Book - The Hormones in Human Reproduction (1942) 4
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Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.
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Chapter IV. The Hormone of Preparation and Maturity
- "The hierarchy [of ike organs] is such that incessantly one borrows from another, one lends to the other, one is the other's debtor . . . each member prepares itself and strives anew to purify and refine this treasure . . . each doth cut off and pare a portion of the most precious of its nourishment; and dispatch it downwards where Nature hath prepared Vessels and Receptacles suitable . . . to preserve and perpetuate the Human Race. All this is done by Loans and Debts from one to the other." - Rabelais, Pantagruel (Book III, Chapter 4).
The ovary was very slow to yield the two great secrets of its function. The fact that mammals and man breed by means of eggs, and that the ovary is the source of the eggs, was not even conjectured until 1672, and was not proved (as we have seen, p. 34) until 1827. The fact that the ovary is an organ of internal secretion was not clearly stated until 1900.
The ancients knew of course that the organs we now call the ovaries are homologous with the male testicles and have something to do with reproduction; in fact, the Greeks and Romans called them "the female testes." Castration of female animals to prevent them from breeding is a very old practice. The verb "to spay," meaning to castrate the female, goes back to late Middle English, and practitioners of that art were called "sow-gelders" as early as 1515, judging from a citation in the New English Dictionary. These men must have known that removal of the ovaries stops the estrous cycles, and anybody who butchered a spayed sow would surely notice that in the absence of the ovaries the uterus shrinks far below its normal size. But these facts, even if known from observations on animals, did not get into the textbooks of human physiology until the surgeons began to remove human ovaries. That operation, first made possible in 1809 by the courage of Ephraim McDowell and of his patient, Jane Crawford, was fairly common by 1850. The great physiologist Carl Ludwig said, in his textbook of 1856, that in humans loss of the ovaries not only stops the menstrual cycles, but also causes the uterus to shrink.
This matter of castrate atrophy furnished a really important clue. It deserves careful explanation. When the ovaries of an adult female are removed, the oviducts, uterus, and vagina undergo rapid reduction in size. In the rabbit, in which the phenomenon has been quite fully studied, the uterus loses half its weight in two or three weeks and its tissues become thin and flabby (Plate XIV). This atrophy of the uterus produced by castration of the adult female is obviously just the reverse of what happens at the time of puberty, when the ovaries first become mature. The uterus and the other accessory reproductive organs (oviducts, vagina and mammary glands) which in infancy are small and undeveloped, grow to adult size when the ovaries begin to function. Both pubertal growth and castrate atrophy indicate clearly that the adult uterus is dependent upon the ovary.
It is difficult to realize that less than fifty years ago nobody could guess how this action of the ovary upon the uterus is produced. Some thought that castrate atrophy was due to interference with the blood supply of the uterus when the ovaries were removed, others thought the nerve connections were upset.
A Hormone of the Ovary?
The first step toward demonstrating the endocrine function of the ovary was taken in 1896 by Emil Knauer of Vienna, who took out the ovaries of guinea pigs and grafted pieces of them back into the same animals, at new sites. He demonstrated that such grafted ovaries prevent the occurrence of castrate atrophy. It must be, then, that the ovary makes some sort of chemical substance which acts upon the uterus. This is lost when the ovaries are removed, but again becomes available if the ovary is successfully regrafted, no matter where, in the animal's body.
In 1900 Knauer definitely suggested this idea of an internal secretion of the ovary. In the same year Josef Halban, also of Vienna, took three infantile guinea pigs, grafted bits of adult ovaries of the same species under their skin, and found that their uteri promptly grew to adult size. On the basis of Knauer's work and his own he stated the hypothesis of an internal secretion in perfectly clear terms : *'We must assume that a substance is produced by the ovary, which when taken into the blood is able to exert a specific influence upon the genital organs ; and that the presence of this substance in the body is absolutely necessary for the maintenance — and, as my researches show, for the development - of the other genital organs and the mammary glands."
