Book - The Hormones in Human Reproduction (1942) 8
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Corner GW. The Hormones in Human Reproduction. (1942) Princeton University Press.
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Chapter VIII. The Hormones in Pregnancy
- "Long was I hugg'd close - long and long. Immense have been the preparations for me. Faithful and friendly the arms that have help'd me. Cycles ferried my cradle, rowing and rowing like friendly boatmen. For room to me stars kept aside in their own rings. They sent influences to look after what was to hold me. Before I was born out of my mother generations guided me. My embryo has never been torpid, nothing could overlay it." - Walt Whitman, Song of Myself.
The maintenance of pregnancy is a truly complex affair. A living creature is growing at a tremendous rate inside a hollow chamber, the uterus. This organ must at first tolerate, even support the newcomer. It must grow in size and strength so that its enterprising tenant may not overwhelm it (Fig. 28). All the other muscle-walled organs of the body are built to keep things moving — the heart, the intestines, the bladder for example — and so, ultimately, is the uterus. For nine months, however, it must be kept in check and not allowed to expel the infant prematurely. Then all of a sudden its energies are released and it is called upon to deliver its contents into the world, through the narrow bony canal of the pelvis, with sufficient force and speed on one hand, and sufficient gentleness on the other, to avoid wearing out the mother or crushing the baby. To use a current expression of bewilderment, figure out all that if you can ! Nature, indeed, has figured it out reasonably well ; but when the physiologist attempts to discern the factors of this multifarious process and to see how they are set in motion, timed, and controlled, he finds he has yet a long research ahead of him.
In this book we can do no more than sketch the problems involved. In outline, what has to be worked out is the growth and function of a muscular organ, controlled in part by the nervous system, in part by hormones. The latter are those which come from the ovary, the pituitary and the adrenal, together with the output of a new source, peculiar to pregnancy, the placenta.
The Placenta
Once the embryo is safely lodged in the uterus and has begun to grow, a new era of hormone activity begins. The task of the ovary is not yet over, but its functions are in large part to be taken up, reinforced, and even superseded by a new organ of internal secretion, the placenta. The human placenta is an object of considerable size, as shown in the fine old engraving from Casserius (Plate XX). When fully developed it is about 18 centimeters (7.5 inches) in diameter, and weighs 500 grams (a little more than one pound) on the average. When in place in the uterus, its structure is like nothing else so much as the matted roots of a tree planted in a tub. The roots simulate the villi of the placenta, which carry within their slender strands the finest branches of the blood vessels coming from the infant in the umbilical cord. Through these delicate vessels the blood of the infant circulates in a constant and rapid stream. The tub in which we imagine the tree planted simulates the pool which the embryo has excavated for itself in the wall of the mother's uterus (Fig. 14, p. 58).
Fig. 28. Enlargement of the human uterus during pregnancy. At v, virginal uterus; the large hatched area is the pregnant uterus, at full term, drawn to same scale, approximately % natural size. Adapted from a figure by Stieve.
Through this pool the mother's blood slowly flows, out from the arteries that supply the region and back into the veins, bathing the rootlike villi of the placenta. From the mother's blood to the blood of the embryo, oxygen and dissolved foodstuffs filter through the covering cells of the villi and through the thin walls of the blood vessels that run along within them, just as nutritive substances pass into the roots of a plant from the moist soil in which they grow. The infant sends back carbon dioxide, urea, and other wastes from its tissues, to be filtered out through the placental vessels into the mother's blood, which carries away these wastes to be disposed of with the products of her own metabolism.
