|Today's Medicine, Tomorrow's
Essays on Paths of Discovery in the Biomedical Sciences
"By their diseases ye shall know them - the endocrines." The title of this essay by J. H. Means aptly characterizes the development of endocrinology, a field to which his own clinically -oriented researches on the thyroid contributed so greatly (Means 1960). For, endocrinology is a science which grew out of the interest of physicians in the malfunctioning of glands whose functions were not yet well understood, and it has continued to draw many of its problems from the study of endocrine disorders.
In the pages that follow, we will look at the ways in which research on endocrine disorders gradually revealed the nature and functions of the hormones - the chemical messengers produced by the endocrine glands - and the complexity and integration of the endocrine system's interactions. Our account of endocrinology's development defines four phases of research which, though often overlapping in time and effort, are each marked by the appreciation of a new level of complexity in the functions of the endocrine glands. Phases one and two, in which physicians and physiologists recognized the effects of individual endocrine glands on other parts of the body, and then discovered how glands communicate with one another, will receive the most detailed treatment in this chapter. For it was in these phases of inquiry that problems of medicine raised a fundamental biological problem, that of the nature of the chemical regulation of physiological processes: a problem around which endocrinology emerged as a new field of research in the early years of the twentieth century. To provide some understanding of the problems that endocrinologists subsequently pursued we will sketch, more briefly, the content of endocrinology's third and fourth phases. Phase three was marked by discoveries about how the endocrine glands and the nervous system influence each other's activities, while in the fourth and current phase, endocrinologists and molecular biologists seek to understand the elaborate mechanisms of communication between the endocrine system and the organelles of individual target cells.
The broad approach to the development of endocrinology taken in this chapter in part reflects the nature of the endocrine system itself. The system's most striking feature is its ability to coordinate extremely complex interactions among its own disparate elements, the rest of the body, and the external environment. Each gland's activity impinges on the others and on the body as a whole. As textbooks of endocrinology despairingly point out, it is artificial and misleading to depict the development and nature of endocrinology in terms of a particular disease, gland, hormone, or even a set of interacting parts. The fact that often the peculiar manifestations of endocrine disorders initially drew attention to the interrelationships of glands, hormones, nerves, environment, and target cells underscores the importance of treating the history of research on the endocrine system in as holistic a manner as possible.(1)
Like most other branches of science, endocrinology has no obvious birthday to celebrate. Most of the endocrine glands were discovered by the "kitchen anatomy" of hunters and cooks in prehistory or by the medical anatomists of classical antiquity and the Renaissance; a few - like the tiny parathyroids embedded in the thyroid - were not found until the last century. Similarly, ancient, medieval, and Renaissance physicians noted several disorders diabetes, goiter, cretinism, dwarfism, and gigantism - which we now know are caused by endocrine malfunction; but other equally striking endocrine diseases were not described until this century. And, whether by superstition or empirical trials, physicians in many cultures and periods have employed animals' glands as drugs -precursors of such modern glandular products as insulin and cortisone. These early observations of anatomy, disease, and therapy were not linked together, however, until the latter half of the nineteenth century and the beginning of the twentieth. Only then did a combination of clinical studies and the physiological experiments they generated suggest that these mysterious glands had an important role in the coordination of growth and metabolism.
It was well before the latter half of the nineteenth century, however, that physicians and biologists began to formulate the concept of animal hormones or internal secretions. In 1766, for example, the celebrated Swiss [END OF PAGE 52] physiologist, Albrech von Haller, grouped together the thyroid, spleen, and thymus because of their common anatomical peculiarities - the lack of a secretory duct and a plentiful supply of blood vessels - and suggested that these "vascular glands" poured special substances directly into the veins and thus into the general circulation. A few years later, in Recherches sur les maladies chroniques, French physician Theophile de Bordeu formulated a concept akin to what we now think of as a hormone. De Bordeu speculated that "each organ of the body gives off emanations which are necessary and useful to the body as a whole," and he particularly stressed "the tonic effects of testicular and ovarian emanations, and their influence on the secondary sex characteristics as demonstrated by the obvious alterations in the body in general which follow castration" (Young 1970, p. 129, 130).
Thus, although the great French physiologist, Claude Bernard, has often been credited with first formulating the concept of internal secretion in the 1850s, the idea that what we now call endocrine glands secrete substances into the circulation was current well before Bernard's time. It is to Bernard, however, that we owe the term "internal secretion," and the first direct demonstration of one internal secretion (the liberation of glucose into the bloodstream by the liver) (Houssay 1967; Young 1970). Although Bernard's conception of internal secretions, which included the possibility that these substances might function to maintain the composition of the blood, was far broader than that later formulated by endocrinologists, his preeminence in nineteenth century physiology helped to focus attention on the ductless glands.
It was in 1855, in a lecture at the Collège de France, that Bernard discussed the liver's internal secretion. The same year, a book appeared that, perhaps more than any other single work, deserves to be called the foundation of modern endocrinology: Dr. Thomas Addison's On the Constitutional and Local Effects of Disease of the Supra-renal Capsules. Addison's work epitomizes a sequence of observation and experiment that textbooks often call the "classic method" of endocrine research, in which the clinical features of a disease were compared and correlated with pathological changes in a gland. Along with, or usually following, this study, went observations on the effects of removing a gland thought to be overactive, or, conversely, the effects of administering an extract of a gland that was atrophied or damaged.
Addison, a physician at Guy's Hospital in London, was renowned in his own lifetime for his keen observations of his patients and diagnostic skill. Comparably, his monograph is such a descriptive masterpiece that modern works on Addison's disease have not been able to improve greatly upon its accuracy of detail (Hartman and Brownell 1949, p. 343). From the study of only eleven cases, Addison was able to pick out the "leading and characteristic features of the morbid state. . .: anemia, general languor and debility, remarkable feebleness of the heart's action, irritability of the stomach, and a peculiar change of the color in the skin (Addison 1885, p. 214). Post-mortem examinations revealed a diseased condition of the "supra-renal capsules," as Addison and earlier anatomists called the small pyramidshaped glands which sit on top of the kidneys. In some of his cases the adrenals had been damaged by tuberculosis or cancer, but Addison could point to at least one case in which the adrenals were the only abnormal organs in an otherwise healthy body. This was good evidence that the symptoms and condition he described were, in fact, due to a malfunction of this gland alone (Addison 1855, p. 210).
The monograph did more than describe a new disease, however, for Addison saw clearly that his study of the adrenals was a "first and feeble step towards inquiring into the functions and influence of these organs" (Addison 1855, p. 210). It seemed probable to him that the general state of ignorance about the adrenals, as well as the other "gland-like" organs, the spleen, thymus, and thyroid, would be overcome by pathological studies where physiological research had previously failed. "Although pathology . . . is necessarily founded on physiology," he wrote, "questions may, nevertheless, arise regarding the true character of a structure or organ, to which occasionally the pathologist may be able to return a more satisfactory and decisive reply than the physiologist" (Addison 1855, p. 209). Indeed, Addison himself had "stumbled upon" these "curious facts" about the disease of the adrenals while searching for the organic lesion of another mysterious disease, a fatal anemia of unknown etiology. (His description in 1849 of this anemia, now known as pernicious anemia and known to be caused by a vitamin deficiency, also is classic.) Among his anemic patients, Addison had noticed a few with a distinctive darkening or bronzing of the skin, who at autopsy were found to have abnormal adrenals. Addison was, of course, unable to say why damage to the adrenal glands should alter the complex-[END OF PAGE 54]ion or cause a gradual, fatal debility. But, by directing attention to the disease and the site of its lesion and by emphasizing the utility of studying a diseased organ to understand the functions of a healthy one, Addison invited systematic research into the role of the ductless glands in the general economy of the body.
Thirty years after Addison's monograph, a French physician, Pierre Marie, described and named another remarkable malady, again exemplifying the early classic method of endocrine research. In his 1866 paper, "Two Cases of Acromegaly: An Unusual Hypertrophy of the Head and Upper and Lower Extremities," Marie discussed two patients whom he had observed and another seven cases he had found described in the medical literature. He pointed out the excessive growth of the viscera and the bones of the face, hands, and feet, and the thickening of soft tissues like the tongue, lips, and nose, which made the features of acromegalic patients gradually become strikingly coarse and elongated. Other signs and symptoms that Marie noted as characteristic of the chronic condition included severe headaches, intense thirst and appetite, cessation of menstruation, changes in the thyroid, and damaged vision. Later papers by Marie, his student Souza-Leite, and other physicians added to the number of cases and confirmed Marie's orginal description of the disease.
