The evolution of endocrinology. Plenary lecture at the 12th International Congress of Endocrinology, Lisbon, Portugal, 31 August 2004
2005; Wiley; Volume: 62; Issue: 4 Linguagem: Inglês
10.1111/j.1365-2265.2005.02209.x
ISSN1365-2265
Autores Tópico(s)Pituitary Gland Disorders and Treatments
ResumoThe invitation to give this lecture suggested that it would be appropriate to take a broad look at the discipline of endocrinology, where it came from and its current state of development. Such an undertaking is timely because the discipline that we celebrate at this Congress, namely the concept that chemical messengers constitute one of the major physiological control systems, is a development of the twentieth century. Most students of the subject agree that the concept of chemical messengers secreted into the blood to exert systemic effects arose from the presentation of a paper in 1889 to the Societe de Biologie in Paris by Charles-Edouard Brown-Séquard, a professor at the College de France and one of the most distinguished physiologists of the nineteenth century. In this lecture, Brown-Séquard1,2 reported that self-administration of aqueous extracts of animal testes had enhanced his physical strength, improved his intellectual capacity, and increased his sexual potency. This dramatic claim was widely publicized in the lay press as well as within the medical community and made him an instant, controversial celebrity. Brown-Séquard's father was a sea captain from Philadelphia, his mother was French, and he was born on the British island of Mauritius; he claimed citizenship and worked as a scientist in all three countries during his career, so that endocrinology was international from its founding.3,4 Although an uneasy fascination with rejuvenation continues to haunt our field, the aim today is not to focus on Brown-Séquard but rather on the aftermath of his lecture. Whatever the weakness of the rejuvenation claims (and it took many years to disprove them), many scientists recognized the explanatory potential of the concept of chemical messengers and were stimulated to investigate extracts of other organs. Within a short time proof was obtained for the existence of multiple chemical messengers, and a dynamic discipline was born. Early milestones in the field are summarized in Table 1. In 1891, only two years after Brown-Sequard's lecture, Murray administered thyroid extract to a woman with myxoedema. In 1894 Oliver and Schäfer described epinephrine in extracts of the adrenal medulla. In 1903 Bayliss and Starling discovered secretin, and Starling chose the term hormone to describe all chemical messengers. In succession, Bouin and Ancel deduced the role of the Leydig cells in development of the male phenotype; MacCallum and Voetlin discovered the link between the parathyroid glands and calcium metabolism; Farmi and von den Velden treated diabetes insipidus with posterior pituitary extracts; Evans and Long described growth hormone; and in 1922 came the discovery of insulin by Banting and Best. By this time it was clear that hormones influence almost every function in the body. More importantly, at a time when few drugs of any type were effective, epinephrine was in use as a pressor substance, and organ extracts were available for three major disorders – hypothyroidism, diabetes insipidus and diabetes mellitus. This brief summary does not do justice to the rapid, almost explosive growth of the new discipline. In 1910, Artur Biedl, Professor of General and Experimental Pathology at the German University in Prague, published a textbook of endocrinology5 that was promptly translated into English. The book listed more than 8500 references, only about 1% of which had been published prior to 1889. This averages to more than 400 papers a year during the first 20 years of the field. The second edition in 1916 had almost 10 000 references. Endocrine societies (under a variety of names) were formed in many countries, and dedicated journals were established, beginning in 1917 with the publication of Endocrinology in the United States, followed by endocrine journals in Italy (Endocrinologia e Pathologica Constituzionals), France (Revue Francaise d'Endocrinologie) and Germany (Endokrinologie). According to Medvei,6 the publication rate in the field increased to about 1500 papers a year by the end of the 1920s. A major impetus for this growth came from the fact that by the end of the nineteenth century many disorders were known to be associated with pathology in specific organs. For example, diabetes mellitus was linked to the pancreas, adrenal insufficiency and pheochromocytoma to the adrenals, hyperthyroidism and myxoedema to the thyroid, and acromegaly and gigantism to the pituitary. In addition, the effects of surgical castration of men and women were understood in considerable detail. The possibility that such disorders might be due to over- or underproduction of chemical mediators had been widely discussed. For example, shortly after the description of adrenal insufficiency by Thomas Addison in 1855, Brown-Séquard showed that surgical removal of the adrenal is lethal to dogs but was unable to keep adrenalectomized dogs alive by administering adrenal extracts. Subsequent investigators were also unsuccessful in prolonging life in Addison's disease with adrenal extracts.7 Consequently, it is not surprising that Brown-Séquard's lecture stimulated a variety of collaborations between basic and clinical scientists. As formulated by Doisy,8 hormone development involved a series of stages: