Book - The Hormones in Human Reproduction (1942) 3

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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 III. The Ovary as Timepiece

"They hounded to the horizon s edge And searched with the sun's privilege saw the endless wrack of the firmament And the sailing moon where the cloud was rent, And through man and woman and sea and star Saw the dance of Nature forward and far. Through worlds and races and terms and times Saw musical order and pairing rhymes." - Ralph Waldo Emerson - The Poet.

Our western plainsmen used to watch, in August I and September, milling herds of bison, blackening the prairie for miles. It was no uncommon thing to see thousands of them, eddying and wheeling about under a dense cloud of dust raised by the bulls as they pawed in the dirt or engaged in desperate combat. In these herds the males were continually following the females and mating with them. The whole mass was in constant motion, all bellowing at once in deep and hollow sounds, which mingling together seemed at the distance of a mile or two like the noise of distant thunder.[1] This was the yearly period of estrus,[2] the mating time, when the females were ready to produce their eggs, and the males to fertilize them. Such a season of mating is well-nigh universal in nature, though fortunately not all the denizens of earth react as violently as the bison. The rhythm of sex is manifested in infinite variety, assuming every aspect ; now to our human eyes tensely dramatic, now gently romantic, now bestial or merely matter-of-fact, sometimes even comical.

"About the groves of Silarus and Alburnus evergreen In holm-oak swarms an insect

We call the gadfly ('oestrus' is the Greek name for it) - A brute with a shrill buzz that drives whole herds crazy Scattering through the woods, till sky and woods and the banks of Bone-dry rivers are stunned and go mad with their bellowing."

{Georgics, Book III, C. Day Lewis's translation.) In its Latin neuter form oestrum this word long ago became an English word meaning any recurrent excitement, e.g. the poetic frenzy. Heape adopted the masculine form as his special technical term. In England it is spelled oestrus and the first syllable is pronounced e as in "me." In the United States, following a general trend of our language, it is now commonly spelled estrus and pronounced with e as in "west." The adjectival form is estrous; cf. mucus, m,ucous. The interval between two estrous periods, in Heape's terminology, is diestrus; a long period between sexual seasons (as for example in sheep during the winter) is anettrus.

In springtime two robins nest beneath my window, and soon a group of eggs in the nest gives evidence that the ovaries of the female bird have responded to the rhythm of the year. Twice a year my neighbor's spaniel gives unmistakable signs that she is ready to mate, and I know, being an anatomist, that if we could inspect her ovaries we should see the Graafian follicles enlarging, and the microscope would show us a crop of ripening eggs.

The ovary as a timepiece runs at curiously different rates in different animals. Many creatures living wild, both plants and animals, necessarily time their breeding with the seasons of the year, because their offspring must begin life when conditions of temperature, shelter, light and food are most favorable. Hence the vernal growth of plants and all the annual breeding seasons of animals such as those of migratory birds and of the fish, salmon and shad for example, that swarm into the bays and rivers every spring, teeming with roe and milt and seeking a sheltered place in which to spawn. Many marine plants and animals have reproductive cycles controlled by the tides and therefore breed at intervals of a month or multiples of a month. There are seaweeds, for instance, that fruit only on the highest tides, and worms that breed at particular phases of the moon. The Japanese palolo, an annelid worm living on the sea bottom, swarms to the surface to breed on four nights of every year, namely on the new moon and the full moon of October and November (Appendix II, note 2).

In the course of evolution, however, many animals have adopted cycles not directly related to the yearly seasons or the tides. Some of these are domesticated species which man has freed from dependence upon the wild crops and has improved for more rapid breeding; others have acquired their cycles for no obvious reason. The shortest cycle is that of the domestic fowl, which lays an egg once a day ; the longest, that of the locusts that come swarming from the ground at intervals of seventeen years, in obedience to some obscure signal, to deposit their eggs and then to die.

