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Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.

   Hormones in Human Reproduction (1942): 1 Higher Animals | 2 Human Egg and Organs | 3 Ovary as Timepiece | 4 Hormone of Preparation and Maturity | 5 Hormone for Gestation | 6 Menstrual Cycle | 7 Endocrine Arithmetic | 8 Hormones in Pregnancy | 9 Male Hormone | Appendices
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Appendices

Appendix I

More About the Chemical Structure of the Sex Gland Hormones

WHEN discussing the chemistry of the ovarian and testicular hormones, in Chapters IV, V, and IX, I tried first to make their general nature as clear as possible to readers who have not studied chemistry at all, and then I gave the structural formulas for the benefit of those who are familiar with organic chemistry. Most of my readers, however, probably belong to a middle category. They have studied the elements of chemistry in a college course that included a few weeks on the compounds of carbon, so that they can comprehend an organic formula, at least of the more familiar sort, especially if written out in full and its significant features are explained. They are on the other hand hardly prepared to grasp at once the full meaning of one of these complex and unfamiliar hormones or to perceive its relation to the simpler substances chiefly dealt with in college chemistry. For the guidance of such readers I propose to write the formulas of the more important sex gland hormones as clearly as possible and to explain their nature exactly as I had to have them explained to me when I found that nowadays even an anatomist must struggle with chemistry and that he comprehends the general significance of simple formulas such as that of ethyl alcohol and benzene :


^ I assume that the reader recalls that the valence of carbon is 4, of hydrogen and the hydroxyl group (OH) is 1, and of oxygen 2:


1 In preparing this discussion, I have drawn freely upon the standard textbooks of organic and biological chemistry. See also The Chemistry of Natural Products Related to Phenanthrene, by L. F. Fieser, New York, 1936; Sterols and Related Compounds, by E. Friedmann, Cambridge, England, 1937; and The Chemistry of the Sterids, by Harry Sobotka, Baltimore, 1938.



The basic hydrocarbon of the sex gland hormones. All the naturally occurring sex gland hormones can be understood in relation to certain basic hydrocarbons. One of these, called estrane, has the following structure:


CH2


CH2


HpC


H2C


ESTRANE

For the sake of convenience we number the carbon atoms arbitrarily, as shown in the diagram. We can save time and trouble henceforth by omitting the obvious CH's, as follows :


ESTRANE

This means the same as the complete formula above. Whenever, in formulas cited hereafter, a linkage point is written without indication of the elements, it means a carbon atom with enough hydrogen atoms to fill up its quota of 4 valences. Unsaturated carbon atoms will be indicated by double bonds.

The relation of estrane to simpler organic compounds. Those substances derived from estrane which are of interest to us as hormones belong to a group of compounds called sterols, which have already been characterized briefly in Chapter IV. The relation of the sterols to more familiar substances can be explained as follows :

Three benzene rings condensed in line form the substance anthracene :


ANTHRACENE


In a slightly different arrangement, exactly the same atoms constitute phenanthrene :

PHENANTHRENE

With one more ring, this time of 6 carbons instead of 6, we get cyclo-penteno-phenanthrene :


CYCLOPENTENOPHENANTHRENE


This structure of 4 rings, two upstairs and two downstairs, has a great significance to the chemist and physiologist, for it is the basis of many important substances in the body. When the rings are unsaturated at various linkages and provided with various side groups and side chains, an enormous series of compounds occurs, which are known as steroids. These include the sterols (one of which, cholesterol, is a widespread constituent of the animal body), the bile acids, and the sex gland hormones. The unravelling of their constitution has been one of the great feats of modern organic chemistry, and it is now being followed up by the rapid production of scores and hundreds of new synthetic compounds of similar constitution.