Identification of the tissue that produces a hormone Development of bioassay methods to identify the hormone Preparation of active extracts that can be purified, using the relevant bioassay Isolation, identification of structure, and synthesis of the hormone. Clinicians were adept in identifying candidate organs and hormones, development of bioassays was made possible by advances in physiology and pharmacology, and purification, structural analysis and synthesis required organic chemists. The most dramatic example of early hormone development is that of epinephrine.6 In 1894 George Oliver, a physician in Harrogate, had the idea that patients with low blood pressure might benefit from extracts of the adrenal. Therefore, he prepared a glycerin extract of beef adrenal medulla obtained from the local butcher, injected the extract into his son, and observed contraction of the boy's radial artery. [Sir Henry Dale9 commented that the boy deserved a memorial.] Oliver went to London and persuaded the somewhat sceptical pharmacologist Edward Schäfer to inject the extract into a dog that had an intra-arterial monitor in place. This famous experiment is illustrated in Fig. 1– a kymograph tracing of the rise in arterial blood pressure in the dog following the administration of Oliver's extract. In 1897 Abel and Crawford at the Johns Hopkins Hospital used the Oliver/Schäfer bioassay to purify the active principle as a monobenzoyl derivative of epinephrine that was not very active physiologically. The effect of extracts of the suprarenal capsule in the dog: (a) pressure in the ventricle; (b) pressure in the atrium; (c) blood pressure; (d) injection interval. From Oliver and Schäfer, Journal of Physiology, 1895, republished by Schäfer (1916).51 The therapeutic and financial potential of hormones had been apparent from the first, and it was inevitable that pharmaceutical companies would become involved in hormone development. In 1901 support from the Parke-Davis company allowed the Japanese-American Jokicki Takamine and an American, T. B. Aldrich, to purify the native hormone independently and establish its structure. To complete the story, the German chemist Friedrich Stolz synthesized epinephrine in 1904. The importance of the bioassay in this process cannot be overemphasized. Such assays varied in simplicity and sensitivity from measurement of blood sugar response for insulin and the chick comb assay for testosterone to tedious and inefficient systems such as prolongation of life in the adrenalectomized dog by cortisone or assaying the regression of mullerian ducts in organ culture for antimullerian hormone. Some hormones were purified using bioassay systems that were not related to the main action of the hormone in mammals. For example, vasopressin was characterized as the pressor substance of the posterior pituitary rather than for its antidiuretic properties, and prolactin was purified using the pigeon crop assay. By the mid-1920s endocrinology had completed its adolescence. It was an international undertaking that was stimulated by clinical problems; it involved collaborations between clinical and basic scientists; the research was financed in large part by the pharmaceutical industry; and it had undergone a remarkable growth to become a major branch of medicine and of biomedical science. In the past 75 years the field has undergone major changes or, in current jargon, paradigm shifts. These changes include recognition of feedback control, the impact of organic chemistry, the introduction of artificial isotopes, recognition of the developmental role of hormones, development of the radioimmunoassay, the shift of focus to hormone action, the impact of molecular biology, and the unification of endocrinology, immunology and neuroscience into a single discipline. The fact that production rates and blood levels of hormones are controlled by negative and positive feedback mechanisms is the central and unifying paradigm of endocrinology from dynamic tests of endocrine function to the development of oral contraceptives. The concept of feedback control was first formulated in reproductive endocrinology.10 In 1909 Tandler and Grosz described pituitary enlargement after castration of men,11 but the first experimental evidence for feedback control of gonadotrophins was obtained by Carl R. Moore and Dorothy Price,12 who described a reciprocal relationship between the testes and the anterior pituitary. They showed that testicular hormones suppress the pituitary, making available a reduced amount of gonadotrophins, that gonadotrophins are essential for spermatogenesis and for androgen production by the testes, and that androgens act directly and independently on target tissues. Moore and Price13 subsequently showed that the ovaries and pituitary have a similar reciprocal relationship. In 1932 McCullagh described separate roles for inhibin and gonadal steroids in the regulation of the pituitary,14 and Walter Hohlweg and Karl Junkmann, scientists in the Schering laboratory in Berlin, extended the concepts of Moore and Price by deducing that the gonads, central nervous system and pituitary interact in a triangular system.15,16 Dorothy Price17 recounted that she did not find a diagram of the pituitary–gonadal relationship in her laboratory notebooks or early published work. The diagram of Hohlweg and Junkmann shown in Fig. 215 appears to be the first such schematic. The gonads (either ovaries or testes) secrete hormones that feed back on the central nervous system, which in turn controls the