THE DOCTRINE OF THE 
Internal Secretory Activity of Glands 
IN RELATION TO THE 
Pathological Anatomy of Sundry Morbid Conditions 
Diabetes, Addison’s disease, Myxoedema, Cretinism, Graves’ 
Disease and acromegaly. 
BY 
J. GEORGE ADAMI, M.A., M.D., 
Professor of Pathology, McGill University, Montreal. 
REPRINTED FROM THE MONTREAL MEDICAL JOURNAL, MAY, l8q?. THE DOCTRINE OF 
THE INTERNAL SECRETORY ACTIVITY 
OF GLANDS IN RELATION TO THE PATHOLOGICAL 
ANATOMY OF SUNDRY MORBID CONDITIONS.1 
(of diabetes, addison’s and graves’ diseases, myxcedema, cretinism 
AND ACROMEGALY.) 
BY 
Professor of Pathology, McGill University, Montreal. 
J. George Adami, M.A., M.D. 
To remove an organ and study the effects of the operation is clearly 
an exercise in experimental pathology and only secondarily and indi- 
rectly a physiological investigation, while the greater the precision 
with which the course and symptoms of any morbid condition are 
studied, the more the study becomes a matter of science, a matter of 
pathology rather than of medicine. In other words, asked as a 
pathologist to enter into this discussion, I find that all other partici- 
pants have trespassed into pathological territory. This is one of the 
penalties of sure advance in our common subject: the pathology of 
yesterday becomes the medicine of to-day, and I might add, the medi- 
cine of to-day yields place to the surgery of to-morrow. But this 
being the case, so as not to reiterate, I am impelled to make my con- 
tribution to this discussion a resume of the results obtained in a 
branch of pathology which others are not likely to dwell upon. It is 
in many respects an unsatisfactory branch—a branch capable of 
testing rather than of originating any theory. I refer to morbid 
anatomy. 
I propose, therefore, during the next few minutes, to lay before you 
what may be gleaned from the post-mortem room bearing upon this 
subject of internal secretion. But first it is necessary to call your 
attention to the very narrow limits of the information to be gained 
from a study of the gross and fine anatomy of diseased organs in this 
connection. 
Morbid anatomy alone can tell us singularly little concerning 
alterations in function. The existence of . lesions recognisable to the 
naked eye or under the microscope may support conclusions reached 
by other means. It can do little more. We know from experiment 
1 Being a contribution to the discussion upon “ Internal Secretions,” at the Tri 
ennial Medical Congress, Washington, May sth, 1897. ' that three-quarters of the liver, for example, may be removed from 
the healthy animal with no pronounced disturbance of the bodily 
functions, that whenever one-fifth or less of the pancreas is left in the 
dog it may be weeks before diabetes shows itself, that only when 
fifteen-sixteenths of the thyroid are removed may the dog succumb. 
In this enormous reserve of material and force may truly be said to 
lie the secret of the continued existence of living beings. Thus the 
mere fact that the greater part of an organ is found wanting by the 
anatomist, or replaced by tissue of another nature, is not in itself 
absolute evidence that what remains of the organ is functionless or 
incapable of meeting the needs of the organism. So long as any con- 
siderable number of what may be termed the specific cells of an organ 
are to be determined we must proceed very cautiously in our reason- 
ing ; only when the destruction is absolute or nearly so are we on sure 
ground. Contrariwise, if the cells of an organ appear very slightly 
altered, while we are accustomed to argue that there has been but 
little disturbance of function, it is questionable whether we are justi- 
fied in this opinion. So also if an organ like the thyroid be markedly 
hypertrophied, that is not in itself proof positive that there is accom- 
panying increased activity and increased internal secretion. In the 
thyroid, for instance, the boundary line between pure hypertrophy 
and overgrowth of adenomatous nature is peculiarly vague. It may 
very possibly be that a simple adenoma of a ductless gland continues 
to supply an internal secretion ; it is difficult to imagine that gland 
structure of almost perfect type can be present in the body without 
affecting the body at large.1 Nevertheless we have no conclusive 
evidence that this is the case; hence, it is only after most exact 
and extensive histological study that we can advance any very secure 
arguments upon the existence of apparent simple hypertrophy, more 
especially of the ductless glands. The force of this statement will be 
seen when we come to discuss the bearing of disease of the hypophysis 
cerebri. 
Another matter that has to be taken into account, one that has until 
now received scant attention, is the existence of vicarious activity. 
Because one organ is seriously diseased it does not follow that the 
organism as a whole exhibits disturbances commensurate with the 
lesions in that organ ; other parts may vicariously fulfil its functions. 
