Emergence of the concept of endocrine function and endocrinology

Beginnings 

1. Humors 

The unity of the body and the concept of disease as the result of some disturbance of the internal balance of “humors” were formulated in Greece during the sixth and fifth centuries B.C.4 The term humor in Greek designates any fluid or bodily juice. The humoral concept derived from the speculation of pre-Socratic philosophers on the makeup of the world, which they ultimately decided consisted of 4 basic elements: earth, water, fire, and air. Against this wider cosmological composition, the doctrine of 4 corresponding body humors were formulated as phlegm, blood, yellow bile, and black bile, which, in turn, determined four characters—hot, cold, dry, and wet—and defined four qualities—sweet, salty, sour, and bitter. By the second century A.D., Galen (129–200) provided an eclectic synthesis of the various schools (dogmatist, pragmatist, pneumatist, and empiric) that had formed around these invisible philosophical entities, recognizable only by logic.4 This archaic prototype of biochemistry was to form the basis of the Western tradition of medical knowledge and therapy down to the nineteenth century.3, 4, 5, 6, 7, 8, 9, 10

The Galenic theory gained dominance because of its basis in a divinely created universe, which had its parallel in the balance of the humors of the divinely created human body, a concept acceptable to the cresting dominance of the Christian Church in the fourth century. By the Middle Ages, this theory was to become the notion of cosmic sympathy, which linked the microcosm of man to the macrocosm of the universe, and was popularized in the Medieval illustrations of cosmic man that decorate books on the history of medicine.3, 4

A shift away from humoralism began during the anatomical studies of the Renaissance. Stimulated by the epochal work of Morgagni (1682–1771), The Seats and Causes of Diseases Investigated by Anatomy, and climaxed in the subsequent flourish of clinicopathologic descriptions of diseases from studies in morbid anatomy, diseases came to be perceived as limited to organs and tissues—the solid parts of the body. The now forgotten phase of vitalistic doctrine was to change this perception. The concept of a vital force was introduced by J. C. Reil (1759–1813), when the chemical composition of animal matter began to be investigated. Herman Boerhaave (1668–1738), a leading chemist of his times, greatly advanced interest in the chemistry of body fluids, on the basis of which the concept of humoralism once again attained ascendancy.11 The development of new methods of chemical analysis in the nineteenth century provided further support to this new humoralism. Thus, the mysterious substances of Galen that altered the theoretical humors resumed a new phase in which blood, rather than humors, or bodily juices, transmitted chemical messages from one part of the body to another and, thereby, regulated and integrated the functions of different organs (Fig 1). The subsequent changes that engulfed medicine by the middle of the nineteenth century are best summarized by G. O. Rees (1813–1889) in his statement,“The philosophical revival of a humor pathology bids fair to render the analysis of diseased blood one of the most useful adjuncts to our medical knowledge.”11 In this context, then, the study of endocrine organs, which had been fomenting all along as organotherapy, found a fertile ground in which to flourish and evolve (Fig 1).

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Figure 1. A schematic timeline of the emergence of endocrinology.

2. Organotherapy 

The primitive belief that in each organ resides some peculiar virtue that is transferred to anyone who consumes the organ arose from totemism, itself a derivative of animism—the doctrine that the phenomenon of animal life is produced by an immaterial “anima,” or soul. Hence, the drive to acquire the physical, mental, and moral characters of the totem.3 This practice has been postulated to have started from the consumption of rejects of sacrificial offerings to the god or totem to drive out a disease then believed to be caused by the angry god.12

Over time, these religious rites and totemic rituals began to be used medicinally. Egyptian papyri and Chinese medical texts mention heart preparations for cardiac disease, toad’s skin for edema, hen’s gizzard for gastric disorders, and whale’s semen for impotence. Organotherapy was practiced by Hippocrates (459–355 B.C.) and detailed by Pliny (22–79), Dioscorides (first century A.D.), and Galen, who list hare’s brain for neurological diseases, wolf’s liver for hepatic disorders, the testis of donkeys and stags for impotence, and coagulated blood for hemoptysis. Avicenna (980–1037) lists brain for melancholia, pig’s kidneys for kidney disease, lung substance for pulmonary afflictions and shortness of breath, powdered testis of a hog for sexual power, and uterus of a hare for feminine infertility. By the middle of the sixteenth century, bodily parts had become medicinal favorites, including those from human mummy extracts. Their use was espoused and promulgated by leading authorities of the time. As stated by Thomas Vicary (1490–1561), first Master of the United Barber Surgeons Guild, chartered by Henry VIII (Fig 2): “in what part of the body the faculty which you would strengthen lies, take the same part of the body from another creature in whom the faculty is strong, as a medicine.”; and stated more succinctly by Paracelsus (1493-1544): “heart cures heart, spleen spleen, lung lung.”3, 6, 7, 8, 9, 10

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Figure 2. Henry VIII and the Barber Surgeons, 1541 by Hans Holbein the Younger (1497–1543). Note: Thomas Vicary (1490–1561), First Master of the United Barber Surgeons Guild, to whom the king is handing the royal charter establishing the guild. Reproduced with permission granted by The Worshipful Company of Barbers in London.