With such a downright challenge as this, the inevitable next step was for somebody to try to make a chemical extract of ovarian tissue which should contain the potent substance postulated by Halban, and which could be injected into castrated animals instead of grafting ovaries into them. Several investigators actually tried it, but they were working in the dark and failed to hit upon the proper chemical steps. Thereafter for a few years experimenters went off on another trail. From 1911 to 1914 several Viennese and German gynecologists spent a great deal of time and effort searching for chemical extracts of the ovary which should produce menstruation in animals. This was a bad idea, for apparently these doctors never stopped to think that the rabbits and guinea pigs they were using do not menstruate anyway. We can see now that if they had used monkeys, which do menstruate, they might have found a clue. As a matter of fact, these men — Adler, Aschner, Schickele — did get a clue, but not exactly what they were looking for. They did not accomplish the miracle of making guinea pigs menstruate, but many of their extracts did have the property of increasing the blood flow through the vessels of the immature uterus, thus making it grow. Unfortunately they did not all use similar methods, and, what was more confusing, some of the extracts were made from whole ovaries, some from the corpora lutea (of swine or cows) and some even from human placentas. The situation was so confused that the results were almost meaningless.
In 1912 and 1913 two workers, Henri Iscovesco in Paris and Otfried Fellner in Vienna, found that a really potent preparation could be made by extracting the ovary with fat solvents (alcohol, ether, acetone). Their products readily prevented castrate atrophy, developed the infantile uterus, and enlarged the mammary glands. In the last year or two before the War of 1914-1918 these results were refined and standardized by several workers, the best work being that of Robert Frank of New York and Edmond Herrmann of Vienna.
The sum total, then, of twenty years of investigation was the demonstration that there is a substance in the ovary in general, in the corpus luteura, and in the placenta, which has the property of causing growth of the uterus of the infantile animal and of preventing castrate atrophy in adult animals. The relationship of this substance to the estrous cycle and to menstruation was decidedly a problem for the future, and its presence in so many tissues hindered rather than helped the effort to untangle the specific endocrine functions of the ovary and of the corpus luteum.
The Vaginal Test - Isolation of the Hormone
During the war the European laboratories dropped such problems as this, but in the United States the discovery (or rather, rediscovery and clarification) of the vaginal cycle of rodents by Stockard and Papanicolaou turned the work in another direction. I mentioned in Chapter III that Edgar Allen in 1922 described a similar cycle of vaginal changes in the mouse. Allen was very much impressed by the striking coincidence of the peak of the vaginal changes with the presence of mature follicles in the ovary. This led him to consider the possibility that there is a hormone in the follicles and particularly in the follicle fluid. The hypothesis that the special events of estrus are due to a secretion of the follicle, rather than of some other element of the ovary, was already widely, if somewhat vaguely entertained, because various observers had noticed that the mature phase of the follicles is closely associated with the phenomena of estrus. The pioneer American worker, Leo Loeb, said in 1917 that some of the cyclic changes in the uterus might be due to a secretion of the follicles. Arthur Robinson of Edinburgh in 1918 went so far as to write "It can scarcely be doubted that the phenomena of heat are due to something produced by the follicles." Edgar Allen now had the added evidence of the vaginal cycle pointing him in the same direction. Enlisting the collaboration of Edward A. Doisy, then a young biochemical colleague at Washington University (St. Louis), he proceeded to test this hypothesis by injecting a few drops of fluid, drawn from mature follicles of the sow, under the skin of castrated female rats and mice. In such animals, of course, cycles do not occur, and the vaginal lining becomes very thin and undeveloped and remains unchanged from day to day. An injection of follicle fluid, however, produced in 48 hours a typical estrous condition of the vagina, which could be easily detected by scraping or washing out the vagina and looking at the cells under the microscope. This result is shown in Plate XV, originally published in illustration of Allen and Doisy's earliest results. When administered to infantile rats and mice, the injections caused the uterus to grow to adult size and the vagina to open as in sexually mature animals (see Plate XVI, illustrating similar growth of the uterus in monkey and rabbit).
This astonishing result provided at once a new test, simple, precise, and rapid, by which the chemists could follow the hormone through various steps as they attempted to purify it. A sample suspected to contain it can be injected into a castrated rat or mouse and the vaginal cells examined under the microscope at intervals until the estrous change is seen. By giving graded doses to a series of animals the amount of hormone in a sample can be measured.
Follicle fluid is a complicated mixture of water, salts, a little fat, a lot of protein. Doisy faced the task of extracting from this "soup" a substance that could be present, as he knew well, only in very slight amounts. He guessed that like Iscovesco's, Fellner's, and Herrmann's materials it might be soluble in fat solvents. Fortunately this was correct, and he found at once that the potent substance is soluble in alcohol, a very helpful thing because when strong alcohol is added to a beaker of follicle fluid it throws down the troublesome proteins but leaves all the potency in the clear supernatant fluid, which can be decanted and subjected to further analysis. The hormone is also soluble in ether, chloroform, and acetone. In this respect it resembles the fats and therefore goes along with them through the various solutions ; but Doisy was able to get rid of these substances by the familiar expedient of cooking the extract with a little alkali. The fats were thus converted to soaps and could be washed away with water, leaving a small amount of non-saponifiable oil, in which was now concentrated almost all the potency of the original follicle fluid.
