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==Chapter VIII The Hormones in Pregnancy==
{{Corner1942 pregnancyhormone header}}
=Chapter VIII. The Hormones in Pregnancy=


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.
:"''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 PLACENTA


Once the embryo is safely lodged in the uterus and has begun to grow, a new era of hormone activity begins. The
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.


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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 HORMONES IN HUMAN REPRODUCTION
==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.


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).


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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.




THE HORMONES IN PREGNANCY


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.
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.^ 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


1 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).
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.<ref>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).</ref> 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.


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THE HORMONES IN HUMAN REPRODUCTION
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.


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
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.


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THE HORMONES IN PREGNANCY
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.
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
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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.


THE HORMONES IN HUMAN REPRODUCTION
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.
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
==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.^ 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
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.<ref>Physiology of the Uterus, with Clinical Correlations, by Samuel R. M. Reynolds, New York, 1939.</ref> 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.


2 Physiology of the Uterus, with Clinical Correlations, by Samuel R. M. Reynolds, New York, 1939.
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THE HORMONES IN PREGNANCY
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,
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THE HORMONES IN HUMAN REPRODUCTION
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.
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.


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THE HORMONES IN PREGNANCY


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,
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
==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.
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 con { 207 }




THE HORMONES IN HUMAN REPRODUCTION
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.


dition, 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.
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.
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
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THE HORMONES IN PREGNANCY




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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
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.


{ 209 }
THE HORMONES IN HUMAN REPRODUCTION
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.
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


i 210 }
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).




THE HORMONES IN PREGNANCY
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.


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
{ sii }
THE HORMONES IN HUMAN REPRODUCTION
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.
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.'* 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


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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.<ref>Sex and Internal Secretions, edited by Edgar Allen, Baltimore, 2d ed., 1939; Chapter XI, The Mammary Glands, by C. W. Turner.</ref> 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.


THE HORMONES IN PREGNANCY
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.
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.


8 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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THE HORMONES IN HUMAN REPRODUCTION


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.
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.




