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

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* DUCTLESS GLANDS, INTERNAL SECRETIONS AND HORMONIC EQUILIBRIUM. III
By FIELDING H. GARRISON, M.D.
WASHINGTON, D. C.
IV
THE most remarkable fact about the internal secretions is that they are correlated with one another. Not only has this been abundantly demonstrated by experiment, but, in many cases, pathological lesions of the individual glands cause some disturbance in the functional relations of the other glands—the so-called "pluriglandular syndromes." The idea of a correlative relation is not necessarily new, was perhaps implicit even in Bordeu's statement of the theory, but it did not begin to acquire tangible and intelligible form until the complex chemistry of the metabolism of the body had beeen better understood. On the physiological side, it has been noted, for instance, that excision of the pancreas produces glycosuria, even after thyroidectomy and parathyroidectomy, but not after excision of the adrenal bodies; that partial excision of the thyroid in bitches will produce a mild myxœdema, if pregnancy supervenes, the symptoms disappearing after littering; that the thymus gland is often enlarged in exophthalmic goiter but will atrophy after thyroidectomy; that castration is followed by enlargement of the thymus, and, conversely, excision of the thymus produces swelling of the ovaries. On the pathological side, the thyroid is often enlarged during puberty, menstruation, excessive venery (e. g., in prostitutes) and pregnancy; swelling of the ovary and menstrual disturbances often accompany goiter. Myxœdema often comes on at the menopause or in connection with sterility. Acromegaly, as was shown by Edwin Klebs, is often accompanied by enlargement of the thymus. Enlargement of the pituitary often accompanies pregnancy or hibernation, yet castration causes enlargement of the pituitary in the young and acromegaly is often associated with loss of sexual power. The fact that many of these experimental results and pathological findings do not harmonize makes the problem one of extreme complexity. Furthermore, it is known that lesions of different ductless glands will produce isolated identical effects, which overlap each other in a group of symptoms, making the causal relation dubious when there is a "pluriglandular syndrome." Glycosuria (lowered tolerance for carbohydrates) may be produced by goiter, by injection of thyroid extract in acromegaly or by injection of pituitary extract, by excision of the parathyroid body, by ​injection of adrenalin, by excision of the pancreas or by a lesion of the islands of Langerhans in that organ. On the other hand, an increased tolerance for carbohydrates (obesity) occurs after destruction of the posterior lobe of the pituitary body, as well as in myxœdema or after thyroidectomy; increased blood pressure follows upon injection of the pituitary, adrenal, placental and kidney extracts; lactation is accelerated by injection of extracts of the thymus, pineal and pituitary bodies and the corpus luteum (ovary); the pupil is dilated by extracts of the thymus, pituitary, pancreas, suprarenals, kidney, sexual glands, liver and muscle. Effects of this kind are analogous to the mystifying "enharmonic cross relations" in modern music, in which the same note (on the piano scale) is so employed that it is brought into relation with two different tonalities. C sharp and D flat, G sharp and A flat produce the same sounds when given on the piano scale, although they can, if necessary, be distinguished on stringed instruments, which render an exact account of the difference in the number of vibrations. Similarly, these apparently identical effects of the different ductless glands indicate that their functions are correlated, that they are somehow concerned in maintaining the hormonic equilibrium of the body.
Concerning the mechanism of correlation, two prominent theories have been advanced. The first is the doctrine of the hormones of Bayliss and Starling (1902) in which the chemical control of the body is assumed to be effected by means of hormones, or chemical messengers, which pass from the various organs and ductless glands, via the bloodstream, to other parts of the body, producing biochemical effects upon irritable protoplasmic tissues. In the initial experiment of Bayliss and Starling, the secretion of pancreatic juice following upon introduction of acid into the duodenum was found to be not a local reflex, as had hitherto been assumed, but due to the action of a hypothetical substance (secretin) discharged by the intestinal mucous membrane under the influence of the acid and carried to the pancreas by the blood channel. Many experiments, particularly those of Howell on the coagulants and anticoagulants of the blood (thromboplastin and antithrombin) indicate the existence of hormones. Adrenalin, iodothyrin and pituitrin are the only hormones of the ductless glands which have been isolated to date.
