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Natural Control of Fertility
Natural Control of Fertility EMIL WITSCHI, PH.D.
THE American Fertility Society was organized in 1944 after a period of economic and of reproductive depression, with the declared aim "for the study of sterility." Parkes tells how the British government, earnestly concerned about a birth rate that in the thirties had fallen below the replacement level, appointed a Royal Commission on Population. Leading geneticists expressed dim views about the seeming decline of fertility in western women, but before any remedies could be proposed the worldwide "baby boom" of the mid-forties dispelled these worries-if only to create new ones. Two reassuring conclusions can be drawn from these recent events. Evidently the human species still holds considerable reserves in natural fertility, and its reproductive rate responds readily to environmental factors. Hence both are open to willed management. Mankind striving to direct its future could choose and maintain the optimal size of its own population, depending only on concerted resolution and social organization. Man was aware of this even in ancient times. In the thi:(d century when every life was highly prized-because excessive mortality rates combinea with a great demand for workers, soldiers, and slaves-Tertullian held that not only the destruction of a child in the womb of the mother but also the prevention of conception was sinful. Sanctifying such once well-considered teaching has created a dogma, adherence to which leads to difficulties under present, radically changed medical and social conditions. Intentional restriction of the human reproduction rate has become a generally recognized necessity. Fortunately at this critical juncture, scientific study of ovarian cycles, of fertilization, and of gestation already provides a fairly wide choice of means and ways for the application of such control. NATURAL METHODS OF CONTROL
Reviewing some of nature's own ways of fertility restriction, one cannot, without mention, pass by the claim that calculated rhythmic abstinence by From the Anatomy Department of the University of Basel, Basel, Switzerland. The Ayerst lecture, presented at the 23rd Annual Meeting of The American Fertility Society, Washington, D. C., Apr. 14-16, 1967.
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man should also be valued as a "natural" control method. Unfortunately it is based on a misinterpretation of human sex physiology. In lower veltebrates and wild birds sex drive and reproduction as a rule are seasonally restricted. In many mammals cycles of shorter duration have been established. The females then become receptive and attractive to the males only during a relatively short period, the "heat," coinciding with ovulation time. However, the corresponding human cycle is circadian. Recognition of ovulation time is lost, but the gain of this evolution is that it keeps males and females constantly interested in each other, thereby creating a basis for close and durable family life. The abstinence method opposes nature's intentions by setting up a new rhythm, biweekly alternating "les plaisirs du vice et les honneurs de la vertu" (Rousseau). Not only disregarding a powerful psychophysiologic component of adult sex life, its practice also endangers the quality and well-being of the offspring. If the "safe period" is not conservatively observed, or when ovulation is retarded, chances are that fertilization may occur after its optimal time has passed and when a waiting egg has become overripe. It is now a well-established fact that delay of insemination causes deterioration of vertebrate eggs, with consequent chromosomal abnormalities,5,44 polyspermy,25 and teratologic development. 4 • 11. 13. 14 Intrafollicular and postovulatory overripeness can clearly be recognized as a major cause of the relatively high incidence of malformations in early human embryos and fetuses. B • 24 Repression of reproduction potentials is, however, not a rare occurrence in nature and the study of some examples leads to interesting discoveries. One may wonder how much knowledge the old Israelite had about the organization of hymenopteran states, when he counseled: "Go to the ant, thou sluggard; consider their ways and be wise." More than 2000 years later, we now realize that the social states of ants and honey bees have long solved many problems which for man still are matters of foremost concern, such as unemployment, predetermination of sex, of fertility, and of social relationships. Of the 50,000 to 80,000 female bees ordinarily inhabiting the hive, only 1 is fertile-the queen. Worker bees are almost entirely sterile. Their rudimentary ovaries consist of only 4-10 short ovarioles, while those of the queen total 150--200. Queens and workers are genetically identical. Queens are raised in larger cells than workers and are fed more abundantly, but the differentiating factor is rather qualitative than quantitative. One-dayold larvae can be raised in incubators, and those taken from worker cells can become queens if fed with "royal jelly," that is, with diets that had been prepared for queen larvae. All nursing food is produced by young workers. In their heads they carry 3 large glands which secrete the food-
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saps. These include all special inductor substances in a proteinic base. Rembold found much higher concentrations of pantothenic acid and biopterin in the royal jelly than in the fare for worker larvae. However, incubation experiments indicate that the determination of "royal class" really depends on still another but less known factor: "chromatographic fraction f." At any rate, infertility in worker bees results here from a nutritional deficiency, possibly a specific avitaminosis. In lower vertebrates the survival of a species usually is attained by abundant fertility, with production of billions of sperms by the male and millions of eggs by the female. In batches of thousands of frog eggs one rarely finds even a single nonfertilized or abnormally developing ovum. Protected by tough jelly masses, the entire offspring reaches the stage of hatching larvae. But then follows a carnage; even the parents like to swallow juicy larvae and little metamorphosed frogs. However, the most important limiting factor is the availability of niches that offer food and shelter. When frog populations today are rapidly decreasing or disappearing it is less because of predation than drainage of swamps and the massive use of insecticides. Severe population problems arise with the evolution of nurture. Parents of the 3 highest classes of vertebrates supply their offspring with food, protect them from unfavorable environments, and defend them against aggression. 40 Nevertheless, the ovaries of Hedging song birds contain several hundred thousand egg cells. Obviously these are far more than the number of nestlings any pair of parents could ever care for. In the course of evolution ways and means had to be found to reduce their number. Even before females reach adulthood all their gonia enter the maturation or ovocyte stage, precluding further multiplication. This is an important advance over amphibians, where year after year new generations of eggs proliferate from residual ovogonia. Furthermore, in most birdsexcept some hawks-the right ovary is vestigial and seldom ripens an egg. However, the most characteristic means of fertility restriction in amniots is the regulated intraovarial germ cell degeneration. In song birds it is linked with the seasonal breeding cycles. At the approach of a reproductive phase-usually in spring-several hundred ovocytes start growing, though only a few eggs will mature fully and be ovulated. All other enlarged follicles degenerate, many during the incubation time. Only small primary egg follicles persist throughout the sexual rest (eclipse) periods-usually fall and winter. They serve as a store for subsequent reproductive seasons (Fig. 1). Thus an effective reduction in propagation rate is attained by restriction of sexual life to just a few months every year. Hormonal factors play obvious roles in the mechanism of such seasonal
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breeding. The common starling produces only 1 brood yearly, and other species possibly 2 or 3. In free nature the female lays 1 egg per day and ovulation stops as soon as a set of 5 is in the nest. Experiments have shown that laying does not cease because of exhaustion of the ovary. If, after the second egg is laid, 1 egg is removed daily, birds have been seen to continue
Fig. 1. Ovaries of song birds: (left) in eclipse season (winter); (center) in breeding season (spring); (right) during incubation (early summer). (about X 3)
daily production over 2 full months. 41 After laying the fifth egg, undisturbed birds immediately become broody. According to Riddle and Bates this comes about by a change from gonadotropic to luteotropic (lactogenic) hormone secretion. Observations by Lehrman and Brody also indicate a closely related elevation of progesterone output. The quick change from egg production to atresia starts from a peripheral sensory perception (probably mostly visual) that sets in motion a whole sequence of reactions passing through the central nervous system, the hypothalamus, and the hypophysis, and ending with drastic changes in the gonad. Beyond doubt, changes in day length and other environmental conditions play important roles in the timing of these annual sex cycles. However, their rhythm depends even more on an inborn and genicly fixed biologic clock that regulates the output of LH by the hypophysis. The development of seasonal nuptial plumages of many male birds is induced by high luteinizing hormone ( LH ) levels,36 while bill colors more often reflect concentrations of gonadal steroidsY In male bishop birds (e.g., Euplectes franciscanus) a resplendent red and black cock plumage is donned at the advent of the mating period, replacing the drab hen plumage which is worn by males in eclipse, and by females throughout the year (Fig. 2). After castration the plumage changes continue synchronously with those of normal males, but the bills are always white. Ovariectomized females also participate in the plumage changes, with the same rhythm. Naturally, the bills of all castrates are white. One would have expected, from the seasonal development of the ovaries, that females must have the same kind
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of hypothalamo-hypophysial circadian timepiece as the males. In the intact female the cock plumage, however, does not manifest itself, because it is suppressed by the output of ovarian estrogens41 (Fig. 3). It is not known whether an autonomous cycle exists also for follicle-stimulating hormone (FSH) release. Weaver finches are the only animals, as far as is Reproductive Season
Eclipse Season
Fig. 2. Cock and hen plumages in nonnal and in castrated weaver finches (Euplectes) , with indication of honnonal conditions.
