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

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* 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 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: $A$ (arterial blood) $=S$ (secretion) $+V$ (venous blood), and Legallois's idea: $V$ (venous blood) $=A$ (arterial blood) $-S$ (secretion) are identical. When $A$ and $S$ are chemically known, $A$ being constant, $V$ will be known; or, when $A$ and $V$ are known, $S$ will be known. $V$ 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, 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 CO$_2$ 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 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.
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. 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, 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, 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 (C$_5$H$_{14}$N$_2$). 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:
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.
From the time of Brown-Séquard on, experimental investigation of the subject moved so rapidly and in so many different directions that the general trend of the theory became obscured or lost in the details of controversy. And further obfuscation was brought about by the constant succession of dissolving views of the subject of carbohydrate ​metabolism. In 1886, von Mering produced an experimental diabetes by the ingestion of phlorhizin. In 1889, von Mering and Minkowski obtained diabetes by an experimental excision of the pancreas. The histological, pathological and clinical studies of E. I. Opie (1901), L. W. Ssobolew (1902) and W. G. MacCallum (1909), indicated that the source of this pancreatic glycosuria is to be found in a specialized group of cells, called the islands of Langerhans. Thus it would appear that the pancreas possesses an internal secretion-as well as a digestive function. The discovery of iodothyrin in the body by Eugen Baumann, in 1896, suggested the relation of the thyroid gland to iodine metabolism and an adjoining pair of ductless glands, the parathyroids, discovered by the Swedish anatomist, Ivar Sandström, in 1880, would appear, from experiment, to have an influence on calcium metabolism. In 1891. Eugen Gley showed that where excision of the thyroid is negative in certain animals, these animals will speedily die if the four parathyroids are also removed. In 1892, the Viennese surgeon Anton von Eiselsberg made a successful transplantation of the parathyroid glands from the neck to the abdominal wall in a cat and showed that tetany may be produced upon its removal from this site. Subsequent experiments by H. Leischner (1907) and by W. S. Halsted, at the Johns Hopkins (1909), showed that the production of tetany is really due to removal of the closely adjacent parathyroids. These observers found as in Schiff's experiments, that the tetanoid spasms will be abolished upon injection of an extract of the gland or after parathyroid feeding; or upon regrafting the gland itself. In 1908 W. G. MacCallum and C. Voegtlin showed, at the Johns Hopkins Hospital, that tetany may be abolished by treatment of the patient with calcium salts. Another ductless gland, the pituitary body, has been shown to have a marked relation to carbohydrate metabolism and, like the suprarenal and parathyroids, to be essential to the maintenance of life. The pituitary body, which the anatomist Soemmering called the hypophysis cerebri in 1778, was, as we have seen, regarded as an organ discharging a mucous secretion into the nostrils until this theory was disproved in the seventeenth century. This structure consists of an anterior glandular lobe (pars anterior) and a smaller posterior lobe (pars nervosa), the whole being connected with the floor of the fourth ventricle of the brain by means of a stalk or infundibulum. In 1838 the embryologist Rathke showed that the anterior lobe is developed by the protrusion of an ectodermal pouch (Rathke's pouch) from the roof of the pharynx and is made up of epithelium derived from the buccal cavity. It lies in the embryonic rest of Rathke's pouch "as a ball is held in a catcher's mitten" (Gushing). The posterior lobe is made up of nervous tissue and is derived from a corresponding prolongation from the anterior ​cerebral vesicle. Until recently the pituitary body has been inaccessible to surgeons and to physiological experimenters by reason of its encasement in the sella turcica of the sphenoid bone. Experimental removal of the pituitary (hypophysectomy) was essayed by Horsley (1886), Marinesco (1892), Vassale and Sacchi (1892-4), Gatta (1896), Biedl (1897), von Cyon (1898-1900) and others, with negative or contradictory findings, resulting no doubt from the difficulties encountered in approaching the gland through the skull and