The covering cells of the villi are called upon, however, not only to take part in the process of filtering foodstuffs inward and waste products out, but also to produce a whole series of endocrine substances. This important fact is unfortunately masked by a great deal of confusion in our present knowledge. The placenta differs greatly in different species, not only in its structure but also in its endocrine activities. Statements which are true of one species may not apply at all in others. For this reason our discussion will be limited to the human species (except as specifically stated) and even then we shall be restrained by a certain amount of uncertainty. To begin with, the placenta begins very early in pregnancy to elaborate a hormone of its own, having profound gonadotrophic properties (that is, power to stimulate activity of the ovary and the testes) much like that of the pituitary gonadotrophic hormones.[1] This activity begins, indeed, before we can properly speak of the placenta, for the hormone in question is made by the cells (i.e. the trophoblast) covering the early villous processes that surround the embryo, as soon as they begin to grow. Knowledge of this subject goes back to 1928, when Aschheim and Zondek, then of Berlin, found that during pregnancy the human urine contains something that has a powerfully stimulating effect on the ovaries of young mice and rats. This provided the basis for the now famous AschheimZondek test for pregnancy. The urine of a pregnant woman, injected into an infantile mouse or rat, produces prompt and characteristic signs of activity in the ovarian follicles. An even quicker test for pregnancy is provided by a modification of this procedure, introduced by Maurice Friedman, an American investigator. In the Friedman test the urine, either raw or partially purified by precipitation with alcohol, is injected into the ear vein of a rabbit. If the patient is pregnant, the rabbit ovulates about 10 hours after the injection. This hormone test for pregnancy is (in both variations) probably more nearly infallible than any other biological test used by physicians, for when properly performed it is accurate in better than 98 per cent of all cases.
The gonadotrophic hormone complex of the urine can also be extracted from the placenta and in all probability is made there. George O. Gey, a tissue culture expert of Baltimore, recently showed that placental tissue growing in his test tubes | was able to produce a gonadotrophic substance. Chemically the urinary gonadotrophic material is protein, like the gonadotrophic hormone that is produced in the pituitary gland, and indeed it is so much like the latter that it was for a time considered to be identical with it, but clear differences between the two substances have been observed, as evidenced by the details of their effects on animals of various species. The placental gonadotrophic hormone complex appears in the urine in the first month of pregnancy, in sufficient amount to give a positive Aschheim-Zondek or Friedman test. It is present throughout pregnancy, but reaches its greatest amount in the second month and falls off rapidly thereafter. In the Rhesus monkey it is found only between the 18th and the 25 th day. In the blood of the pregnant mare there is a gonadotrophic hormone which also has a stimulating effect on the ovaries of test animals, such as rats, differing considerably, however, in detail. This does not get into the urine in significant amounts, which means that it must be different chemically from the human hormone of similar action.
We do not know why these substances can be found in some species of animals and not in others, nor do we know what function they perform in pregnancy. The whole series of pituitary and pituitary-like hormones has been extremely difficult to investigate chemically because the substances are proteins and they defy purification. The ovaries of the rat and the rabbit can distinguish them better than the chemist. For the present we must content ourselves with being grateful for the pregnancy test and await the day when these troublesome substances yield themselves to chemical isolation.
As mentioned previously (Chapter IV) the urine of pregnant women contains relatively large amounts of estrogenic substances, which increase as pregnancy advances and disappear after parturition. These substances have been found in the urine of several other species during pregnancy. The human placenta also contains large amounts of estrogenic hormones, chiefly estriol, and is almost certainly the source of those which appear in the urine. As mentioned in Chapter IV, when the ovaries are removed during pregnancy, estrogens continue to be excreted in the urine, a fact which proves that some other source exists, and this can hardly be anything else than the placenta. A similar situation, produced experimentally in the monkey, has been studied very carefully and reported by R. L. Dorfman and Gertrude Van Wagenen of Yale Medical School.
There are several possible ways in which the production of estrogens by the placenta may be useful. It has been suggested that these hormones are needed, in larger amounts than the ovaries can provide (a) to promote the growth of the uterus which occurs during pregnancy; (b) to cause growth of the mammary glands to get them ready for the production of milk; (c) to set up contractions of the uterus when the time comes for parturition ; (d) to cause persistence of the corpus luteum. These possibilities will be discussed again later in this chapter.
