composition of 
the gummy residue obtained from the iodine-containing product that was 
extracted from the thyroid gland according to Baumann’s method have 
not been investigated by me except to test it for iodine, therefore I am 
unable to give further information as to its origin. 
It is evident that the above-described facts concerning the production 
of toxic symptoms similar to those of exophthalmic goitre still harmon- 
ize with the general results discussed elsewhere in this paper. Also it is 
readily conceivable that should the least post-mortem decomposition 
have occurred in any of the thyroid glands before being put through the 
various stages of Baumann’s process, some portion of the toxic sub- 
* Gottlieb, Deutsch. med. Wochenschr1896, No. 15, 235. R. II. Cunningham 
221 
stance or substances might still contaminate the thyro-iodine, so that in 
the hands of some observers one lot of thyro-iodine would give rise to 
certain disagreeable symptoms, while other observers using thyro-iodine 
prepared from a different lot of thyroid material would not observe the 
occurrence of those symptoms, even though very large doses were given. 
Even in a city of the size of New York, where large numbers of sheep 
and oxen are slaughtered daily, it is exceedingly difficult to gather 
together large amounts of absolutely fresh thyroids from animals that 
have been killed but a few minutes, and it is extremely likely that when 
very large quantities have to be collected for the preparation of thyroid 
products on a commercial scale, and twelve to twenty-four hours elapse 
between the death of the animals and the extraction of the glands, some 
decomposition has occurred in the material.* 
D. The effect of the thymus extractives upon the acute cachexia in 
thyroidless dogs. 
Concomitantly with the previously mentioned experiments with 
extractives derived from the thyroid gland, I have also carried on a 
series in which the thymus gland of the young ox served as the source 
of the extractives. 
* Hutchison (Journ. of Physiol., xx, 1896; Brit. Med. Journ., 1897, 194) states 
that the active part of the thyroid is found in the colloid substance which 
he finds is precipitated by acetic acid and redissolved by excess of acid. 
From chemical experiments performed since the publication of his papers, 
I find that after precipitating cold alkaline aqueous extracts of fresh 
sheep’s thyroid with acetic acid, some of the substance that palliates the 
cachexia still remains in solution. When this solution is further treated 
with acetate of lead, etc., this substance finally appears as one of the 
probably many components of the waxy mass of extractives. The greater 
the quantity of this substance in the waxy mass, the more active the mass 
of extractives seems to be. The presence of this substance in the mass 
that I have termed “ extractives ” possibly accounts for the different results 
that I have obtained by injections of the so-called extractives. 
In rabbits and monkeys I have not been able to produce toxic symptoms by 
administration by mouth of colloid from perfectly fresh sheep’s thyroid, 
although large doses were given. The colloid was obtained in the manner 
Hutchison describes, but the fresh glands were extracted only for one 
hour. The toxicity of colloid after an 18 hour extraction of the fresh 
glands has not been tested, but from Hutchison’s account of the rise of 
temperature, etc., after doses as small as .05 gm., its toxicity can evidently 
be considerable. (January, 1898.) 222 
Experimental Thyroidism 
Only the perfectly fresh glands were used after being carefully exam- 
ined for accessory thyroid bodies and were treated preferably by the 
acetate of lead method, which was also employed in the extraction of 
creatin and other constituents of muscle, and which Fraenkel * first rec- 
ommended for the extraction of the substance that he calls “ thyreo- 
antitoxin.” All of the methods that have been given for the extraction 
of the fresh thyroid apparently yield the active substances to which I 
refer in this section, hut the acetate of lead process has always proved 
the least laborious and yielded considerable quantities of the waxy mass, 
consequently I have usually employed it. 
Whether or no the process recommended by Drechsel for the extraction 
of his two thyroid principles will yield from the thymus substances that 
possess a physiological activity which is similar to that possessed by the 
products which I have obtained from the thymus by the acetate of lead 
method, I am not at present able to state positively. So far I have ap- 
plied Drechsel’s method to the thymus hut twice. As in the case of the 
thyroid, the method yields with the thymus gland two brownish oily 
products, both of which contain numerous varieties of crystals. Many 
of these crystals are evidently identical with those that the thyroid gland 
yields by Drechsel’s method, if one judges by their microscopical appear- 
ances only, but it must be admitted that I have met with no better suc- 
cess here in obtaining either these thymus crystals or the mother liquor 
in an absolutely pure state, than I did when the fresh raw thyroid gland 
was extracted according to Drechsel’s method. One of these mixed 
crystalline products evidently possessed considerable activity, but the 
results with the other are not at all conclusive, for the five thyroidec- 
tomized dogs to which the substance was given proved at the autopsy to 
have moderately well developed accessory thyroid glands in the aortic 
region. Further experiments at present in progress will he necessary 
before I can conclude definitely whether both of the products that the 
method yields possess activity. 
Precipitation of a solution of the brown gummy mass of thymus ex- 
tractives that results from the acetate of lead method, by phospho- 
molyhdic or by phospho-tungstic acid, boiling the precipitates first in 
water and then in an ammoniacal solution, decomposing with baryta, etc., 
appears to yield with the thymus also two active portions containing 
sundry varieties of crystals which deposit from the mother liquor. 
Whether the active principles of the two portions are really two chemi- 
cally different bodies or not I am not prepared to say in this preliminary 
* Fraenkel, loc. cit. R. H. Cunningham 
223 
notice of the phenomena that I have observed to follow the injection of 
these thymus extractives. If the active principles be two different 
chemical bodies, both are evidently contained in the gummy waxy mass 
which the thymus, like the thyroid, yields by the acetate of lead process. 
This waxy mass of mixed thymus extractives has, therefore, usually been 
employed, and the following remarks refer to its effects unless it is speci- 
fically stated to the contrary. 
Before entering into the description of the actual experiments with 
the thymus extractives I deem it pertinent in this connection to state 
briefly that at the outset of the experiments a filtered thymus bouillon 
was employed. This of course was concentrated by boiling, filtered, and 
a large quantity injected into two thyroidless dogs that presented marked 
prodromal symptoms of an impending dyspnoeic attack, considerable con- 
junctivitis and rhinitis, enophthalmos, frequent muscular twitchings, and 
considerable stiffness in the hind legs. In about one hour both animals 
appeared to be improved, for the symptoms of the impending attack sub- 
sided. Owing to the lateness of the hour no further observations of the 
animals were made until the following morning, when it was found that 
the thyroidless dog that had received the concentrated bouillon to the 
amount of 122 ccm. (= 244 grm. of fresh thymus) was lying sprawled out 
and apparently paralyzed in the hind legs, hut the dog was still able to 
elevate itself upon the forelegs and drag the rear part of the body along 
for a short distance in a very unsteady manner. When the animal at- 
tempted to move, slight muscular twitching appeared in the forelegs, but 
when the dog was lying quietly no tremor could be detected. The con- 
junctivitis and rhinitis had almost subsided and the eyes no longer ap- 
peared sunken. The animal took its food with fair appetite and recov- 
ered the use of its rear legs by the afternoon. The following morning 
the dyspnoea returned and the dog had several convulsions, dying about 
98 hours after the thyroid glands had been excised. A most careful 
post-mortem examination revealed no accessory bodies. 