Marie hesitated in his first paper to offer an explanation of the disease he had defined, because only one autopsy had been performed. In that one case, published a few years earlier by another physician, an egg-sized tumor had been found in the brain "in the position of the pituitary body" (Marie 1886, p. 20). Marie considered this a lesion of the nervous system and thought that the hypertrophy or enlargement of the pituitary gland was suggestive of the hypertrophy of the bones of the face and extremities. But, he carefully added, the two might have had no cause and effect relationship this was only one of several plausible hypotheses about the cause of acromegaly. Marie's reluctance to seize upon the abnormality of the pituitary gland as the primary cause of acromegaly may also have been influenced by the prevalent belief among physiologists that this gland had "little, or perhaps no, use in the organisms of the higher vertebrates" (Rolleston 1936, p. 55). But Marie's clear account of the syndrome, even without speculations about its cause, encouraged others to search the literature, clinics, and anatomical museums for further examples. Two years after Marie's first paper, Otto Minkowski - more famous for his work on the pancreas and diabetes - explicitly made the connection between acromegaly and a disease of the pituitary gland. Then, in 1890 and 1891, Marie reported that enlarged pituitaries always were found in post-mortern examinations of persons with acromegaly, and he hypothesized that the abnormal growth of the pituitary caused a glandular deficiency and hence toxemia (Rolleston 1936, p. 86).
By implicating a particular gland in a specific disease, Addison and Marie gave physicians and physiologists both a reason and a method for studying the ductless glands. Over the centuries, as we have indicated, there had been occasional attempts to see what happened when a gland was removed or transplanted, but no one had followed up on them seriously. The well-known effects of castration on men and animals, for example, had led the eighteenth century surgeon, John Hunter, to try transplantation experiments with the gonads and accessory sex organs of hens and roosters. In 1849 similar experiments were carried out by the German physician, A. A. Berthold, out of a particular interest in the structural changes in the transplanted gonads and a general interest in the nature of sex, heredity, and the "sympathies" between different parts of the body (Jdrgensen 1971, pp. 27-30). Astley Cooper and T. W. King tried removing the thyroids of dogs in the 1820s and 30s and suggested that the thyroid might form some "particular material" which exerted an influence "upon the circulating fluid [which] may be more or less needful for the healthy subsistence of the entire animal" (Rolleston 1936, pp. 18, 50). Addison's monograph immediately inspired the French physiologist, BrownSdquard, and others to do systematic extirpation experiments on the adrenals, with contradictory results. Brown-S6quard believed that the adrenals were necessary to life because he found that the removal of both adrenals from various animals was always fatal; Phillipeaux, on the other hand, was able to excise the adrenals and other glands from white rats without killing them. The different results were due partly to different surgical techniques and precautions against infection and partly to the existence of unnoticed accessory adrenals in white rats which enabled them to survive the loss of the main pair, as well as differences in resistance to stress and infection among different strains of animals. Similar debates over the indispensability of the pituitary and the thyroid glands took place in the 1880s.
The variable results of extirpation experiments underscores the importance of surgical and aseptic [END OF PAGE 55] techniques for the development of endocrinology. When Emil Theodor Kocher received the Nobel Prize in Medicine in 1909 for his work on thyroid diseases, he began his lecture by exalting Pasteur's discoveries in bacteriology and Lister's application of them to surigical practice. Thanks to aseptic procedures, Kocher emphasized, it at last was possible for surgeons and physiologists to "make all the organs accessible to direct observation, and to alter the conditions in which they exercise their functions (Kocher 1909, pp. 330-33). Surgical technique, too, often meant the difference between a clearcut and an inconclusive experiment. The results of thyroid extirpation had been complicated by the failure to recognize and leave intact the tiny parathyroid glands in the midst of the thyroid tissue; the effects of removing the pituitary gland were confused by the effects of surgical damage to the hypothalamic region of the brain.(2)
Perhaps the most celebrated example of the importance of surgical skill for the development of endocrinology is Minkowski's discovery of the role of the pancreas in diabetes in 1889. The physician von Mering was studying the problem of fat absorption in diseases of the pancreas and wanted to know how the decreased secretion of pancreatic juices into the intestine affected the breakdown of fats. When Minkowski asked why he did not remove the pancreas, von Mering answered that this was impossible. Minkowski, proud of his surgical skill, replied brashly, "Why should it be impossible? Bring me a dog and I will remove the pancreas." The operation succeeded, but to Minkowski's annoyance the supposedly well-trained dog began urinating frequently and copiously. On an impulse, or at the suggestion of his chief, von Naunyn - stories differ - Minkowski collected some of the urine from the floor and tested it for sugar. The sugar content was surprisingly high, a familiar sign of diabetes mellitus. After a week of further operations on other dogs, Minkowski was able to tell von Mering that total removal of the pancreas resulted in diabetes mellitus (Nothman 1954, pp. 272-274; Allen et al. 1919, p. 38; Young 1970, pp. 137-140).
Surgical skill and asepsis also helped to decide between two competing theories of the function of the ductless glands. The first of these theories, widely held in the late nineteenth century and well into the first two decades of the twentieth, was that these glands somehow neutralized or removed poisons in the blood; consequently, disease or removal of these organs caused toxemia. It is easy to see in this theory the strong influence of bacteriological and immunological modes of explanation current at the time. However, the alternative explanation, that the glands secret necessary substances into the bloodstream, had a long history of illustrious proponents such as von Haller. Cooper and King's experiments in thyroid removal in the 1820 and 30s, as we have seen, led them to this thesis: that glands such as the thyroid released a special substance directly into the blood. In the 1840s George Gulliver, surgeon and Fellow of the Royal Society, reported that under the microscope spheroidal bodies could be seen in both the adrenals and the veins leading from them; he argued that the veins served as the duct for some "peculiar matter which doubtless had some special use" and which was produced by the adrenals. Gulliver considered this "an interesting and important subject for further inquiry," but neither he nor anyone else pursued it at the time. Like many other early examples of the internal secretion hypothesis, this work was ignored until the hypothesis was firmly established and its history began to be written (Rolleston 1936, pp. 18-20).
The first good evidence for the internal secretion explanation of the glands' function came through research on thyroid diseases and the unhappy results of thyroid surgery on humans in the 1870s and 80s. In England W. W. Gull and W. M. Ord described a condition which Ord called myxedema: a swelling of the face and body from an excess of a gelatinous substance, mucin, accompanied by impairment of the mental faculties, lethargy, and extreme sensitivity to cold. In its advanced stages, myxedema strongly resembled cretinism. Cretinism, in turn, was associated with thyroid abnormalities but in very confusing ways; many victims of "endemic cretinism" had immense goiters, while cases of "sporadic cretinism" generally had tiny atrophied thyroids. Ord noted that in all five of his cases of myxedema the thyroid was small, but he thought it had simply been squeezed by the excess mucin. In Switzerland, meanwhile, where goiter was especially common, removal of the grossly enlarged thyroids became popular once the antiseptic method made such surgery a less dangerous affair. Unfortunately, some patients whose goiters had been removed began to suffer a new malady which was variously ascribed to injury of the nerves or trachea or to loss of some "blood-making" function of the gland.
In both England and Switzerland a few bold physicians speculated that all three conditions - sporadic cretinism, myxedema, and the illness that followed [END OF PAGE 56] thyroid operations - resulted from the absence or degeneration of the thyroid. Schiff, who had done experimental thyroidectornies on animals thirty years earlier and thought then that the thyroid produced an internal secretion, now saw the clinical significance of his earlier research; he tried implanting thyroids into the abdomens of thyroidectomized animals and succeeded in preventing myxedema. At this point it was clear that the thyroid was necessary for health, but the blood cletoxification hypothesis was still tenable. Then, in 1891, George Murray described his successful attempt to treat human myxedema with extracts of sheep thyroid glands; and three years later, Magnus-Levy showed that such extracts speeded up metabolism. Thus, the thyroid and its secretion gradually was recognized as having an active function unrelated to detoxifying the blood but indispensable to health (Paget 1919, pp. 54-67; Rolleston 1936, pp. 29-30, 151-153).
The discovery that thyroid extracts or grafts could restore normal intelligence and vigor to the myxedematous patient attracted a great deal of both scientific and popular attention,(3) for it showed that a disease could be caused by an insufficiency of the secretion of a ductless gland and, in turn, that the symptoms of such a disease could be cured by what was termed replacement or substitution therapy. The interest caused by clinical studies of the thyroid gland, however, was overshadowed by more sensational claims for the actions of internal secretions, associated with the theories and activities of Charles-Edouard Brown-Séquard.
