# Popular Science Monthly/Volume 86/January 1915/Ductless Glands, Internal Secretions and Hormonic Equilibrium II

(1915)
Ductless Glands, Internal Secretions and Hormonic Equilibrium II by Fielding Hudson Garrison

 DUCTLESS GLANDS, INTERNAL SECRETIONS AND HORMONIC EQUILIBRIUM. II

By FIELDING H. GARRISON, M.D.

WASHINGTON, D. C.

In the first half of the nineteenth century the accepted view of the phenomena of secretion was that enunciated by Johannes Müller, viz., that the process consists of two phases—secretion proper, or the casting out of substances upon a surface inside the body, as in the case of the gastric juice; and "excretion" or the voiding of such secreted substances into the external world, as in the case of bile or urea. This distinction was somewhat artificial, since bile, urea and other excreted substances are also secretions in the first instance. In 1801 [1] the French physiologist Legallois, as Gley has noted, surmised, from the identity in composition of all varieties of arterial blood and the diversity of venous blood in different parts of the body, that this diversity is acquired, in each case, from the loss of some substance to the organ from which the vein proceeds. Thus Borden's idea: ${\displaystyle A}$ (arterial blood) ${\displaystyle =S}$ (secretion) ${\displaystyle +V}$ (venous blood), and Legallois's idea: ${\displaystyle V}$ (venous blood) ${\displaystyle =A}$ (arterial blood) ${\displaystyle -S}$ (secretion) are identical. When ${\displaystyle A}$ and ${\displaystyle S}$ are chemically known, ${\displaystyle A}$ being constant, ${\displaystyle V}$ will be known; or, when ${\displaystyle A}$ and ${\displaystyle V}$ are known, ${\displaystyle S}$ will be known. ${\displaystyle V}$ is always a variable. This remarkable intuition of Legallois, like the hypothesis of Borden, remained on a theoretical basis and was not put to experimental proof. In 1849, A. A. Berthold, [2] a Göttingen professor, is said to have transplanted the testes of a fowl to another part of its body, with complete retention of its sexual characters, a phenomenon which he inferred to be due to "the productive relation of the testes, i. e., to its effect upon the blood and thence through the corresponding effect of such blood upon the entire organism." This aperçu, again, does not differ materially from that made by Bordeu in the eighteenth century. In the meantime the ductless glands were coming to be known among the German physiologists as "blood-vessel glands" (Blutgefässdrüsen) or "blood glands" (Blutdrüsen) and were regarded by the histologists Henle and Kölliker as preparers of different chemical substances which are utilized by the organism through the blood. Beyond this general theory, which is identical with Borden's, no special function could be assigned to the different ductless glands. Even Henle asserted that these glands have no influence whatever upon animal life, that they can be extirpated or undergo pathological degeneration without affecting either the sensory or motor functions of the body. The path-breaking importance of Addison's great monograph on the effect of disease of the suprarenal capsules may be thrown into relief by citing Hyrtl's witticism about the suprarenal—that the known nature of its functions insures it from bothersome investigation at the hands of medical men ("Die unbekannte Funktion der Nebenniere sichert dieses Organ von lästigen Nachfragen in der Heilwissenschaft").

If we regard the lungs or the individual cells of the body tissues provisionally as ductless glands, then it will be perceived that the truth of the equation formulated by Legallois had already been demonstrated quantitatively when Lavoisier proved that inspired air is converted into carbon dioxide and water, and when Lagrange, through his pupil Hassenfratz, proved that the oxygen in inspired air, being dissolved in the blood, takes up carbon and hydrogen from the body tissues as the blood courses through them (1791). We now know that the respiratory center in the medulla is stimulated by the CO2 in the venous blood, which Lavoisier and Lagrange had shown to be, in effect, a true metabolite, or waste-product of tissue-oxidation. Their work was in fact the starting point of the chemical study of metabolism, which received its next great advancement in Claude Bernard's study of glycogen; for although the latter may not be, in the strict sense, a true internal secretion, discharged from a gland into the blood, yet its investigation led Bernard to the classical statement of the doctrine of internal secretions as such:

In animals, the glycogenic secretion is an internal secretion because it is discharged directly into the blood. I have considered the liver, as found in the higher vertebrates, as an organ with a double secretory function. It seems to reunite, in effect, two distinct secretory elements and it represents two secretions, one external, the biliary secretion, the other internal, the glycogenic secretion, which is discharged into the blood.[3]

