The evolution of endocrinology

Abstract

The 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 the of the American for Clinical and Roberts from the and Hamilton and from the University of California both reported of hyperthyroidism with and and his in regression of thyroid with had the thyroid field, and therapeutic and making it one of the most of clinical Development of other isotopes, of and made possible the elucidation of the involved in hormone synthesis and development of techniques for improved hormone of the rates of hormone production and and development of hormones of specific for use in characterization of hormone The first developmental in endocrinology involved gonadal hormones. It had been recognized in the nineteenth century that male and during the first of and that of the two does not become apparent until in development. Bouin and that the testicular hormone of the is produced by the Leydig suggested that the of the Leydig cells of the development of the male The effects of hormones on sexual development were then in many of gonadal steroids can gonadal and in and by the 1920s to the that gonadal steroids control the development of both the gonads and the sexual However, this concept into when to beginning with in the American by of with gonadal steroids does not gonadal or the basic sexual when the or In the a of the sexual is directly by the the experiment in in which he showed that castration of the early male rabbit in formation of a and that two testicular hormones, androgen and antimullerian control male development. In the gonadal and gonadal in turn controls development of hormonal insight into sexual and made possible of the disorders of and animal was also a in the effects of other hormonal systems in a field that is a major branch of Most chemical assays are not or specific for the measurement of hormones in and isotope derivative assays were developed for hormones in and but had to patients so that clinical endocrinology This state of dramatically with development of the radioimmunoassay, the result of between a and a physician In observed to insulin in the of who had been treated with insulin and this to a for on the insight that of of insulin to the could be used to the amount of insulin in biological Within a short of were developed for many thyroid and steroid hormones, the field and the of assay from to levels and This had on endocrine research and on clinical It was not until that was first used of endocrinology to in assays and techniques can with had endocrinology from the states of hormone or and the other on the effects of hormone was to the mechanisms by which hormones exert effects within target tissues. Endocrine research – clinical and basic – was by the by and that is due to a in substance in target cells with which parathyroid hormone In papers the and of the of resistance to many other hormones were subsequently identified by and in and the concept that can result because the cannot to or increased levels of a hormone as a major impetus to shift the focus from hormone measurement to hormone action and hormone The concept of arose from by the of in the nineteenth According to the first description of for was in a paper by G. and who deduced that in The of hormones of specific to the characterization of two broad of hormone – that influence and that control of function were by of and

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