In retrospect, Brown-Séquard has been recognized as "a remarkable pioneer in endocrinology," whose therapeutic studies, "although they later fell into disrepute, sparked the imagination of many investigators [and) led to an active search for 'internal secretions' in animal tissues" (Rolleston 1937, p. 261; Borell 1975, p. 1). Elected to England's Royal Society and France's Academie des Sciences, Brown-S6quard's peripatetic career saw him practicing medicine, teaching, and doing research in locales such as Paris, Boston, New York, Philadelphia, London, and Dublin.
Addison's book on the symptoms of adrenal insufficiency, as we noted, sparked Brown-Séquard's interest in the ductless glands, and in 1856 he concluded that the adrenals are essential to lite after performing total adrenalectomies on dogs. In his 1869 course of lectures at the Paris Faculty of Medicine he set aside his earlier views about the detoxifying function of the adrenals in favor of the theory that the, "glands have internal secretions and furnish to the blood useful if not essential principles" (Major 1943, p. 375). Then, in 1889, after he had succeeded Claude Bernard as professor of medicine at the College de France, Brown-Séquard reported to the Society of Biology that, in experiments performed on himself, he had shown the rejuvenating effects of testicular extracts from healthy young guinea pigs. Between 1889 and his death in 1894, Brown-Séquard and his assistant, d'Arsonval, extended their investigations to include the therapeutic effects of extracts from other animal tissues, based on Brown-Séquard's expanded concept of internal secretions. Every tissue of the organism, he postulated, secretes its own special product into the blood and this influences "all other cells which in this way are dependent on each other, by a mechanism different from the nervous system" (Houssay 1967, p. 165; Brown-Séquard 1889, pp. 415-422).
To the world at large, including many physicians, the details of Brown-Séquard's concept were far less exciting than the therapeutic possibilities it implied; by 1890, an estimated 12,000 physicians were giving testicular extracts to their patients, despite the skepticism and embarrassment expressed by many medical journals (Olmsted 1964, pp. 209-211).
Brown-Séquard, too, was concerned about the sensational publicity that his experiments received, and angered at the lucrative business of glandular extracts engaged in by some physicians. Nonetheless, he believed strongly that his experiments with testicular and other extracts were premised on sound physiological thinking, and would open up a new realm of therapeutics.
. . .now we believe that all the tissues, glandular or not, give something special to the blood, that every act of nutrition is accompanied by an internal secretion. We believe, in consequence, that all the tissues will be able to be and ought to be employed in special cases as a mode of treatment; that there is, in short, a new therapeutics to create, in which the medicaments will be products produced by the different tissues of the organism.
The bacterial products taught us how active the chemical compounds created by the infinitely small were: the living cell, of each tissue that belongs to the organism, must, by analogy, secrete some products, of which the efficacy is no less. (Brown-Sdquard and d'Arsonval 1891; trans. Borell 1975, pp. 3-4) [END OF PAGE 57]
The therapeutic movement called "organotherapy," sparked in large part of Brown-Séquard's work, was a flamboyant, controversial chapter in the history of endocrinology, one that many later endocrinologists would have preferred to ignore because of the cloud that it cast over clinical endocrinology. The editor of the British Medical Journal in 1937, for example, wrote of the organotherapy movement as follows:
After the discovery that preparations of thyroid gland taken by mouth were of benefit in myxoedema and cretinism, thyroid extract began to be given for many and varied conditions, an extracts of other ductless glands were prescribed with an enthusiasm that outran knowledge. Indiscriminate endocrine therapy brought about the inevitable reaction, and clinical endocrino ogy came to be looked upon with suspicion. The intensive research work carried out over the past decade has gone far to remove the disfavour into which endocrinology had fallen, and it is now becoming possible to put the matter in some kind of perspective. Solid achievements have been made. Possibilities are daily becoming probabilities. But the exploitation of these probabilities in the interest of the patient must be carried out with due caution and a healthy skepticism if endocrinoloby is not to be done at the disservice of again becoming a fashion. (The Endocrines in Theory and Practice 1937, Preface)
Despite the negative effects of the excesses committed in the name of organotherapy, however, the movement was a positive force for the development of endocrinology in other respects. For, as historian of endocrinology Merriley Borell points out, "much was learned about the action of internal secretions by means of these therapeutic efforts. The organotherapy effort was fundamental in attracting the attention of scientists to the field, who then sought to set up standards for the proper investigation of these therapeutic effects. Here, clearly, clinical concerns pointed the way to new scientific problems" (Borell, personal communication).
One such route was followed by the British physician George Oliver, who experimented with extracts of various tissues, including the adrenal and thyroid glands and the brain. Oliver had been administering extracts to his son, and then using an instrument he had developed to measure their effects on the diameter of his son's radial artery. In 1893, he observed that adrenal extracts from sheep and calves caused a sudden rise in blood pressure, while other glandular extracts generally lowered it. Oliver took his adrenal extract to E.A. Schafer, professor of physiology at University College, London, and caught him - so tradition has it - at a moment when he was measuring the blood pressure of an anaesthetized dog. Schafer was dubious about Oliver's claim, but agreed to inject some of the extract into the animal's veins. To Schafer's astonishment, the mercury in the blood-pressure manometer shot up so quickly and so high that the recording float was nearly lifted out of the tube (Dale 1938, pp. 461-463; Barcroft and Talbot 1968, pp. 6-8). Oliver and Schafer's studies of this pressor effect of adrenal extract not only led to the first isolation of a hormone (epinephrine), but also to a better understanding of the physiological role of the glands of internal secretion.
The arguments over the possible blood detoxifying function of the adrenals subsided once the definite, measurable effect on blood pressure was demonstrated. Oliver and Schafer also correlated function with anatomy; they showed that extracts made from the inner part of the adrenals, the adrenal medulla, would raise blood pressure, while extracts from the outer layer, the cortex, were ineffective (Rolleston 1936, pp. 29, 331). Research into the physiological implications of anatomical distinctions between parts of other glands, such as the anterior and posterior lobes of the pituitary, and the islets of Langerhans in the pancreas, quickly followed and proved fruitful. The fact that the internal secretion of a gland might actually contain several different active substances, each produced by a particular kind of tissue or cell, was at first confusing but later became axiomatic, and helped to direct attention to the complicated interactions of hormones and glands. Finally, the isolation of the pressor substance from the adrenal medulla at the end of the nineteenth century and its crystallization as a pure compound by Jokichi Takamine and T. B. Aldrich (working independently) in 1901 demonstrated concretely the existence of an internal secretion, and enabled scientists to study the pressor effect and other characteristic actions of epinephrine in much more carefully controlled experimental situations (Martilbanez 1952, p. 233).
When Oliver and Schafer first reported their study of the pressor effects of adrenal extract to the Physiological Society in March 1894, their audience included two young investigators in Schafer's laboratory, William Bayliss and Ernest Starling. In 1902, investigating the [END OF PAGE 58] control of pancreatic secretions, Bayliss and Starling identified a new internal secretion that they named secretin. Their discovery was made when they attempted to pinpoint the pathway of the neural reflex that the Russian physiologist, Ivan Pavlov, had declared must be responsible for the flow of pancreatic secretions into the intestine to neutralize digestive acids. Bayliss and Starling, however, found that even when all the nerves between the small intestine and the pancreas were severed, acid in the duodenum would still provoke the flow of pancreatic juices. According to C. J. Martin, who was present when the experiment was performed, Starling concluded at once, "Then it must be a chemical reflex." He promptly made a crude extract from a piece of duodenum, injected it into the jugular vein of the dog, and within a few moments had the pleasure of seeing the pancreas respond with a heavy secretion (Barrington 1975, p. 11).
Starling used the occasion of the Croonian Lectures to the Royal College of Physicians of London in 1905 to bring together what was known about "the chemical correlation of the functions of the body." In these lectures he introduced the word "hormone" (from the Greek, hormao, to excite or arouse to action) for the general class of substances "which, speeding from cell to cell along the blood stream,. . .coordinate the activities and growth of different parts of the body" (Starling 1905, p. 340). As examples of these chemical messengers, he named epinephrine, secretin and a number of similar gastric hormones which had been discovered in the meantime, extracts from the thyroid and from the interstitial cells of the testes and ovary, and - more tentatively - the supposed internal secretion of the pancreas. The simplicity and convenience of the word "hormone" soon made it popular even though, as etymological and physiological purists pointed out, it applied to substances which could inhibit activity as well as excite it. The words "endocrine" and "endocrinology," (from the Greek, I separate within) came into use about half a dozen years later (Rolleston 1936, pp. 24).
Building upon the observations and clinical studies of physicians, the discovery of secretin in 1902 and Starling's elaboration of the hormone concept in 1905 represent a watershed in the emergence of endocrinology as a field of basic as well as clinical research. In the case of the thyroid, adrenals, and the duodenal extract named secretin, physicians and physiologists had succeeded in their effort to confirm the long-presumed existence of potent secretions in animal tissues. That proof came both from the ability of glandular extracts to cure specific diseases such as myxedema and from the analysis of specific physiological responses to the chemical substances in adrenal and duodenal extracts.