In mammals, and in the human race, the ovary is no less cyclical than in lower animals. Many wild mammals have an annual cycle so timed that they may bring forth their infants when food is plentiful for the mothers. Other species have estrous cycles at intervals throughout the year, or a sexual season of several cycles at a favorable time of the year. Rats and mice have very short cycles, ovulating every 4^ to 5 days, except when the cycles are interrupted by pregnancy. The guinea pig has a 15-day cycle. Cows, mares, and swine have estrous periods at 21-day intervals throughout the year. Sheep have several cycles in the late summer; during the winter they are anestrous. Dogs and cats have two or three estrous periods each year ; so, apparently, have lions. Many other carnivores are monestrous (having one period each year). Not only do the time intervals vary in different species, but fhere are all sorts of different behavior patterns at estrus and a good many differences in the details of internal physiology.

The cycle of the sow

To make this matter clear, let us follow through the cycle of one particular species and then discuss some of the variations. That valuable creature, the domestic sow, will serve us admirably for this purpose. She has an estrous cycle of 3 weeks' duration. During 2% weeks of each cyclic interval she goes about her usual program of eating and sleeping and if there is a boar in the herd she shows no interest in him. Then there is a change of mood and behavior. For 3 days she undergoes a well-marked phase of estrous excitability, marked by restlessness, diminished appetite, and heightened sexual interest. If there is no boar present she sniffs and nuzzles at the genitals of other sows, but if there is a boar she promptly accepts mating and in the normal course of events becomes pregnant. The cycles then cease until the young are born. If she does not mate, or if the mating is not fertile, cycles continue as usual every 3 weeks throughout the year.

These events in the life of the sow have been known to every swineherd for ten thousand years, but nobody knew until the present century just what is going on inside the animal every 21 days to stir her two hundred pounds of meat, bones, and fat into three days of such specialized conduct. It turns out, when we investigate the matter, that during the diestrous phase of the cycle (the 21/2 weeks of no sexual activity) the Graafian follicles in the ovaries are all small, with unripe eggs in them. About two days before the onset of estrus, a crop of follicles begins to grow. The ovaries of sows killed on the first day of estrus contain large follicles with mature eggs. Late on the second day we find that the follicles have ruptured and the eggs are on their way down the oviducts. The follicles are being converted into corpora lutea (see diagram, Fig. 15). By the sixth or seventh day after ovulation the corpora lutea are fully developed and (as we shall see in Chapter V)' are at work producing their hormone, progesterone. This hormone acts upon the uterus, altering its lining to make it ready to receive the eggs, as a plowman tills the fields to receive the seed. If the sow has mated while she was in estrus, the eggs will be fertilized and they will settle down in the uterus and develop there. Once the pregnancy is well established, the cycles cease, possibly because a hormone produced by the placenta (or rather the outer part of the embryonic tissues, destined to form the placenta) signals the ovary, via the pituitary gland, to stop development of follicles for the time being. If not fertilized, the eggs will degenerate and go to pieces; then the corpora lutea, no longer useful, begin to degenerate on the 15th day of the cycle (i.e. 14 days after ovulation) and shrink out of existence. About the 19th day a new crop of follicles begins to mature and the cycle repeats itself.

The whole process of the estrous cycle is therefore a beautifully timed arrangement by which, first, the eggs are matured and discharged from the ovary; second, the sow is induced to mate at just the right time to get the eggs fertilized; and third, the uterus is prepared to receive the embryo, by action of the corpus luteum, which is formed and thrown into action at just the right time. If all this preparation for maternity fails for lack of opportunity to mate, then the cycle repeats itself as soon as the changes in the ovary and uterus have cleared away.

Variations of the cycle in other mammals

What I have described in the sow is the fundamental plan of the cycle ; this animal happens to illustrate it with diagrammatic simplicity. A whole book could be filled with variations displayed by various animals.[3] In guinea pigs, for example, the female not only will not mate between estrous periods, but actually cannot, because the skin grows over the vaginal orifice and blocks entry of the male, except during estrus, when it temporarily opens. Such an arrangement exists in no other animal. In cats and ferrets the ovarian follicles behave peculiarly; although they ripen in each cycle, they will not rupture and discharge their eggs unless mating occurs. In rabbits the follicles will not even ripen without mating. This means that in these three species the corpus luteum phase of the cycle does not occur if the animal does not mate. In all other animals known at present, including man, the follicles ripen and rupture spontaneously.