anterior pituitary. The pituitary in turn secretes gonadotrophins that regulate hormone formation by the gonads. A role for the central nervous system in this process was deduced by demonstrating that testes continue to secrete hormones after transplantation to other sites in the body as long as the pituitary is intact, whereas transplanted pituitaries lose the capacity to function. The interdependent relationship between the gonads (keim-drüse), the central nervous system and the pituitary. Reproduced courtesy of Springer-Verlag© 1932.15 Geoffrey Harris18 identified the hypothalamus as the control site for the pituitary–gonadal axis in the central nervous system by inducing ovulation in the rabbit after electrical stimulation of either the pituitary or the hypothalamus. Thus, in a short interval, the essential components of the hypothalamic–pituitary–gonadal system were defined. Reciprocal relationships between the pituitary and other peripheral organs were then established. For example, W. T. Salter19 diagrammed the relation between the thyroid, the hypothalamus and the pituitary in what he termed the pituitary–thyroid axis. The term feed-back was first applied to endocrine control systems by Roy G. Haskins20 in an editorial in the Journal of Clinical Endocrinology. Engineers had developed the theory of servo mechanisms in the 1930s and 1940s to describe automatically controlled systems such as thermostats, a field that came to be termed cybernetics, and Norbert Weiner,21 a theoretician in the field, had pointed out that insight might be gained into biological control mechanisms by application of servo theory. Hoskins, who had been the first editor of Endocrinology, expanded on Weiner's suggestion and pointed out that resetting of the sensitivity of the pituitary to feedback by thyroid hormones could result in either hyper- or hypothyroidism, a remarkable anticipation of the pathophysiology of hormone resistance states and pituitary adenomas. Introduction of the term 'feedback' to describe control mechanisms for all hormonal systems had a unifying effect similar to that of Starling's introduction of the word 'hormone'. The field expanded dramatically with the discovery of the hypothalamic–portal blood system and characterization of the hypothalamic releasing and inhibiting hormones. The epinephrine paradigm for hormone discovery was not easy to repeat because of obstacles to hormone purification and structural analysis. These difficulties included: cumbersome and inefficient bioassay systems that consumed large portions of the extracts at every stage of purification; primitive purification techniques; the fact that hormones constitute only trace components of most organ extracts (cortisol is approximately 1 millionth of the weight of adrenal glands); and inadequate spectroscopic methods for structural analyses. As a consequence, only three hormones (epinephrine, thyroxine and insulin) had been crystallized by 1926, and the structure had been solved only for epinephrine. Most early endocrine research (and most early endocrine drugs) involved impure tissue extracts that varied in purity and potency in different laboratories. The impact of advances in organic chemistry in the late 1920s began with solution of the structure of thyroxine by Harrington and Barger.22 Then, elucidation of the phenanthrine structure of cholesterol and bile acids by Wieland and Windaus initiated a remarkable era in which vitamin D2 and 10 steroid hormones were purified between 1929 and 1954 (Table 2). The term 'heroic' is appropriate because of the enormous quantity of starting materials required for all except vitamin D2; in the most extreme case, Kendall23 estimated that his laboratory processed 150 tons of beef adrenals between 1930 and 1950. Steroid hormone development was an international undertaking, involving German, Dutch, Polish, Swiss, British and American laboratories. Considering the enormous expense involved in these purifications, it is not surprising that drug companies financed the development of many steroid hormones. Some of the investigators were employees of the companies, and in other instances the companies supported academic laboratories. Elucidation of structure also made possible the chemical synthesis of many hormones. As noted above, epinephrine was synthesized by Stolz in 1904, and Harrington and Barger synthesized thyroxine in 1927. However, pharmaceutical companies continued to produce both of these drugs from animal extracts for many years. Steroid hormones synthesized from plant sterols had a more immediate clinical impact. Ruzicka synthesized the first steroid hormone androsterone, and synthetic deoxycorticosterone, corticosterone, and cortisone became available for use in patients. Advanced synthetic techniques made possible development of superagonists, contraceptives and antihormones for a multitude of purposes. Structural analysis was slower for the peptide hormones and did not break until the 1950s with elucidation of the structures of vasopressin and oxytocin by du Vigneaud and of insulin by Sanger. The discovery in the 1930s by the Joliot-Curies in France that artificial isotopes can be produced by neutron bombardment had an enormous impact on every branch of biological science. The first impact of isotopes in endocrinology was in the thyroid field.24128Iodine with a half-life of 30 minutes was supplied in 1938 by Karl Compton at the Massachusetts Institute of Technology to the thyroid clinic at the Massachusetts General Hospital (MGH), where