CASTRATES
known, that exhibit LH cycles by somatic reactions in· the absence of gonads. Slight rhythmic changes in the vaginas of spayed adult rats have been observed but have not been hormonally clarified. 21 GERM CELL PRODUCTION IN MAMMALS The well-known initially high productivity in germ cells by mammals must be considered a relict-a sort of memory persisting from times hundreds of million years ago, when coelacanth-like ancestors spawned eggs by the thousands and produced sperms in uncountable trillions. In the course of evolution the actual need for mature eggs and sperms has fallen to only a small fraction of what it was then. That extreme economy in the use of spermatozoa could possibly be practiced is exemplified by the queen bee. She releases scarcely one dozen sperms in fertilizing each egg. She is also extraordinary in keeping mature sperms stored in her seminal receptacle alive and fit for insemination for lilS long as 4 or 5 years.
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Quite to the contrary, male germ cells are still squandered at incomprehensible rates by mammals. According to Mann the average human ejaculate contains about 350 million sperms. Of the trillion spent by a man in a lifetime, only 3-5 may actually enter an egg. Least understood is the fact that ejaculates containing below 20 million actively moving
rrm .... mT1 •.•• mn Fig. 3. Pathways in control of gonad development and of coloration of feathers of weaver finches. Seasonal timer (horizontal arrow) in hypothalamus determines alternating phases of activity (bars with vertical lines) and inactivity (dots) regarding production of LHRF (LH-releasing factor). Squares in anterior lobe of hypophysis indicate cells producing LH on stimulation by LHRF. Three oblique arrows point at responses to LH in target organs: maturation and ovulation of ovarian follicles (right), pigment production by melanoblasts of feather papillae (left), and blockage of latter reaction b)' estrogens (center).
sperms per milliliter (less than 80 million per ejaculate) are subfertile. 3 , 9, 19 Nevertheless, first steps toward economy are recognizable even here. Quantitative studies in spermatogenesis have disclosed that not more than 30% of the gonia of perinatal male rats become progenitors of spermatogonia in adult testes. 7 Since the size of testes and of ejaculates differs greatly from species to species, it is to be assumed that the proportion of germ cell degeneration varies accordingly and probably is relatively high in the human. 20 More extensively studied is the complex system of natural restriction during human ovogenesis. 2 ,lO, 80, 42 The primary separation of soma and germ cells has not been observed so far, but it must occur before or close to the time of implantation of the blastocyst (about the 125- or 250-cell stage) . In an embryo of 16 somites, 109 primordial gonia were identified,
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which probably means that the full number was near 128-the product from an original pair of stem cells by 6 mitotic divisions. At this stage they are imbedded in the endoderm near the body stalk. Table 1 illustrates the germ cell increase toward a maximum at mid-pregnancy, in female embryos and fetuses. Starting at about the twelfth week, ovogonia enter the meiotic stages. First, some small primary ovocytes, the auxocytes of the leptotene stage, make their appearance. At this time chromosome duplication and DNA synthesis come to an end. 28 The chromosomes of the mature egg have already formed. Their composition may persist, essentially unchanged, for as long as 50 years. At 6 months virtually all germ cells have passed through these transformations; most have reached the pachytene and some the early diplotene stages. From this point, no further mitotic activity occurs; the population of female germ cells has attained its acme.,.... about 6 million ovocytes. 2 , 40 Throughout the prenatal phases one also observes degenerating germ cells. Elimination of ovocytes continues through birth, and through the juvenile and mature phases, until complete disappearance at menopause. The organization of primary, secondary, and tertiary ovarian follicles starts even before birth and continues throughout childhood and maturity. The history of the ovary in infancy and childhood has been outlined by Potter and by van Wagenen and Simpson. While at birth the compact cortical body of ovocytes and follicles is covered only by a thin peritoneal surface epithelium, fibrous connective tissue cells gradually intervene and TABLE 1. Number of Germ Cells in Human Embryos and Fetuses Size Stage*
16 18 20 24 26 27 28 29 33 35a 35b 36
(mm.)
3.0 3.8 4.2 5.5 8 9 11 15 24 60 115 320
Age (days)
Sex
Germ cell type
No.
26 29 31 35 38 40 42 44 56 77
Indet. Indet. Indet. Indet. Indet. Indet. Indet. Indet. F F
109 586 1366 451 873 1874 1536 2057 100,000 1 million
105 Birth
F F
Gonia Gonia Gonia Gonia Gonia Gonia Gonia Gonia Ovogonia Ovogonia + ovocytes Ovocytes Ovocytes + prim. foIl.
Both gonads are included in counts.
* From Altman and Dittmer.!