In rats and mice there is a very peculiar situation, first worked out by Long and Evans.[4] The cycles are rapid, averaging less than 5 days in length. Since it takes about 7 days to get the embryos down into the uterus and safely implanted there, we see that unless something were done to prevent it, there would be two batches of early embryos on their way at once. Before the first were soundly attached, the second lot would be claiming space and nourishment in the uterus, with resultant confusion and damage. To prevent this a special mechanism has developed in rats and mice : the act of mating signals the ovary to postpone the next cycle 10 days instead of five, thus giving time to get the pregnancy under way. This can be imitated experimentally by simply inserting a smooth glass rod deeply into the vagina during estrus, in lieu of the male organ.

The human cycle: menstruation

The most peculiar variation of all occurs in the human species and in our near kin, namely the apes and higher monkeys. The length of the cycle is about 4 weeks, but in these animals there is no well-defined estrous period. Mating can occur at all times of the cycle.

The follicle matures and discharges its egg silently, without any marked changes of behavior. The corpus luteum forms from the discharged follicle and functions as in other animals, but when it breaks down, about two weeks after ovulation, its effect upon the lining of the uterus does not merely subside. There is, instead, a sharp breakdown of the endometrium with hemorrhage. This periodic menstruation occurs only in the higher primates ; nothing like it is seen in other animals. The question of its relationship to the estrous cycle of non-menstruating animals has puzzled and confused naturalists and physicians since the days of Aristotle. Because animals like the sow and mare have in their cycles one prominent event, namely estrus, and humans display also one definite cyclic change, namely menstruation, the two phenomena were thought to be the same. Serious misconception of the human cycle caused by this error has been cleared up only in the twentieth century.

For the sake of perfect clearness on this point, let us compare diagrams of the estrous and the menstrual cycles (Fig. 16) . It will be seen that the two are fundamentally alike, since the important feature of each is ovulation followed by the corpus luteum phase. In lower animals ovulation is accompanied by an outspoken period of sexual receptiveness, in the primates (man, apes, and higher monkeys) it is not; in the primates the end of the corpus luteum phase is accompanied by menstruation, in the other animals there is no bleeding at this time.

Fig. 16. Diagram comparing the estrous cycle in general with the menstrual cycle of the higher primates.

How menstruation is brought about by the ovarian hormones, and what purpose it may serve, we shall discuss in Chapter VI.

The vaginal cycle. Obviously, the periodic ripening of the ovarian follicles sets in action large forces that can alter the state of other organs, change the reactions of the body, and determine the behavior of the female animal. By means of the ovarian hormones released at this time, there are ( as we shall see) cyclic changes in the whole reproductive tract. Not only is the lining of the uterus modified, but the Fallopian tube, the vagina, and in some species even the external genital organs also take part in these rhythmic alterations. This fact led to the discovery, twenty-five years ago, of an extraordinarily useful method of research, which greatly increased our rate of progress in unraveling the problems in this field ; and because it was made in the United States, helped put the American investigators of this generation in the forefront.

To grasp the importance of this discovery, we must remember in the first place how very helpful to science in general are the rat, mouse, and guinea pig. These little rodents are hardy, inexpensive, and easy to feed, house, and handle in the laboratory. Their small size is also a great advantage when experiments call for treatment with scarce or expensive hormones and other chemical reagents. Unlike cats, they breed freely in cages. Unlike dogs, they have rapid cycles, requiring no long waits in the course of experimental study. Unfortunately, among all the mammals they give the least conspicuous signs of estrus. They show no genital swellings like the bitch, no excitement like the sow. They normally mate only at night, and to be certain they are in estrus, the investigator had to put them with males and sit up all night watching them, or else use roundabout methods of observation which were not perfectly reliable. As an illustration of the difficulties, I recall that before 1917 a distinguished biologist who was working chiefly with guinea pigs supposed their cycle to be 21 days instead of 16, and a first-class embryologist who made a determined effort to work out the estrous cycle of the rat by the best means at his command, came out with a result of 11 days, just twice as long as the correct figure, having somehow missed alternate cycles.