Hertz, Roberts and Davis demonstrated specific uptake of the isotope by the rabbit thyroid.25 In 1939 Glenn Sebourg at the University of California Berkeley produced 131iodine with a half-life of 8 days, and Hamilton and Soley26 used the isotope to demonstrate increased thyroid uptake of radioiodine in hyperthyroidism. At the 1942 meeting of the American Society for Clinical Investigation, Hertz and Roberts from the MGH and Hamilton and Lawrence from the University of California both reported successful treatment of hyperthyroidism with 131iodine, and Seidlin and his co-workers27 in New York induced regression of functioning thyroid cancer metastases with radioiodine. Radioactive iodine had completely transformed the thyroid field, providing powerful diagnostic and therapeutic tools and making it one of the most quantitative of clinical disciplines. Development of other radioactive isotopes, including those of carbon, hydrogen, sulfur and phosphorus, made possible the elucidation of the pathways involved in hormone synthesis and degradation, development of isotopic dilution techniques for improved hormone assays, quantification of the rates of hormone production and turnover, and development of radioactive hormones of high specific activity for use in characterization of hormone receptors. The first developmental studies in endocrinology involved gonadal hormones. It had been recognized in the nineteenth century that male and female mammals develop identically during the first portion of embryogenesis and that anatomical dimorphism of the two sexes does not become apparent until later in embryonic development. Bouin and Ancel,28 having established that the testicular hormone of the adult is produced by the Leydig cells, suggested that the secretions of the Leydig cells of the pig embryo cause development of the male urogenital tract. The effects of hormones on sexual development were then studied in many species. Administration of gonadal steroids can reverse gonadal and anatomical sex in amphibia, fish, reptiles and birds, leading by the 1920s to the general belief that gonadal steroids control the development of both the gonads and the sexual phenotypes. However, this concept fell into disrepute when attention shifted to mammals, beginning with studies in the American opossum (reviewed by Burns29). Treatment of opossum pouch young with gonadal steroids does not change gonadal differentiation or alter the basic sexual phenotype even when the urogenital tracts partially feminize or virilize inappropriately. In the marsupial, a portion of the sexual phenotype is determined directly by the sex chromosomes. Then Alfred Jost30 performed the critical experiment in placental mammals in which he showed that castration of the early male rabbit foetus results in formation of a female urogenital tract and that two testicular hormones, androgen and antimullerian hormone, control male phenotypic development. In the placental mammal genetic sex determines gonadal sex, and gonadal sex in turn controls development of anatomical sex through hormonal secretions. Jost's landmark studies provided insight into sexual differentiation and made possible investigation of the disorders of human and animal intersex. Jost31 was also a pioneer in studying the effects of other hormonal systems in embryonic development, a field that is now a major branch of endocrinology. Most chemical assays are not sensitive or specific enough for the measurement of hormones in plasma. Fluorimetric and isotope derivative assays were developed for some hormones in plasma and urine, but they had limited applicability to patients so that clinical endocrinology remained largely descriptive. This state of affairs changed dramatically with development of the radioimmunoassay, the result of collaboration between a physicist, Rosalyn Yalow, and a physician scientist, Solomon Berson.32,33 In 1956, they observed antibodies to insulin in the plasma of diabetics who had been treated with insulin and extrapolated this observation to develop a radioimmunoassay for insulin, based on the brilliant insight that displacement of binding of radioactive insulin to the antibody could be used to measure the amount of nonradioactive insulin in biological fluids. Within a short period, sensitive radioimmunoassays of high specificity were developed for many peptide, thyroid and steroid hormones, eventually encompassing the entire field and extending the range of assay from nanomolar to picomolar levels and below. This technique had equally important impacts on endocrine research and on clinical endocrinology. It was not until 1970 that radioimmunoassay was first used outside of endocrinology to detect hepatitis virus in plasma.34 Immunometric assays and chromatography/mass spectroscopy techniques can now detect molecules with even lower concentrations. Two endeavours had dominated endocrinology from the beginning. One concerned states of hormone deficiency or absence, and the other focused on the effects of hormone excess. Little attention was addressed to the mechanisms by which hormones exert their effects within target tissues. Endocrine research – clinical and basic – was changed by the deduction by Albright, Burnett, Smith and Parson35 that pseudohypoparathyroidism is due to a defect in some hypothetical substance in target cells with which parathyroid hormone normally reacts. In subsequent papers they established the hereditary nature and variable expressivity of the disorder. Syndromes of hereditary resistance to many other hormones