As regards progesterone in the placenta, it has already been pointed out that in some animals the corpora lutea are indispensable until the end of pregnancy. In the rat and the cow, for example, the ovaries cannot be removed at any time without causing loss of the embryos, and the corpora lutea appear to be functional until almost the end of gestation. In the human species, on the other hand, the ovaries can be removed without affecting the survival and birth of the infant, as early as the third month of pregnancy. After such an operation pregnanediol has been found in the urine, an indication that progesterone has continued to be produced somewhere. Naturally the placenta has been suspected, and assays have yielded small amounts of progesterone or a substance of closely similar kind.
Action of the Hormones in Pregnancy
We can do hardly more here than sketch what is known about the multifarious interactions of the hormones in pregnancy. Readers who wish to follow the subject in detail may consult the excellent book on this subject by my colleague S. R. M. Reynolds.[2] In the first place, the two ovarian hormones contribute to the growth of the uterus. Growth of the muscular wall is known to involve (as one might well expect) first an increase of the number of the muscle cells, and then an increase of the size of the individual cells. In the human uterus the measurements of the German histologist Stieve indicate that the muscle cells are 17 to 40 times larger at the end of pregnancy than in the empty uterus. Other elements of the uterine wall, namely the connective tissue, blood vessels, and nerves, also increase in amount. In this process the estrogenic hormone contributes its general growth-promoting effect, which it exerts by augmenting the blood flow through the tissues of the uterus. Under its influence there is some increase in number of the uterine cells. Progesterone in turn causes a decided wave of cell division in the muscle, and then within a few days at the beginning of pregnancy there is a large increase in the number of muscle cells. Subsequent growth of the individual cells, and consequently of the whole wall of the uterus, comes about as the result of stretching by the growing embryo. As the uterus is distended it grows in thickness and strength; if this were not so, the infant would soon rupture the walls that confine it. Everyone is, of course, familiar with the fact that working a muscle makes it grow, and this is no less true of the involuntary muscles of the internal organs than of the skeletal muscle; but like most other familiar responses of the body, we often take it for granted without realizing how little we know how it comes about. Why the uterine muscle grows when that organ is distended is a large question of general physiology, beyond the scope of this book. Reynolds has shown that if he distends the rabbit's uterus by introducing pellets of wax, it will grow in thickness just as it does in pregnancy. By this means he has been able to test the eff*ects of the ovarian hormones upon the growth-response to distention, and has found (among many other interesting facts) that treatment with estrogenic hormone cuts down this response. This hormone, then, which at first helps start the growth of the pregnant uterus, afterward helps to control it. In human pregnancy we know there is plenty of estrogen available in the later months; in all probability this serves to keep the growth of the uterus from going too far. With this hint that the interplay of the hormones is indeed complex, we had better leave the subject to the specialists for further study.
Finally the time comes when gestation can go on no longer. The uterus, overburdened by its rapidly growing tenant, must deliver itself. Degenerative changes begin in the placenta, the nourishment of the infant is thereby impaired, and the uterus commences its efforts to expel the child. This it accomplishes by means of strong contractions, efficiently timed and coordinated so that the infant is pushed toward the outlet of the uterus. The uterine orifice, and afterward the vaginal canal, are stretched open to allow passage of the infant, while the rest of the uterus contracts to provide the necessary force. There is no simple explanation of the onset of labor. Many physicians and biologists have tried to discover some simple reason why at a particular time — 9 months in the human, 2 years in the elephant, 21 days in the mouse, or whenever, according to the species, the fated hour arrives — the act of parturition begins. It has been thought, for example, that the uterus is at last simply stretched too far and is thereby irritated into contracting again; or that the breakdown of the placenta constitutes a stimulus to the uterine muscle ; or that some chemical substance from elsewhere in the body sets the muscle into action. When it was discovered that estrogenic hormones stimulate the involuntary muscle of the uterus, and that progesterone tends to relax it, an attractive theory of the cause of labor at once suggested itself. We need only suppose that when the end of gestation draws near, the production of progesterone goes down, and estrogenic hormone is thereby allowed to build up contractions of the uterine muscle. This hypothesis is however much too simple, as Reynolds points out in the book cited above. For one thing, the contractions of the uterus in labor are very different in their timing and coordination from those of the nonpregnant uterus. The fact is that the uterus at the end of pregnancy is operated by a very elaborately organized set of adjustments.