When secretin was discovered, as Borell observes, the term "internal secretion" "no longer provided an adequate description of the phenomenon under study. It did not specify the messenger role, the activity potential of chemicals elaborated by certain tissues," as did the word "hormone" (Borell 1975, p. 8). And, as Starling and other investigators recognized at the turn of the century, the chemical coordination of physiological processes by hormones was now a major subject for biological research, one that seemed of equal import to understanding the integrative action of the nervous system. For, as Starling wrote in Lancet in August 1905:
If control of the different functions of the body be largely determined by the production of definite chemical substances within the body, the discovery of the nature of these substances will enable us to interpose at any desired phase in these functions and so to acquire an absolute control over the workings of the human body. Such a control is the goal of medical science. (Maisel 1965, p. ix)
Building upon the idea of a human control of physiological processes, the next phase of research in endocrinology began to delineate and emphasize the intricate functional interactions among the glands. The early endocrinologists had tacitly assumed that each gland produced its own special hormone and had its own particular effect on the body, and endocrine diseases thus were viewed as the consequence of an increase or decrease in the secretion of a hormone. By the 1920s, however, closer study of endocrine diseases coupled with animal experimentation made endocrinologists see that this picture of the endocrine system was greatly oversimplified. The central fact - and the central problem of endocrinology between the World Wars was that activities of one gland could control and be controlled by the activities of others.
Research now concentrated on pairs or groups of glands, and the choice of which constellation of glands to study was still largely determined by clinical data and interests. The sexual abnormalities found in many [END OF PAGE 59] endocrine disorders, the association of diabetes and acromegaly, the enlarged adrenals common to many different illnesses, the apparent therapetic value of "pluriglandular" preparations, the ability of epinephrine to alleviate but not to cure Addison's disease - each of these clinical observations led to new insights into the complexities of metabolism and to new approaches to therapy.
Three areas of research, moving back and forth from the clinic to the laboratory, proved especially successful and fruitful in this period. First, in the lineage begun by Thomas Addison, there was a body of work on the adrenals by Cannon, Selye, von Euler, Kendall, Moore, and many others. Their researches, in brief synopsis, helped to elucidate the roles of the two layers of the adrenal - the medulla and the cortex - in maintaining homeostasis and coordinating the body's response to emergencies and stress; established the nature of the medulla's close connections to the sympathetic nervous system; provided a better understanding of the relationships between the pituitary gland and the adrenal cortex; and identified, isolated, purified, and ultimately synthesized ACTH, the pituitary gland hormone which stimulates the adrenal cortex, and the several hormones secreted by the adrenal's two layers.
Secondly, there was a focus of research on the endocrinology of sex and reproduction. Work in this area received a powerful stimulus from the joint decision of the Bureau of Social Hygiene, the National Research Council, and the Rockefeller Foundation in 1921 to support "a program of research on fundamental problems of sex," and in 1931 to sponsor a major survey of sexual endocrinology: Sex and Internal Secretions. This review of the recent progress in the biology of sex and the sex glands, first published in 1932, attracted many new workers into the field (Young and Corner 1961, 1, ix-xii; Hall, work in progress).
A third major area of research, dealing with the functions of the pituitary gland and, in particular, the relations between pituitary disorders and diabetes, culminated in establishing for a time a view of the anterior pituitary as "the master gland" or "conductor of the glandular orchestra." The methods shared by all three areas of research included not only the familiar techniques of extirpation and replacement by transplants and extracts, but also the use of isolated and purified hormones like thyroxin and insulin as these became available, and comparative studies of the endocrinology of other species.
In the remainder of this section, we will illustrate the nature of this second phase in the development of endocrinology by highlighting research on the pituitary gland or hypophysis, physiologically the most complex and important of the ductless glands. About 1890, as we have seen, Marie, Minkowski, and others explained the condition of acromegaly in terms of a lesion of the hypophysis which decreased the gland's internal secretion. Five years later, in the course of their experiments on the dramatic power of adrenal extracts to raise blood pressure, Oliver and Schafer discovered that hypophyseal extracts also had a pressor effect. The hypophysis, like the adrenals, has two anatomically distinct parts: the anterior lobe or adenohypophysis and the posterior lobe or neurohypophysis. By 1898, Howell and Schafer and Vincent had shown that only extracts of the posterior lobe exerted a pressor effect, and so research centered on this lobe of the gland for many years. During the first decade of the twentieth century, a bewildering array of specific effects were attributed to the posterior lobe. While an extract of the posterior lobe as a whole increased blood pressure, one fraction of it had the opposite effect of lowering blood pressure. The extract produced in tense contractions of the uterus and weaker contractions in some other plain muscles. It provoked the secretion of urine almost immediately, but this diuretic effect soon gave way to an even stronger anticliuretic effect.(4) In some mammals posterior lobe extracts made milk flow more easily and in greater amounts than usual. In frogs the posterior lobe seemed to control the contraction and expansion of the pigments cells and thus the color of the frog's skin (Sharpey-Schafer 1924-26, 11, pp. 252-257).
These varied effects of posterior lobe extracts were both interesting and useful. The uterine contraction response provided a quantitative bioassay for the potency of posterior lobe extracts and found an application in obstetrical practice. The antidiuretic effect was first discovered when patients with diabetes insipidius - a form of diabetes characterized by a great flow of dilute urine and a correspondingly great thirst - were relieved by experimental injections of pituitary extract; this quickly became a standard treatment of the disease (Sharpey-Shafer 1924-26, 11, p. 244). But none of the actions of the posterior lobe of the pituitary could explain acromegaly. [END OF PAGE 60]
As the American neurosurgeon Harvey Cushing wrote uently, the great difficult for all pituitary gland searchers was getting at the gland in the first place.
Nature saw fit to enclose the central nervous system in a bony case lined by a tough protecting membrane, and within this case she concealed a tiny organ which lies enveloped by an additional bony capsule and membrane like the nugget in the innermost of a series of Chinese boxes. No other single structure is so doubly protected, so centrally placed, so well-hidden. (Cushing 1930, p. 5)
In 1904 Cushing forecast that techniques of brain surgery were improving so much that "it is not impossible that a diseased pituitary may someday be successfully attacked" (Fulton 1946, p. 267). Only two years later the British surgeon, Victor Horsley, successfully operated on several cases of pituitary tumors (Paget 1919, p. 180). Soon Cushing too was actively engaged in pituitary gland surgery and research.
Cushing had been interested in the hypophysis ever since 1901 when he had failed to recognize that a case of sexual infantilism accompanied by obesity, headache, retarded growth, and impaired vision was a case of pituitary tumor. His pride was nettled because, soon after finding the tumor at autopsy, he learned that A. Frohlich in Vienna had seen a similar case, made the correct diagnosis, and had the tumor removed successfully (Fulton 1946, pp. 271-272). In 1907-1908 Cushing's interest was renewed by the announcement of a new technique for removing the gland from dogs and by a series of lectures on the pituitary that Schafer delivered at John Hopkins. Cushing and his students at Johns Hopkins then began a long series of pituitary gland extirpation experiments on dogs, correlating the results with the conditions he found in his patients.
Cushing's chagrin over his misdiagnosis of what came to be called "Frohlich's syndome" was redeemed by the first major result of these experiments. Earlier reports on removal of the gland said that the animals always died after the operation. Some of Cushing's dogs, however, survived the surgery and lived many months although they became "extraordinarily fat, logy, sexless creature(s)." The general opinion among Cushing's students was that somehow the operation had not been complete, but they drew no further conclusions from the peculiar state of the animals. One day in the winter of 1908-1909 Cushing "caught sight of [one of] these animals while it was still alive and said at once, 'Here is Frohlich's asexual adiposity.'" Because the animals lack all or nearly all of the pituitary, Cushing deduced that Frohlich's syndrome must be caused by a lack of the pituitary secretion. Moreover, if this state of asexual adiposity was the result of too little pituitary secretion, then acromegaly must be the result of an excessive secretion - exactly the reverse of Marie's original explanation of acromegaly (Fulton 1946, pp. 280-282).