The second dog that received but 55 ccm. of the thymus bouillon was 
also apparently much benefited by the injection, for the signs of impend- 
ing dyspnoea gradually subsided and on the following morning were en- 
tirely gone. On this and on the two succeeding days the existence of 
the cachexia was only manifested by occasional fibrillary twitchings in 
various muscles, progressive emaciation, periods of restlessness, moderate 
conjunctivitis and the manifestation of but little desire for the food that 
was placed before the animal. On the fifth day the typical fits occurred 
in the very emaciated animal, and death followed about midday. At the 
autopsy several small accessory bodies were found in the aortic and in 224 
Experimental Thyroidism 
the thyroid regions, consequently this experiment indicated in my 
opinion absolutely nothing. 
Although no accessory bodies were found in the former dog, a definite 
conclusion regarding the cause of the apparent, though temporary, dimi- 
nution of symptoms could not of course be made from such imperfect 
data. Nevertheless, the peculiar experience was considered worth a more 
extensive and careful investigation, and the following description of one 
of my experiments, it is hoped, will convey some idea of the effects which 
I have repeatedly observed to occur in totally thyroidless young dogs 
after the injection of a boiled 4 or 6 per cent, aqueous solution of the 
waxy mass of thymus extractives. 
Two young, healthy dogs, respectively weighing 8200 grm. and 5750 
grm., were chosen. The thyroid bodies of both were quickly removed 
(ether anaesthesia) with strict aseptic precautions. On the following 
morning the injections were begun, dog (a) receiving a small dose of the 
thymus extractives; dog (b) a similar amount of a 4 per cent, solution of 
thyroid extractive which had been extracted from fresh raw thyroid, 
also by the acetate of lead method. 
The condensed notes of the experiment are as follows: 
Dog (a). 1st day: 19 minims of a 4 per cent, thymus solution in- 
jected. 
2nd day: 38 minims were given, as the animal was very restless and 
the usual tetany and conjunctivitis were beginning to appear. 
3rd day: 87 minims given in three doses during the day, as the limbs 
of the dog were very stiff, and a mild attack of dyspnoea occurred. 
Weight 8005 grm.; pulse 160; temperature 105f° F. The animal still 
takes its food. 
4th day: 90 minims injected; dog exhibits considerable tremor. 
5th day: 9.45 A. M. 30 minims injected. Animal much brighter 
and is able to run about, although fibrillary twitchings still appear in the 
hind legs. Weight 8300 grm.; pulse 140; temperature 103°. Conjunc- 
tivitis subsided. The animal begins to take but little food. 1.30 P. M. 
Symptoms of an impending dyspnoeic attack being present, 50 minims 
were injected and repeated at 2.30 P. M., after which the distressing 
symptoms quickly subsided. 
6th to 9th day: 125 minims per day injected in three doses. Dog 
very weak and emaciated. Weight 7400 grm. Has refused all food for 
the past two days and has to be given milk by means of the stomach 
tube. Most of the milk was vomited ten or fifteen minutes after the 
withdrawal of the tube. Had a slight fit on the ninth morning, but 
recovered shortly after the injection of 50 minims of the thymus solu- 
tion. R. II. Cunningham 
225 
10th to 13th day: 75 minims per day injected. Weakness and ema- 
ciation steadily increasing and no food is retained in the stomach. 
14th day: 50 minims given, but the dog died about noon. Weight of 
animal at death 5800 grammes. 
Autopsy: The most careful search failed to reveal the presence of 
accessory thyroid tissue. 
Dog (b). Was given 19 minims per day of a 4 per cent, solution of 
the thyroid extractives until the morning of the fourth day, on which 
date the dog was found at 9.15 A. M. having a series of very severe fits. 
After several doses, in all equaling 104 minims, the dog recovered and 
in the course of two hours was able to run about, although a moderate 
degree of stiffness still persisted in the hind legs. From the 4th to the 
9th day, on which the animal died, 25 to 100 minims of the thyroid 
solution were injected per day, the amounts depending upon the condi- 
tion of the animal. During this period several slight dyspnoeic attacks 
occurred, but no more general convulsions. From the 4th day the dog 
refused food, and from this day the progressive emaciation became more 
prominent, 950 grammes being lost in all. At the autopsy a small ac- 
cessory thyroid body about 2 mm. in diameter, which contained a small 
quantity of colloid, was found in the aortic region. 
In this instance the animal injected with the thyroid extractives for 
comparison died before the animal injected with the thymus. Generally 
both animals survive for fifteen or eighteen days, but not longer unless 
they possess a small amount of accessory tissue. 
Normal dogs injected with equal amounts of the above solutions ap- 
parently exhibit no effects. 
The results of the foregoing and of other similar experiments lead 
me to believe, after comparing the effects of the thymus extractives 
prepared by the above method, that the concentrated thymus extrac- 
tives prove just as efficient in palliating the cachexia in totally thyroid- 
less dogs as the thyroid extractives. 
I do not desire that the above statement should be interpreted as 
meaning that the active extractives from the thymus and the thyroid 
are chemically the same. This question has not at present been an- 
swered. It is possible that extracts from other cellular organs may 
be found to modify the acute cachexia as well as the extractives from 
the thyroid gland. 226 
Experimental Tliyroidism 
I am fully aware that the periods of survival of the thyroidless dogs 
that were injected with the thymus extractives or even with the thyroid 
extractives, to which the following remarks likewise apply, will seem 
entirely too short if my results are compared with those of other ob- 
servers who claim to have kept thyroidless dogs alive for many weeks or 
even months by the mere administration of thyroid material by the 
mouth. I have, however, previously called attention to the fact that 
although I have repeatedly given enormous amounts of raw thyroid or 
of the extractives from the fresh thyroid to large numbers of thyroidless 
dogs, I have never been able to obtain such results except in dogs that 
were invariably proved at the autopsy to have several accessory thyroid 
bodies, microscopic or larger in size. Whenever the supposedly thyroid- 
less young dogs continued to take food with their usual appetites, or 
when the profound disturbances of nutrition failed to appear fairly 
rapidly, or, if at the end of twenty days the thyroidectomized dogs that 
were being subjected to the thymus or to the thyroid treatment appeared 
to differ but little from normal dogs, I always concluded that a certain 
amount of living and functionally active accessory thyroid tissue was 
still present in the dogs. At the autopsy the animals were examined 
most carefully in all those regions in which Piana, Puhr, Wolfler, Wag- 
ner, Carle and others have stated accessory thyroid bodies could occur. 