i
{ IBU)
THE MALE HORMONE
'She \^Nature'\ spawneth men as mallows fresh, Hero and maiden, flesh of her flesh; She drugs her water and her wheat With the flavors she finds meet. And gives them what to drink and eat; And having thus their bread and growth. They do her bidding, nothing loath."
Ralph Waldo Emerson, Nature II.
==Chapter IX The Male Hormone==
THE male sex glands (testes) of man and the other mammals, like the ovaries, perform a double task. They exist primarily, of course, to produce the male germ cells. In primitive aquatic animals this is all they need to do. The Hydra, for example, shown in Plate II, C, in the act of discharging its sperm cells directly into the v/ater, has fulfilled its reproductive task for the season, and its empty testes are of no more consequence than a spent skyrocket. In mammals, however, things are not so simple. There are other needs that can be fulfilled only by the coordination of various parts of the body by means of a hormone. Not only must the sperm cells be formed and ripened ; they must also be stored until they are needed in mating. What is more, they must be stored in a most particular way, immersed in a watery environment, for the mammals have never fully shaken off their ancient adaptation to the sea. They spend their lives on land, but when the time comes to reproduce their kind, their spawning requires salt water — not indeed the actual sea, but the internal fluids of the generative organs. The egg ripens in the fluid of the Graafian follicle. The sperm cells accomplish their tortuous journey to the Qgg by swimming, and the offspring of all the mammals spend the long term of gestation in a submarine environment. You and I cannot remember our ancestral life in the water, nor the nine months we ourselves lived beneath the chorio-amniotic sea, but our tissues recall it ; the skin, the kidneys and the adrenal glands working to hold sufficient water and just enough salt, the testes providing through their accessory organs those fluids in which the sperm cells may be effectually launched upon the sea of life.
In another way also the endocrine function of the testis becomes necessary. The higher animals lead complicated lives.
{ 217 }
THE HORMONES IN HUMAN REPRODUCTION
They wage a varied battle for existence and are swayed by many circumstances. Perpetuation of the race amid such distractions requires especially active maintenance of sexual vigor and the urge to mate. This too becomes a function of the testis as an organ of generation.
THE MALE REPRODUCTIVE ORGANS
The testis. To follow the story in detail we must first review the anatomy of the testis and the associated male organs of reproduction. The diagram (Fig. 30) will serve to orient us. The two testes lie in their pouch of skin (scrotum) . They are objects of ovoid shape, about the size of walnuts, that is to say 4.5 x 3 centimeters (2x1% inches) in diameter. Within these small rounded bodies the business of sperm cell production is carried on inside an extraordinary system of tubular canals. The testis, in fact, consists essentially of many hundred small tubules, called seminiferous tubules, each about 30 to 70 centimeters (1 to 2 feet) in length and about as large in diameter as a strand of sewing silk. These tubules are coiled very tightly in the small space available, and thus when we look through the microscope at a section of the testis, we see countless sections of the individual tubules, cut in every possible direction (Plate XXIII, A). How they actually run, and how they are connected, was for a long time one of the most difficult problems of microscopic anatomy. We should get a similar picture if we took a thoroughly tangled ball of twine and cut a section through it with a sharp knife. Nobody could possibly tell from such a cut whether the ball of twine contained one long piece of twine, or several shorter ones, or how they were joined together. Likewise a section of the testis cannot tell us anything about the course of the seminiferous tubules. For a century microscopists applied their various technical tricks to this problem, including the making of magnified models from serial sections, but with only imperfect success, owing to the difficulty and laboriousness of following
{ 218 }
1.#
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Plate XXIII. ^, portion of human testis and epididymis, magnified 10 times. The large circles and loops at the right are sections of the coiled tube of the epididymis; the smaller tubules filling the left two-thirds of the picture are the seminiferous tubules of the testis. B, area of the same testis magnified 200 times, showing 5 clumps of interstitial cells between the tubules. Photographs from preparation lent by Joseph Gillman through I. Gersh.
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Plate XXIV. A, portion of seminiferous tubule of rat, showing formation sperm cells. Note the peculiar hook- or halberd-shaped heads and long tails of tl rat's sperm cells (form of human sperm cells shown in Fig. 7). Magnified 600 time From specimen lent by K. E. Mason. B, portion of seminifierous tubule of unde scended (cryptorchid) testis of pig. Note that sperm cell formation is totally absent, the tubule being lined by ill-defined cells (epithelial cells). The interstitij cells are, however, well preserved. Magnified about 600 times.
THE MALE HORMONE
these minute and lengthy canals. Finally in 1913 the problem was cleverly solved by the late Professor Carl Huber of the University of Michigan, who worked out a method of soften
Fio. 30. The human male reproductive system. From Attaining Manhood, by George W. Corner, by courtesy of Harper and Brothers.
{ 219 }
THE HORMONES IN HUMAN REPRODUCTION
ing the testis with acid and then, with incredible patience and dexterity, dissected out complete tubules under the microscope with fine needles and mounted them, without breakage, on glass slides. He found that they are arranged in loops or arches, all opening into a network of channels at the hilum a of the testis, whence they are drained off by a dozen larger | channels into the epididymis. All these facts have been depicted in Fig. 31.
In cross section under high magnification (Plate XXIV, A ) the tubules are seen to be lined by several layers of cells. The outermost layer (i.e. that farthest from the central channel of the tubule) is made up of large clear cells. As these divide to form the next and succeeding layers, the cells become smaller. Finally little is left except the nucleus, and even this becomes more compact. A long tail-like process grows out of the rapidly shrinking cell. This figure represents the rat's sperm cells with their hook or halberd-shaped heads. The completed human sperm cell is shown in Fig. 7. It has a total length, including the tail, of about 60 microns or 1/400 inch. The head is about 5 microns long by 3 wide. The sperm cell is therefore by far the smallest cell in the body. An idea of its relative dimensions may be gained by comparing it with the printed period at the end of this sentence. If the sperm heads were laid like a pavement, one layer deep, on such a dot, it would take about 2,500 of them to cover it. About 12 eg^ cells could be placed on such an area.