We have the well known example of botal extirpation of so important 
an organ as the spleen being succeeded for years by good health. Here, 
1 It is noteworthy how frequently in attempting to co-ordinate the anatomical 
data in the class of diseases now before us we are brought to regard the possibility— 
nay, probability—that neoplasms are not functionless (as we are too apt to consider 
them), but afford, it may be an abundant, internal secretion. 3 
presumably, the lymph-glandular tissue in general takes over the func- 
tions of the absent organ. There is the compensatory development of 
the parathyroids in athyrea, and further, the frequent, but not con- 
stant co-existence of atrophic disease of the thyroid and hypertrophy 
of the pituitary to which Boyce and Beadles (1) have more especially 
called attention. Similarly and curiously we meet with frequent 
persistence or enlargement of the thymus when either the thyroid or 
the pituitary body is the seat of disease. Thus not only is it a 
matter of peculiar difficulty in that class of diseases, which to-day we 
have specially to discuss, to determine which of the ductless glands is 
primarily and which secondarily affected, but the added difficulty 
besets us, that where the vicarious function is perfect and compensa- 
tion is complete we may, in the apparently unaffected individual, 
meet with lesions of an organ—the thyroid for instance—-of the same 
nature as, and every whit as extensive as, the lesions in well marked 
cases of those special forms of general disease which we are inclined 
to regard as the direct outcome of disease of that organ. 
Time after time this co-existence of apparently identical lesions in 
cases of relative health and pronounced disease places us in a quan- 
dary, time after time we find ourselves groping vainly in a maze of 
facts which seem to point in all directions of the compass. And when 
the facts flatly contradict each other one cause of discrepancy must 
be this vicarious activity. In passing I may suggest that vicarious 
activity affords a possible explanation of the not unfrequent cases 
in which we have the eventual co-existence of more than one of the 
diseases under consideration.' If, for example, the thyroid be the seat 
of atrophic disease the compensatory hypertrophy and over-action of 
the pituitary may lead to eventual affection of that organ. 
Yet another consideration, seriously weighing upon the morbid 
anatomist, is that two opposite processes may produce a similar symp- 
tomatology, one that he can recognise, another that he cannot. If the 
glands afford an internal secretion entering the lymph and so event- 
tually circulating through the system, we know that the ultimate use 
of the secretion must be to effect a chemical transformation of some 
substance in some other part or parts of the system. There are thus 
four possible conditions, (1) production of an insufficient amount of 
internal secretion of any gland in consequence of disease of that 
gland, and (2) the assimilation or production of an excess of that 
substance which normally is acted upon and transformed by the 
internal secretion in question. In both cases there will be a heaping 
up in the system of the substance ; in both cases there may be the 
same train of symptoms. In the one case the gland or glands may 4 
show the clearest signs of disease ; in the other they may appear 
normal. The morbid anatomist may in time discover collateral dis- 
turbances distinguishing these two states ; at present he cannot 
adequately. In one case of diabetes he finds the pancreas unaffected, 
in the next it is extensively diseased. Unaided by experimental 
pathology he is quite incapable of determining the important rote 
played by this organ in regulating the sugar supply of the organism 
and in the production of diabetes. Similarly there may be an 
accumulation of the internal secretion, either due to (3) hypertrophy 
of a gland, or (4) not associated with recognizable glandular change. 
In short, gentleman, I fear that I stand before you as a kind of 
reversed contrary Balaam. Summoned to bless—to illumine this dis- 
cussion—l can only curse (as I take it all my predecessors must have 
done who have attempted to reconcile the anatomical results in the 
class of cases now before us) and can but point out to you the dark- 
ness that is upon the face of the deep. But happily there is this to 
be said to the credit of the morbid anatomist that the demonstration 
of this darkness is of the highest value as indicating the lacunae in 
o O 
our knowledge and suggesting the various factors that have to be 
taken into consideration and carefully studied in order that we may 
gain a comprehensive knowledge of this intensely interesting and 
valuable subject of internal secretion and glandular function. It is 
in itself a step towards higher things to feel acutely our own ignorance. 
And then, perhaps, things are not quite so black as here painted. 
While it may be that I am overbold—it may also be that this darkness 
but precedes the dawn; that facts which seem so flatly to contradict 
each other can, in the growing light of experimental pathology, already 
be seen to range themselves in an orderly manner. Accepting the 
postulates, first, that the glands of the body afford an internal secretion 
capable of acting upon and transposing some substance or substances 
produced or assimilated by other regions of the body, and, second 
that, proceeding with due caution, we can utilise the results of 
anatomical and histological studies, then, applying the considerations 
which I have just urged, we must recognise the possible existence of 
three orders of conditions, each order being capable of further sub- 
division into two well marked groups. It would seem that we have to deal with : 
I, Relative Glandular Inadequacy.—-Excess of sub- 
stance acted upon by the internal secretion of a 
gland, without due compensation. 
(1.) Altered condition of gland leading to diminish- 
ed activity and dimished internal secretion. 
(2.) No disease or alteration of gland but excessive 
production or assimilation of the substance 
acted upon by the internal secretion. 
11. Relative Glandular OvER-AcTiviTY.—Excess of in- 
ternal secretion without compensation. 
(1.) Altered condition of gland leading to increased 
act ivity and increased pouring out of internal 
secretion. 
(2.) No disease or alteration of gland, but diminish- 
ed production or assimilation of the sub- 
stance acted upon by the internal secretion 
of that gland. 
Changes* 
Associated 
WITH 
Symptoms 
Disease. 