5-6 million 5-6 million
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form a moderately hyalinized ovarian tunic. Consequently, at menarche the primary follicles are located deep between the thick "tunic" and the central medulla, in the stroma of the ovary. During infancy more than 90% of the follicles disappear by degeneration. To what extent the process depends on or is accelerated by periods of elevated gonadotropin secretion is not at all clear. In a 19-year-old primipara, by the study of several hundred sections, it was estimated that about 200,000 healthy follicles were still present. 40 Probably there exist great individual differences among normally menstruating women of this age group. Degenerating follicles are found in every adult ovary, but only after age 43 does it become difficult to find the few scattered primary follicles. Degeneration, however, is not restricted to secondary and tertiary follicles-stages that probably already had responded to gonadotropic stimulation. Primary follicles also disappear, becoming enclosed by fibrous cells and resorbed. It is not yet clear whether degeneration starts from the single layered granulosa or the surrounding theca and stroma cells. At early stages the granulosa is incomplete. Fibrous cells encroach upon the follicle, forming whirl-like condensations. Obviously they take part in the resorption of the ovocyte. It is hard to conjecture about the mechanisms by which severa) million ovocytes degenerate over a period spanning 40-50 years, while an adequate number are always spared. In birds and mammals with only a single breeding season, all partly stimulated tertiary follicles are resorbed at the end of each ovulatory period. However, the fact that even in these species not all follicles start enlarging in the same year indicates that at the level of the primary follicle, factors other than gonadotropins are also at work. Even high dosages of injected gonadotropins will not easily exhaust rat ovaries. 3u Progestins and estrogens-in long-term administration as contraceptives largely working by modifying gonadotropin secretion-stop ovogenesis only at the level of tertiary and possibly secondary follicles, but do not speed up degeneration of primary follicles. IS. 18 In mice, hypophysectomy does not prevent the continuous loss of ovocytes from the ovary.15 It cannot be expected, therefore, that prolonged use of contraceptive drugs with consequent suppression of ovulation will appreciably extend or abbreviate the fertile phase of human ovaries. The sequence and time-progression of follicle degeneration are most likely determined by structural qualities of the ovary. By limitation of the reproductive period of women to about 30 years and institution of monthly sexual cycles with only single ovulations, the possible number of eggs delivered per woman is already reduced to about 400. This number is further diminished by a dozen or more by each pregnancy.
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REDUCTION OF FERTILITY IN HUMANS Like other traits of human reproduction, the natural scaling down of fertility can best be understood on an evolutionary basis. All mutational changes must be compatible with the organism's survival or the improvement of its chances. Originally, abundant reproduction had to be reduced when through evolution of nurture the probability of offspring survival increased. The necessary balance was maintained through adaptational changes, mainly in the female. Most important were 3 developments: ( 1) secondary reduction of the number of germ cells by degeneration, beginning at fetal stages and terminating with complete depletion at menopause; (2) establishment of reproductive cycles with single monthly ovulations; and (3) hormonal suppression of ovulation during pregnancy and lactation. With an overwhelmingly large part of reduction of overabundant fertility thus accomplished already by nature, our effort to reduce it further to present day needs might indeed seem a small task. Careful calculations, considering basic fertility and present social conditions, lead to the assumption that without birth control of any kind the average woman should have about seven children,38 which is more than twice the number needed to maintain a stable population. With present technics of birth control it should be possible to establish any desired balance. However, the most recent decline of birth rates in western populations-dropping to levels previously known only in the depression years of the thirties-indicates that with the disorganized use of old-fashioned and modern m"ethods of contraception and abortion, it is difficult, if not impossible, to adjust and maintain rates and quality of reproduction at individually and socially acceptable levels. It is therefore important to continue research in the mechanics of human reproduction. Shifting attention from ovarian to hypophysial physiology and to the role played by the hypothalamus, there appear to be possibilities of preventing not only unwanted pregnancies but also unwanted menses. A normally fertile woman who restricts her pregnancies to 3 has, as a consequence, to pass through an unnaturally high number of infertile menstrual cycles. These, like the seasonal cycles of the bishop birds, are governed by a hypothalamic mechanism that ensures a rhythmic LH··release activity (Fig. 3). Neuroendocrine investigations may reveal ways and means to modify this periodicity. A noncyclic condition can be induced experimentally in perinatal female rats by testiculatimplants 29 or by injection of androgenic and estrogenic steroids. 37 Such "constant estrus" animals have FSH-stimulated ovaries
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with enlarged tertiary follicles that release estrogens at nearly constant levels, but do not contain corpora lutea. This is very much the same condition as is observed in amenorrheic women. In both, ovulationandpregnancy can be induced by administration of luteinizing hormone.12 , 46. The stage which in human development corresponds to the newborn rat is the 2-month-old fetus. 1 It is at this time that in the human male the external genitalia assume their definite shape, provided that testes of normal size and function are present. 45 Apparently at this stage, as in the perinatal male rat, masculinizing substances released from the testes efface the hypothalamic imprint of the sex (LH) cycle. (According to Exley and Corker, in the human male the sexual cycle should only be reduced to a very low level, but not entirely suppressed.) Therefore it is remarkable and possibly of importance that in the development of human ovaries the medullary part often assumes considerable size and testiculoid differentiation43 (Fig. 4). It is very possible that such ovaries release enough masculinizillg substances to reach the hypothalamic center at the critical time. There is then good reason to suspect that at least one type of congenital primary amenorrhea in women is teratogenicly determined by masculinizing agents, from fetal ovaries or from external sources, that reach the hypothalamus late in the second or early in the third fetal month. The genetic and environmental influences which may cause medullary hypertrophy in embryonic ovaries are still entirely unknown. A study of primary amenorrhea and intersexuality giving consideration to possible determinants at the fetal level might furnish some clues about agents that disturb the circadian clock. Sillce evolution has a tendency to run in orthogenic lines, there arises the question of the prospects of fertility in the human female in the relatively not very distant future. True, the recent "baby boom" in the so-called western countries and the "population explosion" in equally so-called development countries give us assurance that in our time the human species shall not disappear from this earth. Nevertheless, medical experts tell us that infertility problems are widespread and plague millions of American couples. Fertility in the human male is much more difficult to assess than in the female, but widespread degeneration of immature germ cells occurs also in the course of testicular development. 2o Infertility seems not less a problem of men than of women. Little is known yet about the genetics of human infertility.27 This is not at all surprisillg ill view of the difficulty in always distinguishing between hereditary and acquired infertility, and of the small number of children in afHicted families. One thing, however, is quite evident-ill modem society the medical help given to patients with infertility problems, by in-
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ducing ovulation with hormone or clomiphene administrations, or by accumulation of oligo sperm ejaculates through freezing methods, counteracts what would be the natural elimination of low-fertility genes. It thereby contributes to the accumulation of infertility in the total gene pool of populations. Thus, rather surprisingly, while the control of overpopulation still is urgently needed, over the horizon there already appears the spectre of doom through infertility. How are future generations going to deal with
Fig. 4. Cross section through ovary of 60-mm. human fetus (11-12 wk.). Cortex contains ovogonia (surface layer) and ovocytes (deep layer). Medulla, testiculoid and with primordial type gonia, is surrounded by connective-tissue layer that contains branching large ovarial blood vessels. (X 145).
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it? Can we trust that macromolecular biologists will have solved the problem of manipulating gene compositions in time to prevent the eventual extinction of our species? Shall humanity always go "the primrose path of dalliance" (Shakespeare) or shall it "go to the ant" and "be wise?" Wise it might be if the majority of people, especially all carriers of multiple defective genes, would renounce the sacred human privilege of self-determining the number of their offspring. While keeping all the other enjoyments of life, they might cede the tasks of reproduction to a selected class, tested for desirable genetic constitutions. It is not unlikely that in a society where women are menstruating and ovulating only after having taken a pill, the old craving for one's own children may subside. The recently deceased, distinguished geneticist H. J. Muller has already proposed a system of future human propagation, relying strongiy on the use of sperms from a restricted number of carefully selected men. In further development of such ideas one may also consider that progress in the methods of organ culture may make it possible to collect as many as 100,000 eggs from 1 ovary of a young woman and make them available for artificial insemination. Together, such methods would permit the highest economy of germ cells in populations with spreading infertility. The mere mention of deviations from traditional ways of reproduction toward industrialized breeding offends widespread sentiments. On the other hand, the laboratory production of homunculus has long been the dream of ambitious scientists. Even though the outlook into the future is obscured by uncertainties, society will at long last not refrain from making use of the discoveries of progressive research. • In summary one can see that the study of the natural ways of fertility restriction by which, in animals and in man, reproduction rates became established that have safeguarded the maintenance of the species, does reveal an imposing system of many cooperating factors and mechanisms. Most of them, like the controlled degeneration of ovocytes in the human ovary and the hypothalamic clockwork regulating breeding cycles, are incompletely understood; b;'if even now the analysis furnishes means and suggestions for improved methods in planned fertility control. The danger of spreading infertility for the future of man is clearly recognized. Possible measures for the preservation of fertile and improved genetic stock that may have to be adopt~d by future generations deserve full attention now. In the meantime, research in the biology of reproduction will continue to be of most vital importance for the evolution and welfare of our species. .'