As the sperm cells are formed, little clumps of them cling to supporting cells in the lining of the tubules until finally they drop off and are carried along the channel toward the seminal ducts. In animals that breed at all seasons of the year, for instance man, rat, rabbit and guinea pig, sperm production goes on continuously, passing in waves along the tubules, so that sperm cells are always available. Many wild species, however, have distinct breeding seasons once a year, and in these there is a cycle of testicular activity. In the seasons of inactivity spermatogenesis ceases and the testis diminishes in size.
Fig. 31. Arrangement of the tubules of the testis, the epididymis, and the seminal duct. Adapted from Spalteholz and Huber. From Attaining Manhood, by George W. Corner, by courtesy of Harper anl Brothers.
The testis, like the ovary, is under control of the pituitary gonadotrophic hormones. One of the most striking results of the brilliant campaign of investigation of the pituitary led by Philip E. Smith, now of Columbia University, has been the discovery (1927) that removal of the pituitary gland from an adult male causes degeneration of the testis, and in an immature male prevents the development of sperm cell formation. The implantation of bits of pituitary gland or the injection of pituitary extracts will substitute for the missing organ and prevent degeneration of the testis. In some species, but not in others, success has been attained in starting sperm formation in immature animals by injecting pituitary extracts.
Another remarkable discovery about spermatogenesis was announced by Carl R. Moore (University of Chicago) in 1924, namely, that the mammalian testis cannot form sperm cells unless it is subjected to a temperature slightly lower than that of the interior of the body.^ In its normal place in the scrotal sac the testis is under temperature conditions exactly suited to its function. It has long been known that a man with undescended testicles is not fertile, and horse breeders are well aware that the same is true of cryptorchid stallions. They often call upon veterinary surgeons to bring down the testes of colts by operation. Moore's investigations have given us the reason for this sterility. In man descent of the testes normally occurs before birth. The sex glands are formed in the abdominal cavity near the lower pole of the kidneys, but they gradually move downward (or as some embryologists prefer to say, the body grows upward past the testes) until they have fully descended and have occupied their permanent place in the scrotum. Just why this elaborate transfer of the testes takes place, seemingly leaving them less protected than if they remained in the abdominal cavity, as in lower vertebrate animals, has never been satisfactorily explained. One can only guess that when the process of evolution of the warm-blooded condition was accomplished, Nature discovered (so to speak) that after all the testes could not stand the temperature at which she had stabilized the mammals, and had to get them to a cooler place; but any such conjecture seems to put Nature (or whatever you choose to call the forces that guide evolution) in a position like that of tariff legislators, chess players and others who find that one change in a complicated situation may set off unexpected changes elsewhere. At any rate, descent of the testes is a deep-seated phenomenon that has become essential to fertility. The inside of the scrotum is several degrees cooler than the abdominal cavity, because the scrotal sac has thin walls and no insulating layer of subcutaneous fat, but numerous sweat glands by which it loses heat. Moore found that if he put the testis of a guinea pig or other animal back in the abdominal cavity (preserving its blood supply) and stitched it there, the seminiferous tubules became disorganized within a week, but recovered if he brought them down again before the damage had become permanent. He took also a fertile ram and wrapped its scrotum in woolen coverings so that the testes were brought to the temperature of the rest of the body. This too caused cessation of sperm production. Actual direct heating of the testis has a similar effect. A single exposure of the guinea pig's testis for 15 minutes to a temperature 6 degrees above that of the interior of the body causes degeneration of the seminiferous tubules. It is known that in man high fevers are followed by temporary loss of spermatozoa.
1 For a full account of this subject, see Sex and Internal Secretions, edited by Edgar Allen, 2d ed., Baltimore, 1939; Chapter VII, "Biology of the Testes," by Carl R. Moore.
Descent of the testis into the scrotum is part of the general pattern of the development of the sex gland and is therefore subject to control by the pituitary and pituitarylike hormones. It has been known for about 10 years that gonadotropic hormones from pregnancy urine can be used for the treatment of non-descent of the testis in boys. It does not always succeed, for adhesions and other obstacles may interfere; therefore the treatment must be used only in selected cases after thorough study. When the hormone fails, surgical methods are usually still available.
Interstitial cells. In the angular spaces between the tubules the microscope reveals little clumps of relatively large cells not in any way connected with the sperm-forming cells (Plate XXIII, B), Although there are only a few cells at any one point, there are so many clumps that the total mass of the interstitial cells adds up to a significant proportion of the whole testis. Some writers call the totality of these cells "the interstitial gland." There is an ample network of capillary blood vessels among these cell clumps. The arrangement is obviously like that seen in the glands of internal secretion; and it is in fact very probable that this is the source of the testicular hormone. We cannot however be sure that the hormone is not made by the cells of the seminiferous tubules, as will be discussed later.
