THE

HE historical development of our knowledge of internal secretions and the predominant tendency in medicine to localize a disease in a definite organ, furnish an explanation for the fact that even today the symptoms of endocrine diseases are often interpreted as consequences of the functional disturbance of but one single gland, and we unwarrantably endeavor to find the specific gland presumably at fault. Of course, as early as the nineties statements were made that more than one gland might be involved, as for example, that in acromegaly other glands outside of the involved pituitary played a rôle, such as the gonads and the thyroid.

A general interpretation of endocrine diseases on the basis of their pluriglandular genesis was at that time hardly possible on account of the lack of exact physiological data. Gougerot's conception of polyglandular insufficiency, announced in 1909, did not alter the situation for the reason that such of his syndromes as thyreo-suprarenal-ovarian, or hypophyseal thyreo- testicular represented mainly only a summation of compo

1 Paper read at the Meeting of Congress of Internal Medicine, St. Louis, February 18, 1924.

nents of their essential relationship. When Falta and Wiesel announced, respectively, the ideas of a pluriglandular sclerosis, and of a general connective tissue diathesis, a step forward was taken toward recognizing a homogenous and simultaneous pathological alteration of several glands or of the whole endocrine system, as the result of either a constitutional diathesis or possibly of an infection. Pluriglandular sclerosis and connective tissue diathesis, as actually found in some of the cases, however, have as their common basis only a pathologico-anatomic change manifest in several of the glands which are genetically or structurally related. The functional relation was not taken into consideration, in spite of the striking fact that the structural changes were accompanied by a functional insufficiency in some glands and by a hyperfunction in others.

The pathological physiology of the endocrine system, that is, the exact analysis of the pathogenesis both of polyglandular and specific glandular diseases must be based upon the broad general fundamentals of (1) the genesis, (2) the structure, and most important of all (3) the functions of the endocrine glands. It is essential to investigate the close functional cor

relations and interrelations of the different endocrines, and both their cooperative and antagonistic actions in the various organs of the body. It is furthermore necessary to take into account the fact, confirmed more and more by recent investigations, that the correlated endocrines not only influence, but in turn are influenced by the nervous system and indeed by all the organs and tissues in the body. In other words, the endocrine system is but one part of an integrating arrangement which secures for the individual undisturbed life and activity, adequate for all requirements, and assuring both individual life and preservation of species.

On this basis a discussion of endocrine diseases, as those of thyroid or pituitary, must embrace the following topics: (1) Their position in the whole endocrine system; (2) the control of their functions in various organs by other endocrines, and by the nervous system; and (3) the importance of autonomy of organs and tissues as dependent solely upon physico-chemical conditions. In a sick individual we can very well see how the pathologic alteration of but one organ upsets the equilibrium of the entire system, and how reactions to the pathologic process, expressed in symptoms, course and outcome of the disease, are determined by the general constitutional habitus of the patient. In centering the attention on one gland and failing to appreciate interrelationships, there has resulted, in my opinion, the existing discrepancy of views concerning pathogenesis.

Obviously it will not be possible for me to cover the entire subject in the limited time at my disposal. I

shall discuss only some phases of the physiology and pathology of the thyroid and hypophysis.

The first question is: How far does morphology in its broadest general sense, that is, comparative embryology and anatomy, normal and pathologic histology explain the genetic and structural relationship between thyroid and pituitary? Whether, or whether not, this information warrants the supposition of functional interaction?

The thyroid originates from the entoderm by a median outgrowth of the lining of the pharynx floor. The participation of ectodermal structures, such as the branchial pouches, in the formation of the lateral thyroids is not as yet established. Organo- and histo-genesis transform this originally externally secreting gland into a new organ, composed of follicles and interfollicular tissue capable of forming new follicles. This is an important fact. Without its proper appreciation it was assumed that the follicles represent the remnants of the active embryonic gland, and that the filling up of the follicles with the colloid substance is the natural continuation of the function of the embryonic gland in postfetal life. The loss of the excretory duct, it was falsely assumed, did not cause any other change but a retardation in the delivery of its product, the colloid substance, looked upon as the internal secretion of the adult gland. Studies of the excretory passways of the colloid led into a blind alley. Pathologic studies easily demonstrated that abundance of colloid did not signify increased secretory activity but rather indicated a decreased function.