The Population Council Bio-Medical Division York Ave. and 66th St. New York, N. Y. 10021
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REFERENCES 1. ALTMAN, P. L., and DITTMER, D. S., Eds. "Growth. VII. Prenatal Vertebrate Development." In Biological Handbooks. Federation of the American Society of Experimental Biology, Washington, 1962, p. 269. 2. BAKER, T. G. A quantitative and cytological study of germ cells in human ovaries. Proc Roy Soc (Bioi) 158:417, 1963. 3. BISHOP, D. W. "Biology of Spermatozoa." In Sex and Internal Secretions (Vol. II), Young, W. C., Ed. Williams & Wilkins, Baltimore, 1961, p. 707. 4. BLANDAU, R J. The effects on development when eggs and sperm are aged before fertilization. Ann N Y Acad Sci 57:526, 1954. 5. BUTCHER, R L., and FUGo, N. W. Delayed ovulation and chromosome anomalies. Fertil Steril18:297, 1967. 6. CARR, D. H. Chromosome anomalies as a cause of spontaneous abortion. Amer ] Obstet Gynec 97:283, 1967. 7. CLERMONT, Y. Renewal of spermatogonia in man. Amer J Anat 118:509 . 8. EXLEY, D., and CORKER, C. S. The human male cycle of urinary oestrone and 17oxosteroids. J Endocr 3.5:83, 1966. 9. FARRIS, E. J. Human Fertility and Problems of the Male. Authors Press, White Plains, N. Y., 1950. 10. FRANCHI, L. L., MANDL, A. M., and ZUCKERMAN, S. "The development of the Ovary and the Process of Ovogenesis." In The Ovary, Zuckerman, S., Mandl, A. M., and Eckstein, P., Eds. Acad. Press, New York, 1962, Chap. I. 11. FUGa, N. W., and BUTCHER, R L. Overripeness and the mammalian ova. Fertil Steril17:804, 1966. 12. GEMZELL, C. A. The clinical use of pituitary gonadotrophins in women. J Reprod Fertil12:49, 1966. 13. HUNTER, R H. F. The effects of delayed insemination on fertilization and early cleavage in the pig. J Reprod Fertil13: 133, 1967. 14. IFFY, L. Time of conception in pathological gestation. Proc Roy Soc Med .56: 1098, 1963. 15. JONES, E. C., and KROHN, P. L. The effect of hypophysectomy on age changes in the ovaries of mice. J Endocr 21:497, 1961. 16. LAUWERYNS, J., and FERIN, J. Effects on the ovary of prolonged administration of Lynestrenol: A histological study. Int J Fertil 9:35, 1964. 17. LEHRMAN, D. S., and BRODY, P. Does prolactin induce incubation behaviour in the ring dove? J Endocr 22:269, 1961. 18. LUDWIG, K. S. Vber die morphologischen Vedinderungen am menschlichen Ovar unter Einwirkung eines hormonalen Antikonzeptivums. Experientia 21:726, 1965. 19. MACLEOD, J., and GOLD, R S. The male factor in fertility and infertility: II. Spermatozoa counts in 100 men of known fertility and in 100 cases of infertile marriages. J Urol 66:436, 1951. 20. MANCINI, R E., NARBAITZ, R, and LAVIERI, J. C. Origin and development of the germinative epithelium and Sertoli cells in the human testis: Cytological, cytochemical, and quantitative study. Anat Rec 136:477, 1960. 21. MANDL, A. M. Cyclical changes in the vaginal smear of adult ovariectomized rats. J Exp Bioi 28:585, 1951. 22. MANN, T. The Biochemistry of Semen and of the Male Reproductit1e Tract. Methuen, London, and Wiley, New York, 1954. 23. MULLER, H. J. "Genetic Progress by Voluntarily Conducted Gelminal Choice." In Man and his Future, Wolstenholme, G., Ed. Churchill, London, 1963. 24. NISHIMURA, H., TAKANO, K., TANIMURA, T., YASUDA, M., and UCHIDA, T. High
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incidence of several malformations in the early human embryos as compared with infants. Biol Neonat 10:93, 1966. 25. ODOR, D., and BLANDAU, R. J. Incidence of polyspermy in normal and delayed matings in rats of the Wistar strain. Feml Steril7:456, 1956. 26. PARKES, A. S. "The Biology of Fertility." In Human Fertility and Population Problems, Greep, R. 0., Ed. Schenkmann, Cambridge, Mass., 1964, p. 23. 27. PENROSE, L. S. Genetical aspects of human infertility. Proc Roy Soc [Biol] 159: 93, 1963. 28. PETERS, H., and LEVY, E. Oogenesis in rabbits. ] Exp ZoolI58:169, 1965. 29. PFEIFFER, C. A. Sexual differences of the hypophyses and their determination by the gonads. AmerJ Anat 58:195, 1936. 30. PINKERTON, J. H. M., McKAY, D. G., ADAMS, E. C" and HERTIG, A. T. Development of the human ovary: A study using histochemical technics. Obstet Gynec 18: 152, 1961. 31. POTTER, E. L. "The Ovary in Infancy and Childhood." In The Ovary, Grady, H. G., Ed. International Academy of Pathology Monograph 3. Williams & Wilkins, Baltimore, 1963, p. 11. 32. REMBOLD, H. Die Kastenentstehung bei der Honigbiene, Apis mellifica L. Naturwissenschaften 51:49, 1964. 33. REMBOLD, H., and HANSER, G. Ueber den Weiselzellenfuttersaft der Honigbiene: VIII. Nachweis des determinierenden Prinzips im Futtersaft der Koniginnenlarven. Hoppe Seyler Z Physiol Chem 339:251, 1964. 34. RIDDLE, 0., and BATES, W. "The Preparation, Assay and Actions of Lactogenic Hormone." In Sex and Internal Secretions, Allen, E., Ed. Williams & Wilkins, Baltimore, 1939. 35. RILEY, G. M., and WITscm, E. Unpublished experiments. 36. SEGAL, S. J., and WITSCHI, E. The specificity of the weaver finch test for the luteinizing gonadotrophins (LH and CGH). ] Clin Endocr 15:880, 1955. 37. TAKEWAKI, K. Some experiments on the control of hypophysealgonadal system in the rat. Gen Comp Endocr (Suppl. 1) :309,1962. 38. TIETZE, C. Pregnancy rates and birth rates. Populatiof,l Studies 16:31, 1962. 39. VAN WAGENEN, G., and SIMPSON, M. E. Embryology of the Ovary and Testis, Homo sapiens and Macaca mulatta. Yale Univ. Press, New Haven, 1965. 40. WITscm, E. Development of Vertebrates. Saunders, Philadelphia, 1956. 41. WITscm, E. "Sex and Secondary Sexual Characters." In Biology and Comparative Physiology of Birds (Vol. II), Marshall, A. J., Ed. Acad. Press, New York, 1961,
p.115.