As a result of this examination it was found that my opinion was invaria- 
bly correct, and consequently it was not allowable to conclude that the 
extractives or the diet of raw gland were responsible for the modified 
cachexia and long survival of the dogs in a practically normal condition. 
Even the activity of the small accessory bodies is not always sufficient to 
keep the dogs alive, and in spite of the aid derived from large amounts 
of thyroid material, some dogs will die as early as the tenth or fifteenth 
day. In other dogs the activity of the inaccessible aortic accessory bodies 
seems to he greater, and aided by the thymus extractives, the thyroid 
juice, etc., the lives of the dogs may he so prolonged that the remaining 
accessory bodies become moderately hypertrophied and sufficiently func- 
tionally active to maintain, with the assistance of the injected thyroid 
juice or extractives, the metabolism of the dogs in a fair state of equil- 
ibrium for a number of weeks or even months. Usually, however, the 
thyroid function seems to be hut imperfectly assumed by the remaining 
accessory bodies, and in spite of the injections the profound disturbances 
of nutrition appear and ultimately bring about a fatal termination. If 
all thyroid tissue has been removed from the dog it is impossible, as I 
have remarked elsewhere, to prevent the comparatively early occurrence 
of this fatal termination, even though enormous doses of a thyroid prep- K. H. Cunningham 
227 
aration that has proved to he extremely efficient in myxoedema be given. 
Further, the unintentional oversight of the smaller and evidently active 
accessory bodies (Plates XV and XYI) which frequently are recognized 
only with extreme difficulty, especially when they are located in the 
mediastinum, fully explains, according to my experience at least, the dis- 
cordant opinions existing at present among the various previous ob- 
servers who have administered thyroid to young thyroidectomized dogs. 
As is indicated in the preceding remarks on the possible behavior of 
thyroidectomized dogs owing to the presence of small, and often unsus- 
pected accessory bodies, it is very essential to definitely determine their 
presence or their absence before a true comparison of the influence which 
the derivatives of the thymus gland appear to exert on the cachexia can 
be made with that resulting from the employment of the thyroid gland 
or its concentrated extractives. 
Naturally the knowledge of the above-described effects on the cachexia 
of the concentrated thymus extractives is not of service in explaining the 
functions of the thymus gland, but it may furnish a partial explanation 
for the favorable results that Owen, Mikulicz, Mclvie, myself and others 
have observed to occur in patients with exophthalmic goitre when the 
thymus method of treatment was employed. I write “ a partial explana- 
tion,” for, besides the effects possibly directly due to the action of the 
extractives, the beneficial effects resulting from the daily ingestion of a 
large amount of very digestible and easily assimilable food, such as the 
sweetbread is, must also be taken into consideration. Granting, how- 
ever, that the beneficial results that have been noticed in exophthalmic 
goitre are due to the extractives, the following question at once presents 
itself: “How can substances such as the thymus extractives which, as I 
clearly show, strikingly palliate the symptoms of the acute cachexia in 
dogs, possibly benefit the symptoms of a disease that are stated by the 
majority of observers to become generally more pronounced when the 
usual thyroid preparations, presumably also containing principles which 
palliate the acute cachexia, are ingested?” Or, in other words, if the 
thyroid extractives and the thymus extractives are equally capable of 
temporarily supporting an animal that has been deprived of all thyroid 
function, how can the administration of these similarly acting extrac- 
tives give rise to beneficial effects in a diseased condition which the 
present consensus of opinion states to be the result of increased thyroid 
activity? 
To attempt to properly elucidate these questions would entail neces- 
sarily a detailed discussion of the entire and still unsettled thyroid 
theory of Graves’ disease. The pros and cons of this theory have been 228 
Experimental Thyroidism 
discussed so fully within recent years by numerous writers that it is not 
necessary to set them forth in detail in this paper. 
In spite of all the evidence brought forward to support the theory 
that the symptoms of Graves’ disease arise in consequence of exaggerated 
thyroid function, it is nevertheless an admitted fact that cases exist that 
present besides symptoms of exophthalmic goitre many of the charac- 
teristics of myxoedema. But it is reasonably conceivable from the facts 
which the observations of Reverdin, SchifT, Kocher, Fuhr, Horsley, von 
Eiselsherg, Poncet, Zesas, Ord and others have brought to light con- 
cerning the sequence of the various groups of symptoms which arise as 
the result of the total suppression of the thyroid function, or even from 
a partial interference of its function, that this class of patients ought to 
exhibit, before the myxcedematous tissue changes occur in the myxoede- 
matous variety of Graves’ disease, some of the symptoms at least that 
arise during the earlier stages of the cachexia that supervenes when the 
thyroid function is sufficiently diminished. The most prominent early 
symptoms, or symptoms of the neurotic stage (Horsley) as taught by 
experiments on monkeys, dogs and other lower animals, as well as by the 
sequence of events that has been observed after operative myxoedema 
(Reverdin) in men, consist of the following: profound general weakness, 
restlessness and periods of depression, fibrillar muscular tremor (rate of 
clonus 8-10 per second), local and general tetanoid spasms, emaciation 
and anfemia, increased lachrymal, nasal and salivary secretion, acceler- 
ated heart-beat, moderate or considerable elevation of temperature (Her- 
zen, Horsley, Hghetti, Alonzo, Rogowitsch, Formanek and Haskovec), 
dyspnceic crises, ocular disturbances, such as enophthalmos * with nar- 
rowing of the palpebral fissure, muscular palsies, corneal and conjunc- 
tival congestion, etc., lowered blood pressure, and frequently dilated peri- 
pheral arterioles manifested by the congested condition of the various 
mucous membranes. Later, trophic disturbances of the hair, nails, etc., 
occur, and various motor palsies are also not infrequent. 