To proceed from cyclopentenophenanthrene to estrane, the hydrocarbon first mentioned above, let us imagine the former compound completely saturated with hydrogen and a methyl group (CH3) attached to the carbon atom which we have numbered 13:


ESTRANE If the first ring is unsaturated, we have estratriene :


ESTRATRIENE

The estrogenic hormones. At last we have arrived at an actual hormone, for the best-known of all the estrogenic substances, estrone^ is like estratriene except that it has a hydroxyl group at carbon 3, and an atom of oxygen at carbon 17; in other words it is 3-hjdroxy, 17-keto estratriene (for clearness, the formula is written in full as well as in the usual simplified form) :


HO-C^^/C^^^CH^


ESTRONE


ESTRONE


As explained in Chapter IV, a large series of naturally occurring estrogens is known. All these are closely related to estrone. Among the representative estrogens are the following:

Estradiol, the hormone which probably exists in the greatest amount in the body, has a hydroxyl group at position 17 instead of the doubly-linked (ketonic) oxygen:


CH3 ^OH


ESTRADIOL Estriolf which occurs abundantly in the human placenta, is


CH3 ^OH


ESTRIOL

Equilenin, isolated from mare's urine, belongs to a group of estrogenic substances which have unsaturated carbon atoms in the second ring as well as the first :


CH3 ^0


EQUILENiN { U9 }

With the foregoing explanation the reader, if he is stiU curious about these relationships and wishes to follow out such problems as the synthesis of estrone, is now in a position to study a more technical discussion of the chemistry of the estrogenic hormones such as E. A. Doisy gives in Sex and Internal Secretions,*

The androgenic hormones. These may be understood by reference to their basic hydrocarbon, androstane, which differs from estrane by having a second methyl group, attached to carbon 10:

CH.


ANDROSTANE


Androsterone, referred to in Chapter IX, as the hormone of male type first isolated from human urine, is 3-hydroxy, 17keto androstane: ^^

o =0


ANDROSTERONE

2 Sex and Internal Secretions, edited by Edgar Allen, 2d edition, Baltimore, Williams and Wilkins, 1939. Chapter XIII, "Biochemistry of the Estrogenic Compounds," by E. A. Doisy.


Testosterone, the male hormone obtained directly from the testis, has a double bond in the first ring :


CH,


oy


TESTOSTERONE

A large number of substances having androgenic potency, and the steps by which they have been prepared synthetically, are discussed by F. C. Koch in Sex and Internal Secretions. Progesterone. The corpus luteum hormone can best be understood by comparison with its basic hydrocarbon, which is called pregnane. This has the two methyl groups already seen in androstane, and also an ethyl group (CH2 . CH3) as a side chain on carbon 17. (The two ethylic carbons are numbered 20 and 21, those of the methyl groups being 18 and 19.)


Progesterone, as will be seen from the following formula, has a double bond in the first ring, and two atoms of oxygen at positions 3 and 20 respectively. It is therefore 3, 20 diketo pregnene :



PROGESTERONE

Its excretion product in the human body, pregnanediol, can be derived from this formula by the addition of 6 atoms of hydrogen; that is, the 2 ketonic atoms are replaced by hydroxyl groups, the extra bonds at these points being satisfied by one hydrogen each, and the two unsaturated carbons are saturated:


PREGNANEDIOL { 252 }


The preparation of progesterone from pregnanediol and from stigmasterol (a natural vegetable sterol) and other chemical matters of interest concerning progesterone and its related substances are fully discussed by W. M. Allen in Sex and Internal Secretions.

As explained in Chapter V, when pregnanediol leaves the body in the urine, it does so in combination with glycuronic acid and with sodium. The resultant compound, sodium pregnanediol glycuronidate, has the following structure :


SODIUM PREGNANEDIOL GLYCURONIDATE

APPENDIX II

Note 1

(Preface, page x, line 30). Bibliographic references. Full bibliographies covering practically the whole field of this book will be found in : Sex and Internal Secretions, edited by Edgar Allen, 2d edition, Baltimore, 1939. Glandular Physiology and Therapy , 2d edition, Chicago, 1942. Biological Actions of Sex Hormones, by Harold Burrows, Cambridge, England, 1945. Endocrinologie de la Gestation, by Robert Courrier, Paris, 1945. Patterns of Mammalian Reproduction, by S. A. Asdell, Ithaca, N.Y., 1946.