The proportion of the infant to the space it occupies; the strength of the uterine wall and the pressure it exerts upon its contents; the rate of blood flow through the uterus; the sensitivity of its muscle and nerves ; the balance of the hormones that affect it; the nutrition of the infant and the placenta — all these factors (and others beside them, for all we know) are balanced one against the other and when the crisis comes they are all involved at once. The physiologist who looks for one specific cause of the onset of labor is up against the same kind of problem as the economist who tries to find one single cause for a stock market crash or to pin down a nationwide problem of unemployment to one specific factor. When dealing with such complex affairs as those of a nation or a pregnancy the investigator cannot isolate one factor at a time and study it singly. He has to unravel a whole system of balanced forces. In the problem we are considering, the hormones are certainly to be numbered among the most important factors, but it is scarcely safe at present to say more,
Lactation
When the mother's body has completed its provision of shelter and nourishment for the child by means of the hormones and has seen him safely into the world, it has yet another service to render on his behalf — namely that the breast for which he will so promptly cry is ready to supply him with milk.
The recent discovery of a specific hormone for lactation, in the pituitary gland, was a great surprise. It involved a simple little piece of scientific logic which the reader may enjoy after the preceding complexities of this chapter. We had better clear the way for this story, however, by recalling to mind the earlier history of the mammary gland. When a girl or a young animal reaches sexual maturity, the mammary glands are brought from the immature state to the adult condition, by action of the estrogenic hormone. Nothing is more striking than to watch the growth of the mammary glands in a young animal receiving estrogen. Each gland is a system of branching channels lined by cells derived from the outer layer of the skin (epidermis). Long before birth these ducts begin to grow from the nipples and to spread out around them in a little circle under the skin. At first the channels are few and short, and only slightly branched (Fig. 29, A). Under the action of the estrogenic hormone they branch extensively and spread to adult dimensions (as indicated in the diagram, Fig. 29, B). In the girl at puberty this is, of course, a gradual change, but in an experimental animal under hormone treatment it can be produced quite rapidly. The nipples quadruple in size in a few days, and the ducts push outward in a widening circle. In pregnancy a much greater development occurs. The branches of the duct system develop extensive terminal twigs ending in secretory alveoli (Fig. 29, C, B). These become more numerous as pregnancy advances. Finally, globules of milk-fat accumulate in the cells of the alveoli (Fig. 29, E). The actual flow of milk in quantity does not begin, however, until after parturition.
From the time it was first conjectured that the corpus luteum is a gland of internal secretion, until quite recently, it was supposed that this particular endocrine organ is responsible for the growth of the mammary gland in pregnancy and the secretion of milk. On the face of it, there could hardly be a more plausible conjecture, for the growth of the mammary gland closely follows the appearance of the corpus luteum, and is so obviously a part of the general preparation for the infant that it seems very logically to go with the other functions that the ovary exerts during pregnancy.
Fig. 29. Diagrams illustrating the development of the mammary gland as seen in laboratory animals. A, mammary gland of immature animal, consisting of simple ducts radiating from the nipple. B, small area of A enlarged to show adult virginal gland. The action of estrogenic hormone has produced extensive growth and branching of the ducts. C, small part of B enlarged again to show the effect of pregnancy; there has been a great development of duct twigs with terminal alveoli. D, terminal alveoli enlarged to show their cell-structure. E, secretion of milk globules by the cells of the alveoli. Based on a figure by C. W. Turner In Sex and Internal Secretions.