When the myxcedematous tissue changes have fully developed it has 
* In two of my meat-fed thyroidless dogs with accessory aortic thyroid 
bodies, in one bread-fed partially thyroidless dog, and in a dog in which 
all the vessels of both thyroid lobes had been ligated with catgut, a con- 
siderable prominence of the eyes developed on the morning after the 
thyroidectomy. The exophthalmic condition was so noticeable that, before 
I had an opportunity to direct attention to it, it was previously remarked 
by a laboratory attendant and others who had not been forewarned to be 
on the lookout for the occurrence. In the latter dog the exophthalmos 
lasted for about two weeks, but gradually became less noticeable owing to 
the marked puffiness that developed in the dog’s face. R. H. Cunningham 
229 
been clearly demonstrated both in man and in the lower animals that a 
reversal of the majority of the above symptoms is the rule; hebetude, 
increased weight, diminished secretions, subnormal temperature, slowed 
heart-beat, etc., thus replacing their opposite of the early stages of the 
cachexia. The enophthalmos with narrowing of the palpebral fissure, 
however, generally persists. 
Thus a great many of the symptoms proper to the early stages of the 
cachexia are, as Mackenzie, Gley and others have specially pointed out, 
strikingly like those that are usually manifested by the average patient 
with exophthalmic goitre. Therefore, if one considers the following 
facts, namely, (a) the remarkable similarity of many of the common 
symptoms of exophthalmic goitre to those of the first stage of the 
cachexia thyroidectomica; (b) the well-known tendency of the struma to 
become indurated or otherwise degenerated, and the clinical fact that the 
partial removal of the supposedly overacting struma from individuals 
that manifested only the usual symptoms of exophthalmic goitre, unac- 
companied by myxcedematous tissue changes, has been followed by the 
appearance of pronounced tetany, general or local swellings, myxoede- 
matous in character, and occasionally by death preceded by all the usual 
symptoms of the acute cachexia, one is led to the conclusion that an 
insufficiency of at least one of the various possible functions of the thy- 
roid gland may be present in exophthalmic goitre without myxcedematous 
tissue changes being evident. 
Thus, from our knowledge of the effects of the fresh thymus and 
thyroid extractives on the symptoms that result from an insufficiency of 
thyroid activity, it is but reasonable to expect that, if a partial “ hypo- 
thyroidation ” (Gley) is directly or indirectly responsible in many cases 
of Graves’ disease, an exhibition of these extractives by mouth would 
probably be followed by more or less amelioration of many of those 
symptoms. My previously described observations with the fresh thymus 
and thyroid glands confirm this, but my observations with the dried 
thyroid preparations conform with the usual experiences of others, that 
the exhibition of the average commercial thyroid preparations, powders, 
concentrated extracts, etc., to patients who have Graves’ disease but no 
evidence of myxcedematous changes, generally results in making the 
patients decidedly worse, an occurrence that is due, in my opinion, to the 
action of the toxic alteration products which further disturb the already 
disordered metabolism. 
Typical myxcedematous patients are also well known to be very sus- 
ceptible to the poisonous preparations, many well-known English, Ger- 
man, French and American observers advising extreme caution in the 230 
Experimental Thyroidism 
thyroid treatment of myxoedema, and in fact, as Ewald has pointed out, 
symptoms of intoxication may develop during the treatment of myx- 
oedema without the appearance of any curative or beneficial effects. Son- 
nenburg’s * experience which was related in the historical retrospect (Part 
I) clearly shows, however, that in operative myxoedema enormous quan- 
tities of thyroid may he taken without development of any toxic symp- 
toms whatever, the patient even improving and gaining in weight from 
the very commencement of the treatment. 
These observations, coupled with various facts described in connection 
with the symptoms that occur in rabbits and monkeys after the adminis- 
tration by mouth of the concentrated toxins extracted from stale or dried 
thyroid, clearly indicate that the prominent katabolic effects which 
rapidly occur in myxoedema, obesity, etc., in consequence of the inges- 
tion of the average dried thyroid preparations, are probably almost 
entirely due to the action of the contaminating and varying cadaveric 
poisonous derivatives. 
Further, one is almost led to believe that, although an increased sus- 
ceptibility to these toxins exists in myxoedema, if very small amounts of 
these powerful stimulators of kataholism are given in combination with 
those thyroid substances which are capable of modifying the early symp- 
toms of the acute cachexia, the myxoedematous individual may be some- 
what benefited by the reduction in weight from the decided destructive 
metamorphosis of the myxoedematous tissues and the increased excretion, 
which the toxic varieties of the thyroid preparations have been experi- 
mentally shown to produce. I am not, however, in a position to sub- 
stantiate the above by clinical proof, for, as has been already stated, the 
palliative and the toxic activities of the thyroid preparations in general 
use, at least in the United States, are so variable and the clinical re- 
ports describing the various effects that have followed their ingestion in 
large and in small doses are often so conflicting regarding the occurrence 
of early and pronounced destructive metamorphosis and consequent loss 
in weight in myxoedematous individuals who are being treated with the 
different thyroid preparations, that it is impossible to gain a more exten- 
sive information from those clinical reports than the following: 
(1) The majority of myxoedema cases are improved by the various 
preparations, the improvement being accompanied by a considerable loss 
in weight and other trophic manifestations. 
(2) Considerable improvement occurs, but even a gain in weight ac- 
companies the improvement. 
* This observer evidently employed thyroid material in which no appre- 
ciable post-mortem alteration had occurred. R. II. Cunningham 
231 
(3) Loss in weight accompanied by the appearance of very distressing 
symptoms follows, but no evident improvement in the various nervous 
and other symptoms of the myxoedema. 
(4) Neither loss in weight nor improvement in any of the symptoms 
results until a number of different thyroid preparations have been tried. 
These facts are extremely contradictory, but the above-mentioned pos- 
sible dual activity of the average thyroid preparations will probably be 
found to be mainly responsible for the irregularities described by clini- 
cians in connection with the treatment of myxoedema by the thyroid 
method. 
As the results under the fourth heading indicate, some of the prepara- 
tions contain scarcely any of the active extractives, although an exami- 
nation of a large number of samples of various thyroid preparations, some 
of which proved absolutely inactive in palliating the acute cachexia in 
totally thyroidless dogs, showed that iodine, and presumably the thyro- 
iodine of Baumann and Roos, was present in considerable amounts in all 
of those preparations of the crude powdered gland. This substance may, 
as Roos states, be the substance which causes the reduction in the goitre, 
but reduction in the goitre will also follow the ingestion of the thymus 
gland (Owen, Mikulicz and myself), and the thymus contains, according 
to Baumann,* no iodine, a fact that has been repeatedly verified by 
myself. Other organic bodies besides thyro-iodine consequently possess 
the property of causing the struma to diminish. In fact, the recent 
experiments of Gottlieb f with the concentrated thyro-iodine prepared 
according to Baumann’s method are confirmed by my own experiences 
with the inactive or, rather, non-palliative iodine-containing thyroid 
preparations. The conclusion reached by this writer, that the thyro- 
iodine is not capable of keeping thyroidless dogs alive, is in my opinion 
perfectly correct, and from his experiments I judge that chemically pure 
thyro-iodine does not influence in the least \ the cachexia in totally 
thyroidless dogs. 