For theoretical reasons not now important, Allen and Doisy believed their active principle was peculiar to the large ovarian follicles, but other workers soon found it in the rest of the ovary. There is a little in the corpus luteum, and very much in the placenta. Robert Frank and his colleagues found it in the blood of female animals. It even turned up in the sex organs of plants, for example in the catkins of willow trees and in palm kernels.
Plate XV. Effects of the estrogenic hormone on the vagina of the rat. A^ section of vagina 10 days after castration. B, cells from contents of vagina at this time; leucocytes only are seen. C, section of vagina of castrated animal 36 hours after an injection of estrogen. Note thickening of vaginal lining. D, cells from vaginal contents of same animal. Epithelial cells now predominate in the vagina. E, section of vagina in estrous condition 48 hours after beginning of treatment with estrogenic hormone. Surface cells cornified, forming clear surface layer. F, vaginal cells of same animal, showing cornified cells only. Greatly magnified. From Sex and Internal Secretions, by courtesy of Edgar Allen and the Williams and Wilkins Company.
Incidentally, it was now obvious that this estrogenic hormone (as we may call it, because it initiates the estrous changes in the vagina) is the very same substance that Halban had predicted and that Iscovesco, Fellner, Frank, Herrmann and many others had extracted, in varying degrees of impurity, from ovaries and placenta. It not only acts upon the vagina and makes the immature uterus grow with remarkable speed, but it also stimulates growth of the external genital organs and of the mammary glands.
Complete chemical purification proved very difficult. After, collecting a supply of follicle fluid by tapping hundreds of ovaries, or grinding up a batch of ovaries or placentas, extracting with alcohol and putting the extract through twenty chemical steps, it was disheartening to find that various oily contaminants, some known and some unknown, insisted upon following the hormone through all the processes of purification.
At this point another unexpected discovery came to the rescue. In two European laboratories (Loewe, 1926, and Aschheim and Zondek, 1927) it was found that a substance having the same potencies is excreted in the urine of adult human females. Especially during pregnancy, when the hormone is present in the placenta in large quantities, it passes through the kidneys and into the urine in large amounts. Investigators now began to look for it in the urine of other animals, and Aschheim made the almost incredible discovery that it is present in enormous amounts in the urine of stallions, surely the least feminine of animals. The reasons for this strange fact may be put aside for the moment ; the important thing is that a watery source of the hormone is very much easier to work with than follicle fluid or chopped-up placenta. Starting with human pregnancy urine or stallion's urine, the biochemists did not have to contend at all with fats and proteins, the most troublesome ingredients of their former sources of supply. When the kidney secretes urine it strains out and retains these substances in the body. With the aid of this great simplification, Doisy was able to announce in 1929 that he had obtained the active principle in crystalline form, that is to say, absolutely pure; in the same year the great German biochemist Butenandt produced it and in 1930 it was announced at Amsterdam by Dingemanse, de Jongh, Kober and Laqueur and from Denver by d' Amour and Gustavson. All four laboratories had found exactly the same substance.
PLATE XVI. A, cross sections of uteri of immature Rhesus monkeys showing the eflPect of estrogenic hormone. Left, untreated anftnal. Right, treated animal. Note growth and differentiation of tissues. Magnified 8 times. From the Journal of Morphology, by courtesy of Edgar Allen and the Wistar Institute of Anatomy and Biology.
B, uteri of immature rabbits, showing effect of estrogenic hormone. Left, untreated rabbit, 6 weeks old. Right, litter-mate sister after 10 days' treatment. Note growth (thicker horns), increased circulation of blood (shown by darker color of horns), and improved muscle tone (shown by coiling of the horns). 2/3 natural size. Preparation by author.