If this is true, however, why does not the corpus luteum produce mammary growth and even lactation not only in pregnancy but in each ovarian cycle.? To this query A. S. Parkes of London in 1929 offered the tentative reply that perhaps in the ordinary cycle, in which the corpus luteum lasts but two weeks, there is not time to build up the mammary gland sufficiently. He therefore ingeniously proposed to apply the discovery, then quite new, that the corpora lutea can be made to persist for weeks by injection of anterior pituitary extract. He tried this experiment in rabbits, by mating them to males rendered infertile by having their seminal ducts blocked, so that these females ovulated but did not become pregnant. The corpora lutea, which under these circumstances would normally degenerate after about 14 days, were made to persist by the pituitary hormones. The expectations of the experimenter were brilliantly fulfilled by the occurrence of mammary growth and lactation. When the report of these experiments reached the United States, we had in our University of Rochester laboratory a fair amount of the then new corpus luteum hormone in crude form (progestin) and took the obvious step of trying to produce mammary growth and lactation with the progestin alone. To my surprise we got no lactation and no marked growth of the mammary gland. From this failure, however, an important deduction could be made. Parkes had subjected his rabbits to the action of two hormones (pituitary and corpus luteum) ; I had given only the latter. He obtained lactation, I did not. Subtracting my procedure from his, it looked as if the anterior pituitary hormone was the only necessary factor. We made up a flask of pituitary extract from sheep and injected it into six adult castrated virgin female rabbits. In 3 days milk began to drip from their nipples ; in 10 days the mammary glands had thickened and spread all over the chest and belly as in advanced pregnancy and when we milked them the milk spurted across the room.
I thought at first that this discovery of the lactogenic potency of the anterior lobe of the pituitary was completely new, but study of the scientific journals revealed that a few months previously two Alsatians, Strieker and Grueter, working in Strasbourg in the laboratory of Paul Bouin, had done exactly the same experiment with the same result. By what process of logic they were led to try it was not narrated in their report.
The extracts were very crude and we set out to purify them. One of the large drug houses provided more extract by the quart and one of their research staff started to work out the chemical separations, but be and I found only that we were dealing with a protein, after which we simply got lost in this most difficult field of biological chemistry. Meanwhile my genial and versatile friend Oscar Riddle of the Carnegie Institution (Department of Genetics, at Cold Spring Harbor), ably assisted by his colleague R. W. Bates, applied his allround knowledge of tissue chemistry to the task and succeeded in purifying the hormone to a considerable degree. He called it prolactin. The complete chemical isolation and chemical identification of this important substance is now a problem for the most advanced special experts in the chemistry of proteins (Appendix H, note 17).
There is a queer sequel of this discovery of prolactin, which opens a vista of the long past origin of the hormones in evolutionary history. This story has to do with pigeons' milk. Not that pigeons have mammary glands ; but females of the genus actually secrete into their crops a kind of milky secretion which they regurgitate and feed to their nestlings. This crop-milk is produced by special glands in the lining of the crop. Dr. Riddle knows all about pigeons ; he has been studying their physiology for years and had a fine collection of them at Cold Spring Harbor. Impressed by the parallelism between the formation of crop-milk and mammalian lactation, he administered his extract of beef pituitaries to some of his female pigeons and got proliferation of the crop glands just as if they were mammary glands. This reaction is so easy to produce that it is now the standard test for prolactin. The strangest part is, however, yet to be told. The eggs of the amphibians (frogs, toads, and salamanders for example) are laid in the water and the embryos have the benefit neither of nest and crop-milk nor of uterus and mammary gland. When the eggs are shed by the mother, however, they are protected by an envelope of jelly, laid on in the mother's oviduct. An Argentine physician, already mentioned in this work. Dr. In^s de Allende of Cordoba, has discovered that a hormone like that found in extracts of beef pituitary glands is responsible for the secretion of the protective jelly of the eggs of toads. She elicited this function by inserting pieces of toad or beef pituitary gland under the skin of her toads, thus increasing the available amount of pituitary hormones; and in a few cases she could even elicit it by injecting Riddle's prolactin.