OF 
Unaccompanied by 
Svmptoms 
* 
Disease. 
111. Compensation.—Lesions of gland or altered systemic 
condition unaccompanied by symptoms. 
(1. Altered condition of gland leading to (a) in- 
crease or (b) diminution of internal secretion, 
with due compensation. 
(2.) (a) Increased or (b) diminished production or 
assimilation of substance acted upon by in 
ternal secretions, with due compensation. 
Let me here emphasise the fact that I do not pretend that this table 
includes every possible condition leading to local or general distur- 
bance of these glands affording an internal secretion, and leading to 
the symptoms most often associated with disease of these glands. 
For example we know from experiments with phloridzin that 
glycosuria may, among other things, be the result, not so much of 
increased production of sugar as of increased removal of this body 
through the kidneys. Such cases are not embraced in this table. 
Again, what I may term compound cases as, for instance, of glandular 
inadequacy, in part from disease, in part from increased production of 
the substance acted upon by the secretions are presented only by 
implication. All I urge is, that this table, conforming Avith what 
experiment has shown may occur, may very possibly be utilised to 
explain the apparently contradictory revelations of the post-mortem 
room. 
I would now proceed rapidly to review those conditions, local and 
general, concerning which we have already a modicum of knowledge 
and which fall within the scope of to-day’s discussion. 
THE PANCREAS AND DIABETES. 
Let me in the first place take into consideration lesions of the 
pancreas and their relationship to diabetes. Much more than a cen- 
tury has passed since attention was first called to the pronounced 
changes to be seen in the pancreas in some cases of diabetes. We all 6 
know that not until 1889, when Yon Mering and Minkowski in 
Germany, and de Dominicis in Italy, published the results of their 
researches did the belief in the existence of a pancreatic diabetes 
begin to become generalised, but even at the present moment the fact 
that two cases, closely resembling each other clinically, may post- 
mortem show, the one, extensive pancreatic disturbance, the other’ 
an apparently healthy pancreas, creates great confusion. 
What then are the facts gathered so far as to the relative frequency 
and the nature of the lesions of the pancreas which may be associated 
with diabetes ? 
We have at least three careful studies upon this subject, those of 
Hausemann (2), Williamson (3) and Dieckhoff (4), and all demonstrate 
that three conditions may be distinguished (1) extensive pancreatic 
disease with associated diabetes ; (2) extensive pancreatic disease with- 
out diabetes; (3) diabetes unassociated with recognisable pancreatic 
disease. Hansemann from a careful investigation of the records of the 
Pathological Institute and the Augusta Hospital at Berlin, found that 
the first condition (of pancreatic disease with diabetes) is more common 
than the two others combined. It may be that in Berlin the consump- 
tion of much beer predisposes to the pancreatic form of the disease, it 
may be that the material upon which Hansemann worked was imper- 
fect to this extent, that full care was not taken to distinguish between 
extensive and extreme destruction of the pancreatic tissue, but it will, 
I think, be the experience here, as it was that of Williamson in Eng- 
land, and Dieckhoff in Rostock, that advanced pancreatic disease, 
associated and unassociated with diabetes, are to be encountered the 
one but little more frequently than the other. 
This much, howevar, stands out very prominently that where in 
diabetes the pancreas is found affected, the morbid process within 
the gland is some one or other form of atrophy and destruction 
of the gland substance. Most commonly it is a form of periacinous 
fibrosis, originating it would seem secondarily to arterio-sclerosis, in 
which with thickening of the arterial walls there is malnutrition of 
the gland cells, atrophy and, what I have elsewhere termed, replace- 
ment fibrosis. Other forms of atrophy and fibrosis have not infre- 
quently been observed—simple atrophy, congenital syphilitic fibrosis, 
obstruction of the ducts with calculi, dilatation of the ducts and 
atrophy of the gland tissue, scirrhous cancer of the pancreas, and I 
have found recorded five cases of necrosis, or haemorrhagic necrosis 
(two by Fitz and a third, a case under Drs. Bell and Finley, in my 
own experience at the Montreal General Hospital) 
There can, therefore, be no question that the pancreatic lesions found in some cases of diabetes are such that there must be a marked 
diminution in the secretory activity of the gland. To this extent, in 
this one class of cases the results of autopsies are clearly in accord 
with the results of experiments. We have here examples of rela- 
tive glandular inadequacy brought about by altered condition of the 
pancreas leading to diminution of internal secretion. 