The Chemical Nature of Estrone
It was now up to the organic chemists to tell us the chemical nature of this hormone from pregnancy urine, or estrone,[1] as it came to be called. What they found, I shall have difficulty in stating for my readers, except those who are familiar with the chemistry of hydrocarbons, because estrone belongs to a group of substances not within the ken of the general public, nor even indeed, of many chemists. It is a sterol. To explain this by saying that sterols are complex higher cyclic alcohols is correct but not very helpful. They are colorless solids occurring in crystals ; in bulk they look a good deal like powdered sugar or table salt, but when compressed into a mass, a quantity of sterol looks and feels more like a hard white crystalline wax. Sterols are plentiful in yolk of eggs, brain tissue and many plant tissues. Wool fat (lanolin) is largely composed of sterols mixed with softer, greasier fatty substances. Most of the sterols have no hormone action; in fact they tend to be rather inert substances, but since the identification of estrone it turns out that several particular sterols that are found in the male and female reproductive systems and the adrenal gland, as well as related substances prepared synthetically, have powerful effects in the animal body. Estrone is one of this group.
Readers who are interested in the chemical structure of estrone and the other sex gland hormones will find in the Appendix of this book a detailed account, written for those who remember a little of their elementary chemistry. What follows here will be intelligible to those who are familiar with organic chemistry ; other readers are advised to read Appendix I before proceeding further. The structural formula of estrone is as follows :
Estrone
The molecule contains 18 atoms of carbon, 22 of hydrogen, 2 of oxygen, arranged as 3-hydroxy, 17-keto estratriene. In 1936 Marker, Kamm, Oakwood and Laucius gave us absolute and final proof of this structure, by producing estrone artificially in the laboratory (at Pennsylvania State College) by conversion of one of the sterols obtained from vegetables, of which the formula was already known. This was of course a partial synthesis or rearrangement, the investigators having taken advantage of Nature's work in building up the substance with which they started. Bachmann, Cole and Wilds of the University of Michigan reported in 1939-1940 that they had achieved the total synthesis of an estrogenic hormone,[2] building it up in the laboratory from simple materials. These examples of chemical magic made a fitting climax to years of brilliant work on estrogenic hormones by the chemists of many nations.
A substance as complicated as this affords many opportunities for slight modifications by rearrangement, addition, or subtraction of the constituent atoms. It is not surprising, therefore, that a whole series of estrogenic hormones has been found, each differing slightly from estrone in chemical structure and in potency or even in details of physiological action. These have been obtained from the urine of other species (as for example equilenin from the mare), from male urine and from the human placenta.
It is a curious fact that Allen and Doisy's originally discovered hormone of the swine ovary, being immensely difficult to purify because of all the fats, oils and proteins of the tissues that come out in the extract with the hormone, was not actually identified for a long time. Finally MacCorquodale, Thayer and Doisy in 1935 extracted two tons of ovaries and obtained as the chief active substance a few milligrams of a compound differing from estrone only in having an OH group at position 17 instead of the doubly-bonded oxygen. This is estradiol. It is probably the form which is actually made in the ovary.
It has been found that esters of these hormones, i.e. combinations of estrogens with organic acids, are more slowly eliminated from the body than the estrogens themselves and therefore give longer and more intense effects. The propionic and benzoic esters have been widely used in the treatment of human patients.
Chemists are always interested to know just what part or feature of such a molecule is responsible for its effects. They learn this (if they can) by making up similar but definitely different substances until they find the simplest substance that has the same action. E. C. Dodds of the Courtauld Institute of Biochemistry, Middlesex Hospital, London, and his fellow workers have thus found a long series of synthetic estrogens, of which the most important is diethyl stilbestrol:
This compound is practically identical in its effects with the naturally occurring estrogens and is being tried by physicians in place of them. Students of chemistry will be interested in the fact brought out by Dodds, that the formula of diethyl stilbestrol can be written so that it resembles, in spatial relations, the formula of estrone and the other natural estrogens.
Diethylstilbestrol
The outstanding difference is that in stilbestrol two of the rings are open. Dodds compares this sort of similarity to that of a particular key, made for a given lock, with the skeleton key which will also open it. When, however, the molecules of diethyl stilbestrol and estrone are represented by 3-dimensional models, as was kindly done for me in connection with the Vanuxem Lectures, by Mr. MuUer of the Princeton Chemistry Department under the direction of Professor Hugh Taylor, they do not show the same degree of similarity as do the two diagrams on paper. The relation between the chemical structure and the action of these substances can hardly, therefore, be explained by a hypothesis as simple as that suggested by Dodds. All we can say is that all the estrogens thus far known, both natural and synthetic, have a ring structure more or less like these examples and possess phenolic properties, as indicated by the OH group in at least one ring. Until we know definitely just what the hormones do when they reach the cells upon which they act, these facts will have to suffice us.