42. WITscm, E. "Embryology of the Ovary." In The Ovary, Grady,' H. G., Ed. International Academy of Pathology Monograph 3. Williams & Wilkins, Baltimore, 1963, p. 1. 43. WITscm, E. "Grundlagen der sexuellen Differenzierung." In Gyniikologie und Geburtshilfe (Bd. I), Kaeser, E., et al. Eds. Thieme, Stuttgart. In press. 44. WITscm, E., and LAGUENS, R. Chromosomal aberrations in embryos from overripe eggs. Develop Biol 7:605, 1963. 45. WITscm, E., and MUNEMITSU, S. Fetal stage of a male pseudohermaphrodite. Rev Suisse Zool71:287, 1964. 46. WITscm, E., and PFEIFFER, C. A. The hormonal control of oestrus, ovulation and mating in the female rat. Anat Reo 64:85, 1935.
THE American Fertility Society was organized in 1944 after a period of economic and of reproductive depression, with the declared aim "for the study of sterility." Parkes tells how the British government, earnestly concerned about a birth rate that in the thirties had fallen below the replacement level, appointed a Royal Commission on Population. Leading geneticists expressed dim views about the seeming decline of fertility in western women, but before any remedies could be proposed the worldwide "baby boom" of the mid-forties dispelled these worries-if only to create new ones. Two reassuring conclusions can be drawn from these recent events. Evidently the human species still holds considerable reserves in natural fertility, and its reproductive rate responds readily to environmental factors. Hence both are open to willed management. Mankind striving to direct its future could choose and maintain the optimal size of its own population, depending only on concerted resolution and social organization. Man was aware of this even in ancient times. In the thi:(d century when every life was highly prized-because excessive mortality rates combinea with a great demand for workers, soldiers, and slaves-Tertullian held that not only the destruction of a child in the womb of the mother but also the prevention of conception was sinful. Sanctifying such once well-considered teaching has created a dogma, adherence to which leads to difficulties under present, radically changed medical and social conditions. Intentional restriction of the human reproduction rate has become a generally recognized necessity. Fortunately at this critical juncture, scientific study of ovarian cycles, of fertilization, and of gestation already provides a fairly wide choice of means and ways for the application of such control. NATURAL METHODS OF CONTROL
Reviewing some of nature's own ways of fertility restriction, one cannot, without mention, pass by the claim that calculated rhythmic abstinence by From the Anatomy Department of the University of Basel, Basel, Switzerland. The Ayerst lecture, presented at the 23rd Annual Meeting of The American Fertility Society, Washington, D. C., Apr. 14-16, 1967.
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man should also be valued as a "natural" control method. Unfortunately it is based on a misinterpretation of human sex physiology. In lower veltebrates and wild birds sex drive and reproduction as a rule are seasonally restricted. In many mammals cycles of shorter duration have been established. The females then become receptive and attractive to the males only during a relatively short period, the "heat," coinciding with ovulation time. However, the corresponding human cycle is circadian. Recognition of ovulation time is lost, but the gain of this evolution is that it keeps males and females constantly interested in each other, thereby creating a basis for close and durable family life. The abstinence method opposes nature's intentions by setting up a new rhythm, biweekly alternating "les plaisirs du vice et les honneurs de la vertu" (Rousseau). Not only disregarding a powerful psychophysiologic component of adult sex life, its practice also endangers the quality and well-being of the offspring. If the "safe period" is not conservatively observed, or when ovulation is retarded, chances are that fertilization may occur after its optimal time has passed and when a waiting egg has become overripe. It is now a well-established fact that delay of insemination causes deterioration of vertebrate eggs, with consequent chromosomal abnormalities,5,44 polyspermy,25 and teratologic development. 4 • 11. 13. 14 Intrafollicular and postovulatory overripeness can clearly be recognized as a major cause of the relatively high incidence of malformations in early human embryos and fetuses. B • 24 Repression of reproduction potentials is, however, not a rare occurrence in nature and the study of some examples leads to interesting discoveries. One may wonder how much knowledge the old Israelite had about the organization of hymenopteran states, when he counseled: "Go to the ant, thou sluggard; consider their ways and be wise." More than 2000 years later, we now realize that the social states of ants and honey bees have long solved many problems which for man still are matters of foremost concern, such as unemployment, predetermination of sex, of fertility, and of social relationships. Of the 50,000 to 80,000 female bees ordinarily inhabiting the hive, only 1 is fertile-the queen. Worker bees are almost entirely sterile. Their rudimentary ovaries consist of only 4-10 short ovarioles, while those of the queen total 150--200. Queens and workers are genetically identical. Queens are raised in larger cells than workers and are fed more abundantly, but the differentiating factor is rather qualitative than quantitative. One-dayold larvae can be raised in incubators, and those taken from worker cells can become queens if fed with "royal jelly," that is, with diets that had been prepared for queen larvae. All nursing food is produced by young workers. In their heads they carry 3 large glands which secrete the food-
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saps. These include all special inductor substances in a proteinic base. Rembold found much higher concentrations of pantothenic acid and biopterin in the royal jelly than in the fare for worker larvae. However, incubation experiments indicate that the determination of "royal class" really depends on still another but less known factor: "chromatographic fraction f." At any rate, infertility in worker bees results here from a nutritional deficiency, possibly a specific avitaminosis. In lower vertebrates the survival of a species usually is attained by abundant fertility, with production of billions of sperms by the male and millions of eggs by the female. In batches of thousands of frog eggs one rarely finds even a single nonfertilized or abnormally developing ovum. Protected by tough jelly masses, the entire offspring reaches the stage of hatching larvae. But then follows a carnage; even the parents like to swallow juicy larvae and little metamorphosed frogs. However, the most important limiting factor is the availability of niches that offer food and shelter. When frog populations today are rapidly decreasing or disappearing it is less because of predation than drainage of swamps and the massive use of insecticides. Severe population problems arise with the evolution of nurture. Parents of the 3 highest classes of vertebrates supply their offspring with food, protect them from unfavorable environments, and defend them against aggression. 40 Nevertheless, the ovaries of Hedging song birds contain several hundred thousand egg cells. Obviously these are far more than the number of nestlings any pair of parents could ever care for. In the course of evolution ways and means had to be found to reduce their number. Even before females reach adulthood all their gonia enter the maturation or ovocyte stage, precluding further multiplication. This is an important advance over amphibians, where year after year new generations of eggs proliferate from residual ovogonia. Furthermore, in most birdsexcept some hawks-the right ovary is vestigial and seldom ripens an egg. However, the most characteristic means of fertility restriction in amniots is the regulated intraovarial germ cell degeneration. In song birds it is linked with the seasonal breeding cycles. At the approach of a reproductive phase-usually in spring-several hundred ovocytes start growing, though only a few eggs will mature fully and be ovulated. All other enlarged follicles degenerate, many during the incubation time. Only small primary egg follicles persist throughout the sexual rest (eclipse) periods-usually fall and winter. They serve as a store for subsequent reproductive seasons (Fig. 1). Thus an effective reduction in propagation rate is attained by restriction of sexual life to just a few months every year. Hormonal factors play obvious roles in the mechanism of such seasonal