* Baumann, loc. cit. 
Baumann (Munch, med. Woch., 1896, No. 14) states, since the above was 
written, that by using large amounts of calf thymus he was able to detect 
the presence of iodine in it, although the quantity of iodine was very 
small. I have repeatedly tested the thymus for iodine, but it did not 
appear to be present in any of the thymus glands that were tested. I have, 
however, found traces of iodine twice in the salivary glands of the ox, and 
once in the parotid gland of the dog. Possibly accessory thyroid bodies 
were present in the thymus tissue examined by Baumann. 
t Deutsche med. 1 Yochenschr., Apr. 9, 1896. 
$ Experiments performed by me since this paper was sent to the editor 
show that some lots of commercial iodo-thyrine (Bayer) do moderately 232 
Experimental Thyroidism 
Is the presence of all the principles which Fraenkel, Dreclisel and 
Baumann describe necessary in a thyroid preparation in order that the 
preparation may produce all the good effects that one observes in myxoe- 
dema? This remains to be seen, for further very carefully conducted 
observations are certainly necessary to determine this point. And in 
conclusion I add that only absolutely pure principles should be employed 
for such observations. 
E. The intravascular injection of the extractives. 
1. Intravascular injection of boiled thyroid extracts. 
While some of my subcutaneous injection experiments were in progress, 
Oliver and Schafer * having investigated the blood pressure effects of in- 
travascular injections of decoctions of various glands, published the fact 
that the intravascular injection of the thyroid extract gives rise to an al- 
most immediate but transient diminution of the blood pressure by increas- 
ing the calibre of the arteries, although the beats of the heart remain at 
about the same rate and of the same strength. Schafer f states, “ Before 
this effect upon the blood pressure was discovered by us it had been shown 
by my co-worker, Dr. George Oliver, that the exhibition of thyroid juice 
and other preparations of thyroid in the human subject has a tendency to 
increase the calibre of the radial artery.” Haskovec l also noted the 
fall of the blood pressure and, besides, an acceleration of the pulse. 
Fraenkel tested the effects of intravascular injection of his thyreo-anti- 
toxin and found that this produced an acceleration of the pulse but no 
fall of blood pressure. Nor does a cold aqueous extract of dried sheep’s 
thyroid produce, according to this observer, a fall of blood pressure, al- 
though an increase in the number of heart-beats does occur. Fraenkel 
states that he does not understand this difference and, therefore, gives no 
explanation. 
influence the cachexia in totally thyroidless dogs and monkeys when the 
dose is rather large; other lots do not appear to affect the course of the 
cachexia at all, although the preparations contain iodine. When solutions 
of these active iodo-thyrine preparations were treated according to Drechsel’s 
method they yielded small amounts of two brownish gummy substances, 
neither of which contained iodine. Injections of a mixture of these 
gummy substances into totally thyroidless dogs palliated the cachexia 
somewhat, but not as much as boiled aqueous extracts of fresh raw thyroid 
usually do. 
* Journal of Physiol., xvi, 1894; xvii, 1895, and xviii, 1895. 
f Internal Secretion, BrU. Med. Journal, 1895, 341. 
$ Haskovec, quoted by Fraenkel, loc. cit. R. H. Cunningham 
233 
In order to compare the blood pressure effects produced, according 
to Schafer and Oliver, by aqueous decoctions of fresh raw or of dried 
thyroid material with those produced by the thyroid extractives which 
I had found capable of modifying the acute cachexia thyroidectomica 
in dogs, I repeated Schafer and Oliver’s experiments, and also per- 
formed a number in which the various thyroid and thymus extractives 
were employed. My results with the decoctions prepared from abso- 
lutely fresh sheep’s thyroid and from calf thymus practically agree 
with those of Schafer and Oliver; the injections produced, as these 
observers have pointed out, a transient fall in the blood pressure, al- 
though the strength of the heart-beats and the rate remained almost 
the same (Plate XVII, Fig. 1). I state “ almost,” for usually the rate 
diminished by three or four beats per minute, and frequently, if a 
very large amount of the concentrated neutralized decoction was 
injected, a diminution of eight or ten beats occurred. This slight 
•diminution in rate, like the fall of the blood pressure, was but tem- 
porary, and as the blood pressure gradually returned to its original 
height, the number of the heart-beats became the same as before the 
injection. Although the above effects were striking when fresh de- 
coctions of the fresh raw material were injected into the external 
jugular of etherized dogs,—especially when both vagi had been cut,— 
I found that if the decoctions were kept and allowed to become more 
or less putrefied, their effect upon the blood pressure became markedly 
less and less and finally disappeared. 
In several different anaesthetized and morphinized dogs a number 
of reboiled and filtered thyroid and thymus decoctions in various 
stages of decomposition were injected, and though the majority of 
them produced scarcely any diminution in the blood pressure, several 
of the stalest solutions caused a transient acceleration of the heart-beat. 
In no instance, however, did the acceleration amount to more than 
•eight beats per minute when 2 ccm. (= 2 grm. of raw gland) of the 
stale solution were injected. 
When the dried commercial thyroid preparations were employed as 
the source of the decoctions—of course allowing the pulverized gland 
to macerate for a number of hours before boiling the mass—my 234 
Experimental Thyroidism 
results were not nearly so striking or so uniform as those produced by 
smaller doses of the decoction of fresh raw thyroid which had not 
been allowed to macerate more than a few minutes before boiling. 
To sum up the cardiac and blood pressure effects of these decoc- 
tions of stale and dried material: 
(1) Some produced a moderate fall of blood pressure, the number 
of heat-beats remaining unaltered or occasionally diminishing three 
or four beats per minute. The fall of the blood pressure was always 
more prominent after both vagi had been divided. 
(2) Some produced apparently no effect at all. 
(3) Some caused no fall of blood pressure, but the frequency of the 
heart-beat temporarily increased six to ten beats per minute when the 
vagi were intact. 
(4) A decoction from one preparation invariably gave a faint in- 
crease in the blood pressure in a morphinized dog with both vagi cut. 
Thus, in (1) it will be seen that the effects practically agree with 
those that, according to Schafer and Oliver, the decoctions from the 
dried preparations produce, while in (3) the effects correspond with 
those that Traenkel states are produced by the “ thyreo-antitoxin.” 