of insuring its entire removal under these conditions. In 1908, an important advance was made by Nicholas Paulesco of Bucharest, who devised an operation by the temporal route and showed that the pituitary body is essential to life, its removal being fatal to the animal. At the same time, he found that removal of the anterior lobe is equivalent to entire removal and that excision of the posterior lobe is negative. Paulesco's experiments were put to the test by Harvey Gushing, now professor of surgery at Harvard, and his associates at the Johns Hopkins Hospital, their experiments being performed mainly upon dogs. They found that total removal or removal of the anterior lobe alone are alike fatal, the animal dying in three days with a peculiar train of symptoms consisting of lowered temperature and blood pressure, sluggishness, unsteady gait, rapid emaciation, slowing of pulse and respiration, diarrhœa, diminished urine in adults; polyuria and glycosuria in puppies. Partial removal of the anterior lobe in normal dogs was found to produce a pronounced state of obesity, with a remarkable shrinkage of the external (male) genitalia. In other words. Gushing produced, by experiment, a genuine pathological reversion to the condition known as sexual infantilism or "dystrophia adiposo-genitalis" (Fröhlich's syndrome). In the case of the posterior lobe, which, as shown by Gushing and Goetsch, discharges its secretion into the cerebro-spinal fluid, partial removal or the production of insufficiency of the secretion by putting a clip upon the stalk of the gland, produces, at first, a temporary lowering of the animal's assimilation-limit for sugars, followed by a marked and permanent increase in its tolerance for carbohydrates, which is again promptly lowered by injection of an extract of the posterior lobe. In 1895 Oliver and Schäfer found that the mammalian pituitary possesses an active principle which, upon injection, elevates the blood pressure and increases the force of the heart beat. In 1898 Professor William H. Howell, of the Johns Hopkins University, showed that this property is possessed by the extract of the posterior lobe alone. In his Harvey Lecture of December 10, 1910, Gushing introduced the pathological idea of "dyspituitarism" or perverted function of the gland, as a generic concept, covering excess or insufficiency of its function, and for the following reasons. In accordance with the clinical and pathological findings of Parry, Graves and Basedow, exophthalmic goiter was regarded as a state of "hyerthyroidism," or excessive secretion of the gland, while the myxœdema of ​Gurling, Gull and Ord was termed "hypothyroidism" (diminished secretion or insufficiency). But it was found that, in many cases the two conditions may be blended, as Paracelsus had originally surmised in the Salzburg region, producing an overlapping of the cardinal symptoms of either. For this condition, the term "dysthyroidism" was proposed by Marie for both. In like manner, states of over activity in the pituitary (hyperpituitarism) or of under activity (hypopituitarism) may be superimposed, one upon the other, making the term "dyspituitarism" most appropriate in the majority of cases. As a goitrous mother may have a cretinous infant, so, as originally observed by Crookshank and confirmed by Gushing, a big, bony acromegalic woman may have a son afflicted with pituitary infantilism or obesity. Gushing has also shown that there is evidence of pituitary activity in pregnancy and hibernation (1912) and his experiments upon its relationship to the sympathetic nervous system (1913) have led him to the conclusion that a lesion of the posterior lobe is the principal cause of the increase of normal urine (polyuria) otherwise known as diabetes insipidus. Finally, he had devised a standard surgical procedure for approaching the almost inaccessible pituitary gland, which was first operated upon in man with success by H. Schloffer in 1907. Gushing's work is thus a brilliant contribution to physiological or Hunterian surgery which had almost fallen into abeyance until the twentieth century and which has been the principal means of elucidating the obscure physiology of the ductless glands.
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)
* ↑ Legallois, "Œuvres," Paris, 1824, II., 209-210. Cited by Gley.
* ↑ Berthold, Müller's Arch., Berlin, 1849, 42.
* ↑ Bernard, "Leçons de physiologie expérimentale," Paris, 1855, I., 96.
* ↑ Sir Michael Foster, "Claude Bernard," London, 1899, 89-90.
* ↑ Brown-Séquard, Compt.-rend. Acad. d. Sc, Paris, 1856. XLIII., 422; 542.
* ↑ Schiff, "Imparziale," Florence, 1863, 234-237.
* ↑ Tr. Clin. Soc, London, 1888, Suppl. to Vol. XXI.
* ↑ Brown-Séquard, Arch, de physiol, norm, et path., Paris, 1891, 5 s. . III., 506. Cited by Gley.
* ↑ Von Mering and Minkowski, Arch. f. exper. Path. u. Pharmakol. Leipzig, 1889, XXVI., 371.