Over the next four years, Cushing confirmed his deductions in further experiments and studies of patients with a variety of pituitary gland disorders. He demonstrated that under- or over-secretion by the anterior lobe alone was responsible for Frohlich's syndrome and acromegaly, as well as for gigantism and a form of dwarfism. He also stressed the effects that pituitary lesions had on the rest of the endocrine system:
In view of the apparent interrelation of many of the glands of internal secretion it is quite probable that certain of the symptoms known to accompany hypophyseal disease may be consequent upon a secondary change in other glands which follow the primary change of the hypophysis. These changes are seemingly more outspoken and more widespread after a lesion of the pituitary body than after a corresponding lesion of any other member of the group of ductless glands, and in view of its unusually well-protected position one might have conjectured that it must represent a vitally important organ, (Fulton 1946, p. 301)
Cushing's strong awareness of the secondary endocrine effects of hypophyseal disorders led twenty years later to his elucidation of what had been vaguely known as "polyglandular syndrome" and usually ascribed to a malfunction of the adrenal cortex. In acromegaly he had noted in the anterior lobe a preponderance of cells which take up eosin dyes, and he concluded that acromegaly was due to oversecretion by these eosinophilic cells. At the same time he argued that oversecretion by the other distinctively staining cells of the anterior lobe, the basophiles, must also be responsible for some kind of syndrome, even though he could not say what that syndrome was. In 1930 he read of a case of "adipositalgenital dystrophy" which at autopsy revealed a tiny adenoma (tumor) of the basophilic cells. The case resembled in every detail cases of "polyglandular syndrome" he had seen over the years, and further post- [END OF PAGE 61] mortem evidence of basophilic tumors confirmed the matter. By comparing the characteristic features of acromegaly and poiyglandular syndrome, Cushing had long ago concluded that the eosinophilic cells secreted a hormone which regulated growth. Now he could add that the basophilic cells elaborated "a sex-maturing principle" or "a gonad-stimulating factor" (Cushing 1932, pp. 114-119, 155-161; Fulton 1946, pp. 614-616).
Inevitably, the situation turned out to be more complex than Cushing's account in 1932 made it appear. More sophisticated cell staining techniques revealed many specialized cell types within the general categories of eosinophile and basophile. Moreover, the original explanation of the polyglandular syndrome (since renamed "Cushing's syndrome") in terms of an adrenal cortex disorder was vindicated: excessive production of the steroids of the adrenal cortex was the immediate cause of the symptoms of the disease, although such hypersecretion of steroids was often in turn the result of oversecretion of ACTH by the anterior pituitary. However, the main outlines of Cushing's explanation of the syndrome and his characterization of a growth factor and a gonad- stimulating factor proved to be sound.
Concurrent research by Bernardo Houssay in Argentina and by Herbert McLean Evans at Berkeley did much to confirm and extend Cushing's clinical insights into the workings of the anterior lobe and its ties to other endocrine glands. In 1907, the year that Cushing began his extensive work on the hypophysis, a precocious young medical student in Buenos Aires saw a patient with acromegaly and immediately became interested in the gland. Forty years later, in his Nobel Prize lecture, Bernardo A. Houssay commented that he had been attracted to the hypophysis by both its medical and physiological aspects: "the microscopic picture showed glandular activity and its lesions were accompanied by serious organic disturbances, such as acromegaly, dwarfism, etc." (Houssay 1947, p. 211; Young and Foglia 1974, p. 254). Beginning with his medical thesis in 1911, and continuing through a long series of researches, Houssay developed techniques for removing the hypophysis from frogs, toads, and dogs, and examined the physiological effects of posterior lobe extracts and implants on muscles, the uterus, carbohydrate metabolism, the thyroid, and the adrenals.
Houssay's most important research in endocrinology began after Banting and Best announced the discovery of insulin in 1921, a year that Houssay later saw as a critical year for endocrinological research and thinking. The secretion of insulin by the islets of Langerhans had been predicted years before Banting and Best succeeded in extracting it from the pancreas, but with insulin's existence proven in 1921, no one could doubt any longer the existence of hormones or their ability to regulate metabolism. Moreover, as the association between acromegaly and diabetes had been noted often by clinicians, Houssay saw that insulin could serve as a new tool for investigating the suspected physiological reactions between the hypophysis and the pancreas (Houssay 1956, p. 213; 1967, pp. 167-168).
Houssay had to devote several years to the preparation and standardization of insulin for his experiments, for large-scale extraction of insulin for treatment began only in 1923-1924, and pure crystalline insulin was not prepared until 1926. He and Magenta demonstrated in 1924 that a dog without its hypophysis became remarkably sensitive to insulin's ability to lower blood sugar levels. It was not clear from their experiments, however, whether it was the loss of the anterior lobe or of the posterior lobe that was responsible for this hypoglycemic effect. Until 1929 the general opinion was that "if the hypophysis had any action on carbohydrate metabolism and on the diabetes of acromegaly it was due to its posterior lobe" (Houssay 1943, p. 247). The anterior lobe was ignored by researchers because the actions of its extract seemed to be transient and because it was hard to extirpate the lobe surgically (Houssay 1956, p. 213).
Houssay's early studies of the hypophysis in amphibians, dogs, and man proved their value in 1929 when he realized that the anatomy of the toad's pituitary made it the ideal experimental animal for testing these widely-held views of the pituitary's role in carbohydrate metabolism. Houssay found that removing the lobe which corresponds to the anterior lobe in man produced great sensitivity to insulin, while removal of the posterior lobe had no such effect. Without the anterior lobe, the toad rapidly used up glucose, and the injection of insulin exacerbated this high rate of sugar utilization. Thus the anterior lobe clearly was implicated in the regulation of carbohydrate metabolism (Houssay 1936 a, b). The diabetic's problem, though, was that his body used sugar too slowly. Houssay and Biasotti proved in 1929-1930 that the effect of the anterior pituitary on glucose metabolism was antagonistic to the effect of the pancreas. If a toad or dog was made diabetic by the removal of its pancreas, the removal of its anterior lobe [END OF PAGE 62] would then counteract the diabetes. If, on the other hand, the animal was made mildly diabetic by the partial removal of its pancreas, an injection of anterior pituitary extract would drastically increase the severity of the diabetes. While the pancreas secreted insulin to increase the utilization rate of sugar, the anterior pituitary secreted something with the opposite effect, something which inhibited the supply of sugar.
These experiments and results were not well understood or accepted in the early 1930s, both because Houssay published them in Spanish-lanquage journals, and because they contradicted the current theories of hypophyseal function so completely that journals in the U. S. would not publish his English summaries. One distinguished physiologist declared that Houssay had to be wrong because it was well-known that the posterior lobe's primary function was metabolic control (Barrington 1975, p. 54; Young and Foglia 1974, p. 256). In addition, others who tried to reproduce the experiments failed, chiefly because they did not follow Houssay's techniques for preserving the activity of pituitary extracts (Houssay 1943, p. 252; Wrenshall et al. 1962, p. 65). Eventually, however, the "diabetogenic" effect of the anterior lobe in mammals was confirmed in 1931-1932 through the researches of Herbert McLean Evans and Miriam Simpson, who had been working with anterior lobe extracts from a very different point of view.
Evans and Simpson observed the diabetogenic effect in the course of a wide-ranging program of basic research on the effects of the anterior pituitary extracts on growth and reproduction, work which in turn fed back into clinical aspects of endocrine disorders through the type of feedback cycle so characteristic of the development of endocrinology (Evans 1923-24). In the midst of their efforts to isolate and purify the growth hormone (a task achieved' in 1944-45),. Evans and Simpson noticed in 1931 that one of their dogs in which gigantism had been induced with the growth hormone ate and drank excessively, yet became thin and weak. The dog also "excreted great amounts of urine to which flies were attracted." Like Minkowski in 1889 (and Evans, who was very interested in history of science, surely knew the anecdotes about Minkowski's discovery), Evans and Simpson tested the urine and blood for sugar and found that the dog was suffering from diabetes. The experiments proceeding from that observation gave the first clear evidence that the anterior lobe produced an antagonist to insulin and reassured Houssay that his remarkable results with amphibians were correct (Amoroso and Corner 1972, pp. 128-129).(5)
By the mid-1930s, then, there were strong medical and experimental reasons for believing that the anterior lobe was, as Houssay put it, "the central and directing organ in the endocrine constellation" (Houssay 1936 b, p. 961). Little over a decade later, concentrated research in biochemistry had proven that the gland's control of growth, reproduction, metabolism, and the activities of other endocrine organs was carried out through the secretion of six different hormones, and all six hormones were purified by 1950. However, immed iately after proclaiming the central importance of the anterior lobe in his Dunham Lectures at Harvard in 1935, Houssay was forced to add that the other endocrine organs "in some . . . cases ... also have an influence on the pituitary" (Houssay 1936 b, p. 961). Intensive research into the reciprocal influences of the endocrine glands and the hypophysis on rates of internal secretion kept pace with identification and purification of the anterior lobe's trophic hormones through the 1930s and 40s. The general conviction of the early 1920s that the endocrine organs did not act independently - an opinion based primarily on clinical data - now rested on the solid ground of physiological and biochemical experimentation, and the availability of newly purified hormones gave hope that many more of the complex interactions would be successfully untangled in the future.