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breeding. The common starling produces only 1 brood yearly, and other species possibly 2 or 3. In free nature the female lays 1 egg per day and ovulation stops as soon as a set of 5 is in the nest. Experiments have shown that laying does not cease because of exhaustion of the ovary. If, after the second egg is laid, 1 egg is removed daily, birds have been seen to continue
Fig. 1. Ovaries of song birds: (left) in eclipse season (winter); (center) in breeding season (spring); (right) during incubation (early summer). (about X 3)
daily production over 2 full months. 41 After laying the fifth egg, undisturbed birds immediately become broody. According to Riddle and Bates this comes about by a change from gonadotropic to luteotropic (lactogenic) hormone secretion. Observations by Lehrman and Brody also indicate a closely related elevation of progesterone output. The quick change from egg production to atresia starts from a peripheral sensory perception (probably mostly visual) that sets in motion a whole sequence of reactions passing through the central nervous system, the hypothalamus, and the hypophysis, and ending with drastic changes in the gonad. Beyond doubt, changes in day length and other environmental conditions play important roles in the timing of these annual sex cycles. However, their rhythm depends even more on an inborn and genicly fixed biologic clock that regulates the output of LH by the hypophysis. The development of seasonal nuptial plumages of many male birds is induced by high luteinizing hormone ( LH ) levels,36 while bill colors more often reflect concentrations of gonadal steroidsY In male bishop birds (e.g., Euplectes franciscanus) a resplendent red and black cock plumage is donned at the advent of the mating period, replacing the drab hen plumage which is worn by males in eclipse, and by females throughout the year (Fig. 2). After castration the plumage changes continue synchronously with those of normal males, but the bills are always white. Ovariectomized females also participate in the plumage changes, with the same rhythm. Naturally, the bills of all castrates are white. One would have expected, from the seasonal development of the ovaries, that females must have the same kind
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of hypothalamo-hypophysial circadian timepiece as the males. In the intact female the cock plumage, however, does not manifest itself, because it is suppressed by the output of ovarian estrogens41 (Fig. 3). It is not known whether an autonomous cycle exists also for follicle-stimulating hormone (FSH) release. Weaver finches are the only animals, as far as is Reproductive Season
Eclipse Season
Fig. 2. Cock and hen plumages in nonnal and in castrated weaver finches (Euplectes) , with indication of honnonal conditions.
CASTRATES
known, that exhibit LH cycles by somatic reactions in· the absence of gonads. Slight rhythmic changes in the vaginas of spayed adult rats have been observed but have not been hormonally clarified. 21 GERM CELL PRODUCTION IN MAMMALS The well-known initially high productivity in germ cells by mammals must be considered a relict-a sort of memory persisting from times hundreds of million years ago, when coelacanth-like ancestors spawned eggs by the thousands and produced sperms in uncountable trillions. In the course of evolution the actual need for mature eggs and sperms has fallen to only a small fraction of what it was then. That extreme economy in the use of spermatozoa could possibly be practiced is exemplified by the queen bee. She releases scarcely one dozen sperms in fertilizing each egg. She is also extraordinary in keeping mature sperms stored in her seminal receptacle alive and fit for insemination for lilS long as 4 or 5 years.
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Quite to the contrary, male germ cells are still squandered at incomprehensible rates by mammals. According to Mann the average human ejaculate contains about 350 million sperms. Of the trillion spent by a man in a lifetime, only 3-5 may actually enter an egg. Least understood is the fact that ejaculates containing below 20 million actively moving
rrm .... mT1 •.•• mn Fig. 3. Pathways in control of gonad development and of coloration of feathers of weaver finches. Seasonal timer (horizontal arrow) in hypothalamus determines alternating phases of activity (bars with vertical lines) and inactivity (dots) regarding production of LHRF (LH-releasing factor). Squares in anterior lobe of hypophysis indicate cells producing LH on stimulation by LHRF. Three oblique arrows point at responses to LH in target organs: maturation and ovulation of ovarian follicles (right), pigment production by melanoblasts of feather papillae (left), and blockage of latter reaction b)' estrogens (center).
sperms per milliliter (less than 80 million per ejaculate) are subfertile. 3 , 9, 19 Nevertheless, first steps toward economy are recognizable even here. Quantitative studies in spermatogenesis have disclosed that not more than 30% of the gonia of perinatal male rats become progenitors of spermatogonia in adult testes. 7 Since the size of testes and of ejaculates differs greatly from species to species, it is to be assumed that the proportion of germ cell degeneration varies accordingly and probably is relatively high in the human. 20 More extensively studied is the complex system of natural restriction during human ovogenesis. 2 ,lO, 80, 42 The primary separation of soma and germ cells has not been observed so far, but it must occur before or close to the time of implantation of the blastocyst (about the 125- or 250-cell stage) . In an embryo of 16 somites, 109 primordial gonia were identified,
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which probably means that the full number was near 128-the product from an original pair of stem cells by 6 mitotic divisions. At this stage they are imbedded in the endoderm near the body stalk. Table 1 illustrates the germ cell increase toward a maximum at mid-pregnancy, in female embryos and fetuses. Starting at about the twelfth week, ovogonia enter the meiotic stages. First, some small primary ovocytes, the auxocytes of the leptotene stage, make their appearance. At this time chromosome duplication and DNA synthesis come to an end. 28 The chromosomes of the mature egg have already formed. Their composition may persist, essentially unchanged, for as long as 50 years. At 6 months virtually all germ cells have passed through these transformations; most have reached the pachytene and some the early diplotene stages. From this point, no further mitotic activity occurs; the population of female germ cells has attained its acme.,.... about 6 million ovocytes. 2 , 40 Throughout the prenatal phases one also observes degenerating germ cells. Elimination of ovocytes continues through birth, and through the juvenile and mature phases, until complete disappearance at menopause. The organization of primary, secondary, and tertiary ovarian follicles starts even before birth and continues throughout childhood and maturity. The history of the ovary in infancy and childhood has been outlined by Potter and by van Wagenen and Simpson. While at birth the compact cortical body of ovocytes and follicles is covered only by a thin peritoneal surface epithelium, fibrous connective tissue cells gradually intervene and TABLE 1. Number of Germ Cells in Human Embryos and Fetuses Size Stage*
16 18 20 24 26 27 28 29 33 35a 35b 36
(mm.)
3.0 3.8 4.2 5.5 8 9 11 15 24 60 115 320
Age (days)
Sex
Germ cell type
No.