The genital duct system. When the sperm cells have reached completion in the testis, they are perfectly formed but inactive. Freed from their parent cells, they are swept passively along the tubules into the larger ducts that drain the tubule system. If the sperm cells were discharged from the body in this nonmotile state they could not fulfill their task of reaching and fertilizing the egg cell. They require a further period of ripening and conditioning until they become fully motile and potent. Furthermore the seminal fluid in which they are to be carried must be made and added to them, bringing suitable substances for their nourishment and stimulation.
These needs are served by a complex system of ducts and accessory glandular structures. The dozen or more ducts that leave the testis all drain into a single tube about 7 meters (21 feet) long, which is tightly coiled, as shown in Fig. 31, into a dense mass, the epididymis, which lies upon the testis. This coiled duct is lined by special secretory cells and is believed to function as a storage place for sperm cells, which take many days to be carried through its whole length. During this journey they have time to mature. If one examines under the microscope sperm cells taken from the epididymis of a freshly killed animal, they are found to be in active motion, whereas those taken from the testis are motionless. There has been a good deal of discussion, not yet settled, as to whether the activation of the sperm cells is brought about by stimulatory substances secreted by the cells lining the tube of the epididymis, or merely by the process of maturing. Regardless of this question, it is at least certain that the epididymis is a favorable place for the sperm cells, for when experimenters have tied off its tube in two places, leaving sperm cells trapped between the ligatures, the cells have been found to remain active for two weeks or more.
Emerging from its coiling in the epididymis, the seminal canal becomes less tortuous and finally runs directly upward under the skin toward the groin, as shown in Fig. 30. This part of the system is called the seminal duct or vas deferens. The two ducts (one from each testis), pass over the front of the pelvic bones to enter the interior of the pelvis. Proceeding down the side and rear of the pelvis the two ducts approach each other under the urinary bladder. Before they unite each of them gives rise to a small saccular offshoot or branch, the seminal vesicle. These vesicles are clubshaped hollow structures, really side branches of the seminal duct. They are each about 10 centimeters (4 inches) long, but folded to half that length as they lie in place. They are glands of external secretion, producing in their cavities a clear gelatinous substance which becomes part of the seminal fluid. There is an old notion, hardly yet cleared out of the medical textbooks, that the seminal vesicles are reservoirs for sperm cells, but the fact is that sperm cells are not normally found in them.
The whole course of each seminal duct from epididymis to their junction, is about 30 centimeters (1 foot) long. As shown in Fig. 30, the two ducts unite just below the bladder and enter the urinary channel, the urethra^ just after it makes its exit from the urinary bladder. The combined seminal and urinary channel then passes through the prostate gland and enters the penis.
The prostate gland. To most people the name of the prostate gland probably conveys no clear impression, but only a vague and slightly ominous suggestion of something one hardly speaks of unless it makes trouble. Years ago Mr. Henry Mencken, when a columnist on the Baltimore Sun^ wrote an amusing article on the relative respectability of the human organs. The heart and lungs, he said, are perfectly respectable, the liver not quite, the spleen dubious and the kidneys definitely vulgar. In those days the prostate gland was so far below the standard of respectability that it could not even have been mentioned in the newspaper. Possibly the fact that its prosaic name, from the Greek prostates ("standing before" the urinary bladder), is often confused with the word "prostrate" adds to its flavor of indignity.
This unjustly disparaged organ is actually a gland of external secretion. It consists of 15 to 30 branched tubular glands, imbedded in connective tissue and muscle, forming a round mass 20 grams (2/3 ounce) in weight and almost completely surrounding the urethra just below the urinary bladder. The branching tubules of the prostate gland deliver a special secretion to the spermatic fluid, about which we know very little except that it is favorable to the activity and function of the sperm cells.
The various portions of the duct system and accessory glands are connected through the autonomic nerves so that all of them contribute to the seminal fluid when it is ejaculated at the climax of sexual excitement.
The prostate gland is one of those organs which carry on their useful functions in complete silence, never making known their presence or their action as long as they are in good working order ; but when something goes wrong with one of them it suddenly becomes the focal point of the universe for the sufferer. Its bad reputation as a source of trouble in elderly men is due to the fact that for some obscure reason, probably of endocrine nature, the gland tends to enlarge in men past 50. Situated as it is around the urinary channel (see Fig. 80), and enveloped in a heavy capsule, which prevents it from swelling outward, any marked enlargement of the prostate inevitably blocks the outflow of urine, with serious consequences. The hope that prostatic enlargement may (when we know enough about it) be brought under control by treatment with hormones, lies temptingly before the investigators and may some day be realized.
Secondary sex characters. Before we can discuss the hormone of the testis we must take account of certain other matters that form part of the pattern of sex. Primarily a male animal differs from the female, or a man from a woman, because the one has in all his cells the chromosomes for maleness, the other the chromosomes for femaleness. One therefore develops testes, the other ovaries. The sex glands then begin, even in the early embryo, to call forth the secondary sex characters of their respective sexes. When the individual reaches the age of puberty these characters become prominent. In most mammals the males are larger, and possess heavier, rougher skeletons and stronger muscles. The shape of the pelvis, and to a lesser extent that of the skull and the other bones, is different in the two sexes. In humans the anatomy of the larynx is different and therefore the voice becomes either male or female. The distribution and growth of the hair are different. One sex has well developed mammary glands, the other only rudiments.