===Note 2===(page 64, line 32). The Atlantic palolo. An interesting account of the swarming of an Atlantic species closely related to the oft-cited palolo of the Pacific Ocean, has recently been published by L. B. Clark and W. N. Hess, "Swarming of the Atlantic Palolo W6rm," Carnegie Institution of Washington^ Publication d'^l).. Papers from the Tortugas Laboratories, vol. xxxiii, 1943.

Note 3

(page 96, line 24). Action of the sex-gland hormones on the embryonic sex organs. Since the preparation of these lectures, there has been a considerable clarification of our knowledge of the action of the estrogens and of the male hormones (androgens) upon the growth of the accessory sex organs of the embryo and in particular upon their differentiation into male and female types.

Stating the fundamentals of the problem briefly, the original determination of the sex of an individual mammalian animal is made at the time of fertilization of the Qgg, by a mechanism which operates through the chromosomes of the ^gg- and sperm-nucleus. No visible difference between the sexes appears however until the embryo reaches an age (in the human species, about six weeks after fertilization) when the sex glands begin to show the characteristics of the ovary or testis respectively. The accessory sex organs, when they first develop, are capable of being directed toward the pattern of either sex. All the necessary rudimentary tissues for the development of both the male and the female sex organs are present in every embryo, regardless of the sex of the individual as determined by fertilization. About the 9th week of embryonic life (in humans) the sex-pattern of the accessory organs begins to be distinguishable, and after that the male organs (epididymis, vas deferens, prostate, seminal vesicles), and the female organs (uterus, vagina) begin to be recognizable to the embryologist, according to the sex of the individual.

Experiments on a number of species of laboratory animals, done at these early stages, reveal that before the definite characteristics of the accessory organs of the two sexes appear, and to a gradually diminishing degree thereafter, their differentiation may be modified and controlled by treatment with estrogens and androgens. For example, an embryonic animal which is genetically a male (as determined at the time of fertilization) may be made by suitable doses of estrogenic hormone to develop accessory sex organs of female type. Reversal in the opposite direction may be accomplished by subjecting a genetic female to treatment with androgenic hormone. The hormone administered by the experimenter thus overrides and contradicts the influences which normally control the sex-pattern of the accessory organs.

Such experiments were first done on the relatively accessible embryos of aquatic animals, especially the amphibians. The extensive literature which has grown up on this subject is well reviewed in Sex and Internal Secretions, Baltimore, 1939. Experimentation on mammals has been more difficult because of the inaccessibility of the embryos in the uterus. R. K. Burns, Carl Moore and others have cleverly taken advantage of the peculiar reproductive processes of the opossum. This creature, the only marsupial dwelling north of Mexico, gives birth to its young at the extraordinary age of 13 days after ovulation ; that is to say, the embryos leave the uterus at that time and migrate to the brood pouch on the lower belly of the mother, where each embryo firmly grasps a nipple with its mouth and goes on growing and developing for many weeks. At the time of transfer to the pouch, the young are so embryonic that the accessory sex organs, including even the external genitals, are in the indifferent stage. The sex cannot be clearly determined by inspection until ten days after birth, when the scrotum of the male and the pouch of the female are definitely recognizable.

Once in the pouch, the young are accessible to the experimenter, who needs only to anesthetize the mother to get at them and inject them with micro-doses of the hormones. As in the salamanders and other lower vertebrates, so also in the opossum it has been possible to reverse the sex pattern of the accessory organs and to make genetic males acquire the structure of females, and vice versa. The gonads (testis or ovary) remain unchanged in their sex- affinity. In higher mammals, such as the rat, mouse, and guinea pig, in which the young are carried in the uterus until birth, very similar results have been obtained by the expedient of giving relatively enormous doses of the hormones to the mother during pregnancy. For detailed reviews of this subject the reader is referred to articles by R. K. Burns, "Hormones and the Growth of the Parts of the Urinogenital Apparatus in Mammalian Embryos," Cold Spring Harbor Symposia on Quantitative Biology, X, 1942 ; and C. R. Moore, "Gonad Hormones and Sex Differentiation," American Naturalist, 78, 1944.