Examples of diabetes unassociated with disease of the pancreas are 
so well known that I need but refer to them. While such are difficult 
to explain from purely anatomical considerations the fact that they 
are found, and found relatively frequently is, in itself, an evidence 
that glycosuria is of at least a two-fold origin. That they are found 
is in conformity with the results of experiments, experiments which, 
on the whole, must be regarded as proving that there can be heaping 
up of sugar in the organism beyond the transforming power of the 
pancreatic internal secretion, or otherwise an incomplete burning up 
of the sugar. If this heaping up be in general due to increased 
glycogenesis, increased production of sugar, we should expect to find 
some evidence of increased activity of some glycogenetic organ, and 
here the recent researches of Glenard (5) and Triboulet (6) tend to 
show that this may be the case. Contrary to the older and generally 
accepted teaching, Glenard finds that clinically in over sixty per cent, 
of diabetics, there is evidence of some hepatic enlargement. Anatomi- 
cally he finds that three conditions may be recognized, each possibly a 
stage in one morbid procees, namely, hyperaemia, general cellular 
hypertrophy (hyperplasia) and hypertrophy with cirrhosis (hyper- 
trophic cirrhosis). Thus while I will not say that anatomical con- 
siderations prove the existence of my second subgroup in this 
connection, I must point out that the existence of this class of cases 
of diabetes without adequate recognizable pancreatic disturbance, is 
best explained on the supposition that there may be excessive pro- 
duction or assimilation of sugar with accompanying relative pancreatic 
inadequacy. 
There is yet a third group of cases to be considered, that of exten- 
sive atrophic disease of the pancreas without diabetes. Here we have 
to proceed cautiously in our reasoning. As I have already indicated, 
Sandmeyer (7) has found that if only one-fifth to one-ninth of the organ 
be left in the dog, it may be months before sugar appears in appreciable 
quantities in the urine. Vaughan Harley (8) gives an even smaller 
amount, namely, one-fifteenth, but evidently he refers not to the 
eventual development of diabetes, but to its onset within a few hours. 
We can thus state that so long as from one-ninth to one-fifteenth of 
the glandular tissue of the organ is functional, for so long glycosuria 8 
need not manifest itself in the dog1. There is no valid reason why 
we should not apply these facts to the human being. Hence so long 
as a very small proportion of fairly healthy gland tissue is left, we 
have a satisfactory explanation why diabetes should not show itself, 
even though the major portion of the pancreas exhibits fibroid and 
atrophic or neoplastic changes. There are, however, aspects of that 
subject not capable of so simple an explanation. I remember my 
friend, Dr. H. D. Rolleston, of St. George’s Hospital, showing to me a 
series of sections of the fibroid pancreas taken from both diabetic and 
non-diabetic cases, from which the only conclusion to be reached was 
that a given extent of fibrosis might or might not be associated 
with diabetes. Again, Hansemann has called attention to cases of 
complete replacement of normal pancreas by a diffuse cancerous infil- 
tration. He seeks to explain these by the hypothesis already indicated, 
that the cells of a primary new growth of a ductless gland may 
continue to furnish an internal secretion. This may or may not be 
the case. Where there is primary cancer of the hepatic parenchyma, 
the new growth in the liver may be devoid of bile, the secondary 
growths are without exception free from bile. A more simple ex- 
planation of these and other examples of complete or almost complete 
destruction of the pancreatic glandular tissue is that of compensation, 
whether by vicarious function of Brunner’s and other glands (the 
duodenal glands have frequently been found enlarged) or by diminished 
assimilation or production of sugar. 
THE SUPRARENAL BODIES AND ADDISON’S DISEASE. 
We meet with an identical series of cases in connection with another 
organ in which experimentally the existence of an internal secretion 
has been fully demonstrated. We may have (1) Addison’s disease 
associated with disease of the supra-renal bodies, (2) Addison’s disease 
with intact supra-renals, and (3) extensive, if not complete, destruc- 
tion of the supra-renal bodies without the symptoms of Addison’s 
disease. 
Here as with the pancreas in diabetes the affection of the gland in 
Addison’s is some form of atrophy or destruction of the specific gland 
tissue. Most frequently, I need scarce say, the change is tuberculous 
and necrobiotic, resulting in the disappearance of the gland tissue and 
its replacement by caseous material. But cases are on record of 
simple atrophy, hmmorrhagic necrosis and malignant growth of the 
bodies associated with or leading to all the symptoms of Addison’s 
dioease. In the vast majority of cases both glands are affected, but 
cases are on record (I have come across one such) where only one of 9 
the bodies has been the seat of recognisable disease. Of the three 
conditions above mentioned the most frequent found is the associa- 
tion of the disease with complete or almost complete destruction of 
the gland. So frequent is the association that the attempts to explain 
away the other two rare states of Addison’s disease with intact supra- 
renal bodies and suprarenal disease without the Addisonian symptoms 
have been almost painful in their ingenuity. Yet undoubteedly well 
authenticated cases are on record of both of these conditions. 
We have in this connection singularly full statistical collections of 
cases. That of Lewin (9) is well known ;he collected accounts of 285 
cases, of which 211 showed caseous lesions of the suprarenals (74 °/). 
Gilman (10) found an even greater proportion of either primary or 
secondary tuberculosis (80 °/o) ; in the remaining 20 °/o there were 
either other forms of atrophic disease or absence of recognisable dis- 
turbance. 