The results in (2) depended upon the probable absence of or, as I 
found subsequently after extracting large quantities of the dried prep- 
arations, upon a considerable decrease in the relative quantity of sub- 
stances that produced the fall of blood pressure. In (4) it was clear 
that considerable alteration of the constituents of the preparation had 
occurred, a fact that was further proved by the failure of injections of 
the decoction to modify in the least the symptoms of the acute cachexia 
in totally thyroidless dogs. 
2. Intravascular injection of the thyroid and other extractives. 
Extending the above blood pressure tests to the ultimate thyroid 
and thymus extractives, the following extractives isolated by methods 
previously described in detail (page 203 et seq.), were tested and 
found invariably to produce a very decided fall of the blood pressure 
when they were injected directly into the external jugular vein or into 
the portal circulation. Briefly, these substances were: P. II. Cunningham 
235 
(a) Solutions of the brownish, waxy, impure mixed extractives, ob- 
tained from perfectly fresh thyroid and thymus glands, by the three 
methods which we have described. 
(b) The brownish waxy mass obtained from the waxy mass by treat- 
ment with 90 per cent, alcohol and repeatedly precipitating the alcoholic 
solution by anhydrous ether. (That from the thyroid should correspond 
to Fraenkel’s thyreo-antitoxin.) 
(c) The two crystalline mixtures obtained by decomposing the waxy 
thyroid mass with phospho-molybdic acid, etc. 
(d) The two crystalline mixtures obtained by decomposing the waxy 
thyroid mass with phospho-tungstic acid. 
• (e and f) The crystalline mixtures from the thymus as in c and d. 
(g and h) The two crystalline mixtures from the fresh raw thyroid by 
Drechsel’s process. 
(t and j) The two crystalline mixtures from the fresh raw thymus by 
Drechsel’s thyroid process. 
Intravascular injections of each of the above extractives produced 
effects practically similar to those produced by the decoctions of the 
fresh raw material (Plate XVII, Figs. 1 and 2, and Plate XVIII, 
Fig. 3). When neutral 5 or 10 per cent, solutions were employed 
the fall of the blood pressure was very pronounced, and frequently 
the number of heat-beats very perceptibly, though temporarily, 
diminished. 
When the dried commercial thyroid preparations were used as the 
source of the extractives, it was found that generally the extractives 
from them affected the blood pressure in just the same way as the 
extractives from the fresh thyroid, but relatively small amounts of the 
extractives were yielded by most of the dried preparations, a circum- 
stance which probably accounts for the results in (2) with the more 
dilute decoctions of those dried preparations. 
Two especially foul-smelling dried preparations were extracted by 
the acetate of lead method, and the resultant waxy mass of extractives 
treated by alcohol, ether, etc., the cleaned ether precipitate dissolved in 
normal saline solution and injected. Xo fall of blood pressure fol- 
lowed, but a slight acceleration of the heart-beat (about eight beats 
per minute) was produced several times when 1.5 ccm. of a 5 per cent. 236 
Experimental Thyroidism 
solution were injected at one dose. This acceleration, however, was 
often variable and frequently did not occur when the above quantity 
or even a larger quantity (2.5 ccm.) was given. 
Comparing these effects with those produced by the various extrac- 
tives obtained from the absolutely fresh raw thyroid, it was evident 
that the blood-pressure-reducing substances had undergone consider- 
able alteration in many of the dried thyroid preparations. Why I 
cannot say, for I do not know exactly the process by which the dried 
preparations were prepared, nor do I know how long a time was con- 
sumed in the slaughter-houses in gathering the raw thyroid glands 
together for the various manufacturers of the desiccated preparations. 
I have stated that if the extractives (a-h) were injected into one of 
the tributary veins of the portal circulation, a diminution of the blood 
pressure resulted, but, as might be expected, the abrupt fall that 
usually occurred when the injection was made directly into the exter- 
nal jugular vein was not produced. The total fall, however, was 
about the same as if an equal dose had been injected into the jugular 
vein. 
Wishing to see if the extractives would affect the blood pressure 
after being absorbed through the stomach and the intestines, I injected 
into the stomachs of etherized fasting dogs very large quantities of the 
extractives a, c, d, e and f mixed, a mixture of g and h, and also one of 
i and j, but without producing the least diminution in -the blood 
pressure. 
The method pursued was as follows: After previously inserting a 
cannula into the carotid artery and determining the blood pressure, 15 
grammes of a were injected into the empty stomach of a dog weighing 
4300 grms., and a continuous tracing was taken during a period of two 
hours and twenty-five minutes, and except for slight irregular changes 
that one usually sees occur with prolonged antesthesia, no alteration of 
the blood pressure could be detected. Had the same amount been in- 
jected directly into the external jugular vein almost instantaneous death 
would probably have occurred, for I have seen it occur when even 5 
grms. of a from the thyroid or from the thymus were injected in this 
manner. Such enormous quantities appear to cause very profound chem- 
ical alterations of the blood. R. II. Cunningham 
237 
Extractives from the aqueous decoctions of certain other glandular 
organs, for example the submaxillary glands of the ox, also produce a 
fall of the blood pressure, and so do the extractives yielded by muscle, 
and also those from commercial meat extracts. The effects of injecting 
one derived from an ordinary sample of Liebig’s extract by the acetate 
of lead method are shown in Plate XVIII, Fig. 4, and no further com- 
ment is necessary except the remark that a transient increase of eight to 
ten heart-beats was usually produced by these injections. 
From the above experiments it is evident that Fraenkel’s thyreo- 
antitoxin, which, he states, does not lower the blood pressure, and the 
active palliative substance which I obtain from the perfectly fresh raw 
thyroid gland by the process that he recommends, possess entirely dif- 
ferent properties in respect to their influence on the blood pressure and 
on the rate of the heart. The cause of this difference is at present inex- 
plicable, unless it be that the dried thyroid material which he employed 
as the source from which he extracted his thyreo-antitoxin had under- 
gone extensive alteration during its manufacture. The blood pressure 
effects that I have got with the thyroid extractives by Fraenkel’s method, 
that is to say, with the extractives of those preparations that had un- 
doubtedly modified the acute cachexia in totally thyroidless dogs, and 
with the two substances obtained according to Drechsel’s methods, prac- 
tically accord with those that Schafer and Oliver noticed with the aque- 
ous decoction of the raw glands. 