The other theory is that of the clinicians and pharmacologists of the Vienna school, Eppinger, Falta and Rudinger, which asserts that the suprarenal and thyroid bodies act upon and are controlled by the nerves of the sympathetic system, while the pancreas is similarly related to all nerves acting upon smooth (involuntary) muscle and not originating from the chain of sympathetic ganglia. The two systems have been termed "autonomic," because they seem to be detached from and independent of the controlling impulses arising from the ​cerebro-spinal axis, while themselves controlling all organs containing unstriped muscle, secreting glands or both, e. g., the smooth muscle of the bronchi, stomach, intestines, blood vessels, genitalia, eye and all the glands of external and internal secretion. The sympathetic or visceral nervous system has also been called the "vegetative" system, because the organs under its dominion functionate involuntarily or unconsciously, as with vegetables or plants. At present, the term "vegetative system," formerly termed the autonomic system by Langley, is restricted to that part of it which originates from the sympathetic ganglia, while the antagonistic system governing involuntary muscle, which is largely made up of fibers from the vagus nerve, is now styled the "vagal autonomic."
The difference between the two autonomic nervous systems and the central (cerebro-spinal) system is that, in the former, the nerve fibers never proceed, as ordinarily, directly from the nerve center to the organ controlled, but pass, as neurons, from the gray substance to a ganglion in which they encounter a break or synapse (separating surface), on the other side of which a similar post-ganglionic neuron proceeds to the organ controlled. The synapse, a term first proposed by Sir Michael Foster, has been likened to a switch over which the nervous impulse jumps to proceed on its way. Langley, the original investigator of the autonomic systems, discovered that wherever there is a switching of the nervous impulse across a synapse; the effect can be abolished in other words the post-ganglionic fiber can be paralyzed, by painting over the exposed ganglion with nicotine solution, thus determining whether an autonomic nerve fiber passes through a ganglion without interruption or not. If, after painting the exposed ganglion with diluted 0.5 nicotine solution, or even after internal administration of the alkaloid, the effect of central excitation of the post-ganglionic fiber at the ganglion is the same as ordinarily, then there is no interruption; but if the effect is abolished under these conditions, then the pre-ganglionic fiber terminates in a synapse. Langley's nicotine effect holds good for all ganglia of the autonomic systems, whether of sympathetic or vagal origin. In other respects, however, these two systems are antagonistic, both in respect of physiological functions and response to the action of drugs. The effect of electrical stimulation of a sympathetic fiber is just the opposite of that of a vagal autonomic fiber. The sympathetic fibers check, the vagal autonomic fibers excite, the movements of the intestines; the sympathetic dilates, the vagal autonomic contracts, the pupil; the sympathetic hastens, the vagal autonomic slows, the heart. Adrenalin (epinephrin), which the Viennese clinicians assume to be the specific hormone of the sympathetic autonomic, produces, on ingestion or injection, effects similar to those produced by electrical ​stimulation of the sympathetic, viz., dilatation of the pupil, dry mouth from diminished salivary secretion, rapid heart action, glycosuria and increased secretion and motility of the stomach and intestines. Hence adrenalin, and drugs, like ergotoxin, which resemble it in action, are variously termed sympathicotropic, sympathicotonic or sympathicomimetic. On the other hand, certain drugs, such as pilocarpin, muscarin, physostigmin, cholin and digitalis, which stimulate the autonomic fibers of the vagus, producing effects diametrically opposite (contraction of the pupils, profuse salivation, slow heart action, pollakiuria, etc.) are termed vagotropic, vagotonic or vagomimetic, because their action simulates the vagal autonomic. Thus the Viennese clinicians postulate two opposing diathetic conditions, sympathicotonus and vagotonus, the symptomatology of which can be thrown into relief by certain pharmacodynamic tests, which have been likened by Januschke to "tuning keys by means of which we can operate upon the complicated stringed instruments of