The existence of cases of Addison’s disease without obvious disease 
of the suprarenals is generally acknowledged. Lewin found that as 
many as 12 °/Q of his cases were of this type. The explanation gener- 
ally given is that in these there had been alterations in the neighbouring 
semilunar ganglia and abdominal sympathetic. Certainly disturbance 
of the nervous system, and especially of the sympathetic, does lead to 
pigmentation of the skin, We see this in cases of hysteria and again 
in Graves’ disease, in which from whatever cause (I shall speak of this 
later) we have most marked nervous changes, but I must confess that 
I feel some little impatience towards the upholders of this semilunar 
ganglion theory of Addison’s disease, for scarce two of them describe 
the same order of lesions. Most of the changes described would 
appear to be quite common in the adult dying from other causes; thus 
Hale White (11) found that examining 83 semilunar ganglia removed 
indiscriminately, if we leave out of account 3 perfectly normal taken 
from young children, 24, or 80 per cent of the remainder exhibited 
more or less extensive degenerative changes with frequent presence of 
granular masses of pigment. Dixon Mann (12) also making a careful 
comparative study of the abdominal syrapathetics and semilunar gan- 
glia from two cases of the disease and from the unaffected individual 
came to a like conclusion. He found them not more affected than are 
those of other individuals. Under the circumstances, therefore, I see no 
valid reason why cases in which the bodies are found apparently 
unaffected may not, in the light of our present knowledge, be most 
satisfactorily classed as possible examples of relative glandular inade- 
quacy of the second order. This suggestion may to some appear revolu- 
tionary • but let me reiterate my main argument: We acknowledge that 10 
glands like the suprarenals produce an internal secretion: We must 
inevitably admit that the function of such secretion is to affect a chemi- 
cal transformation of some substance or substances distributed in other 
parts of the body. We must admit that when, for example, the supra 
renal bodies are diseased, or removed, some, at least, of the symptoms that 
follow are due to the absence of the internal secretion, or, in other 
words, are due to the accumulation in the system of the substance or 
substances acted upon by the internal secretion. The same symptoms 
must be produced whatever the cause of the accumulation of the 
substance or substances, whether by diminution of the internal 
secretion or by excessive production or assimilation of the aforesaid 
substance or substances. When, therefore, a morbid condition, such as 
diabetes or Addison’s disease, which may be caused by destruction of 
a gland is found to exist without recognisable disease of that gland, 
a very possible explanation of the condition is what I have termed 
relative glandular inadequacy due to excessive production or assimi- 
lation of the substance acted upon by the internal secretion. I would 
but ask you clearly to picture this, that in diabetes and Addison’s 
disease it is not the internal secretion that causes the symptoms, but, 
if experimental data are to be trusted, the lack of the same—and that 
this lack may be absolute or relative. 
I am far from suggesting that the whole corpus of symptoms will 
be the same in both conditions. Thus as Harley and others have 
pointed out where the pancreas is atrophied there are profound diges- 
tive disturbances not necessarily accompanying diabetes unassociated 
with pancreatic disease. But lam inclined to think that the cardinal 
symptoms in both will closely resemble each other. 
A few wTords only are necessary concerning affections of the supra- 
renal bodies without symptoms of Addison’s disease. If bronzing be 
required as the one essential symptom then cases of tuberculous 
disease of the suprarenal without ‘ Addison’s’ are fairly frequent. 
Addison himself noted this condition. We must however, it seems to 
me acknowledge with Chvostek (18) and numerous previous observers, 
that bronzing is but one of a group of symptoms even though we be not 
prepared to accept Bedford Fenwick’s (14) suggestion that bronzing is 
especially connected with disease of the cortical layer. Leaving this 
category out of consideration, cases of extensive atrophic or neoplastic 
disturbance of both suprarenals without Addison’s disease are few in 
number, far fewer than the cases of extensive pancreatic disease with- 
out diabetes, and in general the descriptions given are not sufficiently 
exact to be relied upon. Nevertheless they exist. Greenhow (15) 
apparently met with a case of almost complete atrophy without sym- 11 
ptoms, and, in 1050 autopsies upon subjects dying from diseases other 
than Addison’s, Uolleston (16) met with an example of caseation of 
the right and atrophy of the left suprarenal and with three cases (under 
the age of forty-five) in which both were peculiarly small. All these 
were without symptoms intra-vitarn. There are more frequent ex- 
amples recorded of cancerous growth destroying both bodies without 
noticeable symptoms. There is a possibility that the new growth 
here was so rapid and so recent that symptoms had not time to 
develop. In the atrophic and tubercular cases it is not so easy to 
accept this explanation. Therefore, I am inclined to believe that 
compensation may occasionally manifest itself in man as it does 
occasionally in animals which have suffered complete ablation of both 
organs. 
THE THYROID GLAND AND MYXCEDEMA. 
I have already approached the limits of the time allotted to me and 
there is yet for me to pass in review the gland and its affections, 
which in this connection have created the most general interest. I 
refer to the thyroid and to the conditions of myxoedema, cretinism 
and exophthalmic goitre. 