Between the World Wars endocrinology became firmly established as a scientific discipline with a distinct perspective of its own towards physiological problems. Endocrinologists regarded the endocrine glands, hormones, and their interactions under the pituitary gland's direction as the body's long-term system for coordinating and regulating its activities, a system that neatly complemented the more rapid integrative functions of the nervous system. Most endocrinologists would have described the two systems as separate but equal, although some enthusiasts claimed that the glands controlled the brain and nerves (Vincent 1925, pp. 11, 18; Rolleston 1936, pp. 57-9; Liljestrand 1936, p. 398; Berman 1930, pp. 200-218). For some time, though, evidence had been building up in a variety of fields human pathology, psychology and psychiatry, comparative anatomy, experimental physiology and endocrinology, and animal behavior - to suggest that, once again, the picture was more complicated than either [END OF PAGE 63] the independent modes of internal communication after all, but interconnected in very interesting ways.
Out of the study of these interconnections a new hybrid discipline, neuroenclocrinology, emerged in the 1940s and 50s. Early clues to a relationship between the endocrine and nervous systems came from observations of the emotional disturbances associated with abnormal endocrine activity in the thyroid and adrenal medulla. Graves' disease (thyrotoxicosis, toxic goiter), for instance, seemed to be triggered by severe psychic distress, such as a sudden shock or long, continuing anxiety, and nervous irritability was among its most common symptoms. Because clinical manifestations of nervous system involvement in the thyroid matched anatomical observations of sympathetic nerves in the thyroid, it seemed possible that the thyroid's secretions were directly controlled by the sympathetic branch of the autonomic nervous system. Although research in the 1930s concentrated instead on the humoral control of the thyroid by the anterior pituitary's thyrotropic hormone, the earlier notions of neural control continued to interest physicians, psychiatrists, and physiologists (Rolleston 1936, pp. 222-224, 240: Reichlin 1966, pp. 445-446, 502-506).
The isolation and synthesis of epinephrine in the early years of the twentieth century made it comparatively easy to study the relations between the sympathetic nervous system and the adrenal medulla. Almost immediately after Oliver and Schafer's discovery of the pressor effect of adrenal medulla extracts, neurophysiologists noted how closely the actions of the extract (and later, of pure epinephrine) mimicked the effects of the sympathetic nerves. As early as 1904, T. R. Elliot hypothesized that the sympathetic nerves acted by releasing epinephrine at the ends of the nerve fibers. The histology and embryology of the adrenal medulla hinted at this possibility too, for the medulla was laced with sympathetic nerve fibers which ended on the medullary cells, which had themselves developed from embryonic nerve cells. And, electric stimulation of the nerves leading to the medulla were found to induce the medullary cells to secrete epinephrine (Rolleston 1936, pp. 321-323; Dale 1962, p. 72).
From 1909 on, the American physiologist, Walter Cannon, emphasized the psychosomatic importance of the neural connections to the adrenal medulla. In the course of studying the mechanics of digestion in cats, he had noticed that whenever sudden noises or other distractions made the cat angry or afraid, the movements of its stomach and intestines would stop equally suddenly. Over the next five years Cannon investigated the effects of emotional stimuli on epinephrine secretion, which led to his famous theory of the emergency function of the adrenal medulla. In his 1915 monograph, Bodily Changes in Pain, Hunger, Fear, and Rage, he argued that strong emotions stimulated the sympathetic nerves and thence the secretion of ep inephrine; all the varied effects of the hormone on the body could be seen as quick preparations for "fight or flight" (Brooks and Koizumi 1975, p. 52).
Although neural control over the adrenal medulla and the thyroid seemed probable, the physiological mechanisms were obscure. How did the nerves provoke secretion? In 1921 Otto Loewi in Austria showed that the nerve cells themselves secrete neurohumors, tiny amounts of chemical substances which travel the short distance from the secreting end of the neuron to the membrane of the cell being excited. In one of the most elegant biological experiments ever devised, Loevvi proved that, when the parasympathetic vagus nerve to the heart is electrically stimulated, it releases a neurohumor which will slow the heart.
H. H. Dale and Loevvi subsequently identified this Vagus-stoff as acetylcholine, a compound which was already known to mimic the actions of the parasympathetic nerves as closely as epinephrine mimicked the sympathetic nerves. (Later, acetylcholine proved to be the neurohumor released by the voluntary nerves as well.) Meanwhile, Cannon and his co-workers believed that the sympathetic nerves also liberated chemical transmitters. After much controversy and reinterpretation of experimental data and theories, Cannon's younger colleague, Bacq, and Ulf von Euler, proved that the sympathetic nerves do indeed secrete epinephrine in order to inhibit activity of the target cell, and that they also release norepinephrine to excite the target cell (Bacq 1975, pp. 68-76).
The most logical place to look for neurcienclocrine interactions, however, was in the connections between the brain and the pituitary gland. The posterior lobe attracted attention first, for anatomically it possesses a rich supply of nerve fibers which join the lobe to a tract of the hypothalamus by way of the pituitary gland's stalk. Oliver and Schafer's discovery of internal secretions from the posterior lobe raised a difficulty, however: histologically the posterior lobe had many [END OF PAGE 64] nerve fibers but no obvious secretory cells. How then did it produce its blood-borne effect on blood pressure, ter metabolism, and uterine contraction?
Studies of diabetes insipidus further complicated the problem. In 1913 two clinical investigators noted the ability of posterior lobe extracts to relieve the excessive urine flow of patients with diabetes insipidus. Presumably, in these patients a damaged posterior lobe failed to secrete enough antidiuretic hormone, but there was conflicting evidence. Emotional and physiological stress also seemed to have an antidiuretic effect, which implied that the nervous system exerted some control over water metabolism - the parallel to Cannon's emergency theory of adrenal medulla function was easily drawn (Pickford 1975, pp. 209-210). In 1912 and 1913 Aschner and Roussy and Camus argued that diabetes insipidus (not to mention obesity, sexual dysfunction, genital atrophy, and increased sugar in the blood - many of the symptoms, in short, associated with pituitary gland disorders) were caused by damage to the brain in the hypothalamic region. In 1920 they produced experimental diabetes insipidus in dogs by making lesions only in the hypothalamus, leaving the pituitary gland untouched, a feat that led them to deny any function at all to the hypophysis (Rolleston 1936, pp. 56-56; Abel 1923-24, pp. 202-207; Harris 1955, pp. 200-204).
These rival explanations of diabetes insipidus and of the roles of the posterior lobe and the hypothalamus were gradually reconciled through new studies of the nerves uniting the brain and hypophysis.(6) By 1940 it was reasonably clear that the hypothalamus exerted direct control over the antidiuretic and oxytocin secretions of the posterior lobe, and that this control was somehow mediated by the nerves leading from a well-defined tract of the hypothalamus to the posterior lobe. The source of the secretions themselves remained a question that was not fully answered for another decade, although the most important clues had already been discovered. Ernst Scharrer had shown in his doctoral thesis in zoology in 1928 that certain hypothalamic neurons in fish functioned like glandular secretory cells, and he and his wife Berta subsequently found neurosecretory cells in many vertebrate and invertebrate species. But for many years, in a pattern typical of resistence to scientific discoveries, they could not persuade either the endocrinological or the neurological communities that their cytological evidence would explain the confusing relationship between the hypothalamus and posterior pituitary. For, as Berta Scharrer later wrote, the proposition that there were special hypothalamic neurons with an endocrine function "was a bold concept that did not fit into any existing mold, and it is not surprising that it was received with skepticism. Why should members of a class of cells as readily defined as neurons be capable of functioning as glands of internal secretion? " As Scharrer goes on to note, however, "What is less understandable . . . is the almost universal rejection by the scientific community of the validity of cytological evidence for the existence of a secretory process" (Scharrer 1975 b, pp. 225-260).
After World War 11, an old friend of the Scharrers, Wolfgang Bargmann, became irritated by the negative attitude of his fellow scientists toward the Scharrers' conception of neurosecretion. Bargmann decided to try a new approach based on the well-known usefulness of cell staining techniques in endocrinology. His first trial in 1948-1949 of a recently developed staining technique succeeded splendidly, for he could see individual neurons of the hypothalamic tract extending themselves without interruption down into the posterior lobe. By 1957 Bargmann and the Scharrers had established the fact that the posterior lobe was little more than a storage depot for the hormones produced by the hypothalamus (Bargmann 1975, pp. 38-43; Scharrer 1975 b).