It can be imagined with what enthusiasm those of us who were working in the field learned of the simple discovery announced in 1917 by C. R. Stockard 6f Cornell Medical College and his colleague G. N. Papanicolaou.[5] These men found that in the guinea pig the cyclic changes, which take place in the reproductive tract under the influence of the ovarian hormones, are seen with especial clearness in the lining of the vagina. Here there is a cycle of growth and shedding of the surface cells, which follows events in the ovary so closely that the time of rupture of the follicle can be determined within one hour. It is only necessary to scrape the vaginal lining gently with an instrument, or to wash the cavity out with a medicine dropper and a little salt solution, and study the findings under the microscope. This can be done in a few minutes and does not harm or upset the animal in any way. The vaginal closure membrane, mentioned on page 68, as a peculiarity of the guinea pig, is of course kept open by these daily examinations.

In justice it ought to be added here that something of what Stockard and Papanicolaou found had been described in the 1890's in more or less forgotten papers by several investigators, particularly the French observer, Lataste; but it was their masterly and complete investigation of the matter which made it available to science.

By the use of this method Stockard and Papanicolaou promptly ascertained the correct length of the guinea pig's cycle and secured a much more accurate timing and description of the subsequent events of the cycle than we had before.

The method was soon applied to the rat by Long and Evans of the University of California and to the white mouse by Edgar Allen of Yale Medical School, then at Washington University, St. Louis. We shall see in subsequent chapters some of the important work that was made possible because the cycles of these three animals were now so much better known. The detection of the ovarian estrogenic hormone by E. Allen and Doisy (1923) was a direct result; so was the discovery of Vitamin E by H. M. Evans and his colleagues (1922). In conjunction with the growing knowledge of the cycle of the sow and of reproduction in the rabbit, it led indirectly to the discovery of the corpus luteum hormone and to a far clearer general comprehension of the whole field than was possible before.

The exact details of the vaginal changes are of no particular importance except to those who need to follow them in the laboratory. Briefly stated, there are two kinds of cells that get free in the vagina. One kind is of course the cells of its lining. These are epithelial cells like those of the external skin except that they are ordinarily moist. Those that lie on the surface of the lining are not infrequently shed into the cavity. The cyclic changes can be followed in the accompanying figure, taken from the monograph on the rat's cycle by Long and Evans. In Plate XIII, B we see the vaginal cells as they are in the interval or diestrous phase ; there are fairly large numbers of white blood cells or leucocytes (the small rounded cells with irregular nuclei) intermingled with a few large flat epithelial cells. At C we see signs of approaching estrus; the leucocytes have disappeared, and the epithelial cells are swollen and rounded, by action of the ovarian hormone upon them before they were shed from the wall into the cavity of the vagina. In figure D of Plate XIII we see that the epithelial cells now being shed are dry, scaly, and lack nuclei — they are cornified, as we say, like the cells on the dried-out surface of ordinary skin. At the time when the ripe follicles are about to rupture, the process of cornification of the vaginal wall is very active, and cornified cells are shed in thousands, yielding thick caseous scrapings that can be identified without a microscope. The next day the leucocytes come back (E), the masses of cornified cells disintegrate, and the interval picture reappears. In sexually mature rats and mice this change repeats itself every 5 days, in guinea pigs every 15 days.