the body, and voluntarily make one string tighter to increase its vibration or another looser to dampen its function." To complete the analogy of their tripod of ductless gland correlations, Eppinger and Hess assume that the pancreas, controlled by the vagal autonomics, secretes a hormone "autonomin," which is supposed to antagonize adrenalin, the hormone of the sympathetic system proper. So far, this is a very cogent and fascinating theory, but, as often happens, it does not work out according to specifications in all cases, and is strongly opposed by Gleg. The symptomatology Id vagotonic and sympathicotonic patients, too complex to be considered here, is extremely variable and the reaction to drugs sometimes unreliable. Thus, Eppinger and Hess themselves found that pilocarpin and adrenalin sometimes produce strong reactions in the same patient. The interest of their theory for present purposes lies in its capacity for elucidating the action of the ductless glands and internal secretion, for behind the ductless glands and the hormones themselves there must be some controlling mechanism. It is assumed that when the vegetative and vagal autonomics are over-excited (sympathicotonia, vagotonia), these act upon the viscera and the ductless glands, the hormones or internal secretions of which in turn react with redoubled force via the blood channels upon the autonomic nerve centers, vegetative and vagal, producing a vicious circle, as Hemmeter maintains. Thus the hormones of the viscera and the internal secretions of the ductless glands regulate the tonus of the nervous system, while the autonomic nerve fibers themselves regulate the action of the ductless glands, the viscera, blood vessels and all organs containing involuntary muscle. ​The importance of the subject in relation to clinical medicine has been well emphasized by Professor L. F. Barker."
The balance maintained normally between the two antagonistic systems is one of the most interesting of physiological phenomena. Think, for example, of the rate of the heart beat—how constantly it is maintained at a given level in each individual when the body is at rest; the impulses arriving through the vagal system just balance those arriving through the sympathetic system, so as to maintain a rate of approximately seventy-two beats per minute. And a similar balance is maintained in other autonomic domains (e. g., pupils, bronchial musculature, gastric glands, gastro-intestinal muscle, sweat glands, bladder muscle, etc.).
Another set of correlations advanced by the Vienna school is connected with the causation of diabetes. Eppinger, Falta and Rudinger regard the thyroid, pituitary and adrenals (chromaffinic system) as the accelerators or mobilizers of glycosuria, in that all three increase exchange or metabolism of proteins, the adrenals mobilizing carbohydrates and the thyroid increasing fat absorption. The pancreas and the parathyroids, on the other hand, are held to be inhibitors of glycosuria, retarding protein metabolism and restricting the mobilization of carbohydrates. Diabetes following excision of the pancreas is held to be due to the mobilizing power of the adrenal hormone on the ​glycogen of the liver, the normal inhibitory action of the pancreatic hormone being removed, and is thus at once a positive adrenal diabetes and a negative pancreatic diabetes. This harmonizes with the glycosurias following injection of adrenalin or following increase of the adrenal function from stimulation of the sympathetic system. Hyperthyroidism (exophthalmic goiter) produces a tendency to glycosuria from relative pancreatic insufficiency and increased adrenal activity. Myroedema or the corresponding removal of the thyroid gland produces an increased tolerance for carbohydrates (obesity) because the inhibitory function of the pancreas is removed and adrenal action diminished. There is a lowering of carbohydrate tolerance after parathyroidectomy. The lowered carbohydrate tolerance in hyperpituitarism and the increased tolerance in hypopituitarism, demonstrated by Gushing, is explained by the inhibitory action of the secretion of the posterior lobe of the pituitary on the pancreatic hormone, mobilization of glycogen and glycosuria resulting when the pituitary secretion is in excess and the restraining influence of the pancreas thus impaired. Gushing and Jacobson found that the obesity or high sugar tolerance following excision of the posterior lobe of the pituitary will persist even after subsequent excision of the pancreas, no glycosuria developing.