In the various divisions of the animal kingdom there is a vast array of secondary sex differences. The tail of the peacock, the antlers of the stag, the beard and the smell of the billy goat, are evidences of what Nature can do in this way. The subject would fill a large book.^ Perhaps the most familiar of all, the comb of Chanticleer, has been seized upon by the experimenters (as we shall see) and has been made to tell us, more than any other one sign, just how the hormones control the secondary sex characters.
THE HORMONE OF THE TESTIS
People have known since prehistoric times that castration of men and domestic animals suppresses the development of secondary sexual characters and causes atrophy of the accessory male sex organs, such as the seminal vesicles and prostate gland. The gelding of stallions, the castration of male calves to make steers, of cockerels to produce capons, and even of boys for the production of eunuchs, has long been practiced. If anyone asked how the testis can control the size and form of the skeleton, the distribution of hair, or the tone of the voice, the explanation was vaguely to the effect that some sort of "sympathy" existed between the parts of the body, with the implication that the nervous system is the connecting agent. In 1849, however, Arnold Adolph Berthold, a physician and zoologist of Gottingen, proved once for all that the influence of the testis is carried by something that travels in the circulating blood. Berthold's little contribution (it is only four pages long) belongs to the fundamental classics of endocrinology.' He tells us that on August 2, 1848, he castrated 6 cockerels, 2 to 3 months old. Their combs, wattles and spurs were not yet developed. From two of them the testes were completely removed. These became typical
2 See many, chapters of Edgar Allen, Sex and Internal Secretions. 8 A. A. Berthold, "Transplantation der Hoden," Archiv fur Anatomie, Physiologie, und Wissenschaftliche Medizin, 1849 (Appendix II, note 18).
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THE MALE HORMONE
capons, fat, docile, without cocks' combs, wattles and spurs, unable to crow. In the case of two others, Berthold removed both testes but put one of them back, dropping it among the intestines. Anatomical examination months later showed that the reimplanted testes had become attached to the intestines and had acquired a good blood supply, so that the testicular tissue flourished in its new site. Both these cockerels became typical cocks ; they grew combs and wattles, crowed, fought their rivals, and, as Berthold delicately observes, "showed the customary attention to the hens." One of these was later opened surgically, the implanted testis was removed, and the comb and wattles cut off. The head furnishings did not regenerate, and the bird, now fully castrated, reverted to the status of a capon. The other two each had one testis removed, then Berthold exchanged the remaining testes, giving each bird the other's sex gland, which he implanted on the intestine. These also became typical cocks. This beautiful experiment showed that the testis by no means depends upon specific nerves to maintain its control of the secondary sex characters, but works through the blood.
A long story could be told of all the efforts that were made to follow up this discovery, and there would be many divagations to relate. There was, for example, the episode of Charles-Edward Brown-Sequard, a brilliant, restless FrancoIrish- American (181T-1894!), who made two incursions into the field of the internal secretions. In 1856 he was the first to remove the adrenal glands from animals and to observe the fatal disorder thus produced, like an exaggerated Addison's disease. In 1889, when he was seventy-two years old, he began to dose himself with extracts of dogs' testicles. He was feeling the debility of age, and hoped to rejuvenate himself. BrownSequard had been a good scientist and it is almost incredible that he could have hoped to do critical experiments with himself as the only guinea pig, prejudiced by all his hopes and fears for his own health. He thought that after the injections
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he felt much stronger and more alert, and reported his experience with pathetic enthusiasm and intimate personal detail before the medical societies of Paris and in the journals. The medical profession was on the whole incredulous and Paris made a good deal of fun of him. We know now that the extract could have had little or none of the genuine testis hormone in it. It was made by putting mashed-up testes in water and filtering the mixture. We are now well aware also that when a man grows old he ages all over, not only in his testicles. Nevertheless the idea of administering gland extracts had its up-to-date appeal in those days of the earliest discoveries about the endocrine organs. German biochemists had recently isolated from animal testes a peculiar nitrogenous substance called "spermine." Various people leaped to the conclusion that this might be the active substance in Brown-Sequard's extracts. Spermine was therefore put on the market under the auspices of the chemist Poehl, and thus became (to the best of my knowledge) the first endocrine product to be commercialized. Thus Brown-Sequard's notoriety was probably responsible, more than anything else, for the exploitation of endocrine preparations in the drug trade ahead of scientific knowledge. Since then, barrelfuls of extracts and millions of tablets have been fed and injected into human patients, with uncritical optimism, before the chemists and physiologists could learn the facts. The benefits of endocrine research on the reproductive glands have almost been stifled by this exploitation. Even today the practicing physician finds it difficult to distinguish what is sound and practical amid the flood of well advertised endocrine drugs.
There have been premature efforts also to apply Berthold's experiment of transplantation of the testis to the rejuvenation of senile men. The most widely publicized of these was that of the Franco-Russian surgeon Serge Voronoff, who was busy from about 1912 to 1925 implanting monkey testes into human patients. The American journalists of those days
{ 230 }
THE MALE HORMONE
could not refer to the testicles by name in the newspapers, and introduced the expression "monkey glands," which became a byword and finally a joke. Some of the patients reported hopeful results. The grafts may indeed have yielded a little of their hormone to the body before they disintegrated and disappeared. More often, no doubt, the benefit was entirely psychic. It is now clearly established that tissues from one species of mammal cannot grow in another species, and indeed it is practically impossible to secure a permanent transplant from one human to another. Grafting of the testis has therefore not been adopted as a sound procedure.