These experiments teach us that the hormones of the kind produced by the adult sex glands can be used in the laboratory to induce differentiation of the originally indifferent accessory sex organs into structures typical of the male and female respectively. The experiments obviously do not tell us whether the substances that are produced in the embryonic gonads, acting under natural conditions to induce the development of the sex organs, are themselves hormones of the steroid estrogen-androgen types which are effective in adult physiology. For all we know at present, the embryonic hormones may be chemically like or unlike the known estrogens and androgens. This query has implications too large for further discussion here, leading us into the whole question of the nature of the embryonic inductor substances and their relation to growth-inducing and morphogenetic hormones. (For a brief elementary statement of the theory of embryonic inductors or "organizers," see G. W. Corner, Ourselves UnborUf New Haven, 194«4, pages 103-106; for a detailed discussion, see Joseph Needham, Biochemistry and Morphogenesis ^ Cambridge, England, 1946.)

Paradoxical effects. It has frequently been observed, in experiments with the sex-gland hormones upon embryonic tissues, that higher dosages of the androgenic substances may induce female rudiments to accelerate development in the female direction, and there is evidence that estrogenic substances may sometimes act similarly upon male structures. The studies of Burns (see the article cited above) have shown that these so-called "paradoxical" effects occur in his embryonic opossums only when the dosage of the hormones is relatively high. By reducing the dose of the male hormone Burns was able to limit its stimulative effects to male structures only, all the female structures being unaffected. We may suppose therefore that the action of these hormones upon embryonic rudiments is fundamentally sex-specific, and that the "paradoxical" effects reported by various authors for a number of animals are the result, in some way, of excessive doses.


Note 4

(page 111, line 33). Is the corpus luteum necessary for segmentation of the egg and for implantation of the embryo? Nothing has turned up, since the first edition of this book was published, to cast any doubt upon the conclusion that the hormonal action of the corpus luteum is necessary for the survival of the early embryo in the uterus before its' attachment, and for its implantation in the endometrium. A number of considerations make it necessary, however, to restate the matter somewhat differently. In a recent striking investigation M. N. Runner of the Jackson Memorial Laboratory at Bar Harbor (Anatomical Record, 98, 1947, p. 1) removed fertilized eggs of the guinea pig from the oviducts and placed them in the anterior chamber of the eye, where they could be observed with a microscope through the clear cornea. It has been known for some time that the fertilized mammalian egg can go on segmenting and reach the blastocyst stage outside the mother, in tissue-culture dishes. The motion pictures of W. H. Lewis (see page 56 and Plate XI) were made from eggs cultured in that way. The anterior chamber of the eye is well-known to be a favorable place for the growth of transplanted tissues, for the aqueous humor is an excellent physiological salt solution, and a good bloodsupply is readily available for tissues that become attached to the iris (cf. Markee's grafts of endometrium, page 150). Runner found that when placed in the eye, the fertilized eggs of the guinea pig would continue dividing, would proceed to the blastocyst stage and become implanted, or at least begin to implant upon the iris. All these phenomena of embryonic growth were found, moreover, to occur even though the ovaries were removed or the eggs placed in the eye-chamber of another animal which had not ovulated and therefore had no corpora lutea. Indeed, the eyes of male mice proved to be as favorable for growth of embryos as those of females.

Some years ago J. S. Nicholas of Yale University operated upon rats in such a way that the fertilized eggs passed out of the oviduct into the abdominal cavity. Among a large number of animals thus prepared there were a few cases in which the embryos thus misplaced grew, attached themselves to the mesenteries or elsewhere on the peritoneal lining of the abdominal cavity, and lived out the full term of gestation.