The question arises, how do the internal secretions or hormones act upon the central nervous system? Here we encounter what Ehrlich calls that obscure province of physiology, the specific irritability of organized tissues, or the capacity of protoplasm to react to chemical and other stimuli. If a chemical substance in the blood comes in contact with the chemoreceptors or special groups of atoms in the periphery of a cell, the two sets of substances may remain inert in relation to each other, they may combine, producing equilibrium, or they may induce a vigorous reaction through difference in their chemical potentialities. The complexity of this phase of the subject is fairly indicated in Abderhalden's studies of intracellular metabolism, in which he shows that by linkage of three different amino acids. A, B, C, the following isomeric arrangements can be produced by permutation and combination, viz.,
A-B-CA-C-BB-A-CB-C-AC-A-BC-B-A.
In like manner, from linkage of four amino acids, 24 structurally isomeric compounds may result, from five, 120; from six, 720; from seven, 5,040; from fifteen, 1,307,674,368,000; from twenty, 2,432,902,008,176,640,000. We have as yet no calculus of variations fine enough to estimate even the rate of change of these evanescent combinations, which we may assume, are constantly taking place within the cell.
Again, it may be asked, is the hormonic equilibrium of the body identical with thermodynamic equilibrium? And here we have another problem which may be described as transcendental. In the ordinary ​metabolism of the body, it is agreed that the first law of thermodynamics—conservation of energy or constancy of the sum of energy in an isolated system—applies in every respect. Does the second law—irreversible dissipation of energy in one direction—apply to such relatively isolated (adiabatic) systems as a cell enclosed in its cell-wall or the animal body encased in its integument. Does the cell or the organism act like a heat engine or an electric cell, dissipating its energy in one direction, or is it a reversible mechanism, like a dynamo. In the animal body, the food stuffs of high chemical potential, proteids, carbohydrates and fats, are degraded and transformed into substances of low chemical potential (carbon dioxide, urea and water), the energies passing, as in a Carnot cycle, from a source of high potential to a sink at low potential energy. The second law is operative here, but the process is more economical than in a heat engine. Still more economical is it in cold-blooded animals, while in green plants there seems to be an actual reversal of the process, in that substances of low chemical potential (nitrogen compounds, carbon dioxide and water) are transformed into substances of such high chemical potentiality as carbohydrates, proteids and oils. There is thus some indication that in plant cells, or those organisms, like bacteria, which lie between animals and plants, there is a possibility of reversal of those physical processes which take place in inanimate nature. Of this we have further examples in the nitrification of the soils by bacteria buried in it (without the aid of radiant energy from the sun) or in the Brownian movements of bacteria contained in a liquid. Of the possibility of reversing the second law in the human organism Lord Kelvin said that "even to think of it, we must imagine men with conscious knowledge of the future, but no memory of the past, growing backwards and becoming again unborn, and plants growing downwards into the seeds from which they sprang." This would assuredly be an extreme case, but Cushing's production of sexual infantilism in dogs by partial excision of the anterior lobe of the pituitary body fulfils some of these conditions. At best, we can only affirm that the whole matter is transcendental, that is, so far beyond our ken, since it involves an assumption of the old metaphysical "vital principle," which Bergson revamps as the élan vital.
A very complex view of the internal secretions and hormones is that which connects them with the general protective mechanism of the body. The earliest to advance this view was Dr. Charles E. de M. =, of Philadelphia, whose treatise on the internal secretions, published in 1903, has passed through six editions, and has undoubtedly played a prominent part in bringing the subject to a focus in this country. In relation to immunity, Sajous's main position is that the ​germicidal and antitoxic substances in the body are originally derived from certain ductless glands, the immunizing mechanism in question comprising the "adrenal system" (adrenals, pituitary and thyroid). He holds that the adrenal secretion mobilizes zymogens in the body, endowing them with their ferment-activities, that secretin is "adrenoxidase," that enterokinase is adrenoxidase plus nucleo-proteid, that the pituitary body has no internal secretions, but is the general and governing center of the sympathetic system and of all vegetative functions, that, as an immunizing center, it is the homologue of the "test organ" of mollusks and other invertebrate animals, and that the body at large is protected from disease by an "auto-antitoxin" composed of the internal secretions of the adrenal (adrenoxidase; Ehrlich's amboceptor), of the pancreas (trypsin; Ehrlich's complement), of the spleen and leucocytes (nucleoproteid), and of the thyroid and parathyroids (thyroiodase; Wright's opsonins). Upon this theoretical substructure, which was arrived at by deductions based upon clinical and experimental data, including some of his own, the work of a mind of mathematical cast, Sajous has erected a complete system of medicine, connecting his ideas with all known diseases and their treatment.