Potency of estrone. Estrone is a very powerful substance; that is to say, only a very small amount is required to produce large effects. It has to be used and talked about in quantities too small for ordinary measures of weight, and so we mention it in terms of the chemists' tiny unit, the gamma (y) which is 1/1,000 of one milligram. An ordinary U.S. postage stamp, gummed, weighs 60 milligrams ; one gamma is therefore 1/60,000 part of the weight of a stamp. As little estrone as 1/100 gamma, or 1/6,000,000 of a postage stamp, per day for 3 or 4 days may be enough to produce estrous changes in a castrated mouse, and even in a woman 20 gammas per day (1/3,000 of a postage stamp) for 10 days may be sufficient to produce certain profound effects upon the uterus which we are going to consider in Chapter VI. Some of the other estrogens are three or four times as potent as this.
The total amount produced in one day by the two ovaries of an adult woman is believed to be equal in potency to about 300 to 400 gammas of estrone, or something over 1/200 of the weight of a postage stamp.
By worldwide agreement through the League of Nations an international unit of estrone was set up, for the benefit of scientists and the drug industry. This is the amount of potency in 0.1 gamma of the pure hormone. At first the League of Nations Committee on Standardization of Drugs and Hormones set aside in London a stock of the pure hormone to serve in much the same way as the international standards of weight and length (metric system) in Paris. Any responsible person who wished to test his own product could get a few units from London and compare the effectiveness of the two samples in rats or mice. It is good to know that if the precious store of standard estrone should ever be lost the hormone can be recreated to the exact formula and as long as the powers of destruction leave us a good organic chemist alive on earth this product and symbol of constructive international effort will survive.
Administration of the hormone. Most of the pure estrogens must be administered hypodermically, because they are not well absorbed from the digestive system and are therefore not effective when given by mouth. Some of them can be dissolved in water for hypodermic injection, but the effects last longer when they are injected in oil. For this purpose bland vegetable oils such as corn (Mazola) oil and sesame oil are used. The neutral triglycerides are also coming into use as solvents for injection; they dissolve the hormones better than do the oils and are generally better tolerated by the tissues into which they are injected. It has been a great surprise to find that the oil-soluble sterol hormones will enter the body through the skin if made up into ointment and applied by thorough rubbing (inunction). This is not a very exact way of giving a drug, for we can never be sure how much is lost or not absorbed, but at least it avoids disagreeable hypodermic punctures. Some of the new synthetic estrogens of relatively simple form, such as stilbestrol (mentioned above) can be given by mouth. There are also certain new compounds of the higher estrogens (e.g. ethinyl estradiol) which are effective by mouth. We may expect that after a due period of experiment, injections of the hormones will give way, at least to a considerable degree, to medication by mouth and by inunction.
The English investigators Deanesly and Parkes suggested, a few years ago, a brand new method of administering the estrogenic hormones (and equally well the other sterol hormones, whether from corpus luteum, testis, or adrenal gland, or from the chemist's beaker). This is to compress the hormone into a little rod-shaped pellet like a short segment of graphite from a lead pencil, and to bury this pellet under the skin. A hypodermic needle of large diameter can be inserted and the pellet pushed through its canal. Once buried, the surface of the pellet is slowly dissolved and the hormone is thus received by the animal in very small but continuous dosage. In this way it acts very effectively over long periods of time with the minimum disturbance of the animal. The method is extremely useful in laboratory experiments and there are reports of its successful use in certain human cases. There is still much to be learned, however, about the rate of absorption of these pellets, before we can know what daily dose we are actually giving when we administer the hormone in this way.
What part of the ovary makes the estrogenic hormone? After a great deal of investigation it is generally considered by the experts that the estrogenic hormone is probably made in the walls of the follicles, both large and small. The evidence for this conclusion is indirect, for there is no way to locate the hormone directly. The best we can do is to put little fragments, taken from various parts of the ovaries of large animals, under the skin of castrated mice to see if they contain estrogenic potency. Some years ago A. S. Parkes of London astonished his fellow workers by reporting that he had found a way (by use of X-rays) to break down the follicles in the ovaries of mice and thus to reduce the ovaries to masses of nondescript cells. Such mice became sterile, of course, because they could not produce eggs, but they went on having estrous cycles more or less regularly. This teaches us that the ovarian cells which make the estrogenic hormone can do so even when not actually organized into follicles.