were subsequently identified (reviewed by Verhoeven and Wilson in 197936), and the concept that endocrinopathy can result because the tissues cannot respond to normal or increased levels of a hormone served as a major impetus to shift the focus from hormone measurement to hormone action and hormone receptors. The concept of ligand–receptor interaction arose from pharmacology (anticipated by the studies of Erhlich in the nineteenth century).37 According to Bennett,38 the first description of receptors for endogenous substances was in a 1957 paper by G. L. Brown and J. S. Gillespie,39 who deduced that norepinephrine receptors must exist in nerve endings. The availability of radioactively labelled hormones of high specific activity led to the characterization of two broad categories of hormone receptors – cell surface receptors that influence signal transduction and intracellular transcription regulatory proteins that control gene transcription. Studies of receptor function were facilitated by comparisons of normal and abnormal receptors (or the associated G proteins) from subjects and animals with loss-of-function or gain-of-function mutations of hormone receptors. Molecular biology has had a profound impact on endocrinology. First, cloning of the genes that encode peptide hormones made it possible to produce hormones by recombinant DNA technology. This technology turned out to be of enormous significance because it had never been possible to extract enough human growth hormone from pituitaries to supply clinical needs and because increased demands worldwide made it impractical to produce sufficient insulin from animal organs. Many hormones are now being produced by this technology. Second, new hormones (such as leptin and orexin) have been identified by positional and/or functional gene cloning. Third, cloning of the cDNAs for hormone receptors and the enzymes involved in hormone synthesis and metabolism made it possible to identify mutations that influence the function (or amount) of the proteins. Molecular diagnosis became commonplace, and critical genes in development, such as those involved in sex determination and differentiation, have been identified. Fourth, use of knock-out and knock-in technologies to investigate hormone action has liberated the field from dependence on experiments of nature such as the human hormone resistance states and provided new approaches for investigating hormone action in individual organs or cells. Fifth, functional genomics and proteomics have great promise for investigating hormone action. Brown-Sequard was credited by Weil40 with formulation of chemical control as follows: We assume that every single tissue and, in general, every separate cell of the organism secretes certain products or ferments which are poured into the blood current, and which influence every other cell. In this way a solidarity is established between all the cells of the organism by means other than the nervous system. The belief that the chemical and neurological control systems were independent was elaborated by Starling41 in the Croonian lectures, and the immune system was identified as the third major control system by which cells communicate. The concept of three separate control systems began to erode almost immediately, first with regard to the separation between the endocrine and neural systems. The first suggestion that neurotransmission is humorally mediated is attributed to T. R. Elliott,42 who proposed that epinephrine is the chemical mediator liberated when the nerve impulse arrived at the periphery. Other pioneers who formulated a unified neuroendocrine control system included Henry Dale, Otto Loewi, Walter Cannon, and Ernst and Berta Scharer.6,43 It is difficult in retrospect to understand the slow acceptance of the concept of the neuroendocrine system. A similar evolution in understanding has unified immunology and endocrinology (reviewed by Munford44), beginning with demonstration that hormones such as glucocorticoids regulate immune responses. This was followed by demonstration that cytokines from immune cells influence many endocrine systems and that endocrine tissues also synthesize cytokines. Finally, it became apparent that stress activates a communication network involving cytokines, hormones and neural pathways. Independent evidence has also accumulated for direct communication between the immune and nervous systems. In short, the concept of three independent systems of communication among cells has been replaced by recognition of a complex, interacting control network involving immune, neural and chemical messengers. With regard to its anchoring in clinical medicine and continuing interaction between clinical and basic scientists, endocrinology today resembles the field in the early twentieth century. The profound changes in the field in the past 75 years are largely due to the application of advances in other fields – chemistry, physics, cell and molecular biology, genetics, immunology, neuroscience and cybernetics – so that hormones are now discovered, synthesized, measured and investigated in new ways. The shift of focus to hormone action moved molecular endocrinology into the mainstream of cellular and developmental biology, and advances of several types have eroded the separations between endocrinology, neurobiology and immunology. Endocrine science continues to be one of the most dynamic disciplines of biomedical science, and endocrinology is the most quantitative of the clinical specialties. There is probably no arena of