The distinguished French biologist Robert Courrier in his Endocrinologie de la Gestation (Paris, 1945) reports a curious observation upon a rabbit in which, on the 19th day of pregnancy, one embryo was caused by surgical means to escape from the uterus into the abdominal cavity, where it attached itself to the peritoneum. Two other embryos were allowed to remain in the uterus. The ovaries were removed at this same operation. At the end of the usual term of gestation, the fetus in the abdominal cavity was alive, whereas those left in the uterus had died as a result of the loss of the ovaries. Evidently the corpora lutea are essential for the welfare of the embryos only if the latter are in the uterus.

We must assume from such experiments that the early mammalian embryo has a strong inherent vitality which will enable it to grow wherever it has the necessary warmth, a supply of oxygen and nutritive materials, and a generally suitable chemico-physical environment. Since, on the other hand, as experiments have proved, the early embryo cannot survive in the uterus except under the influence of progestational changes induced by the corpus luteum, it follows that the uterus, when not so prepared, is actually an unfavorable place for the early embryo as compared with the anterior chamber of the eye, the peritoneal cavity, or even a tissue-culture slide.

This seemingly paradoxical situation is made intelligible by thinking of the evolutionary background of mammalian reproduction. It is characteristic of eggs and early embryos of lower animals that they are prepared to develop without shelter and nutriment from the mother. When the mammals evolved the phenomenon of utero-gestation, the chosen place of shelter, the uterus, was developed from part of the oviduct, a channel that had for its purpose the efficient transportation and discharge of the eggs, not their retention and maintenance. To fit it for gestational functions, the endocrine mechanism of the corpus luteum was evolved. In the light of this thought it is not surprising that the uterine chamber is actually a less favorable place for early embryos than, say, the anterior chamber of the eye, except when the hormones of the ovary act upon it and change it into a place of superior efficiency for its new function.

Note 5

(page 118, line 11). Progestin by mouth. The progesterone-like substance that can be administered orally is called pregneninolone (preg-nene-in-ol-one) or ethinyl testosterone. Its chemical structure is


PREGNENINOLONE

Note 6 (page 122, line 6). Excretion products of progesterone. The statement in the text is not quite correct. Marker, Wittle, and Lawson have found pregnanediol in the urine of pregnant cows and mares, in concentrations not greatly different from those in human pregnancy urine. They found, strangely, that the urine of bulls contains about twice as much pregnanediol as human pregnancy urine. It unfortunately remains true that the end-products of progesterone metabolism have not been identified in the common laboratory animals.

Note 7

(page 126, line 2). /« the corpus luteum necessary throughout pregnancy? Experiments on the Rhesus monkey by C. G. Hartman and G. W. Corner, which were under way when the first edition of this book was published, have been completed (Anatomical Record, vol. 98, August 1947). They prove that the corpus luteum of pregnancy, and probably the whole of the ovarian tissue, can in this species be removed as early as the 25th day of pregnancy without disturbing gestation.

Note 8

(page 132, line 11). Clinical use of progesterone and pregneninolone. Five years after these pages on the practical use of progesterone were first written, they may be reprinted with little or no modification. The same hopes, the same successes, the same cautions, still stand. Some progress has been made in selecting cases suitable for progesterone therapy, thanks to the use of pregnanediol excretion as a test of the need for progesterone. In the large university hospitals, where there are laboratories in the women's clinics equipped for the assay, only those cases of habitual abortion and of menorrhagia that show a low excretion of pregnanediol are treated with progesterone or pregneninolone. In these selected cases, naturally, the percentage of favorable results is higher than when all cases of a given disease are treated on a hit-ormiss basis.

Sterility, when there is similar evidence that a low progesterone level is involved, is to be added to the list of pathological conditions in which progestin therapy is now being tried.