I have already mentioned that during pregnancy the human placenta contains a large amount of estrogenic hormones. We know that these are not made in the ovary but in the placenta itself. There are several cases on record in which the ovaries were removed during pregnancy but the supply of estrogen continued. In humans and animals that are not pregnant the ovaries are the only effective source of estrogenj and if they are removed all evidence of estrogenic action disappears.
Recent investigations begin to hint that under special circumstances the adrenal glands may produce estrogenic hormones. It is too early however to see what relation this has to the general theory of the estrogenic hormones.
Action of the Estrogenic Hormones
Once the hormone gets into the blood stream, whether from the subject's own ovaries, or by the experimenter's needle, it is carried all over the body, through all the organs and tissues. But — and this is characteristic of all the hormones — it is selective in its action, like a key that opens certain locks and not others. The major point of attack of this particular hormone is the reproductive tract. This is strikingly seen if we give small doses to an immature female animal, whose uterus has never yet been subject to the action of estrogen. Half an hour after an injection of the hormone the blood vessels in the uterus begin to dilate and the blood to flow faster through them, reddening the whole organ. The microscope tells us that the rate of cell multiplication in uterus, Fallopian tube and vagina is sharply increased. All the constituent tissues of these organs become better defined or differentiated, as the histologists say (see Plate XVI, A). The muscle cells of the uterus grow longer and thicker and the uterine glands increase in size. Plate XVI, B shows the remarkable stimulation of growth and intensification of blood supply, produced in a young rabbit, 10 weeks old, by treatment with estrogen for 10 days. In two weeks or thereabouts, if the treatment is continued, the baby rabbit develops a uterus of adult size; but to the best of my knowledge, the hormone will not carry the growth of the uterus beyond the normal mature state. Further treatment, if forced, might cause damage to the uterus but would not make a larger-than-normal organ. The old hereditary pattern of the body does not yield readily to these upstart hormones.
As will be understood from the introductory discussion of castrate atrophy (at the beginning of this chapter), these same effects of estrogens occur in adult animals that have been deprived of their ovaries, just as in immature animals. In short, the action of estrogens is to bring up the immature uterus to the full adult stage, and then to keep it up, ready and waiting for the further changes that will be imposed upon it by the action of the corpus luteum. All this has been amply confirmed in the highest animals ; in monkeys by direct experiment on immature and castrated animals, in human patients by therapeutic treatment of women whose ovaries had been removed for surgical reasons.
We once saw a fantastic outcome of estrogen treatment. Thomas R. Forbes, while a student in my laboratory at the University of Rochester, tried estrone on some 18-inch female alligators. These creatures were still several years short of sexual maturity, and their oviducts (they have no uteri, being oviparous) were very immature. The heavy dosage of estrone crowded years of development of the oviducts into a few weeks, while the rest of the alligator's body remained small. Before long their bellies began to bulge, they sickened and died. At post-mortem Forbes found the abdominal cavities full of nothing else but coil after coil of hypertrophied oviducts, which had pushed the liver up toward the head, jammed the intestines into the flanks, and finally killed the unfortunate creatures when they could no longer find room for these redundant viscera. It would not be possible (I hasten to add) to produce such tragically disproportionate growth in humans or other mammals except perhaps by treatment during the embryonic period.
In mammals, of course, the vagina shares in all this response of the reproductive system to estrogenic hormones, and in the rat, mouse and guinea pig it gives tell-tale signs of its response by such changes in the vaginal wall and in the free vaginal cells as we have already discussed and illustrated (page 83; Plate XV). In human females who have passed the menopause, and younger women whose ovaries have been removed surgically, the vagina shows the effect of diminished or absent estrogenic hormone. When such patients are given the hormone, its effect can be detected by studying the vaginal cells. This method is now used to diagnose loss of ovarian function and to follow the progress of treatment with hormones.
The estrogenic hormones act on the mammary glands in a very definite way. These glands, when fully developed, are constructed on a plan resembling a little cluster of trees, in which the trunks come together at the nipple, forming the main milk canals. The branches form the general duct system, and the leaves are the milk-producing units (see Fig. 29). In immature animals the twig-like terminal units are scarcely or not at all developed, and even the duct system is rudimentary. Estrogenic hormones make the ducts grow until the gland is a wide-spreading tree, but still without much development of the actual milk-producing terminations on the ends of the twigs. In short, the estrogens bring the infantile mammary glands up to the normal stage of development of a mature virgin animal. As we shall see in Chapter VIII, during pregnancy other hormones, namely the pituitary hormones and in some animals the corpus luteum hormone, carry on the development of the gland and bring about the production of milk.