But, though the transient fall of the blood pressure and tendency 
to slow heart-beats are produced by the intravascular injections of 
thyroid decoctions and extractives, this fact does not conclusively prove 
that the hypothetical internal secretion of the thyroid gland in the 
living body is necessarily continually affecting the blood pressure in 
this manner. On the contrary, injections of large amounts (30-50 
ccm.) of the defibrinated blood from the inferior thyroid vein removed 
while the gland was being massaged, did not produce during any of my 
experiments the above effects; a fact which would of course only tend 
to show that none or, if any, an extremely small quantity of the 
blood-pressure-reducing thyroid substance was present in the blood 
after passing through the gland. 
Nor can one assert from the results of the preceding experiments 
with the thyroid derivatives that the transient blood-pressure effects 238 
Experimental Thyroidism 
that are produced are specific for the secretion of the living thyroid 
gland, for derivatives that produce similar effects on the blood pressure 
may be readily obtained from the salivary glands (ox), from the mus- 
cles, etc. The latter certainly have no internal secretion, in the proper 
sense of the term, and with respect to the muscle extractives that lower 
the blood pressure the only definite fact my experiments indicate is 
that the proteid-free muscle extracts contain certain chemical sub- 
stances that possess the properties of temporarily reducing the blood 
pressure when they are directly introduced in minute quantities into 
the circulating blood. They certainly do not indicate that these sub- 
stances normally enter the blood or the lymphatics from the muscles 
in this particular chemical state. 
Nor are the blood pressure and cardiac effects which the complex 
juice of the minced raw thyroid temporarily produces, when it is 
injected directly into the circulation, definitely apparent in exophthal- 
mic goitre, in which disease too much internal thyroid secretion is 
claimed by many as being the chief pathogenic factor. Thus, in 
exophthalmic goitre, acceleration of the heart-beat is, according to all 
observers, usually the first of the cardinal symptoms to appear. Re- 
garding the state of the blood pressure clinicians differ greatly, and 
from the fact that so many diametrically opposite opinions have been 
expressed, it is evident that the state of the blood pressure is not always 
the same in different patients with exophthalmic goitre. For instance, 
Frangois-Franck and Marie have found the state of the blood pressure 
in Graves’ disease to be normal.* Sachs f states that “ it is owing to 
the increased tension that hemorrhages are frequent from the nose.” 
Starr writes, “ The condition of the heart and arteries in myxcedema 
is exactly the opposite of the condition found in exophthalmic goitre. 
In all the cases of myxcedema a slow pulse is present. The pulse is 
also small and of high tension in myxcedema. In sharp contrast to 
* Frangois-Franck and Marie, quoted by Chamberlain. Maladie de Base- 
dow, Paris, 1894. 
t B. Sachs, Nervous Diseases of Children. New York, 1895, p. 199. 
J M. A. Starr, Med. News, April 18, 1896. R. H. Cunningham 
239 
this condition are the rapid, full, large pulse and throbbing arteries 
constantly complained of in exophthalmic goitre.” * 
On the other hand the removal of the thyroid gland in dogs and 
monkeys is followed by a state of subnormal blood pressure, the very 
condition that the injections of thyroid decoction temporarily pro- 
duce. In both varieties of animals the pulse-rate is accelerated also 
in the early stages of the cachexia, but as the myxcedematous stage 
supervenes (monkeys, rarely dogs), the number of heart-beats becomes 
reduced and falls usually below the normal. 
It is evident, therefore, that many complicating and, at present, in- 
explicable factors are probably concerned in the vascular manifesta- 
tions that arise in consequence of disturbed thyroid function. All 
that one can say from experiments of the foregoing character is, that 
the connection between the effects observed after the intravascular 
injections of aqueous extracts, etc., of ground thyroid tissue, and the 
various cardiac and vascular manifestations observable in conditions 
in which the supposed internal thyroid secretion is presumably dis- 
turbed, is entirely too indefinite in the present state of our knowledge 
of the presumed internal secretion to warrant the inference that the 
internal secretion of the living thyroid gland has for one of its func- 
tions the production of cardiac and vascular effects identical with 
those produced by the direct intravascular injection of the extracts, 
decoctions and various chemical derivatives of the thyroid tissues. 
VI. CONCLUSIONS. 
From the results of the various experiments already detailed I feel 
justified in drawing the following conclusions: 
(1) Absolutely fresh thyroid gland is not poisonous, in the usual 
sense of the term, when absorbed through the alimentary canal. 
(2) The symptoms of induced thyroidism are manifestations of an 
intoxication resulting from the ingestion of decomposed thyroid mater- 
* The blood pressure of six females with well defined exophthalmic goitre 
has lately been investigated by me with the sphygmodynamometer of Oliver. 
130 to 150 grammes were necessary to just occlude the radial arteries. The 
blood pressure in these patients was thus normal, 120 to 160 grammes being 
the normal limit according to Oliver. 240 
Experimental Thyroidism 
ial, a conclusion that agrees in part with the previously related obser- 
vations of Lanz. 
(3) The so-called experimental thyroidism is not specific for the 
thyroid only, for the ingestion of many substances derived from animal 
tissues other than the thyroid gland may produce an intoxication strik- 
ingly similar in every respect to that of experimental thyroidism. 
(4) Most, if not all, animal tissues yield substances which, if in- 
jected in large quantities directly into the circulation or beneath the 
skin, will produce an intoxication often very similar to that produced 
by injections of various substances derived from the fresh thyroid 
tissue. 
(5) The effects resulting from the intravascular or subcutaneous 
injections of aqueous extracts, decoctions and the concentrated extrac- 
tives of the thyroid tissue, of the thymus, of muscle, etc., are by no 
means necessarily indicative of the function and the action of the hypo- 
thetical internal secretions of the same tissues during life. 
(6) The utilization of the fact that ingestion of decomposed thyroid 
material produces on certain occasions an intoxication with certain 
symptoms similar to some of those of Graves’ disease is not justifiable 
for the furtherance of the theory that the symptoms of exophthalmic 
goitre result from an over-production of the thyroid secretion. 
(7) Our results lead us to conclude with Drechsel that the fresh 
thyroid tissue yields at least probably two substances that are capable 
of palliating the symptoms of the acute cachexia in totally tliyroid- 
less dogs. 
(8) The thymus tissue also yields one and probably two substances 
that are as equally capable as the thyroid extractives of palliating the 
acute cachexia in totally thyroidless dogs. 
(9) Neither of the above substances is an enzyme, noy does either 
contain iodine. 