The connections between the anterior pituitary and the nervous system were equally hard to understand, although many observations, especially about the reproductive functions of the anterior lobe, implied the existence of connections. For instance, women had long known that emotional distress and other psychological factors can affect their menstrual cycles. Farmers, hunters, and naturalists had recognized for centuries that many environmental factors like temperature, food supply, light, and the sensation of coitus can alter an animal's ability to ovulate.
Further evidence came from the clinic: tumors of the hypothalamus disturbed many endocrine functions usually associated with the anterior lobe (Fulton, Ranson, and Frantz 1940, pp. xiii-xxx, 864-874). Following this lead, Camus and Roussy produced Frohlich's syndrome of asexual adiposity by making minor lesions in certain tracts of the hypothalamus, just as they had caused diabetes insipidus with lesions in the tract connected to the posterior lobe. Joseph Hinsey and Joseph Markee at Stanford brought together in 1933 Markee's observations on the nervous control of ovulation and Hinsey's experience with the chemical transmitters of sympathetic and parasympathetic nerves. In a [END OF PAGE 65] short note they hypothesized that the lack of direct nerve fiber connections between the hypothalamus and the anterior lobe, in contrast to the rich innervation of the posterior lobe, implied a humoral mechanism for the brain's control over the anterior lobe's civulatory function (Hinsey 1975, pp. 135, 139). But these various observations, experiments, and speculations did not excite much interest until the 1940s. The only mention of "neuro humoral mechanisms" in the authoritative and lengthy 1939 survey, Sex and Internal Secretions, for example, was to be found in a psychologist's review of research an the sex drive (Allen, Danforth, and Doisy 1939, pp. 1213-1220).
Before anyone could make sense of the miscellaneous assortment of observed nervous system-anterior lobe interactions, much more detailed, direct experimentation on the anatomy and physiology of the hypothalamus, pituitary stalk, and anterior lobe was necessary. It was the English anatomist, G. W. Harris, who "more than anyone else brought the new endocrinology into focus in the late 1930s" and 1940s (Price 1975, p. 229). Although Harris' early experiments suggested that nerves led from the hypothalamus to the anterior lobe, his examination of the lobe's anatomy raised doubts in his mind, for the anterior lobe abounded in secretory cells and blood vessels but almost completely lacked neurons.
The other possible path for messages between the central nervous system and the anterior lobe was through the rich network of blood vessel that surrounded the pituitary stalk. A Roumanian pathologist, Rainer, had noticed in 1927 that these blood vessels were especially prominent in people who had died suddenly and violently; he persuaded a young medical student, G. R. Pope, to study these vessels and their connections to the capillaries of the hypothalamus and the hypophysis. Popa and Fielding published an account of this work in 1930, in which they said that the blood in these short portal vessels flowed upwards from the hypophysis to the hypothalamus. Six years later Wislocki and his colleagues in Boston disputed this assertion and argued from histology that the blood flowed down from the brain to the anterior lobe. Wislocki, Popa, and Harris debated ("at times quite vehemently," Harris recalled much later) the question of the direction of blood flow over the next ten years (Harris 1955, p. 30).
In 1947, Harris and Green tried a new approach: they now watched the flow of blood directly in living, anesthetized animals, and in so doing confirmed Wislocki's work. The downward flow of blood together with the absence of direct nerve connections strongly pointed to the neurohumoral system of control that had first been proposed in 1933 by Hinsey and Markee. Harris devoted the next half dozen years to proving the theory that the hypothalamus sends blood-borne chemical messengers down the pituitary stalk's portal vessels into the anterior lobe, where they stimulate the release of the anterior lobe's pituitary hormones (Harris 1955, pp. 20-31; Tepperman 1973, p. 36; Vogt 1972, pp. 310-313; Jacobson 1975).
Once the neural control over the anterior lobe's secretions were widely accepted, research centered on isolating the "releasing factors." Early trials with known nerve transmitter substances showed that these compounds were only indirectly concerned with the hypothalamus/ anterior lobe system. In the mid-1950s and the 60s neurciendocrinologists and biochemists succeeded in assaying, isolating, and purifying a series of small polypeptides from hypothalamic tissue and blood. By 1973 eleven different releasing or inhibiting factors had been found, eight of them purified, and the structure of three worked out in detail (McCann and Dhariwal 1966, pp. 261-296; Williams 1974, p. 5; Maugh 1975, p. 921).
As endocrinologists learned to see the anterior lobe as the "concert master" rather than the "conductor" of the "endocrine orchestra," they reconsidered the interactions among the glands that had been so arduously worked out before. In the 1940s, Norbert Wiener, the inventor of cybernetics, had popularized the concept of feedback control in engineering and in neurophysiology (Dempsey 1975, pp. 85-86; Wiener 1948, pp. 7-33, 113-114). Walter Cannon's concept of homeostasis agreed well with Wiener's ideas, and endocrinologists gradually realized that the language of feedback control provided an effective way of describing and thinking about endocrine interactions. They saw that the presence of the hypothalamus in the endocrine constellation required more elaborate feedback systems than the simple see-saw reciprocity envisaged by earlier investigators.
Following the publication of Harris' monograph, Neural Control of the Pituitary Gland, in 1955, with its diagrams of feedback loops involving the higher brain, the hypothalamus, the two pituitary lobes, the gonads, adrenals, thyroid, and sympathetic nervous system, neurclendocrinologists started intensive research into the mechanisms by which hormones act on the brain [END OF PAGE 66] and hypophysis. The principle of feedback loops has become so fundamental a part of endocrinological thinking in recent years that textbooks now commonly discuss the feedback integration of the endocrine system before they even name and describe the components of the system, the glands and hormones (Williams 1974; Tepperman 1968, 1973; Barrington 1975).
There was a continuity of outlook through the three phases of endocrine research discussed so far, as researchers concentrated on seeking the source of control over the actions and interactions of glands and their secretions. In the earliest phase, control seemed to come from the gland itself, in the second, from the hypophysis, and in the third, from the nervous system as modified by feedback loops. The response of target organs was used to assay hormones, but otherwise that response was simply taken for granted. The interactions of the endocrine system were studied on the tissue or organ level; and, while biochemists played an important role in purifying and characterizing hormones, they could not contribute much to the conceptual foundations of the discipline.
The question, "How do organs and cells receive and read the hormone message?" could not be answered, or even asked, effectively in this context. It made sense only at the cellular level, and this was - until the late 1950s - the separate province of molecular biologists and biochemists. For among biologists "there was a widespread feeling . . . that hormone action could not be studied meaningfully in the absence of organized cell structure" (Sutherland 1972, p. 401). Between 1955 and 1962, however, Earl Sutherland and his co-workers, proceeding on the conviction that "there was a real possibility that hormones might act at the molecular level," proved that breaking up cells did not destroy their sensitivity to some hormones (Sutherland 1972, p. 401). In studying the influence of epinephrine and the pancreatic hormone, glucagon, on the liver's ability to break glycogen down to glucose, Sutherland and his associates found in liver cell fragments a molecule called cyclic AMP which carried the hormone message to the enzymes that governed the rate of glycogen - glucose reactions. Since then, cyclic AMP has also been implicated in the cellular reception of information from the luteinizing hormone, the adrenocorticotropic hormone, thyroid-stimulating hormone, parathyroid hormone, and many others. Its ubiquity in the animal kingdom at all levels of organization suggests that, in evolutionary terms, it may be as significant a compound as DNA, RNA, and ATP (Robison, Butcher, Sutherland 1971, p. 74 and chap. 12). Research on the biochemical and structural details of the hormone-membrane receptorcyclic AMP-enzyme activation pathways in the cell has become one of the fastest growing fields in contemporary endocrinology and molecular biology.
Sutherland's discovery of cyclic AMP came directly out of research on the enzymes and biochemical pathways of carbohydrate metabolism - a tradition very different from endocrinological research in the first half of this century. Unlike endocrinologists, for example, researchers in intermediary metabolism had long been accustomed to experimenting with cellfragments and with enzyme-substrate reactions in cellfree systems. Another difference lay in the primary research orientation of investigators such as Sutherland. His mentors Carl and Gerty Cori, and others who elucidated metabolic pathways in the 1920s, 30s, and 40s, had medical training and clinical experience, and their work was supported largely by medical schools and medical research institutes. But they conducted their research on the hormonal control of carbohydrate metabolism in the tradition of basic research, with questions about the cause or cure of disease playing little part in their discoveries (Sutherland 1972, pp. 401-408; Cori 1969, pp. 1-20).