Without presuming to discuss the merits of these different views, it may be said that their very complexity indicates that present knowledge is in a state of flux and that only the surface of the subject has been scratched so far. We can not object that "facts not opinions" are wanted here, for the collective mass of observations and experiments is enormous. But all recent investigations, those of Abderhalden on the protective ferments of the body, for instance, indicate a general reaching out for a larger correlation or synthesis, which shall weld so many seemingly contradictory observations into a harmonious whole. In 1912 von Behring included as "agents of infection," pathogenic microorganisms and their toxic products and the poisons produced by animals (venoms, etc.) and the higher plants (abrin, ricin, ergotin, etc.), and it would seem even reasonable to include in this group certain mineral poisons like arsenic or lead, the action of which mimics an infectious disease. In February, 1914 von Behring made another generalization of equal sweep, in which he brings such concepts as idiosyncrasy, susceptibility to disease, diathesis, anaphylaxis and super-sensitiveness to toxins into one and the same category. The Viennese clinicians associate diathesis with the ductless glands. Sajous associates the ductless glands with immunity from disease. This is all that can be affirmed of present theories of the subject.
​Perhaps the most interesting feature of the ductless glands is their correlation with the sexual function. It is plain that, except as generic types, these categories have no special application to normal humanity. The dunce's cap is surely ready for him who confuses physiological tendency with individual morality, in each case an artificial inhibition put upon reaction to stimuli. Aside from the other correlations, diminished sexual power is common to the two main groups of pituitary disorders, acromegaly and sexual obesity or infantilism. The acromegalics have been likened to the Neanderthal man, who was probably, as the gorillas are, hyperpituitary (Keith), to eunuchs, who are excessively tall when not over-corpulent, and to the tall, raw-boned, heavy-jawed peoples of the northern countries who are often sexually cold. The obese infantile patients of the Fröhlich type, on the other hand, suggest the fat boys of the Pickwick Papers and the large hotels, and the eunuchoid "Lobengulas" described by Sir Jonathan Hutchinson. Even in folk-lore, obesity always connotes sexual frigidity. In a recent view of Dr. Leonard Guthrie, the autopsy of the great Napoleon at St. Helena indicates that the corpulence of his later years, his gradual loss of intellectual keenness, his general fat-headedness from the time of the Russian Campaign, may have been due to the onset of a pituitary obesity, the dystrophia adiposo-genitalis of Mohr and Fröhlich. The logical opposite of the acromegalics are therefore, not the fat patients of the Mohr-Fröhlich type, but the short, swarthy, goat legged achondroplasics who often exhibit great muscular strength, unusual sexual precocity and general salacity. These have been assimilated to the satyrs of mythology to the short, swarthy, troglodyte peoples such as the Iberians, or the Euskarians, the primitive inhabitants of Britain, to "the short-limbed children, of precocious sexuality," and particularly the "forward female children, with full busts, already boasting of their affairs," who are so common on the streets of modern cities. It was not without reason that the Greeks represented the great god Pan as a goatish individual. Except in the negro the generic sexual type, the differential characters of which are harped upon even in the plays of Dumas fils, is short, swarthy, muscular; the frigid type, of high pituitary index, is either flabby and obese (the kühle Blonde of the Germans) or the lank, raw-boned acromegalic. It is said that many achondroplasic dwarfs of history, like Sir Geoffrey Hudson, were of the salacious type. The records of the obstetric clinics show that female achondroplasics, married or unmarried, have sometimes undergone the operation of Cæsarean section three or four times ​running. The amazing fertility of achondroplasic women has been emphasized in the statistical or biometrical investigations of Karl Pearson, and that this type connotes extreme sexuality is borne out by the observations of Pierre Marie and his co-workers at the Salpêtrière. Crookshank maintains that "the Bengalee is pretty much in the same state as a sufferer from a forma frusta of exophthalmic goitre; while the pigmentation and genital gigantism of the negro are suggestive of adrenal assertion." He further points out that "certain genital malformations or abnormities are almost always accompanied by adrenal tumors; and Iscovesco has shown that adrenal lipoids when administered hypodermically rapidly produce genital overgrowth." On very slender evidence, achondroplasia has been correlated by some observers with disease of the pineal body (epiphysis cerebri), which Descartes regarded as the seat of the soul. Disease of the pineal in young children sometimes results in increased development of the sexual organs with corresponding growth and mental precocity, whence it is inferred that the pineal secretion inhibits growth, particularly the development of the reproductive glands.