The estrogens and puberty. When the time approaches for a young girl to become mature, the pituitary gland begins to put out its gonadotrophic hormones (see p. 141). These in turn stimulate the ovary to produce its estrogenic hormone. All the accessory reproductive organs (uterus, oviducts, vagina, external genital organs, mammary glands) begin to grow toward mature size. The menstrual cycle begins. Hair grows in the armpits and the external genital region. All these changes are due directly to the estrogenic hormone. If the ovaries are removed before puberty they do not occur, and on the other hand they can be brought out in experimental animals and in castrated women by suitable injections of the hormone. Other signs of mature femininity, namely the female type of skeleton and bodily contours, the adult type of voice, are more deeply innate characteristics. It would be a mistake to think that the estrogenic hormone and the male hormone make all the difference of bodily type between men and women, or between male and female animals. Sex is determined when the egg is fertilized.^ The animal develops ovaries because she is a female already. When they begin to function as endocrine organs they make her sex effective by developing the accessory sexual organs so she can ultimately bear her young. In this sense the estrogenic hormone is a sex hormone; but if the ovaries fail to develop or are removed in childhood, and the ovarian hormones are thus unavailable, the girl still becomes a woman — infertile of course, usually somewhat immature or boyish, but still physically a woman, not a male or a neutral individual. For this reason the term "female sex hormone" has been generally abandoned and the safer name, estrogenic hormone, used instead (Appendix II, note 3) .
Estrogens and the estrous cycle. Given a castrated female guinea pig and a syringe of estrogenic hormone, the experimenter can reproduce cyclic changes in the vagina exactly like those found at estrus in the normal animal whose ovarian timepiece is ticking properly; and if he times his injections carefully he can set up a regular vaginal rhythm every 15 days (the normal rate of this species), so that an observer following the cycle by examining the vaginal cells, could not discover the absence of the animal's own ovaries.
This artificial cycle will also affect the uterus. The fort 8 See any of the books on heredity cited in note 2 of Chapter I.
nightly injections of estrogenic hormone will cause it to undergo the changes characteristic of estrus. The ovaries being absent, there will be no follicles to ripen and hence no corpus luteum. If the experimenter wants to make his artificial cycle complete, he will have to follow up his estrogen with injections of the corpus luteum hormone — but that is next chapter's story.
I have chosen the guinea pig as my example, but I might well have spoken of other animals. In the spayed female dog, for example, all the physical signs of "heat" characteristic of that species are brought on by estrogenic hormones, including the swelling of the external genital region and the sanguineous discharge normally seen at estrus or shortly before. In short, we can say that the physical changes of uterus and vagina that go with the ripening follicle of the ovary, are caused by the estrogenic hormone. In the life of the normal animal, however, these changes are accompanied also, during the estrous period, by the psychological urge to mate. Is this also produced by the estrogenic hormone of the ovary? Not all the necessary evidence on this important question is at hand. Psychic reactions are notoriously difficult to study. It is not easy to observe, test, and measure the sex behavior of animals in the laboratory. We know of course that if the ovaries are removed, the female is no longer receptive sexually, but even this statement requires reservations, especially in the case of our own unpredictable species. In many animals that have been studied (e.g. rat, mouse, dog, cat, sheep) there is evidence that the administration of estrogenic hormone to castrated females, or to intact females outside of the mating season, will awaken sexual receptivity. Josephine Ball found the same result in the Rhesus monkeys in the colony of the Carnegie Embryological Laboratory. In the guinea pig, recent work by William Young and collaborators at Brown University and Yale Medical School strongly suggests that not only the estrogenic hormone but also that of the corpus luteum is necessary. At any rate, these investigators obtained more frequent and more normal responses in castrated female guinea pigs if they added a little corpus luteum hormone after a course of the estrogen. This sets up a neat dilemma : there is of course no corpus luteum, in the ordinary cycle of normal animals, until after the animal has been in estrus. We can only conjecture that in the guinea pig at least, the mature follicles must secrete a little corpus luteum hormone before they rupture and become actual corpora lutea.
Important as this question of the relation between estrogens and the estrous urge is, we simply do not know enough as yet to apply the above results to human beings. To what extent the sex urge in women is controlled directly by the estrogenic hormone is a question too complex for analysis at present. The behavior of rats and guinea pigs is difficult enough to understand. Human behavior involves all sorts of mental processes not subject to experimental control. We may be sure, however, that the hormones have an important part in the matter, directly or indirectly, and that without them there could be no human mating.