Vaginal cycles in other animals

If such clear-cut vaginal changes occurred in all mammals, it would be of great advantage in studying their cycles. If they occurred in women, it would be of priceless value to gynecologists, especially in the serious business of diagnosing the cause of sterility. At present we have no certain way of finding out whether a woman is ovulating or not, except by operative exploration. Unfortunately, the vaginal changes are far less clear than in the small rodents. Extreme differences, such as that between normal activity of the ovary on one hand and total inactivity on the other, can be detected, but such changes as occur from day to day in the cycle are faint. The latest word thus far is in volume 31 of our Carnegie Contributions to Embryology, recounting studies made on human patients by Ephraim Shorr of Cornell Medical College and observations of the Rhesus monkey made in the Department of Embryology of the Carnegie Institution by Ines de AUende in consultation with Carl G. Hartman. Dr. de Allende was generally able to diagnose the occurrence or nonoccurrence of ovulation in monkeys, as confirmed by surgical exploration. It seems not improbable that by refining the study of vaginal cells it may ultimately be possible to diagnose ovulation in humans.

The cause of the cycle

Some day no doubt we shall understand the whole mechanism of the ovarian rhythm, and know why and how the cycle is short or long in various animals and why its manifestations vary in so many ways. At present we can do hardly more than guess. We think the alternations of the cycle are due to an interplay or see-saw action between the hormones of the ovary and of the hypophysis or pituitary gland. To make this clear let us continue to anticipate the next chapter by postulating that the ovary produces an estrogenic hormone that acts upon the uterus and the rest of the reproductive tract, producing among other effects the estrous changes of the vagina referred to above. Another fundamental fact is that the whole activity of the ovary, including the production of the estrogenic hormone, is under the control of the pituitary gland (see Plate XIX and Fig. 20). If this remarkable bit of glandular tissue is removed, the ovary quits functioning altogether. By chemical extraction the pituitary yields hormonal substances which can restore ovarian function in the absence of the pituitary gland, or cause the ovary of the immature animal to grow and begin functioning. It has been shown, however, that if we inject the ovarian estrogenic hormone into a female animal, the pituitary hormones that stimulate the ovary are reduced in amount. Here we have, in all probability, the fundamental mechanism of the ovarian timepiece. The pituitary stimulates the ovary, but the latter then sends out its estrogenic hormone and this depresses the pituitary. Then the ovary loses pituitary support. Up goes the pituitary again like the other end of a see-saw. There must of course be other factors in the situation, for such a mechanism, like the see-saw, will come to balance unless it gets a push from time to time. In Chapter VI we shall return to this subject after a more detailed account of the ovarian hormones.

Plate XIII. The vaginal cycle in the white rat. A, section of lining of the vagina. The inner surface, from which cells are shed as seen in following pictures, is at the right. B, cells shed into cavity of vagina during interval part of cycle. The larger masses are the epithelial cells; the small rounded objets with gnarled nuclei are white blood cells (leucocytes) . C, just before estrus. D, during estrus (at time of ovulation) showing complete cornification, with loss of nuclei. The section of the wall of the vagina pictured at A was taken at this time, and shows the cornified cells in place, forming a clear layer at the right. E, at end of estrus, showing return of leucocytes. All magnified about 650 times. From J. A. Long and H. M. Evans, "The Estrous Cycle in the Rat," University of Ccdifomia Memoirs, No. 6.

Plate XIV. Castrate atrophy. Left, normal uterus of young adult rabbit. Righti uterus of litter-mate sister one month after removal of both ovaries. Note thmner horns and vagina, with paler and flabbier walls, in specimen on right. (One Fallopian tube of this specimen has been cut off.) Preparation by author. Natural size.

  1. This passage is largely a quotation from George Catlin, The North American Indians, vol. 1 (p. 280 in the Edinburgh reprint of 1926). Catlin's rather discreet painting of such a scene occurs in the same volume, fig. 105.
  2. Estrus is the technical term for recurrent periods of sexual excitement in animals, popularly called "heat." It was introduced in 1901 by Walter Heape, a prominent student of the physiology of reproduction. The word comes from the insect described by Virgil:
  3. See S. A. Asdell, Patterns of Mammalian Reproduction, Ithaca, N.Y., 1946.
  4. J. A. Long and H. M. Evans, "The oestrous cycle in the rat and its associated phenomena." Memoirs of the University of California, vol. 6, 1922.
  5. C. R. Stockard and G. N. Papanicolaou, "Oestrous cycle in the guinea pig," American Journal of Anatomy, vol. 22, I9I7.

   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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