From an anatomical point of view there is little for me to say in 
elucidation of the pathology of myxoedema beyond the one all-import- 
ant statement that, with very rare exceptions, there is discoverable a 
well marked atrophy of the thyroid. About this all pathologists are 
agreed. In the majority of cases the atrophy is peculiarly extensive, 
the specific cells of the gland being replaced by fibrous tissue ; in some it 
is not so far advanced and areas may be found, not merely of degener- 
ated remains of the vesicular epith*elium, but of vesicles which by the 
superabundant proliferation of their epithelium would seem to be 
undergoing a compensatory hypertrophy. Yet where these are 
present they are localised and few in number ; the main mass of the 
organ shows atrophy. A few cases only are on record, like that of 
Gulliver (17), where there has been a cancerous metamorphosis or re- 
placement of the parenchyma. 
That in these cases the myxoedema is associated with diminished 
internal secretion of the gland is, I need scarce say, substantiated by 
the good effects of treatment by thyroid extract or thyroid feeding. 
It must next be asked whether myxoedema can show itself with 
apparently intact thyroid, id. est, whether there are any cases which 
may possibly be explained by excess of the substance or substances 
acted upon by the internal secretion of the gland. The literature is 
peculiarly silent upon this point. I can find no example of autopsies 
upon cases diagnosed clinically as myxoedema in which the gland was 12 
found normal, or but little affected. I can only recall an autopsy 
upon a patient of Dr. J. Stewart at the Royal Victoria Hospital, in 
which I found a large cancerous tumour of the pituitary. Here there 
had been a myxoedematous swelling of the hands, and of other regions 
to less extent, without bony overgrowth, and no change was found in 
the thyroid. The condition, however, was not sufficiently advanced 
to deter Dr. Stewart from diagnosing tumour of the hypophysis. A 
somewhat parallel case (of apparent atrophy of the pituitary), in 
which the symptoms of myxoedema were more marked, is recorded by 
Codd (f8), but the anatomical details are given very briefly. Simi- 
larly we possess no exact records of atrophic disease of the glands 
unassociated with myxoedema. I can only point out that it is not 
uncommon in the aged who show no signs that can properly be 
regarded as myxoedematous—unless senility itself be regarded as 
such—to find a condition of very extensive chronic interstitial thy- 
roiditis (as it may be termed) with arterio-sclerosis, calcification and 
hyaline changes, with retrograde or pseudo-embryonic type of vesicles. 
I have come across more than one case of this nature. There can be 
no doubt that here the secretory activity of the gland tissue must be 
very greatly reduced. If, however, we turn to cases in which by 
surgical means the equivalent of complete atrophy, namely, complete 
thyroidectomy, has been attained, we then possess abundant evidence 
that the thyroid proper may be absent without myxoedema neces- 
sarily intervening, and almost as abundant evidence from the more 
recent researches that the absence of symptoms is connected with 
vicarious activity on the part of other organs, and especially of the 
parathyroids. These may be regarded either as true accessory 
thyroid tissue, or as distinct organs, according to the point of view of 
the individual. Certainly when the thyroid is functional they do not 
acquire the full characters of thyroid tissue, but similarly there are 
often within the healthy organ scattered areas of embryonal tissue. 
This can be said with precision, that they are independent masses of 
tissue, apparently most closely related to the thyroid, which are at 
times capable of development to, or towards, the adult type of the 
gland, and of assuming vicarious functions. In like manner the 
pituitary body can at times undergo very definite compensatory en- 
largement. This was first demonstrated experimentally by Rogo- 
witsch (19), while Boyce and Beadles more especially have added to 
our knowledge of its enlargement in cases of myxoedema, cretinism 
and cachexia thyreopnva. 
An interesting point in this connection, to which attention has been 
drawn by Rogowitsch, is that the rabbit, from which the thyroid can 13 
be removed with impunity, has a pituitary body relatively five times 
as large as that of the dog, in which ablation of the thyroid leads 
rapidly to symptoms of acute athyrea; or more correctly, the relation- 
ship of thyroid to pituitary is 3 to 1 in the former, 15 to 1 in the 
latter animal. 
On. the whole, therefore, anatomical data in connection with 
rnyxoedema and cachexia thyreopriva support and are capable of 
explanation by this doctrine that where glands afford an internal 
secretion, the development or non-development of symptoms of disease 
depends primarly upon the relative amount of internal secretion pro- 
duced and of the substance or substances acted upon by the same. 
CRETINISM. 
Cretinism presents a far more complicated histologic 1 picture—so 
complicated that Bircher (20) argues with very considerable force 
that “ cretinic degeneration, as also dwarfism and chondrodystrophia 
foetalis hypoplastica have no setiological connection with the functions 
of the thyroid,” Bircher, however, fails to recognize that if we 
accept the existence of an internal secretion, we must also admit the 
presence of substances upon which that acts, and he cannot see that 
widely contrasted anatomical conditions may lead to the same train 
of symptoms. We must, I think, abide by the experimental and 
clinical evidence that removal of the thyroid in the young leads to a 
condition undistinguishable from cretinism. This being so, we find 
that in some few cases of typical cretinism the thyroid is completely 
absent, in a large number it is small, in a yet smaller number accord- 
ing to Von Eiselberg (21) and Kocher (22) there is a goitrous condi- 
tion present, while according to Bircher the goitres may be of all 
possible forms, from simple hyperplasia through soft (parenchymatous) 
and cystic to fibroid. The only point clearly to be made out from 
Bircher’s very destructive criticism is that while in several cases the 
thyroid has been found of normal size, apparently np case exists in 
which by microscopical observation it has been found of normal struc- 
ture. Considering the amount of material lie brings forward this is 
rather remarkable. I further gather that his statements as to the 
frequency of the various forms of goitre are based upon examination 
of the living and not upon post-mortem or surgical material. This 
seriously weakens his case. Beyond this I will not venture to travel. 