Note 9

(page 135, line 24). Menstruation in lower primates. Evidence has accumulated that something like menstruation, in an elementary form at least, occurs in the New World monkeys. In several vspecies of howler, spider and capuchin monkeys there is periodic shedding of small amounts of blood into the tissue of the lining of the uterus. A few red blood cells escape into the genital canal and can be detected in washings made by injecting salt solution into the vagina, removing it again and examining it under the microscope. There is not enough blood lost to show externally.

A process apparently resembling menstruation in the elephant shrew of South Africa has recently been described by Van der Horst and Gillman. The species in question belongs to a family of animals which has been assigned by some naturalists to insectivores and by others to the primates.

In summary, it begins to appear that menstruation is not sharply limited to the higher primates, but that on the contrary it exists in a rudimentary form in other families of primates and primate-like animals. (See S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y., 194!6.)

Note 10

(page 137, line 26). Menstrual cycles in infrahuman primates. Thanks largely to the work of Zuckerman and Gillman, the cycles of two species of baboon have now been studied in numbers large enough to warrant comparison with other primates. The cycles are longer than those of the human species and the Rhesus monkey, averaging about 33 to 36 days, modal length, in various groups of animals. (The subject of menstrual cycles in primates is thoroughly reviewed in S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y., 1946.)

Note 11

(page 141, line 33, and page 201, footnote). The gonadotropic substances of the pituitary gland and the placenta. When this book was first written, it was thought best in the interest of clarity not to refer in detail to the moot question of the existence of two or more gonadotrophic substances. The problem is still not settled, but it has become somewhat better defined, and for the sake of readers who wish to proceed from the very general account given here, to the more technical literature, the following outline is now supplied.

The prime fact is that the pituitary gland, the placentas of certain species, the urine of pregnant females of certain species, and the blood serum of the mare, all contain hormonal substances that stimulate the growth and differentiation of the ovaries and testes of animals into which they are injected. The precise nature of the effects of these hormones differs considerably, however, according to the particular source of the hormone and also according to the species of animal receiving the injections and the dosage. Under these varying circumstances, the constituent tissues of the ovary, for example, respond differently. Sometimes the follicles merely grow larger or even become cystic or atretic ; in other experiments they are caused to form corpora lutea. In the testis likewise, there may be stimulation on one hand of the spermatogenic tubules, on the other hand of the interstitial cells (see Chapter IX). Workers using the ovaries of various species as test objects have found first that as their efforts to purify the gonadotrophic substances advanced, they seemed more and more clearly able to achieve at least partial separation of the two effects just mentioned; that is to say some of the partially purified preparations tended to produce only follicle stimulation, others only to cause luteinization. Separation of the two effects, perhaps even better than can be attained as yet in the chemist's flasks, is observed as a result of biological processes. To mention one example, urine of women after the menopause, or after removal of the ovaries, contains a substance presumably produced by the pituitary gland that has almost pure follicle-stimulating properties. The hypothesis has therefore sprung up that the pituitary gland produces two distinct hormones, usually denoted respectively by the initial letters FSH for "folliclestimulating hormone," and LH for "luteinizing hormone." There is ample evidence that the gonadotrophic substances are of protein nature, and this is sufficient explanation of the fact that as yet, in spite of immense effort, no one has obtained preparations which solely give one or the other effect upon test-animals. The question therefore remains unsettled whether there are two hormones, chemically separable, or one which acts differently under different circumstances; but the hypothesis that there are two has been generally accepted as a working basis for further chemical research and for speculation about the part played by the pituitary gland in the menstrual cycle and in pregnancy.

In the human species, the urine acquires during pregnancy a gonadotrophic potency which appears to depend upon a mixture of properties resembling those of FSH and LH. The same is true for limited periods in the pregnancy of chimpanzees and Rhesus monkeys. Whether the substances producing these effects ("Prolan A" and "Prolan B" respectively) are chemically and biologically identical with FSH and LH, has been debated, and this question, like many others relating to the gonadotrophic hormones, awaits the final purification and identification of the substances. The prolan-complex is undoubtedly produced by the tissues of the placenta.