26 29 31 35 38 40 42 44 56 77
Indet. Indet. Indet. Indet. Indet. Indet. Indet. Indet. F F
109 586 1366 451 873 1874 1536 2057 100,000 1 million
105 Birth
F F
Gonia Gonia Gonia Gonia Gonia Gonia Gonia Gonia Ovogonia Ovogonia + ovocytes Ovocytes Ovocytes + prim. foIl.
Both gonads are included in counts.
* From Altman and Dittmer.!
5-6 million 5-6 million
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form a moderately hyalinized ovarian tunic. Consequently, at menarche the primary follicles are located deep between the thick "tunic" and the central medulla, in the stroma of the ovary. During infancy more than 90% of the follicles disappear by degeneration. To what extent the process depends on or is accelerated by periods of elevated gonadotropin secretion is not at all clear. In a 19-year-old primipara, by the study of several hundred sections, it was estimated that about 200,000 healthy follicles were still present. 40 Probably there exist great individual differences among normally menstruating women of this age group. Degenerating follicles are found in every adult ovary, but only after age 43 does it become difficult to find the few scattered primary follicles. Degeneration, however, is not restricted to secondary and tertiary follicles-stages that probably already had responded to gonadotropic stimulation. Primary follicles also disappear, becoming enclosed by fibrous cells and resorbed. It is not yet clear whether degeneration starts from the single layered granulosa or the surrounding theca and stroma cells. At early stages the granulosa is incomplete. Fibrous cells encroach upon the follicle, forming whirl-like condensations. Obviously they take part in the resorption of the ovocyte. It is hard to conjecture about the mechanisms by which severa) million ovocytes degenerate over a period spanning 40-50 years, while an adequate number are always spared. In birds and mammals with only a single breeding season, all partly stimulated tertiary follicles are resorbed at the end of each ovulatory period. However, the fact that even in these species not all follicles start enlarging in the same year indicates that at the level of the primary follicle, factors other than gonadotropins are also at work. Even high dosages of injected gonadotropins will not easily exhaust rat ovaries. 3u Progestins and estrogens-in long-term administration as contraceptives largely working by modifying gonadotropin secretion-stop ovogenesis only at the level of tertiary and possibly secondary follicles, but do not speed up degeneration of primary follicles. IS. 18 In mice, hypophysectomy does not prevent the continuous loss of ovocytes from the ovary.15 It cannot be expected, therefore, that prolonged use of contraceptive drugs with consequent suppression of ovulation will appreciably extend or abbreviate the fertile phase of human ovaries. The sequence and time-progression of follicle degeneration are most likely determined by structural qualities of the ovary. By limitation of the reproductive period of women to about 30 years and institution of monthly sexual cycles with only single ovulations, the possible number of eggs delivered per woman is already reduced to about 400. This number is further diminished by a dozen or more by each pregnancy.
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REDUCTION OF FERTILITY IN HUMANS Like other traits of human reproduction, the natural scaling down of fertility can best be understood on an evolutionary basis. All mutational changes must be compatible with the organism's survival or the improvement of its chances. Originally, abundant reproduction had to be reduced when through evolution of nurture the probability of offspring survival increased. The necessary balance was maintained through adaptational changes, mainly in the female. Most important were 3 developments: ( 1) secondary reduction of the number of germ cells by degeneration, beginning at fetal stages and terminating with complete depletion at menopause; (2) establishment of reproductive cycles with single monthly ovulations; and (3) hormonal suppression of ovulation during pregnancy and lactation. With an overwhelmingly large part of reduction of overabundant fertility thus accomplished already by nature, our effort to reduce it further to present day needs might indeed seem a small task. Careful calculations, considering basic fertility and present social conditions, lead to the assumption that without birth control of any kind the average woman should have about seven children,38 which is more than twice the number needed to maintain a stable population. With present technics of birth control it should be possible to establish any desired balance. However, the most recent decline of birth rates in western populations-dropping to levels previously known only in the depression years of the thirties-indicates that with the disorganized use of old-fashioned and modern m"ethods of contraception and abortion, it is difficult, if not impossible, to adjust and maintain rates and quality of reproduction at individually and socially acceptable levels. It is therefore important to continue research in the mechanics of human reproduction. Shifting attention from ovarian to hypophysial physiology and to the role played by the hypothalamus, there appear to be possibilities of preventing not only unwanted pregnancies but also unwanted menses. A normally fertile woman who restricts her pregnancies to 3 has, as a consequence, to pass through an unnaturally high number of infertile menstrual cycles. These, like the seasonal cycles of the bishop birds, are governed by a hypothalamic mechanism that ensures a rhythmic LH··release activity (Fig. 3). Neuroendocrine investigations may reveal ways and means to modify this periodicity. A noncyclic condition can be induced experimentally in perinatal female rats by testiculatimplants 29 or by injection of androgenic and estrogenic steroids. 37 Such "constant estrus" animals have FSH-stimulated ovaries
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with enlarged tertiary follicles that release estrogens at nearly constant levels, but do not contain corpora lutea. This is very much the same condition as is observed in amenorrheic women. In both, ovulationandpregnancy can be induced by administration of luteinizing hormone.12 , 46. The stage which in human development corresponds to the newborn rat is the 2-month-old fetus. 1 It is at this time that in the human male the external genitalia assume their definite shape, provided that testes of normal size and function are present. 45 Apparently at this stage, as in the perinatal male rat, masculinizing substances released from the testes efface the hypothalamic imprint of the sex (LH) cycle. (According to Exley and Corker, in the human male the sexual cycle should only be reduced to a very low level, but not entirely suppressed.) Therefore it is remarkable and possibly of importance that in the development of human ovaries the medullary part often assumes considerable size and testiculoid differentiation43 (Fig. 4). It is very possible that such ovaries release enough masculinizillg substances to reach the hypothalamic center at the critical time. There is then good reason to suspect that at least one type of congenital primary amenorrhea in women is teratogenicly determined by masculinizing agents, from fetal ovaries or from external sources, that reach the hypothalamus late in the second or early in the third fetal month. The genetic and environmental influences which may cause medullary hypertrophy in embryonic ovaries are still entirely unknown. A study of primary amenorrhea and intersexuality giving consideration to possible determinants at the fetal level might furnish some clues about agents that disturb the circadian clock. Sillce evolution has a tendency to run in orthogenic lines, there arises the question of the prospects of fertility in the human female in the relatively not very distant future. True, the recent "baby boom" in the so-called western countries and the "population explosion" in equally so-called development countries give us assurance that in our time the human species shall not disappear from this earth. Nevertheless, medical experts tell us that infertility problems are widespread and plague millions of American couples. Fertility in the human male is much more difficult to assess than in the female, but widespread degeneration of immature germ cells occurs also in the course of testicular development. 2o Infertility seems not less a problem of men than of women. Little is known yet about the genetics of human infertility.27 This is not at all surprisillg ill view of the difficulty in always distinguishing between hereditary and acquired infertility, and of the small number of children in afHicted families. One thing, however, is quite evident-ill modem society the medical help given to patients with infertility problems, by in-
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ducing ovulation with hormone or clomiphene administrations, or by accumulation of oligo sperm ejaculates through freezing methods, counteracts what would be the natural elimination of low-fertility genes. It thereby contributes to the accumulation of infertility in the total gene pool of populations. Thus, rather surprisingly, while the control of overpopulation still is urgently needed, over the horizon there already appears the spectre of doom through infertility. How are future generations going to deal with
Fig. 4. Cross section through ovary of 60-mm. human fetus (11-12 wk.). Cortex contains ovogonia (surface layer) and ovocytes (deep layer). Medulla, testiculoid and with primordial type gonia, is surrounded by connective-tissue layer that contains branching large ovarial blood vessels. (X 145).