Virtually all areas and phases of endocrinology, however, are marked by recurring interactions between basic and clinical pursuits, and contemporary molecular endocrinology is no exception. Thus, cyclic AMP workers have begun looking into the relationship between defects in the formation or action of this nucleotide and a variety of human diseases, with the ultimate hope that "The results of this research can eventually be applied to increase the quality of human life... [since] the chief end of all scientific research either is or ought to be the promotion of human happiness" (Robison, Butcher, and Sutherland 1971, pp. 454-455). Simultaneously, the reverse application of knowledge from the study of disease to fundamental questions so common in the earlier history of endocrinology is also taking place in the new molecular endocrinology. For example, physicians have known for some time that the lethal effect of the cholera bacteria's enterotoxin is a devastating diarrheal loss of fluids and salts from the body; the most effective therapy is the immediate replacement [END OF PAGE 67] of the lost fluids and salts. Recent researc on the mechanism of the toxin's action has shown that the toxin mimics the ability of cyclic AMP in intestinal cells to provoke cell membranes into actively transporting fluid and salts out of the cells. Carpenter theorizes that the toxin behaves like a hormone by binding itself to hormone receptors on the cell membrane; the receptors stimulate production of cyclic AMP, which in turn stimulates the membrane's active transport system. Unlike ordinary hormones, though, cholera enterotoxin is not particular about the kinds of cells or the membrane binding sites it will act upon. This makes it a useful, if potentially fearsome tool for investigating basic questions about the structure of hormone receptors and about the biochemical role of cyclic AMP within the cell (Carpenter 1972; McCann 1974, pp. 323-325). Thus, the discovery and study of diseases stemming from cyclic AMP malfunction promises to yield both the objective of treating diseases more effectively, and also that intense intellectual satisfaction which comes to the scientist when his puzzle-solving researches fit together to produce a new understanding of life processes.
As we have explored some of the ways in which endocrinology has evolved from ancient "kitchen anatomy" to present molecular researches, we see clearly the interplay between the clinic and the research laboratory in the generation of problems, concepts, and facts concerning endocrine function. What we have called phases three and four of endocrine research - the development of neuroenclocrinology and current molecular studies of hormone action - belong primarily to that portion of endocrinology's history where research had moved from a disease-initiated focus into the province of basic research. We have, accordingly, treated these phases only briefly, to suggest where that flow led and is leading investigators of the ductless glands.
It is in looking at the emergence of endocrinology as a field of biology in the latter decades of the nineteenth century and early years of the twentieth century that we see, most preeminently, the imprint and influences of medical concerns. For, particularly in France and then Britain, countries in which clinical medicine more generally shaped the problems pursued by physiologists, attention by physicians to disorders of the ductless glands provided a new range of phenomena for scientific investigation. At the turn of the century, as represented most significantly by Bayliss and Starling's researches, clinical work united with advances in chemistry, bioassay methods, and physiology to generate a new and fundamental understanding of the role of the endocrine gland's chemical mediators in physiological and biochemical functioning.
Reflecting in 1933 on the impact of endocrinology upon not only medicine but upon physiology as well, R. G. Hoskins chose to underscore the words of the great British physiologist and pioneer endocrinologist, Edward Sharpey-Schafer:
The changes in physiology which have resulted from this [new endocrine] knowledge constitute not merely an advance in degree but an alteration in character. The doctrine of internal secretions forms a new departure. We must in the future explain physiological changes in terms of chemical regulation as well as of nervous regulation. It is therefore justifiable to speak of the doctrine as a New Physiology, seeing that it has completely altered our outlook on many of the problems with which physiology deals and consequently on those met with in medicine and surgery. (Hoskins 1933, pp. 347-348) [END OF PAGE 68]
(1) Within the confines of a single chapter, we have had to omit some of the most interesting fundamental consequences of disease-related research in endocrinology. Some examples drawn from the history of diabetes and insulin research will give some sense of the range of problems suggested by clinical endocrinology and some sense of our ornissions.
Clinical endocrinologists have imposed great demands on the ingenuity of biochemists, to the benefit of both. For example, the first protein to have its amino acid sequence worked out completely was insulin. Sanger demonstrated conclusively by his analysis of the hormone that "proteins are well-defined molecules in which the amino acid units are linked by pe,)tide bonds to form long polypepticle chains," a definition that was oy no means certain when he began his decade of work in 1945. In the process of analyzing the structure of the insulin molecule, Sanger developed an armory of biochemical techniques for attacking the structure of other proteins and macrornoleculesThese techniques soon revealed subtle differences among the insulins of different species and forced evolutionary biologists to ask why, for example, pig insulin resembles human insulin more than cow insulin does.
Through both human and animal research on the nature of endocrine disorders, investigators have discovered both how universal endocrine mechanisms are in the animal kingdom and how idiosyncratic each group can be. A 1972 review of research on diabetes, insulin, and carbohydrate metabolism, for example, points out that insulin is an especially important hormone in carnivores who cannot count on a steady supply of food and whose metabolism must cope with sudden gluts and long-term shortages. In such creatures - man included -diabetes will be a serious disease; in herbivores and especially the ruminants who nibble all day long, diabetes is much less dangerous (Fritz 1972, pp. 166-180).
Another area we do not treat is that of comparative endocrinology. We deal only with research on the endocrinology of vertebrates; and within the vertebrates, almost solely with laboratory animals - dogs, cats, rats, rabbits - and man. We bypass entirely the fascinating work on invertebrates, plants, fungi, algae, and bacteria. Moreover, we have ignored the contributions of clinical endocrinology to our understanding of evolution, ecology, social and sexual behavior, psychology , embryology, and development. Finally, we have played favorite. within the endocrine system too. Thus, for example, the story of parathyroid and calcium metabolism receives no mention. The elaborate relationships of the sex hormones and glands with reproduction, growth, development, and behavior are only touched upon, chiefly because the history of sex endocrinology currently is being dealt with extensively by historian Diana Long Hall.
(2) The importance of special instruments for the advancement of both neuroenclocrinoiogy and neurosurgery is illustrated by the sterecitaxic instrument developed in 1908 by British neurosurgeon and neurophysiologist Victor Horsley and his colleague R. H. Clarke. The Horsley-Clarke device, a special kind of head-clamp combined with three-dimensional micrometer measuring devices, enabled physicians and laboratory researchers to make surgical or electrolytic lesions in precisely determined spots in the brain.
(3) For instance, the discovery was the basis for Dorothy L. Sayer's 1928 short story, "The Incredible Elopement of Lord Peter Wimsey."
(4) The diuretic response later was shown to be an artifact due to the experimental conditions, in contrast to the antidiuretic response which is in endocrine function of the posterior pituitary (Barrington 1975, p. 93).
(5) Despite their obvious importance, these discoveries of the growth hormone and the cliabetogenic effect of the anterior pituitary were something of a side issue for Evans and his colleagues- So was the laboratory group's participation in the discovery of the thyroid-stimulating hormone (TSH) and the adrenocorticotropic hormone (ACTH), both hinted at in Evan's analysis of Smith's early research on tadpoles (Evans 1923-24, pp. 216-218; Evans, Sparks, and Dixon 1966, pp. 319-320; Amoroso and Corner 1972, pp. 129-131). The interrelationships between the hypophysis and the ovaries remained the central problem for Evans and his co-workers. In seeking the reasons why their gigantic rats who had been treated with growth hormone failed to ovulate, Evans, Simpson, and Smith uncovered the existencd of still another pair of hormones, the gonadotropic luteinizing hormone (LH) and foil icle-stimu lating hormone (FSH). Their method of preparing crude extracts of growth hormone had, they gradually realized, retained both the growth hormone and the luteinizing hormone but destroyed the follicle-stimulating hormone. For successful ovulation both gonadotropic hormones had to be present in the right proportions. Once distinctions among the effects of the luteinizing, foil icle-stimu lating and growth hormones were drawn and analogous effects of these hormones in male animals were recognized, the research effort turned to the isolation and purification of the three hormones; in 1949, Li, Simpson, and Evans finally obtained homogenous FSH.
(6) In the 1930s at Chicago, Fisher, Ingram, and Ranson used the Horsley-Clarke sterecitaxic instrument to make small, accurately placed lesions in different areas of the hypothalamus in cats (see note 2). Lesions in the tract originally described by Ramon y Cajal had two related effects: atrophy of the posterior pituitary, and a polyuria very much like that in clinical cases of diabetes insipiclus. Ranson and his colleagues also noticed that these lesions interfered drastically with labor in pregnant cats a result which correlated well with the strong uterine contractions invoked by the oxytocin ("quick childbirth") fraction of posterior lobe extracts. Injections of posterior pituitary extract counteracted the polyuria and difficult labor. Lesions in other tracts of the hypothalamus did not incur any of these disorders although they did have other effects resembling pituitary malfunction (Harris 1955, pp. 200-204, 224-225). [END OF PAGE 69]
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