The blood serum of pregnant mares contains a gonadotrophic substance, believed to be produced by the placenta, which because of some chemical peculiarity does not get into the urine. This substance, known as equine gonadotrophin or PMS (for pregnant mare serum), acts upon test-animals as if it were a mixture of an FSH-like hormone with a small proportion of LH-like material. The serum of pregnant mares has been much used as a source of gonadotrophic hormones by experimenters and drug manufacturers.

A good review of this subject, bringing it up to 1945, will be found in Burrows, Biological Actions of the Sex Hormones, 1945.

Note 12

(page 153, line 9). The coiled arteries. New questions about the theory of menstruation, and particularly about the. role of the coiled arteries, that have arisen since the first writing of this book, are fully discussed in Note 13. At this point, however, it will be well to modify the assumption that the coiling of the arteries is essential to menstruation. In a pending article, a fellow-worker of the author, Dr. Irwin H. Kaiser, shows that the corresponding arteries in certain New World monkeys that undergo at least a rudimentary type of menstruation, are not coiled. Some, moreover, of the current hypotheses about the structure and function of the arteries in women and in Rhesus monkeys, to be mentioned in Note 13, do not depend upon the coiling.

The reader should therefore substitute for the statement in our text that "menstruation is primarily an affair of the coiled arteries" the more cautious and less specific thought that menstruation is primarily dependent upon special peculiarities of the arterial circulation of the endometrium, meanwhile keeping his mind open until this fascinating problem is further elucidated.

Note 13

(page 170, line 21). Current thought about the mechanism of menstruation. The hypotheses set forth in the original edition of this book may still be read profitably, except that the reader should substitute the term "endometrial arteries" for "coiled arteries" because (as explained in Note 12) there is evidence that the coiling is not per se essential to the menstrual process. The whole subject of the cause of menstruation has been actively revived in 1946-194!'7, largely as the result of studies made in Copenhagen by a group of anatomists and pathologists who did not let the German occupation stop their research.

Most of the thinking still involves the idea that the periodic menstrual flow results from some peculiarity or other of the endometrial arteries which makes them dependent upon hormonal support. As already mentioned, a view now somewhat in disfavor held that it is the coiling of these arteries which renders them sensitive to fluctuation of the ovarian hormones. It was conjectured that as the endometrium grows thicker in each cycle under the influence of estrogen, the coiling becomes more intense until the flow of arterial blood is impeded, the capillary circulation is impaired, ischaemia of the endometrium results and is followed by menstrual breakdown. As a variant of this idea, it has been thought that a drop in estrogen occurring toward the end of the cycle causes involution of the endometrium, with a reduction of its thickness and consequent tighter coiling of the arteries. This was supposed to cause damage to the tissues and consequently to bring on menstrual bleeding.

Another totally different supposition is now put forward by the Danish investigators Schlegel, Dalgaard, and Okkels (see, for instance, J. V. Schlegel, "Arteriovenous Anastomoses in the Endometrium in Man," Acta Anatomica, vol. 1, 1945-46). These workers, using very careful methods of injecting the uterine blood vessels, have shown almost beyond any doubt that in the human endometrium there are frequent direct connections (anastomoses) between the terminal arterioles and the venous spaces from which the uterine veins take origin. Some of the blood flowing through the lining of th^ uterus follows the pathway usual in other organs and tissues, through the capillary blood vessels, thus serving the ordinary metabolic functions of the blood. Some of the blood, however (according to these investigators) passes directly through a shunt, as it were, into the veins. Schlegel off^ers a theory of menstruation based on this finding. He conjectures that as the endometrium grows thicker in each cycle under the influence of estrogen, the number of short circuits between the arterial and venous systems increases. The increasing proportion of blood thus shunted must be compensated for by an increased flow through the capillaries also. Such a flow, it is well known, is eff'ected by the estrogenic hormone. The time comes, however, it is thought, when the estrogenic stimulus is not able to produce further capillary flow whereas the shunts still divert much of the blood. The tissues nourished by capillary blood suffer injury and menstruation is thus initiated.