In the year 1843, Claude Bernard, in his graduating thesis, made the discovery that cane sugar is acted upon by the gastric juice, being converted by it into dextrose. This experimental fact led to a train of reasoning which was to revolutionize the physiology of nutrition and metabolism and at the same time to introduce the new concept of internal secretions and to be the starting point of the experimental production of disease by the artificial use of chemical and physical agencies. All carbohydrates, Bernard reasoned, must get into the blood in the form of dextrose. "What becomes of this dextrose?" he next inquired. Somewhere between the alimentary canal (via the portal vein) and the liver, between the liver (via the right heart) and the lungs, between the lungs (via the left heart) and the various body tissues, this dextrose is either destroyed and disappears or is transformed into some other substance. If the locus of this transformation could be discovered and its activities inhibited, an artificial diabetes might be produced by the induction of excess of sugar in the blood. On feeding a dog on rich sugar diet and killing it at the height of digestion, he found the hepatic veins loaded with dextrose, and although this looked at first as if the liver was not the site of transformation, Bernard changed his mind when he found that the blood from the hepatic vein of another dog fed upon meat only (a sheep's head) was also loaded with grape sugar. Thus it appeared that the liver is a sugar-manufacturing plant, and that its sugar-producing or glycogenic function is in the nature of an internal secretion, a view which he confirmed by many varied experiments, publishing his results in 1849-50. About the same time he discovered that a puncture in the region of the fourth ventricle of the brain in the dog will produce a temporary diabetes (1849), which the later researches of Harvey Gushing and his associates indicate to be a polyuria deriving from the pituitary body. As a simple decoction of the liver substance was always found to contain dextrose, the next step was to ascertain how the liver produced this substance at the expense of the materials sent from the alimentary canal. After perfusing a freshly excised liver until the wash-water from the hepatic vein contained no sugar, Bernard found that if the liver were left in a warm place for a few hours a subsequent perfusion would once more come out loaded with sugar, and, although this property of the hepatic tissue could be destroyed by boiling, the sugar-producing power could be restored by adding to a decoction of the boiled liver a small quantity of fresh liver infusion. From this he inferred that the glycogenic function is, in effect, a fermentative process and that its agency is a kind of starch. In 1855' he succeeded in obtaining this glycogenic substance in the form of a dry powder, which could be converted into dextrose by fermentation, although it did not itself respond to the sugar tests. In 1857, by his potash-alcohol process, Bernard obtained it in the pure state as "glycogen." It was the fact that glycogen could be seen, touched, tasted and experimented upon as such that established the theory of internal secretions as a working principle in physiology. The epoch-making character of Bernard's discovery is best indicated in the language of Sir Michael Foster, who has given the most fascinating appreciation of his work in medical literature:

The view that the animal body, in contrast to the plant, could not construct, could only destroy, was, as we have Been, already being shaken. But evidence, however strong, offered in the form of statistical calculations, of numerical comparisons between income and output, failed to produce anything like the conviction which was brought home to every one by the demonstration that a substance was actually formed within the animal body and by the exhibition of the substance so formed.

No less revolutionary was the demonstration that the liver had other things to do in the animal economy besides secreting bile. This, at one blow, destroyed the then dominant conception that the animal body was to be regarded as a bundle of organs, each with its appropriate function, a conception which did much to narrow inquiry, since when a suitable function had once been assigned to an organ there seemed no need for further investigation. Physiology, expounded as it often was at that time, in the light of such a conception, was apt to leave in the mind of the hearer the view that what remained to be done consisted chiefly in determining the use of organs such as the spleen, to which as yet no definite function had been allotted. The discovery of the glycogenic function of the liver struck a heavy blow at the whole theory of functions. No less pregnant of future discoveries was the idea suggested by this newly found out action of the hepatic tissue, the idea happily formulated by Bernard as "internal secretion." No part of physiology is at the present day being more fruitfully studied than that which deals with the changes which the blood undergoes as it sweeps through the several tissues, changes by the careful adaptation of which what we call the health of the body is secured, changes the failure or discordance of which entails disease. The study of these internal secretions constitutes a path of inquiry which has already been trod with conspicuous success and which promises to lead to untold discoveries of the greatest moment; the gate to this path was opened by Bernard's work.[4]