Bircher’s statements require to be dealt with by one in authority, and 
I await with interest Dr. Osier’s presentation of the matter. 
EXOPHTHALMIC GOITRE. 
I will now briefly refer to the condition which presents a series of 
symptoms so remarkably contrasted with rnyxoedema—which also 14 
anatomically presents an equal contrast. There is to be found in 
exophthalmic goitre, as Greenfield (23) has shown, and as is now 
generally accepted a characteristic hyperplasia of the thyroid paren- 
chyma, complicated, it may be in later stages, by increased fibrosis. 
The one question of immediate concern here, is whether from this we 
can safely deduce that there is accompanying increased internal 
secretion. As I have already hinted, I do not think that from 
anatomical considerations alone we can safely make this deduction. 
There is, however, an important fact in favour of such deductions, 
namely, the strong likeness between the primary glandular changes 
in Graves’ disease and those described by Halsted (24) and others as 
occurring in the compensatory hyperplasia of the thyroid after 
removal of large portions of the gland ; and if, together with the 
anatomical changes, we consider the favourable effects which so often 
follow removal, destruction, or diminution in the blood supply of 
portions of the hypertrophied gland in this disease—of operations 
which must lessen the internal secretion—it is difficult to arrive at 
any other conclusion than that in exophthalmic goitre there is in- 
creased internal secretion, and that this plays a singularly important 
part in the development of the symptoms. Whether this be primary 
or secondary to lesions of the central nervous system—of the restiform 
bodies for example, our present anatomical data are insufficient to 
decide—as again they are incapable of deciding whether the increased 
secretion is altered or unaltered in quality. I may here note that as 
Joffroy and Achard (25) have indicated the symptoms of parenchy- 
matous and adenomatous goitre are at times curiously allied to those 
of exophthalmic goitre. Indeed, together with Vanderwelde and le 
Boeuf, they hold, I think without due cause, that there is nothing 
anatomical to distinguish the one condition from the other. That the 
one condition may lead to the other is a matter of clinical experience. 
As Dr. Shepherd has pointed out to me extirpation of the goitrous 
nodules or cysts leads to the almost immediate amelioration of the 
symptoms. 
The development of exophthalmic goitre without hyperplastic 
alteration of the thyroid is a matter concerning which there is little 
anatomical evidence. I find one case recorded by Joffroy and Achard 
in which the gland was of normal size and, while not normal histo- 
logically, presenting nevertheless a series of changes wholly distinct 
from Greenfield’s classic description. The vesicles instead of being 
small and corrugated, were enormously distended, instead of absence 
there was abundance of colloid material, in place of a columnar and 
proliferating epithelium, the lining cells were flattened. Not a few 15 
believe in the existence of Graves’ disease without goitre. Among 
recent writers Buschan (26) especially holds this view, but save in 
the above case I cannot find anatomical substantiation for the opinion. 
Clinically Graves’ disease without enlarged thyroid has very fre- 
quently been noted ; in some cases enlargement supervenes, in others 
it does not, but there may well be increased activity of the gland 
without marked enlargement. All that can be said at present from 
this evidence is that apparently the condition does occur. So also 
evidence as to the occurrence of marked hyperplasia and presumably 
increased secretion without symptoms is not so full and precise as 
could be wished. I can only point out that if adenomatous nodules 
in the thyroid produce any internal secretion then, while many cases 
of adenomatous goitre show a train of symptoms somewhat allied to 
exophthalmic goitre, and while a few cases pass on to undoubted 
Graves’ disease, many on the contrary appear to last for years with- 
out symptoms. And in autopsies upon those dying from diseases, 
other than exophthalmic goitre, we find a wide variation in the condi- 
tion of the thyroid, from atrophy on the one hand to a condition not 
far removed from what Greenfield and others describe in association 
with exophthalmic goitre. 
Altogether, therefore, while not prepared, from general as from 
anatomical considerations, to state positively that exophthalmic goitre 
is in all cases primarily due to increased thyroid secretion, I cannot 
but admit upon the whole that the facts can be best reconciled by 
assuming the existence of relative increase in glandular activity. 
THE PITUITARY BODY AND ACROMEGALY. 
Finally some few words must be said concerning that strange col- 
lection of symptoms and anatomical changes to which Marie has given 
the name of acromegaly. Yearly it has become more clearly recog- 
nized that the term indicates a definite disease although there is a 
liability towards confusion with gigantism on the one hand, and on 
the other with the remarkable overgrowth of bone in certain cases of 
chronic disease (mainly of the lung) which again Marie was the first 
to group together under the title—voluminous, and in other respects 
unsatisfactory—of hypertrophic pulmonary osteoarthropathy. 