(10) Neither the feeding of minced raw thyroid glands, nor the 
injection of aqueous thyroid extracts, decoctions, and concentrated 
solutions of the extracted palliative thyroid principles is capable of 
keeping totally thyroidless young dogs alive longer than a few weeks 
(possibly three weeks). Still less capable are the thyroid preparations 
containing decomposition products. B. II. Cunningham 
241 
(11) The presence of one, or usually several, small accessory thy- 
roid bodies, which gradually hypertrophy and wholly or partially as- 
sume the functions of the excised thyroid lobes, accounts for the occa- 
sionally long survival of thyroidectomized, thyroid-fed, young dogs. 
(12) Totally thyroidless young dogs are so quickly overwhelmed 
by the cachexia, and the intervals between the thyroidectomy and the 
onset of the severe dyspnoeic attacks and subsequent deaths differ so 
slightly, no matter which of the usual varieties of fresh food are 
employed, that hinds of fresh food cannot be unquestionably affirmed 
to influence the onset of the cachexia in any especially definite manner. 
Animal foods, in which constituents poisonous to rabbits have devel- 
oped, probably slightly hasten the onset of the severer symptoms, and 
the vaunted remarkably modifying influence of a diet of ordinary 
milk, such as Breisacher observed, does not exist in the case of the 
totally thyroidless dog. 
(13) Monkeys whose general metabolism is disturbed in conse- 
quence of the removal of a greater portion of the thyroid gland, evi- 
dently become more susceptible to those constituents of meat that are 
poisonous to rabbits, and sufficient clinical evidence exists for conclud- 
ing that probably a like susceptibility to animal foods containing such 
constituents also exists in men when the function of the thyroid gland 
is sufficiently disturbed. 
(14) And, finally, as regards the thyroid factor in the pathology 
of exophthalmic goitre, I agree with Gley that the majority of the 
symptoms in many patients with that disease can apparently, from 
an experimental standpoint, be as plausibly explained by the hy- 
pothesis of partially deficient thyroid activity as by the hypothesis of 
augmentation of thyroid function. 
DESCRIPTION' OF PLATES XIV-XVIII. 
Plate XIV. 
Photograph of a rabbit with acute thyroidism after the ingestion of 
0.1 gramme of a poisonous mixture of substances extracted from a dried 
commercial thyroid preparation. The acetate of lead method of Fraenkel was 
employed to extract the dried gland, and the resultant waxy mass of 
extractives was washed several times with 85-90 per cent, alcohol. The 242 
Experimental Thyroidism 
alcoholic solution was precipitated with ether, the precipitate redissolved 
in hot alcohol, evaporated, and after it had crystallized, dissolved in dis- 
tilled water and administered through the stomach tube. 
The widening of the palpebral fissure can easily be made out in the pho- 
tograph. (See text, p. 211). 
Plate XV. 
Photo-micrographs of small aortic accessory thyroid bodies. 
Fig. 1. A longitudinal section of an accessory aortic thyroid body 
(x24 diams.) from a normal dog. 
In the more perfectly developed portions the small vesicles contain 
colloid. 
Fig. 2. A more highly magnified view (x300 diams.) of a part of a sec- 
tion of the preceding accessory body; the structure of a portion containing 
no colloid is shown. The appearance is similar to that of the para- 
thyroid body. 
Plate XVI. 
Fig. 3. Cross-section of an aortic body embedded in a mass of fat, from 
a thyroidectomized dog that had a moderate dyspnoeic attack on the third 
day after the operation. The dog was then injected with concentrated 
thyroid bouillon for several days and the injections then stopped, but no 
return of the symptoms occurred; the dog was killed by an over-dose of 
ether at the end of eight days. 
In the cross-section a rather unusual amount of fibrous tissue is seen be- 
tween the vesicles containing colloid. Hardening in alcohol, stained with 
hrematox. and eosin, and magnified 24 diams. 
Fig. 4. Aortic body from a dog in which operative myxoedema had been 
produced by ligating all the thyroid vessels. As the myxcedematous swelling 
was beginning to subside an over-dose of ether was given and this with two 
other small aortic bodies was removed. 
The structure of this body does not differ from that of the main thyroid 
lobes. (x24 diams.). 
Plate XVII. 
These tracings show graphically the cardiac and blood-pressure effects 
that follow the intravenous injection of thyroid and other extractives; in 
each of the tracings the top line is that of the blood pressure, the middle 
line is the base line, the bottom line is the time. At — the injection was 
made. 
Fig. 1. Showing in an etherized dog the fall of blood pressure from an 
injection into the ext. jugular vein of 0.5 ccm. of a neutral 20 per cent, 
aqueous solution of the extractives from fresh raw thyroid. The brownish 
wax yielded by the acetate of lead method of Fraenkel was dissolved in 85 
per cent, alcohol; the alcoholic solution precipitated by ether; the precipi- 
tate redissolved several times in boiling 90 per cent, alcohol, and several 
times reprecipitated by ether. Finally this precipitate was dissolved in a 
small quantity of distilled water; the solution evaporated on a water bath 
at 100° C., and then set aside to crystallize over chloride of calcium. This 
substance, which should be the same as Fraenkel’s thyreo-antitoxin, was 
dissolved in normal saline and injected, producing the result seen in the 
figure. R. H. Cunningham 
243 
Fig. 2. Showing after division of both vagi the effects in an etherized dog 
of 2 ccm. of a neutral 10 per cent, solution of a mixture of the two partially 
crystalline products obtained by treating the above waxy mass of fresh 
thyroid extractives with phospho-tungstic acid, etc., according to the 
method that Drechsel recommends for the fresh raw thyroid gland. Both 
the crystalline products had been repeatedly cleaned by the alcohol-ether 
method. 
Plate XVIII. 
Fig-. 3. Showing the effects of injecting 2.5 ccm. of a 10 per cent, solution 
of a partially crystallized thymus product. The fresh thymus glands were 
extracted by the acetate of lead method and the resultant waxy mass pre- 
cipitated by phospho-tungstic acid. After boiling this precipitate for a 
number of hours, decomposing the decoction with baryta, etc., and finally 
cleaning with alcohol and ether, the partially crystallized product used in 
this instance was yielded. Morphine was given to this etherized dog. 
Fig. 4. The fall of blood pressure produced by 1 ccm. of the neutralized 
mother-liquor from which the creatin and creatinine had been removed. 
Liebig’s extract of meat was the source from which this mixture was 
obtained, and the acetate of lead method was employed to extract the 
creatin. THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. III. 
PLATE XIV. THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. III. 
PLATE XV 
FIG. 1. THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. III. 
PLATE XVI. 
FIG. 3. 
FIG. 4. THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. III. 
PLATE XVII. 
Time: / 
Time: /" 
F I G . 2 
F I G. I THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. III. 
PLATE XVIII. 
Time: l" 
Time• / ' 
FIG. 4- 
F l G . 3