medicine in which collaboration between the clinical and basic sciences has been more productive. This Congress is held to celebrate the recent developments in the field. It is also appropriate to consider the impact that endocrinology has had on other branches of biomedical science. We have described many of these impacts. Probably the most important is scientifically designed therapies such as insulin and oral contraceptives, two of the very important therapeutic advances of the twentieth century. A second was the application of the concept of feedback control to other biological systems.45 A third impact is the radioimmunoassay, which spread from endocrinology throughout biology and is one of the most widely used methods for the measurement of biological mediators. A fourth impact was the discovery of cyclic AMP and the G proteins, which transformed our understanding of signal transduction. Another way to assess the impact of endocrinology on science is to look at the 15 Nobel Prizes awarded in the field since 1909, when Kocher received the Prize in Physiology or Medicine for the surgical treatment of hyperthyroidism (Table 3). A second award (to Huggins) was also for therapy of disease. Nine of the Prizes honoured hormone discovery, structure, synthesis or measurement. Three were for physiological studies (to Dale and Loewi, to Houssay, and to Von Euler, Katz and Axelrod). Only two awards (to Sutherland and to Gilman and Rodbell) were for studies of hormone action. The fact that many advances in endocrinology have been recognized by the scientific establishment is a source of pride. Others will be awarded in the future. Developments in the past several decades have blurred the concept of endocrinology as a discipline of basic science. Hansson, Skalhegg and Tasken46 addressed this issue in a provocative essay entitled 'Is basic endocrinology disappearing?'. To quote their argument: 'Knowledge of the molecular mechanisms through which hormones act is of major importance in trying to understand and solve the problems of clinical endocrinology. However, the elucidation of more detailed molecular aspects, such as the coupling of receptors to intracellular pathways through second messengers and protein phosphorylation cascades, has also posed an important question: is it still meaningful to speak of basic endocrinology, or are all aspects of this discipline now absorbed in the larger field of molecular cell biology?' The biomedical sciences were separated into individual disciplines when research methods were limited, and such divisions were useful for teaching and research. Uncertainty as whether the basic science will survive as a distinct discipline is not unique to endocrinology and can be viewed as a desirable consequence of advances that breach artificial barriers between the branches of biology. Now, endocrinology involves neural science, immunology, cell and molecular biology and genetics as much as it does hormones per se. Careful thought does need to be given to the appropriate training of both clinical and basic scientists in our field,47 but there is cause for optimism that endocrinology will survive as a basic as well as a clinical discipline for at least three reasons. First, a large number of 'orphan' receptors and candidate signalling molecules are known to exist, many of which will turn out to be hormones and hormone receptors that control critical functions. Second, many of the major unresolved issues in the field involve systems or whole animal physiology. Such issues include the control of complex physiological processes such as growth and puberty by multiple hormones; the interaction of biological rhythms with the endocrine system; the integration of the endocrine, neural and immune systems; and the control of complex behavioural and developmental processes such as those involved in sexual differentiation, gender behaviour and reproduction. These problems cannot be solved by genome sequencing or by study of single cell types but will require a renaissance in physiology, a discipline now overshadowed by developments in genetics and molecular biology. The field of endocrinology is appropriately poised to lead such a renaissance. Third, the field continues to be stimulated by clinical problems, the same phenomenon that powered the initial growth explosion in the field at the turn of the twentieth century. Not only are we confronted with many critical unresolved dilemmas about common problems such as obesity, diabetes mellitus, ageing and development, but, in addition, new syndromes and new clinical problems continue to be recognized and to challenge basic as well as clinical scientists. International Congresses of Endocrinology will probably be held in 2104 and beyond, and it is likely that the clinical and basic scientists gathered here today would not feel totally lost in those meetings. It is not always easy to assign credit, and I relied on the judgements of V. C. Medvei,6 A. V. Hughes41 and H. D. Rolleston48 for the early years, on L. F and M. Fieser49 and M. Tausk50 for the steroid hormones, and Becker and Sawin24 for the impact of radioiodine on thyroid disease. Historical articles on this subject that are written in English (with the exception of Medvei) tend to suffer from bias in favour of papers published in English and to focus on mammalian (usually human) physiology at the expense of comparative studies in other vertebrate species. This paper illustrates both of these limitations.
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