Here again the remarkable trio of conditions forces itself upon our 
notice ; there may be acromegaly with disease of the pituitary, acro- 
megaly with apparently unaffected pituitary and extensive disease of 
the pituitary without acromegaly. Where there is acromegaly, there 
in by far the greater number of cases the glandular portion of the 
body is diseased. It is true that the condition is rare. Between 1890. 16 
and the present time less than thirty affected subjects have undergone 
post-mortem examinations. Leaving aside from lack of time sundry 
interesting observations upon the state of the thyroid and thymus, 
I may say that this one gland alone—the pituitary—has been repeat- 
edly found altered, the alteration being especially in connection with 
its anterior or glandular portion. Out of 24 necropsies upon cases 
stated to be acromegaly, Tamburini (27) the latest collector, finds that 
in 17 or over 70 per cent, the pituitary has been found diseased. The 
remaining 7 are subjected by Tamburini to severe criticism with the 
result that he rejects 2 on the ground that the condition had only 
been recognised clinically for a few months and no microscopical 
examination had been made. He presumes that time had not been 
sufficient for the development of naked eye changes. Three other 
cases he holds to have been osteoarthropathy. There remain two 
which he could not definitely reject and consequently classified as 
doubtful. So far as I can follow Tamburini he is strongly of opinion 
that morbid changes in the hypophysis cerebri are essential to acro- 
megaly. The majority of observers do not accept this extreme view, 
and with them I am inclined to believe that here as certainly obtains 
in diabetes and Addison’s disease, there may be typical symptoms 
without recognisable involvement of the pituitary. 
But granting this much, that in the majority of instances the gland 
is diseased, it is difficult to advance much further, for there is a curious 
discord concerning the exact nature of the alterations in the pituitary 
body. In about one half of the cases hypertrophy of the organ is 
described. Stroebe, (28) Tamburini, Boltz (29) and others of later 
date conclude that the change is adenomatous, Marino (80) Dallemagne 
(31) and Gauthier (82) describe a peculiar cystic degeneration, Boyce 
and Beadles a cystadenoma, while in another of Dallemagne’s cases and 
in Wolf’s (38) there was clearly sarcoma, and in Bury’s (84) a 
‘ glioma.’ What are we to conclude ? Is acromegaly accompanied 
by an increased pouring out of internal secretion, or the reverse ? 
Mere hypertrophy and possibly adenomatous overgrowth might lead 
to increase, but surely degenerative changes and sarcoma can have no 
such effect. 
It is difficult to reason by analogy, and if we attempt this and seek 
to base any argument upon what occurs in disease of the gland, which 
anatomically is most closely related to the pituitary—namely, the 
thyroid—we are led rather to the conclusion that acromegaly must be 
due to arrest of function of the former. That is to say there is a 
certain correspondence between the changes occurring in the connec- 17 
live tissues in myxoedema and those affecting the bone, and to some 
extent the subcutaneous connective tissues in acromegaly. 
On the other hand, the pituitary is nearly always found enlarged 
and hypertrophied in general gigantism as distinguished from this 
localised acromegalic gigantism. It is difficult to reconcile such gen- 
eral gigantism with diminished activity on the part of the enlarged 
hypophysis, while again the contrast may be pointed out between 
gigantism and cretinic dwarfism. Tamburini, and independently 
Massolongo (35) have attempted to coordinate the contradictory ana- 
tomical discoveries by suggesting that two stages of the disease may 
be recognised, a first in which the hypohysis undergoes hypertrophy, 
and is in over-action, which may give place to a second in which the 
hypertrophied tissue either undergoes atrophy or adenomatous or sar- 
comatous change. The suggestion is seductive, but for the present 
must be regarded merely as a suggestion. 
Briefly therefore, our knowledge in this connection is miserably ina- 
dequate, and experiments have so far been without result. We cannot 
say whether in acromegaly there is increased or diminished internal 
secretion. While the change in the pituitary appears often to be 
primary, we cannot with certainty lay down that this is the case. It 
has only to be added that if wo admit that lesions of the pituitary 
are associated with acromegaly, we must also admit that compensation 
can occur, for there is considerably over a score of cases on record of 
hypertrophy, adenoma and cystadenoma of the organ, all of consid- 
erable size and presumably of long duration which had developed 
without signs of the disease in question. 
Thus to conclude a long discourse, which in justice to the subject I 
could not well shorten: I have here, gentlemen, followed a single train 
of thought. Some may find it suggestive, to some it may be so simple 
as to be specious, so wide in its embrace that its very comprehensive- 
ness is its damnation. I can only point out that which is here written 
has been already more or less definitely suggested by various writers 
in this country and elsewhere, in connection with most, if not all, the 
conditions here discussed, and impress upon you that, if we are pre- 
pared to accept the results of experimental research and to believe in 
the existence of internal secretions, then, inevitably, we must be led 
to some such views as those brought forward in the course of this 
paper. 18 
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23. Greenfield.—Brit. Med. Jl., 1893, 11., p. 1261. 
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