The true nature of the secretory process of the thyroid, first proposed by A. Kohn in Prague and later confirmed by Bensley in Chicago, is as follows: The epithelium of the thyroid possesses a polarity opposite to that of other gland cells, and delivers its product primarily into the blood vessels rather than into the lumen of the gland. The more active the gland the more quickly it delivers its product into the blood vessel. Only the unrequired surplus is stored in the follicles. There it might undergo chemical changes decreasing its physiologic potency. We urgently need a better understanding of the existing relations between the chemical and morphological processes of production and output of the active principle. Baumann's discovery of iodine in the gland (1894) and Kendall's finding of thyroxin and his studies of its chemistry, on the one hand, and Bensley's histological studies on the other, will have to be correlated.

Recent investigations, made in my laboratory, deal with the distribution of iodine between the cells and the follicular contents, as compared with the iodine contents of the whole thyroid and the blood. In this manner we hope to reveal important details regarding endocrine function. From the pathological point of view it is highly important to recognize this new conception, and to realize that such recognition demands a reconsideration of the interpretation of histologic findings. We must remember the indisputable fact that goitre in reference to function may mean nothing or very much; in the latter case it may mean hypofunction or hyperfunction and even a third pos

sibility-that indefinite something called "dysfunction." We must evaluate anew the histological picture, employing all the latest methods of micro-chemistry, in order to establish new standards for the different phases of functional activity.

Examining recently several series of pathological thyroids, I found striking structural differences in the various parts of the same gland. The tendency was strong to assume variable functional activities. I wonder whether we do not fall into the mistake of schematizing a gland as uniformly normal, or as hypo- or hyperactive in its function. These different stages of function may exist in the same gland in its different parts simultaneously.

As to the pituitary the morphology is as follows: Recent embryologic investigations prove the conception of its purely ectodermic origin to be wrong. The hypophysis originates from four primary indentations of the pharyngeal wall and the head end of the primitive gut. (Two ectodermal pouches form respectively the pars tuberalis and the pars intermedia. Two entodermal pouches form the pars anterior.) Anatomically we must divide the hypophysis into three endocrine segments and if we include the pars posterior nervosa and the stalk, into five parts. The internal secretory parts are: The anterior lobe or prehypophysis, representing a gland of growth; the pars intermedia or juxtaneuralis, influencing metabolism, and third, the pars tuberalis, lying on the eminentia saccularis on the tuber cinereum, the function of which is still to be determined.

Concerning the secretions of the pituitary, I may state briefly that the anterior and tuberalis discharge their product into the blood vessels, and that formation of follicles and their filling up with colloid is merely an accessory storage. Here is an analogy to the secretory mechanism of the thyroid. The product of the pars intermedia does not pass directly into the bloodstream but through lymphspaces of the connective tissue of the pars posterior and hypophyseal stalk into the cerebro-spinal fluid. The relationships between the hypophyseal and thyroid secretions have not yet been studied. Iodine in considerable amounts has been found in the pituitary-a remarkable fact indeed. The morphological interrelation between thyroid and pituitary is apparent from the fact that a hypertrophy of the pituitary follows any deficiency of the thyroid (such for example as congenital aplasia, or experimental removal of the gland in animals). On the other hand, the extirpation of hypophysis or of some of its parts in animals, as well as the operative diminution of the enlarged gland in cases of acromegaly (Hochenegg), is always followed by a change in the structure and volume of the thyroid. Physiologic studies of both glands will eventually answer the question as to the possible functional relations existing between them.

Out of the complex functional activities of these two glands I shall mention only those referring to skeletal growth, body development, development and function of the gonads and to the general metabolism.