However, animal parts were not always used in correlation between the affected part and the organ used. Although initially most parts were selectively used, in time they came to be incorporated into mixtures with herbs and minerals as constituents of compound medicines. The secret formula of “theriac” that flourished through the eighteenth century came to contain over 60 animal parts from different species. The more complex the “theriac” formula and the more exotic its animal constituents, the more costly it became, and the more difficult it became for ordinary people to acquire.

The efficacy of organotherapy began to be questioned in the eighteenth century, and civil authorities started sanctioning “theriac” from medical pharmacopoeias. Consequently, the number of animal extracts that were used in the formula diminished; however, many of these ideas survived in the lay public long after they had been abandoned by orthodox medicine. This situation was to change in the closing years of the nineteenth century, when the rudiments of endocrinology began to bud.1, 3, 6 The contributions of organotherapy to the nascence of endocrinology are perhaps best expressed in an editorial in the January 1917 inaugural issue of Endocrinology: “eventually it (organotherapy) will compare about as the moon does to the sun with the role of ductless glands in the very life process and in disease.” 13

Foundations: internal secretions 

The concept of internal secretions germinated in the anatomical studies of the Renaissance, when organs without ducts came to be recognized. Notable among those organs was the pituitary, which was said to discharge, through invisible foramina, brain waste material called “pituita,” or phlegm, into the nasopharynx. By about 1600, the gonads, adrenals, thyroid, thymus, and spleen were identified as ductless glands, but their functions remained speculative.3, 6, 7, 8, 9, 10 The discovery of the circulation by William Harvey (1578–1657) provided a vector of communication that allowed these ductless glands to deliver their products to a distant site. In fact, ductless organs were initially considered to be connected directly to the circulation and were variously termed “blood glands,” “glands of the blood vessels,” and “vascular ganglia.”3

The discovery of the circulation allowed the first formal suggestion of the concept of internal secretions in 1775 by Theophile de Bordeu (1722–1776), then court physician of Louis XV, to the effect that each organ in the body discharged “emanations which were useful to the whole body.”3, 6, 7, 8, 9, 10 Based principally on available information on testicular and ovarian influences on secondary sexual characteristics, much of Bordeu’s proposals were without supporting experimental data and, thus, can be regarded only as an interesting phase of theorizing in the emergence of endocrinology (Fig 1). Nevertheless, speaking more prophetically than he could have known, Bordeu can be considered to have predicted not only endocrine but also paracrine function, whereby every cell contributes to the integration of body function by secreting its cytokines.

The first experiments that supported the concept of internal secretions were reported by John Hunter (1728–1793) and subsequently in 1849 by A. A. Berthold (1803–1861), who showed that the transplantation of a cock’s testis to another part of the body of a castrated cock prevented atrophy of the comb and resulted in complete retention of its sexual characteristics.

The idea of internal secretions was placed on a firm basis in 1855 by Claude Bernard (1813–1878), who first identified an internal secretion—that of glucose secreted by the liver into the portal vein—as a distinct function from an external secretion—that of bile secreted by the liver into the intestinal tract (Fig 1). The publication in that same year by Thomas Addison (1793–1860) of his monograph On the Constitution and Local Effects of Diseases of the Suprarenal Capsules was the clinical milestone that launched the subsequent experimental studies of Charles Edouard Brown-Séquard (1817–1894), who showed that removal of the adrenals was invariably fatal, except when normal blood was infused in the experimental animals.3, 6, 7, 8, 9, 10

Thus, in the first decade of the twentieth century, the concurrent notions of organotherapy and humoralism converged into the new notion of internal secretions, at a time when chemical analysis was peaking, which allowed for the emergence of endocrinology, a discipline that did not even exist in the opening years of the century (Fig 1). Although this development was the result of the work of many investigators, it was principally made possible by the experimental contributions of Claude Bernard, the clinical observations of Thomas Addison, and the combined experimental and clinical studies of Brown-Séquard, each of whom has been dubbed the father of endocrinology at sometime by different authors. From that time, experimental investigation of the subject grew by leaps and bounds (Fig 1).

Endocrinology comes into being 

Perhaps the greater impact of Brown-Séquard on endocrinology occurred in 1899, when as a septuagenarian he claimed to have experienced an extraordinary rejuvenating effect after self-injection of a solution of testicular extracts from guinea pigs or dogs.14 Although his reports on the rejuvenating effect of testicular extracts were of dubious significance and more pathetic than convincing, they aroused worldwide public interest in endocrinology, generated a whole new industry for the marketing of glandular extracts, and stimulated more careful scientific work on organ extracts.3, 6, 10 One beneficiary of their commercialization was Henry Hanover (1893–1934), who after making a fortune in the sale of organ extracts, was instrumental in the foundation of the Society of Internal Secretions (now the Endocrine Society) and became the first managing editor of its official publication, Endocrinology.15

More importantly, Brown-Séquard’s studies stimulated experimental investigation into glandular function as well as into the function of different organs. The isolation of organ extracts by use of alcohol, glycerin, or saline and of carboxylic acid as a sterilant, which were then desiccated and used experimentally or therapeutically, flourished.16, 17, 18, 19 The first case of successful treatment of a 46-year-old myxedematous woman was reported by George R. Murray (1865–1939) in 1891.20 What began with studies of the thyroid, thymus, adrenals, and pituitary soon expanded to the hypophysis, pancreas, and parathyroids.