The estrogenic hormone as a medicinal drug. When a physician administers an estrogenic hormone he is giving the patient a substitute for her own hormone. He thinks her supply of estrogen is too low for current needs. This lack is, however, not easy to determine or to measure. The signs of hormone deficiency are not very clear, and laboratory tests by examination of the patient's blood, to see how much hormone it is carrying, are expensive and in our present state of knowledge not necessarily decisive. Upsets of the menstrual cycle and other disorders of the female reproductive system may or may not be due to hormone lack; the theory of menstrual disorders is not yet clearly worked out. For this reason their treatment with hormones is at present a matter for very cautious study by specialists who have the facilities to treat their patients as laboratory subjects, which means more attention, more examination and more testing than patients with better-understood diseases usually require, and more expense for somebody, either the patient herself or the research budget of a clinic. The pages of medical journals are, however, nowadays full of reports of research, and day by day the subject is being advanced.
There is one disorder of health in which it is perfectly clear that the trouble is caused by the ovary failing to put out enough hormone and that a supply from the drug store will be helpful. This is the distress that often follows the cessation of the menstrual cycle, both the natural menopause of women at 45 or 50 years of age, and the so-called "surgical menopause" produced by operative removal of the ovaries. When the characteristic symptoms of a stormy menopause, such as hot flushes of the skin and general nervousness, become almost intolerable, large doses of estrogenic hormones often give genuine relief.
Another helpful use of estrogenic hormones is in the treatment of retarded sex development caused by ovarian insufficiency. In certain cases, selected by experienced physicians as likely to be helped, and carefully treated over long periods, the aspects of femininity have been given to underdeveloped girls, with great benefit to their social adjustment and their morale.
These hormones are powerful agents. We have seen that they affect many organs, and even yet we do not know all they may be doing in the body. In careful experienced medical hands they can be beneficent drugs. Used recklessly they may do great damage.
The estrogenic hormones and cancer. There is a whole series of chemical substances that cause cancer or other tumors, malignant and benign, when injected or rubbed into the skin. Some of these are chemically similar to the estrogenic hormones and indeed there are a few synthetic cancer-producing (carcinogenic) substances that are also estrogenic. It becomes therefore a burning question, whether or not the familiar and commonly known estrogens are carcinogenic. This question cannot be answered "no" or "yes" without explanation. Briefly the situation is as follows : The estrogens commonly used in medical practice and in the laboratory do not ordinarily produce cancer by their own direct action. In experimental animals cancer may follow their use under special circumstances, of which the following is a good example. In a certain pure-bred strain of mice, the females have a high tendency to develop cancer of the mammary glands. The males inherit the same tendency but do not suffer from it because the male mammary gland is too scanty to become cancerous. If the males are given large doses of estrogenic hormone, their mammary glands grow larger and then they often develop cancer of the breast.
In our Carnegie Embryological Laboratory, Hartman and Geschickter have given sixteen Rhesus monkeys enormous doses of estrogenic hormones over periods of many months, even for two or three years, and have not found a single tumor. On the other hand Alexander Lipschiitz of Santiago, Chile, with Rigoberto Iglesias, Luis Vargas Fernandez and others has found that in guinea pigs it is very easy to produce fibrous tumors in the abdominal cavity with estrogens. These are not malignant but may kill the animal by their mere size. There is even a recent report (from Gardner and E. Allen of Yale) of tumors of the uterus in mice, which may be malignant, produced by injection of estrogenic hormones in non-cancerous pure-bred strains.
The present definite medical consensus is that in human beings cancer is not produced by ordinary doses of estrogens. The whole subject, however, demands and is getting further investigation.
- ↑ The term estrogen, or estrogenic hormone, has been adopted to signify any and all of the hormones giving eflFects such as described in this chapter. Estrin, now little used, has the same significance. The terms estrone, estradiol, estriol, stilbestrol, equilenin, etc. refer to individual hormones of the series, each of which has its own particular chemical formula. Allen and Doisy, the discoverers of estrone, called it theelin, and this name, with its derivatives, is by agreement of a committee of American scientists alternatively used in this country. Each drug manufacturer making these hormones has his own trade name.
- ↑ Actually not estrone, but equilenin, referred to in the following paragraph.
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