Lewis
H. Saretf
Merck Sharp & Dohme Research Laboratories Rahwoy, New Jersey
I
I I
The Hormones
T h e word "hormone" was coined by W. Hardy working in the laboratory of the English physiologist, Ernest Starling, in 1905 and was designed to be the Greek equivalent of the phrase "chemical messenger." Since hormones are the chemical agents secreted by the ductless glands, and since they act specifically on other target tissues, their identity as chemicals on the one hand and as "messengers" on the other is very reasonable. There are twenty-eight currently accepted mammalian hormones. This is a figure twice as great as the number of identified vitamins. This suggests that for a truly exciting life, a balanced diet is only half the story. The clear-cut anatomical and histological differenti* tion of the ductless glands prompted rudimentary exploration on their effects in the earliest times. The greater tractability of the ox and the gelding in agricultural practice was a pre-Biblical discovery. I n a sense Presented as part of the 50th Anniversary Symposium, Division of Medicinal Chemistry, American Chemiesl Society, September 16, 1959, Atlantic City, New Jersey.
184
/
Journol of Chemical Education
the identification of the hormone testosterone by Laqueur in 1935 was the culmination of a experiment which in one form or another had run for more than twenty centuries. It has been pointed out that most of the hormones are not really essential for existence. Rather they appeared with the phylogenetic evolution of man and enabled him t o respond in a more complex fashion to his environment. I n spite of this dispensibility of most of the hormones for physical existence, it is certainly true that man's progress at the social level would be hampered by their absence. Consider the sluggishness of the cretin and the indifference and languor of the Addisonian. I n agreement with this role of facilitating homostatis, the hormones are secreted in response to specific temporal or environmental stimuli. I n contrast with the energy-producing metabolic mechanisms which roll on in splendid and ceaseless autonomy, most of the endocrine responses are discontinuous ones. The major part of the secretion of growth hormone is accomplished
during the first fifth of the life span. The gonadotropic secretion, on the other hand, only starts at about the time that growth hormone slows up. Aldosterone release is triggered by low serum sodium levels; epinephrine and hydrocortisone by stresses from appropriate environmental stimuli, and so on. The construction of this picture of marvelously regulated responses to a complex environment is undoubtedly one of the great triumphs of biological science over the past fifty years. The hormones are the most potent class of biologically active agents in existence. Only lysergic acid diethylamide, Vitamin Biz, and one or two other agents are effective in such low doses. Starting at the weaker end of the scale the steroid hormones progesterone and hydrocortisone are the two feeblest, 25 mg being the average daily amount required for normal function. I n order to maintain normal carbohydrate metabolism only 1-2 mg of insulin is required per day. The difference between normal growth and pituitary dwarfism is only a milligram or so of growth hormone daily. The estrogens begin to get into the more potent range of the spectrum. Hoskins has calculated that if the human were as sensitive to estrogens as the rat, an effect could be elicited from every female on the North American continent with a total of one ounce of estrone. On the extreme end of the potency scale we find glucagon, vasopressin, oxytocin, epinephrine, and the corticotrophin-regulating factor. An essentially weightless invisible residue amounting perhaps to mg will elicit the full-blown effect of these substances-increase in blood pressure, release of adrenal steroid, induction of labor, and so on. The extraordinary sensitivity of the receptor site is another important aspect of the potency problem. It is perhaps, a matter of greater wonderment that so exquisitely sensitive a receptor can be fashioned, as that so little of an activator can set it off. The hormones have achieved a place in medicine. Fourteen are in routine clinical use, especially in the treatment of deficiency states in which an inadequate amount of endogenous hormone is available. Only three of the hormones are fully active by the oral route: thyroxine, hydrocortisone, and estrone. Threeother* testosterone, progesterone, and epinephrine by synthetic modifications have been converted to orally active analogues. The balance have had to be used parenterally, with emphasis going into longer-acting and repository dosage forms. The importance of the hormones to clinical medicine can conveniently be measured in terms of the annual U. S. sales volume at the manufacturer's level. I n order of importance they range from hydrocortisone and analogue~$100,000,000 (dermatoses, rheumatoid artbitis, lupus, rheumatic fever) through insulin-$20,000,000 and the estragens-$20,000,000 to oxytocin-$600,000 and gonadotrophine-$150,000.
known experiment relating pancreatic secretion with sugar metabolism. Berthold in the middle of the nineteenth century had shown that the effects of castration on comb growth of the rooster could be p r e vented by transplantation of testicular tissue. I n the case of the thyroids it was shown in 1856 that mortality in dogs and guinea pigs caused by thyroidectomy could be prevented by thyroid transplants. Ten years before the turn of the century hypothyroidism in humans was successfully treated with thyroid tissue. Adrenal malfunction had been associated with the symptoms of weakness and pigmentation which we recognize as Addison's disease in 1849. The androgenic hormones of the testis had received great notoriety, particularly through the work of Brown-Sequard in 1889who claimed powers of rejuvenation from testicular extracts. With the estrogens, similar experiments were carried out in which transplantation of ovarian tissue prevented the uterine atrophy which otherwise occurred. In examining reports of these early experiments one is struck by the great reluctance of the age to assign a new explanation to an observed effect, however much the logic of the situation seemed to call for it. The experiments with transplanted thyroid and testis and with pancreatic extracts seem now to demand an explanation on the basis of a physiologically active secretion-in other words, a hormone--but biologists did not give up their earlier interpretations easily. As Hoskins has described it: "Up to near the end of the last century nearly every expert looked to the influence of the nervous system alone as concerned with the coordination of functions in the body; the conception of chemical regulation had achieved no place in the mind of the majority." What broke the spell was epinephrine. It was recognized as a potent pressor substance in 1894 and isolated as a benzoate by Abel in 1900. With ParkeDavis' active support it was crystallized by Takamine and by Aldrich in 1902. It was synthesized in 1904, and marketed shortly thereafter for the treatment of shock. This work was speedy, clear-cut, and medically useful. It demonstrated beyond a doubt that an endocrine gland could produce an exceedingly potent compound, (1 part per billion), that that compound could have useful applications, and that it could he synthesized in a standard manufacturing operation. The way was open for isolation of more new hormones.
Epinephrine
Origin of Hormone Research
Prior to 1900 a few isolated pieces of evidence existed which quite clearly indicated that various glands produced physiologically active secretions. It had been known, for example, since 1683 that removal of the pancreas produced diabetes-like symptoms in dogs. In 1889, Minkowski and von Mering described their well-
Accordingly some of the other portions of the endocrine system came in for a sharper scrutiny. The corpus luteum of the ovary was shown to he essential for maintenance of pregnancy in the rabbit, and the ground-work was thereby laid for Corner and Allen's demonstration twenty years later of progesterone. By 1905 the dominance of the Pavlovian theory of nervous control of phyVolume 37, Number 4, April 1960
/
185
siologic:~lfunction hnd brrn di.*.