Bone growth is a most complicated process, quantitatively depending on

a sufficient supply of materials, and qualitatively (in shape, size, form and time) determined by hormones of practically all the endocrines. It is generally known that longitudinal growth is practically finished at the time of the maturity of the gonads. After that, changes are limited to lateral expansion from the deposit of new periosteal bone. For this reason immaturity of gonads is essential for activation of any stimulus towards bone growth in length. In regard to the height growth periods of humans we have to assume that any considerable increase in height, reappearing periodically, is correlated with changes in the functional ability of the gonads. We cannot decide, however, whether such a functional revolution of the gonads, for instance, in prepuberty, has to be regarded as cause, effect of, or coincidental with, hastened growth. We shall not consider the other endocrines in connection with formation and growth of the skeleton, although we must bear in mind that parathyroids and thymus have a close genetic, topographic and functional relationship to thyroid and hypophysis. We know that both of these glands during infancy and incompleted growth, if absent or deficient, inhibit growth resulting in dwarfism. Hyperfunction of both is accompanied by overgrowth of the skeleton.

The interesting fact must be emphasized that a deficiency of either thyroid or pars anterior of the pituitary results in an inhibition of the maturation of the gonads, and in spite of these seemingly favorable conditions for length growth the actual occurrence of dwarfism in such cases is the more striking. An accept

able explanation of this discrepancy might be found in the fact that the hypoplastic gonads of such an individual are incapable of the periodic changes essential for the periodical length growth phenomenon.

There is no necessity to dwell here in St. Louis on the details of the bone changes in cases of hypothyroidism, since they have been so clearly demonstrated by Dr. Engelbach of this city. I wish to state but this fact: Growth inhibition is invariably accompanied by structural bone changes.

In cases of experimental lesions of the pituitary, and in diseases of the anterior lobe we observe an arrest of skeletal growth. I demonstrated this in my own cases of x-rays. But this inhibition concerns bone growth in all directions with the result of a hypophyseal ateliosis. The significant feature of ateliosis is the fact that the individual almost perpetuates his external status as it was at the time of the onset of the disease. After a shorter or longer time, however, he manifests the evidences of presenility, such as we see in all instances of infantilism. Bone growth is almost completely stopped in all directions. Thus we can explain that cases of hypophyseal ateliosis, preserving a delicacy of bone structure together with a semblance of adult form, are often considered as primary dwarfs (nanosomia primordialis). These individuals make their strongest appeal as human miniatures on the stage. Athyreotic dwarfs are easily recognized by their infantile proportions and coarse bones, by their mental deficiency and by their peculiar skull formation and physiognomy.

Noteworthy differences can also be observed in cases of hyperfunction of thyroid or hypophysis. Hyperthyreosis of adolescent age manifests itself in the abnormal length of the long bones, a fact definitely established by the measurements made by Holmgreen and readily demonstrable in the striking length of phalangeal bones. I have been struck for some time by the slender stature, by the thin extremities and the long hands and fingers of the Basedow patients. I have marvelled at the power of observation of that master artist Botticelli, when I noticed that the necks of so many of his tall and slender figures suggested the presence of an enlarged thyroid. Whatever position one takes in the Basedow problem, whether or not one opposes an exophthalmic goitre or a dysthyreosis to a toxic goitre or a simple hyperthyreosis (my position on this question I shall give later on), the one thing is certain, namely that this abnormal increase of the long bones is a clinical fact, the explanation of which requires nothing else but a thyroid hyperactivity. A surplus of thyroid hormones causes abnormal length growth of long bones in adolescence, in an adult with bone growth finished, such a result cannot ensue. In them, however, a careful x-ray or histological examination of the bones might reveal on increase in either osteoblastic or osteoclastic activity.

A hyperfunction of the anterior lobe of the pituitary is assumed to be the cause of skeletal overgrowth and giantism because in all these cases there is found a hyperplasia, or new growth like adenoma or adenocarcinoma in this lobe. One may quite