While we are on the subject of rejuvenation, we may as well mention the Steinach operation. Eugen Steinach of Vienna, a scientist of good reputation, came forward about 1920 with a proposal based on two premises. The first of these, which has even yet not been proved, was that the testis hormone is made entirely by the interstitial cells. (The question will be discussed more fully below.) The second premise has since been proved incorrect; it was that if the seminal duct is tied off, the seminiferous tubules will degenerate leaving more room for the interstitial cells, and these will increase in number and presumably make more hormone. Steinach believed that such a ligation of the seminal ducts of man (vasectomy) would restore vitality of body and of sexual function to elderly men. He brought forward apparently strong evidence from animal experiments to support the idea. The operation made a strong appeal to men who were yearning to regain their lost youth. It has been tried widely, but the medical profession remains unconvinced, and the scientific basis for it as outlined above has been disproved.
Meanwhile, through all this period of sensationalism and premature publicity, the slow implacable attack upon the problem by inconspicuous investigators has gone forward to notable success. The important thing in endocrine research is
{ 231 }
THE HORMONES IN HUMAN REPRODUCTION
to find a test for whatever hormone one suspects to exist — some sharp-cut characteristic effect that is lost when the gland is removed and that can be restored by giving back the gland in implants or in extracts. At each step of our story in this book such a method has been the key to success. The vaginal smear test for the estrogens, the rabbit uterus test for progesterone, promptly made possible the purification of these substances. If the test is quick and cheap, the results will come that much faster. Berthold's experiment with the cockerels provided an ideal method of testing for a hormone of the male sex gland. Success came to those who followed his lead, putting aside premature efforts to work with slowly growing mammals or to rejuvenate old men. Between 1907 and 1927 two or three European investigators reported that they had extracts of the testis which induced growth of the head furnishings of cocks. None of these experiments, however, was fully convincing. Meanwhile the estrogenic hormones were isolated and discovered to be soluble in fat solvents. In 1927 a graduate student in biochemistry under Professor F. C. Koch at the University of Chicago, L. C. McGee (now a physician in Elkins, West Virginia) applied the new methods of extraction to the tissues of the bull's testis and promptly secured a relatively pure extract that was capable of producing rapid growth of capons' combs (Fig. 32). This lead was followed up by a group of workers in biochemistry and zoology in the University of Chicago, including McGee, F. C. Koch, C. R. Moore, L. V. Domm, and Mary Juhn, and by various workers abroad. The successive steps in the purification and identification of the male or androgenic hormones were much like those in the isolation of the estrogenic substances. In 1929, S. Loewe and S. E. Voss of Dorpat (Estonia) and also Casimir Funk and B. Harrow of New York found androgenic substances in human urine from males. The indefatigable Butenandt and his aides then
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Fig. 32. The effect of testis hormone on the rooster's comb, a, untreated castrated cockerel. 6, castrated cockerel after 11 days' treatment with testis extract. Drawn from photograph by Freud and coworkers.
isolated, completely purified and identified two of these compounds, called respectively androsterone and dehydroandrosterone, in 1931-1932. L. Ruzicka and his colleagues at Basel made them synthetically in 1934. The next year David, Dingemanse, Freud and Laqueur of Amsterdam succeeded in the difficult task of purifying the hormone from extracts of the testis itself, and found the substance called testosterone, which differs slightly in its chemical constitution from the androsterone found in urine. The groups of workers led by Butenandt and Ruzicka immediately synthesized this hormone as well. Now that such substances could be made in the test tube as well as in the testis, and (as we shall see) began to be found in other tissues also, the adjective "male" as applied to them gave place to the more apt word "androgenic," meaning "promoting masculinity"; the latter word defines the effects without implying any particular place of origin and can therefore be used of such substances when, for example, they turn up in female urine, in the cortex of the adrenal gland, or in a chemist's flask.
Chemistry of the androgenic hormones. These substances belong to the same family of chemical substances as the estro
{
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THE HORMONES IN HUMAN REPRODUCTION
genie hormones and progesterone. Testosterone has the following structure :
CH3 ^OH
TESTOSTERONE
Androsterone, prepared from human male urine, has this formula :
ANDROSTERONE
A statement of the relation of these particular sterols to simpler chemical substances will be found in Appendix I.
At the present time at least thirty-five substances of similar composition are known which have androgenic effects. Some of these have been found in the adrenal gland, or in the urine under special circumstances, but most of them are artificial products of the chemical laboratory. A list of them is given by Koch.* The male hormone which is actually at work in the body is probably testosterone itself or a closely similar substance. The reason a definite statement cannot be made on this point is that we are not sure that the chemical procedures necessary to extract and concentrate the hormone do not change it chemically. When testosterone is administered to a castrated animal, it is transformed in the body and is excreted by the kidney as androsterone. Since androsterone occurs in the urine of normal men, this is presumptive evi
Edgar Allen, op, cit.. Chapter XII, "The Biochemistry of Androgens,"
by F. C. Koch.
THE MALE HORMONE
dence that testosterone, or something very much like it, is in circulation in the body.