Here, then, are three particular means of provision for the newborn infant, occurring in three widely different branches of the animal kingdom, and adapted to offspring living under very dissimilar circumstances, yet all these secretions are controlled by the pituitary gland and can be induced by extracts of beef pituitaries. The embryologist perceives a further remarkable feature of this story. The mammary gland, he knows, is derived from the outer of the three fundamental tissue layers of the embryo, the ectoderm'^ the crop glands of the pigeon are derived from the inner layer, the endoderm ; and the secretory lining of the toad's oviduct is derived from the middle layer, the mesoderm. These three tissues from which the pituitary gland elicits reactions of such similar usefulness, are about as widely different in their position in the body, and in their embryological history, as they can possibly be, but when in the evolution of toad, bird, and mammal there was need to call upon them to foster the fledglings of their kind, the pituitary gland took control in each case.
Has the corpus luteum, then, no role whatever in the processes leading to lactation, and can the pituitary extracts induce lactation in a mammary gland prepared only by estrogenic hormone.[3] My rabbits seemed to indicate that this is true, but Strieker and Grueter declared that their pituitary extracts were not successful unless there had been corpora lutea in the ovaries at some time during recent months ; in other words, the pituitary lactogenic hormone appeared able only to jact upon a mammary gland sensitized by progesterone. This difference in the findings led to a great deal of subsequent work by various investigators, well summarized by C. W. Turner of Missouri, himself one of the leaders in this work, in Sex and Internal Secretions} It now appears that the second of the three more or less distinct stages of growth and function of the mammary gland, already referred to and illustrated (Fig. 29), involves somewhat different responses to the hormones in different species. The first stage, that of preliminary growth of the duct system to the adult virginal state, occurs under the influence of estrogenic hormone as already described. In the second stage, the ends of the ducts proliferate and branch into numerous terminal alveoli. This stage in many animals requires the action of progesterone ; in a few species (of which the guinea pig is an example) progesterone is not needed at all and the proliferation can be completely induced by the estrogens ; in some other species growth of the alveoli is at least facilitated or speeded up by progesterone, though not actually dependent upon that hormone. Judging from various observations which have been reported on monkeys, the primate mammary gland is among this intermediate group. Whether this is also true of the human we do not know at present. The third stage, that of secretion of milk, is brought about by the lactogenic hormone of the pituitary. It is a striking evidence of the potency of these hormones to induce lactation that the rudimentary mammary glands of male animals can readily be made to lactate by a suitable course of treatment with the estrogenprolactin or estrin-progesterone-prolactin sequence.
We have yet to discover how the pituitary gland is stimulated to exert its lactogenic effect during pregnancy. The reason the flow of milk does not begin until just after parturition, and then begins suddenly, is that lactation is inhibited by the estrogenic hormone of the placenta. Once the placenta is out of the way, the flow of milk is released.
The induction of lactation in pregnancy is thus another example of those remarkable integrative linkages among the various parts of the reproductive system by means of hormones, by which shelter, warmth, and nourishment are provided for the mammalian egg while it is incubated within the body and at the breast of its mother. By such extraordinary means as this have the children of men, latest of a long series of creatures to haunt the earth, been protected from isolation and danger in their earliest days, and given time to grow for nine months before being exposed to the rigors of the outer world. This privilege of uterogestation, which would be impossible without the ovarian and placental hormones, gives an incalculable advantage to mankind and the other mammals in the struggle for superiority in the animal kingdom.
- ↑ For the sake of clearness, it seems best to refer to the gonadotrophic material in the singular, i.e. "a hormone," but actually it seems to be a hormone complex comprising two substances, one of which tends to stimulate growth of the follicles, the other to convert the follicles into corpora lutea (Appendix II, note 11).
- ↑ Physiology of the Uterus, with Clinical Correlations, by Samuel R. M. Reynolds, New York, 1939.
- ↑ Sex and Internal Secretions, edited by Edgar Allen, Baltimore, 2d ed., 1939; Chapter XI, The Mammary Glands, by C. W. Turner.
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