To distinguish active glandular extracts from other internal secretions, William Bayliss (1860–1924) and Ernest H. Starling (1866–1927) proposed the term “hormone,” derived from the Greek “I excite,” an adjective made to serve as a noun.2, 21 This use of the term was vigorously debated, on the grounds that some of the secreted substances had a depressive effect, before the term was finally accepted.3, 12, 22 The term “endocrinology” was proposed shortly thereafter by Nicola Pende (1880–1970) in 1909. By then, crude extracts from most organs were being prepared. The subsequent decade saw their isolation in pure crystalline form and wider use in the treatment of diseases that had haunted mankind thereto (Table 2).

Table 2. A Selected Chronology of Principal Hormonal Discoveries

	Years	Hormone
	1900–1910	Epinephrine, gastrin, and secretin
	1910–1930	Growth hormone, gonadotropins, estrogen, progesterone insulin, parathyroid hormone, prolactin, thyroxin, and antidiuretic hormone
	1930–1950	Glucagon, steroid hormones, thyroid-stimulating hormone norepinephrine, testosterone, luteinizing hormone, and adrenocortical trophic hormone
	1950–1970	Hypothalamic hormones, aldosterone, angiotensin, endorphins, oxytocin, erythropoietin, renin, prostaglandins, calcitonin, and 1,25 dihydroxy-vitamin D

In the evolution of endocrinology, the role of the kidney as an endocrine organ was relatively late to be recognized (Table 2). What contributed to its recognition, apart from ongoing physiological studies, was the advent of maintenance hemodialysis. The survival of patients with kidney failure on dialysis led to the discovery of a host of endocrine disturbances that had not been encountered theretofore. Notable among those disturbances, and the ones having the most impact on the quality of life of dialyzed patients, are those of sexual dysfunction that result from derangements in the pituitary-hypothalamic-gonadal axis in kidney failure, the subject of the present issue of Advances in Chronic Kidney Disease.

The pituitary-hypothalamic-gonadal axis 

The pituitary gland was described by Galen and named by Vesalius (1514–1564). Its critical role in the release of trophic hormones began to be deciphered when the correlation between glands came to be recognized, and multiglandular diseases were described in the same individual.3, 6, 7 Multiglandular diseases are most evident in those with disturbances associated with diseases of the pituitary. The endocrine syndromes in gonadal dysfunction associated with it and with that of other endocrine organs that were described now are the eponyms that pepper much of the language of endocrinology. Importantly, their deciphering was to provide for the chemical coordination of the body by endocrine function. Fielding Garrison (1870–1935) best summed this finding in his statement, “We are what we are largely through the balance or imbalance of certain internal secretions.”6 Although applicable to any of the metabolic processes of the body in general and to endocrine function in particular, this statement is perhaps most applicable to the hypothalamic-pituitary control of the sex hormones, which are largely responsible for conception, birth, fetal and subsequent growth, and sexual function.

From time immemorial, the gonads have been the objects of greatest solitude, for they were recognized as essential for the continuation of the human race. Of their dual functions, the external secretions for reproductive purposes were the first to be recognized. A foreshadowing of the understanding of its internal secretions was implied in Antiquity from observations on the effect of castration on animals and humans. Aretaeus (c. first to second century AD) declared, “for it is the semen, when possessed of vitality, which makes us to be men, hot, well braced in limbs, well voiced, spirited, strong to think and act.”3 This early interest in “maleness” was accompanied by lively interest in “femaleness” but in a setting that considered the ovary an undescended testis, and the vagina and uterus as an inverted penis and scrotum, respectively. Only in the seventeenth century was the term “ovarium” first used by Fabricius ab Aquapendente (1537–1619), and during the Enlightenment, a gradual shift from a 1-sex model to a 2-sex model in which the male and female organs of generation came to be considered quiet distinct and equally important to reproduction.23

By the time Bordeu formulated the notion of internal secretions, much had been learned about the internal functions of the testis and ovaries, and, in fact, Bordeu had a great deal to say about sex and gender in his theorizing and used them as the most obvious evidence for internal secretions. The experiments of Berthold in 1849 on castrated cocks provided the first evidence of internal secretions by the testis. The role of the ovary as an organ of internal secretions was documented 50 years later by Emil Knauer (1867–1935), who showed that the transplantation of ovarian fragments in rabbits restored menstruation after ovariectomy.

The emergence of endocrinology and its flourishing in the first half of the twentieth century ultimately clarified the complex integration of the pituitary-hypothalamic-gonadal axis, whose disturbances in kidney failure are discussed in this issue of the journal.3, 8, 10