Just what cells in the testis are responsible for producing the hormone is an interesting and debatable question. There are two possibilities, the interstitial cells on one hand, and the spermatogenic cells of the tubules on the other. Let us examine the evidence. In the first place the interstitial cells look like endocrine tissue, since they are large cells provided with a rich circulation of blood but obviously not producing an external secretion, for they are not arranged in channels and ducts. Years ago, moreover, Bouin and Ancel called attention to evidence favoring the interstitial cells as the source of the hormone. When the testes fail to descend and therefore do not form sperm cells, the cells lining the tubules are reduced to an inactive state (Plate XXIV, B). They assume a vague, nondescript form as if they were merely surviving without any function. The interstitial cells however remain in place, they look normal, and indeed have even been thought to increase in amount. Although the cryptorchid animal or man bearing such sex glands is sterile, he develops male secondary sexual characters and male sex psychology. With the spermatogenic cells seemingly inactive (as judged by appearances under the microscope) but the interstitial cells in good condition, it is difficult to avoid the assumption that the latter are making the sex hormone. When bits of the testis are grafted successfully into a castrated animal the same cellular state develops in the grafts, and the animal likewise develops male qualities. It was formerly thought that tying off the seminal ducts produced the same effect. The Steinach operation described above was based upon this whole set of considerations. It is now known, however, that blocking the ducts and thus damming up the semen does not stop spermatogenesis. It is also known that cryptorchid (undescended) testes with inactive sperm cell formation do not
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produce more hormone but considerably less. In short, the two functions of the testis, spermatogenesis and hormone production, run parallel to a certain extent. For this reason some of the soundest of the investigators are not willing to point to one or the other of the constituent tissues of the testis and saj^ "here is the sole source of the hormone." The tubule cells, even if they are inactive in producing sperm cells, may for all we know still be taking part in making the hormone ; or perhaps the two kinds of cells work together. If a time ever comes when the hormone can be recognized in the tissues in very small amounts, say by some sort of super-spectrograph or X-ray analysis, such as the modern magicians of the physics laboratories are using in their easier problems of test tube chemistry, then perhaps we can answer such questions as these.
There is no sharp division between the estrogens, the androgens, and the progestins. Several of these substances give both estrogenic and androgenic effects, and a few have been found even to affect the uterine lining like progesterone, though only in very large doses.
The androgens are usually assayed by testing their effect upon the growth of the comb of the capon. The League of Nations Committee on Standardization of Drugs set up in 1935 an international standard of potency, specified as the equivalent of 0.1 milligram of crystalline androsterone. This is approximately the daily dose required to give a measurable response in a capon's comb in 5 days.
The androgenic hormones are usually injected in oil solution. In recent years the method of implanting pellets under the skin has begun to be tried. The hormones are also effective when applied in suitable ointments. Growth of the cock's comb can be elicited by applying hormone-containing ointments directly to the comb itself (Appendix II, note 19).
Effects and medical use of the androgenic hormones. The
{ 236 }
THE MALE HORMONE
effects of the androgenic hormones, as C. R. Moore" neatly puts it, are measured by the difference between a castrated and a normal man. These substances substitute completely, in animal experiments, for the normal internal secretion of the testis. They counteract castrate atrophy of the seminal vesicles and prostate gland ; when given to immature animals they stimulate precocious growth of the accessory sex organs, and they induce sex activity and mating in castrated and immature males. A castrated male, skillfully treated with potent hormones, will resemble a normal animal of his species in all respects except that he will be infertile because he is producing no germ cells.
These effects have been tested quite thoroughly in an experimental way upon human patients who lack the testis hormone. In these men and boys, as in laboratory animals, the injected hormones bring out all the known responses which the bodily tissues normally make to the natural hormones of the testis. It should be recalled here that the symptoms of deprivation of testis hormone may be due to defects in either one of two glands. The testes may themselves be missing or deficient, or the pituitary gland may be furnishing an inadequate supply of gonadotropic hormone (see Chapter VI). In the latter case the testis will not be functional and the patient will show symptoms of testis hormone deficiency exactly as if the testis itself were the seat of the difficulty. At some time in the future, when endocrine treatment has reached a higher state of perfection, it may become possible to treat the pituitary cases with pituitary hormones, reserving the androgenic hormones for cases of deficiency of the testis itself. At present, however, the distinction is more or less academic. In either case the physician finds himself confronted with signs of male hormone deficiency, and the question of immediate importance is how
8C. R. Moore, "Physiology of the Testis," in Glandular Phytiology and Therapy , 2d ed., Chicago, 1942.
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far he can hope to help the patient by treatment with androgenic hormones.
I write about this subject of the medical use of the androgenic hormones with hesitation, because it is difficult on one hand to avoid raising false hopes without on the other hand underrating the progress that has been made and the future possibilities in this field. To make the problem clearer, let us consider a specific case.® Here is a boy in his middle 'teens who is not exhibiting the usual signs of sexual maturation. We know that if the deficiency persists he will grow to be a eunuchoid man. He will have underdeveloped genital organs, a delicate skin, the childhood type of hair distribution, a highpitched voice; possibly also he will be overfat and he may suffer from muscular and circulatory difficulties causing easy fatigability and inability to do hard muscular work. Another important feature of his general immaturity will show itself in the long bones of the skeleton. The growth zones (epiphyseal junctions) will not close up at the usual time (18 to 20 years), but will go on growing, so that he will develop the long delicate bones of the eunuch and will thus display his defect in the entire configuration of his body. Although the deficiency has nothing to do with intelligence or fundamental character, he is very likely, as he grows up, to suffer from psychological damage due to a sense of defectiveness and of difference from other men.