A variation of this hypothesis, suggested by Professor Okkels, involves also a vasoconstrictor substance (cf. Hypothesis 3, page 171).

American workers of the Bartelmez-Daron school, who have not observed arteriovenous anastomoses in their material, obtained chiefly from monkeys and prepared with great care though by methods differing from those of the Danish investigators, are naturally doubtful of hypotheses that depend upon the arteriovenous shunts.

Other possible mechanisms that have been hinted at, but not as yet supported by thorough anatomical demonstration, depend upon supposed peculiarities of the walls of the endometrial arteries, which are indeed somewhat different in microscopic structure from those of other organs. It is thought, at least vaguely, that their general structure requires in some way the support of estrogenic hormones, or that there are special points or regions on the arteries which are sensitive to hormone fluctuations and thus serve as sphincters to shut off arterial flow.

Enough has been said to show that while the relation of the uterine arteries to the menstrual process is still unsolved, the question is being actively studied and we may hope for better knowledge by the next time this book requires revision.

Note 14

(page 172, line 17) . Toxin theory of menstruation. O. W. Smith and George Van S, Smith have modified their conjectures about the cause of the menstrual breakdown of the endometrium. As explained in an article in Clinical Endocrinology^ 1946, vol. 6, they suggest that catabolic changes of the endometrium resulting from reduction of estrogen at the end of the cycle cause the formation of a toxic substance which damages the finer blood vessels and thus brings on the menstrual necrosis and hemorrhage.

Note 15

(page 185, line 34). Amount of progesterone secreted daily in the human. It is now known that by no means half the progesterone that gets into the blood is excreted in the urine as pregnanediol. If a measured amount of progesterone is administered by injection, only about 10 to 15% of it appears as pregnanediol. On the basis of such results G. Van S. Smith and O. W. Smith, Seeger-Jones and Te Linde, and others now estimate that the corpus luteum secretes about 50 milligrams of progesterone per day at the peak of its cyclic activity.

Note 16

(page 194, line 33). Amount of estrogen produced daily in the human. G. Van S. Smith, O. W. Smith, and Sara Schiller, American Journal of Obstetrics and Gynecology, vol. 44, pp. 605-615, 1943, published an estimate based admittedly on a number of unproved assumptions concerning the metabolism of the estrogens. Their result, 0.08 to 0.70 milligrams, averaging 0.33 mg., is not far from that reached by my totally different method of estimation ; my figure, expressed as estrone, is equivalent to 0.30 milligrams.

Note 17

(page 211, line 12). The isolation and identification of prolactin. Two months after these Vanuxem lectures were delivered. White, Bonsnes, and Long of Yale University announced success in the isolation from beef pituitary glands of a crystalline substance of high lactogenic activity. The hormone is a protein of high molecular weight (32,000 or more). Readers with a knowledge of biochemistry will be interested in their account of their own work and that of Lyons and other investigators upon which their efforts were partly based. {Journal of Biological Chemistry, vol. 143, 1942, pp. 447-464).

Note 18

(page 228, last line of footnote). Berthold's article. A translation of the original paper into English, by D. P. Quiring, was printed in the Bulletin of the History of Medicine, Baltimore, vol. xvi, 1944, pp. 399-401.

Note 19

(page 236, line 33). Oral androgen. Androgenic hormones that can be taken by mouth in tablet form have been prepared by chemical synthesis and are on the market.




   Hormones in Human Reproduction (1942): 1 Higher Animals | 2 Human Egg and Organs | 3 Ovary as Timepiece | 4 Hormone of Preparation and Maturity | 5 Hormone for Gestation | 6 Menstrual Cycle | 7 Endocrine Arithmetic | 8 Hormones in Pregnancy | 9 Male Hormone | Appendices
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