Of the internal secretions of the pancreas and the sexual glands, the thyroid, parathyroid, suprarenal and pituitary bodies, considerable is known; less of the spleen, carotid gland and pineal body (epiphysis cerebri); of the "parathymoid" and the paraphysis of the brain, nothing whatever. The vast amount of recent investigation on the subject has been well summed up in the treatises of Sajous (1903), Arthur Biedl (1910), Swale Vincent (1912) and Wilhelm Falta (1913) on the internal secretions, and such individual monographs as those of Friedleben on the thymus (1858), von Eiselsberg on the thyroid (1901) and Gushing on the pituitary (191-). All these are liberally provided with bibliographies, Cushing's book being a model in this respect, and Gushing and Falta give splendid illustrations. Gushing's work, which a competent critic has pronounced to be the most important American monograph on a surgical subject printed in the last ten years, is also a genuine contribution to internal medicine. With John Hunter the surgeon began to be, not only an experimental physiologist and pathologist, but also a clinical observer. Modern medicine affords many examples of original descriptions of new diseases by surgeons, in particular, Sir James Paget and Sir Jonathan Hutchinson, whose "Archives of Surgery," twelve volumes entirely written by himself, is a great storehouse of unique pathological observations. Professor Gushing's work is in this class, the subject is approached from the physiological, pathological, clinical, surgical and ophthalmological sides, and in its combination of induction from experiment with the Hippocratic induction from experience, it is a fine exemplar of what Sir Michael ​Foster regarded as the ideal method of investigation in internal medicine:
* ↑ Cited by Barker.
* ↑ J. C. Hemmeter, New York Med. Jour., 1914, XCIX., 108.
* ↑ L. F. Barker, Canadian Med. Assoc. Jour., Montreal, 1913, III. See, also, W. B. Cannon, "The Interrelations of Emotions as Suggested by Recent Physiological Researches," Am. Jour. Psychol., Worcester, Mass., 1914, XXV., 256-282.
* ↑ See J. Johnstone, Proc. and Tr. Liverpool Biol. Soc, 1913, XXVII., 1-34.
* ↑ Sajous has given a recent presentation of his views in American Medicine, Burlington, N. Y., 1914, XX., 199-210.
* ↑ E. von Behring, "Einführung in die Lehre von der Bekämpfung der Infektionskrankheiten," Berlin, 1912.
* ↑ Schmidt's Jahrb., Bonn, CCCXIX., 113-124.
* ↑ See, Univ. Med. Record, London, 1912, I., 119-121.
* ↑ "Ein gutar Hahn wird pelten fett," etc.
* ↑ F. Guthrie, Proc. XVII. Internat. Cong. Med., 1913; London, 1914, Sect. XXIII., 143-154.
* ↑ Univ. Med. Record, London, 1912, I., 121.
* ↑ Crookshank, "School Hygiene," London, 1914, V., 71-72.
* ↑ Poster, Huxley Lecture, Nature, London, 1896, LIV., 580.