If this boy could be treated as simply as a guinea pig is treated in the laboratory, we could control all these visible defects by administration of androgenic hormone. The treatment is fairly expensive and must be kept up by frequent injections or inunctions. Administration by pellets buried in the tissues may in time become practical, but is hardly yet ready for use. We are, moreover, not yet free from insecurity about possible danger from long continued administration of


ej. B. Hamilton, "Testicular Dysfunction," in Glandular Physiology and Therapy, 2d ed., Chicago, 1942.


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THE MALE HORMONE


the sex hormones through damage to the tissues of various organs. Finally, whatever improvement is gained by treatment will wear off fairly rapidly if the drug is discontinued. In one feature only, so far as known, the improvement is permanent; that is in the skeleton, for the growth of the long bones will be permanently stopped by closure of the epiphyseal junctions. Even this requires care and forethought, for if the treatment is begun too early, the epiphyses may be closed prematurely and growth stopped before the boy reaches full stature.
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I have no doubt said enough to make it clear that the use of androgenic hormones to correct testicular hormone deficiency is very decidedly still in the stage of exploration, and that every case so treated is an experiment. This does not mean that the attempt should not be made by properly trained physicians and scientists who are in a position both to guard the welfare of the patient and to study the results with rigid scientific standards for future guidance. We have, of course, been considering an extreme case, one in which there is permanent total deficiency. The androgenic hormones are certainly going to be useful in many disturbances of less intensity and as collateral treatment. To make up for partial deficiencies, to tide over the acute deprivation which follows surgical removal of the testicles, to supplement the treatment in various cases of sexual disability and impotence — for such purposes the androgenic substances will no doubt be helpful in competent medical hands.
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At any rate, the contemplation of these distressing deficiencies of the sex hormones must have impressed the reader anew with the thought that the normal processes of reproduction involve a remarkable series of linkages and coordinations within the body. It is indeed a subtle and potent chemistry by which the reproductive glands create the egg and the sperm cell and surround them with all that is needful of nourishment and protection to carry them through their critical journey from conception to birth. In this book we have traced the main outlines of these complex physiological patterns. We have seen the great advance of knowledge that has taken place in less than fifty years, by the efforts of faithful laborious men who worked in peace and quiet, giving their lives to the understanding and improvement of life. When I wrote these closing words, the guns were sounding all over the world. The scientists were dropping their instruments, or turning them perforce to the uses of death and wastage. But life goes on nevertheless, and the problems of life will be studied until the day comes we all dream of, when mankind may everjrwhere seek the truth undaunted by fear of war and oppression. In that day we shall gather the fruits of our labor. The childless wife, the ailing girl, the boy deprived of his birthright of sex by some failure of Nature's process, will call and not in vain for the help that science can bring them, and man shall understand at last the miracle of his birth.
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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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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.



  1. ↑ 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).
  2. ↑ Physiology of the Uterus, with Clinical Correlations, by Samuel R. M. Reynolds, New York, 1939.
  3. ↑ Sex and Internal Secretions, edited by Edgar Allen, Baltimore, 2d ed., 1939; Chapter XI, The Mammary Glands, by C. W. Turner.


   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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