In 1856, one year before Claude Bernard obtained glycogen in the pure state, the doctrine of internal secretions was put upon a firmer basis through the important experiments of Brown-Séquard and Moritz Schiff. Only a year after the publication of Addison's great monograph on suprarenal disease, Brown-Séquard succeeded in producing an exaggerated form of Addison's disease in different animals by removal of the suprarenal capsules, the symptoms being the same and the result of the experiment being rapidly and invariably fatal.[5] If only one capsule were removed, there was no appreciable change in the normal animal, but death would rapidly supervene upon removal, even after a long interval of time, of the other capsule. Furthermore, Brown-Séquard found that a transfusion of normal blood into the veins of an animal deprived of its suprarenal capsules will prevent its death for a considerable time, indicating that the normal suprarenal capsules secrete a material which is necessary for the maintenance of life. In the same year (1856), Moritz Schiff,[6] of Frankfort on the Main, found that excision of the thyroid gland in dogs is invariably fatal. His results were forgotten for over twenty-five years, when, following the description of myxœdema by Gull (1873) and Ord (1878) and the first excision of the thyroid gland for goitre by the Swiss surgeon, Theodor Kocher (1878), J. L. Reverdin of Geneva showed that an "operative myxœdema" is produced in man by complete excision of the thyroid (1882). This was confirmed by Kocher, who found that total thyroidectomy is followed by a "cachexia strumipriva" or "cachexia thyreopriva." Hereupon Schiff returned to the charge and, in 1884, published the results of 60 thyroidectomies in dogs, all fatal, with such significant symptoms as tremor, spasms and convulsions. What is more to the purpose, Schiff demonstrated that these symptoms could be prevented by a previous graft of a portion of the thyroid gland beneath the skin or into the peritoneal cavity of the animal, or by the injection of thyroid juice into a vein or under the skin, or by the ingestion of thyroid juice or raw thyroid by the mouth. This led in time to the remarkably successful treatment of myxœdema by means of thyroid extract by Murray and Howitz in 1893. In 1884, Sir Victor Horsley produced an experimental myxœdema by removal of the thyroid in monkeys, which were found to survive much longer than dogs. It was also found by Allara (1885), Ewald (1890) and others, that experimental thyroidectomy is negative in birds, rodents and herbivorous animals, and that, both in animals and man, operative myxœdema is produced less frequently as age advances. In 1888,[7] Sir Felix Semon, in an important collective investigation, showed that cretinism, myxœdema and operative myxœdema (eachexia thyreopriva) are one and the same. In 1889, Brown-Séquard, then aged seventy-two, found himself vastly rejuvenated as to general health, muscular power and mental activity, by the subcutaneous injection of testicular extracts, the active principle of which Poehl, the Russian physiologist, holds to be the substance spermin (C5H14N2). These experiments of Brown-Séquard easily lent themselves to ridicule, but he followed them up, even to the extent of giving pituitary extract for disease of that organ (1893), and it was his work upon these extracts which led him to formulate the following statement of the old Bordeu theory of internal secretions:

All the tissues, in our view, are modifiers of the blood by means of an internal secretion taken from them by the venous blood. From this we are forced to the conclusion that, if subcutaneous injections of the liquids drawn from these tissues are ineffectual, then we should inject some of the venous blood supplying these parts. . . . We admit that each tissue and, more generally, each cell of the organism secretes on its own account certain products or special ferments which, through this medium, influence all other cells of the body, a definite solidarity being thus established among all the cells through a mechanism other than the nervous system. . . . All the tissues (glands or other organs) have thus a special internal secretion and so give to the blood something more than the waste products of metabolism. The internal secretions, whether by direct favorable influence, or whether through the hindrances of deleterious processes, seem to be of great utility in maintaining the organism in its normal state.[8]

As theory goes, nothing new has been added to the doctrine of internal secretions since Brown-Séquard stated it in this form in 1891. In his essay on "Variation" (1868) Darwin seems to have had a glimmering of the idea when he stated that gemmules are transported from all parts of the body to the ovum to insure their reproduction (pangenesis), and the Bayliss-Starling doctrine of the "hormones" or chemical messengers, as we shall see, is not essentially different from that of Bordeu and Brown-Séquard.

In this connection, it is interesting to note that the first experiment in physiological surgery upon human beings was performed by the gynecologist Robert Battey, of Georgia, who on August 27, 1872, excised the normal ovaries for the relief of a neurotic condition. The physiological basis of this operation, a supposed internal secretion from a specialized set of ovarian cells, has been indicated in many ways. Ovariotomy has been found to have a beneficial effect upon osteomalacia in women. Glass (1899), Morris (1901), Marshall and Jolly (1905) have shown that grafting or transplantation of the ovaries in previously ovariotomized women will reestablish menstruation, sexual desire and general well-being. The experiments of Starling and Lane-Claypole (1906) demonstrated that the inhibitory effect upon pregnancy and lactation of a Battey's operation in rabbits will not be produced by section of the mammary nerves or of the spinal cord. Similarly, the experiments of Brown-Séquard and Poehl on spermin and the fact that ligation of the vas deferens in young animals will abolish the power of reproduction, while permitting full development of the sexual characters and the sexual appetite, go to show that the sexual gonads in the male have an internal secretion, which is supposed to arise from the interstitial cells of Leydig, in the seminal tubules.

(To he concluded)

1. Legallois, "Œuvres," Paris, 1824, II., 209-210. Cited by Gley.
2. Berthold, Müller's Arch., Berlin, 1849, 42.
3. Bernard, "Leçons de physiologie expérimentale," Paris, 1855, I., 96.
4. Sir Michael Foster, "Claude Bernard," London, 1899, 89-90.
5. Brown-Séquard, Compt.-rend. Acad. d. Sc, Paris, 1856. XLIII., 422; 542.
6. Schiff, "Imparziale," Florence, 1863, 234-237.
7. Tr. Clin. Soc, London, 1888, Suppl. to Vol. XXI.
8. Brown-Séquard, Arch, de physiol, norm, et path., Paris, 1891, 5 s. . III., 506. Cited by Gley.
9. Von Mering and Minkowski, Arch. f. exper. Path. u. Pharmakol. Leipzig, 1889, XXVI., 371.