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it? Can we trust that macromolecular biologists will have solved the problem of manipulating gene compositions in time to prevent the eventual extinction of our species? Shall humanity always go "the primrose path of dalliance" (Shakespeare) or shall it "go to the ant" and "be wise?" Wise it might be if the majority of people, especially all carriers of multiple defective genes, would renounce the sacred human privilege of self-determining the number of their offspring. While keeping all the other enjoyments of life, they might cede the tasks of reproduction to a selected class, tested for desirable genetic constitutions. It is not unlikely that in a society where women are menstruating and ovulating only after having taken a pill, the old craving for one's own children may subside. The recently deceased, distinguished geneticist H. J. Muller has already proposed a system of future human propagation, relying strongiy on the use of sperms from a restricted number of carefully selected men. In further development of such ideas one may also consider that progress in the methods of organ culture may make it possible to collect as many as 100,000 eggs from 1 ovary of a young woman and make them available for artificial insemination. Together, such methods would permit the highest economy of germ cells in populations with spreading infertility. The mere mention of deviations from traditional ways of reproduction toward industrialized breeding offends widespread sentiments. On the other hand, the laboratory production of homunculus has long been the dream of ambitious scientists. Even though the outlook into the future is obscured by uncertainties, society will at long last not refrain from making use of the discoveries of progressive research. • In summary one can see that the study of the natural ways of fertility restriction by which, in animals and in man, reproduction rates became established that have safeguarded the maintenance of the species, does reveal an imposing system of many cooperating factors and mechanisms. Most of them, like the controlled degeneration of ovocytes in the human ovary and the hypothalamic clockwork regulating breeding cycles, are incompletely understood; b;'if even now the analysis furnishes means and suggestions for improved methods in planned fertility control. The danger of spreading infertility for the future of man is clearly recognized. Possible measures for the preservation of fertile and improved genetic stock that may have to be adopt~d by future generations deserve full attention now. In the meantime, research in the biology of reproduction will continue to be of most vital importance for the evolution and welfare of our species. .'
The Population Council Bio-Medical Division York Ave. and 66th St. New York, N. Y. 10021
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REFERENCES 1. ALTMAN, P. L., and DITTMER, D. S., Eds. "Growth. VII. Prenatal Vertebrate Development." In Biological Handbooks. Federation of the American Society of Experimental Biology, Washington, 1962, p. 269. 2. BAKER, T. G. A quantitative and cytological study of germ cells in human ovaries. Proc Roy Soc (Bioi) 158:417, 1963. 3. BISHOP, D. W. "Biology of Spermatozoa." In Sex and Internal Secretions (Vol. II), Young, W. C., Ed. Williams & Wilkins, Baltimore, 1961, p. 707. 4. BLANDAU, R J. The effects on development when eggs and sperm are aged before fertilization. Ann N Y Acad Sci 57:526, 1954. 5. BUTCHER, R L., and FUGo, N. W. Delayed ovulation and chromosome anomalies. Fertil Steril18:297, 1967. 6. CARR, D. H. Chromosome anomalies as a cause of spontaneous abortion. Amer ] Obstet Gynec 97:283, 1967. 7. CLERMONT, Y. Renewal of spermatogonia in man. Amer J Anat 118:509 . 8. EXLEY, D., and CORKER, C. S. The human male cycle of urinary oestrone and 17oxosteroids. J Endocr 3.5:83, 1966. 9. FARRIS, E. J. Human Fertility and Problems of the Male. Authors Press, White Plains, N. Y., 1950. 10. FRANCHI, L. L., MANDL, A. M., and ZUCKERMAN, S. "The development of the Ovary and the Process of Ovogenesis." In The Ovary, Zuckerman, S., Mandl, A. M., and Eckstein, P., Eds. Acad. Press, New York, 1962, Chap. I. 11. FUGa, N. W., and BUTCHER, R L. Overripeness and the mammalian ova. Fertil Steril17:804, 1966. 12. GEMZELL, C. A. The clinical use of pituitary gonadotrophins in women. J Reprod Fertil12:49, 1966. 13. HUNTER, R H. F. The effects of delayed insemination on fertilization and early cleavage in the pig. J Reprod Fertil13: 133, 1967. 14. IFFY, L. Time of conception in pathological gestation. Proc Roy Soc Med .56: 1098, 1963. 15. JONES, E. C., and KROHN, P. L. The effect of hypophysectomy on age changes in the ovaries of mice. J Endocr 21:497, 1961. 16. LAUWERYNS, J., and FERIN, J. Effects on the ovary of prolonged administration of Lynestrenol: A histological study. Int J Fertil 9:35, 1964. 17. LEHRMAN, D. S., and BRODY, P. Does prolactin induce incubation behaviour in the ring dove? J Endocr 22:269, 1961. 18. LUDWIG, K. S. Vber die morphologischen Vedinderungen am menschlichen Ovar unter Einwirkung eines hormonalen Antikonzeptivums. Experientia 21:726, 1965. 19. MACLEOD, J., and GOLD, R S. The male factor in fertility and infertility: II. Spermatozoa counts in 100 men of known fertility and in 100 cases of infertile marriages. J Urol 66:436, 1951. 20. MANCINI, R E., NARBAITZ, R, and LAVIERI, J. C. Origin and development of the germinative epithelium and Sertoli cells in the human testis: Cytological, cytochemical, and quantitative study. Anat Rec 136:477, 1960. 21. MANDL, A. M. Cyclical changes in the vaginal smear of adult ovariectomized rats. J Exp Bioi 28:585, 1951. 22. MANN, T. The Biochemistry of Semen and of the Male Reproductit1e Tract. Methuen, London, and Wiley, New York, 1954. 23. MULLER, H. J. "Genetic Progress by Voluntarily Conducted Gelminal Choice." In Man and his Future, Wolstenholme, G., Ed. Churchill, London, 1963. 24. NISHIMURA, H., TAKANO, K., TANIMURA, T., YASUDA, M., and UCHIDA, T. High
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incidence of several malformations in the early human embryos as compared with infants. Biol Neonat 10:93, 1966. 25. ODOR, D., and BLANDAU, R. J. Incidence of polyspermy in normal and delayed matings in rats of the Wistar strain. Feml Steril7:456, 1956. 26. PARKES, A. S. "The Biology of Fertility." In Human Fertility and Population Problems, Greep, R. 0., Ed. Schenkmann, Cambridge, Mass., 1964, p. 23. 27. PENROSE, L. S. Genetical aspects of human infertility. Proc Roy Soc [Biol] 159: 93, 1963. 28. PETERS, H., and LEVY, E. Oogenesis in rabbits. ] Exp ZoolI58:169, 1965. 29. PFEIFFER, C. A. Sexual differences of the hypophyses and their determination by the gonads. AmerJ Anat 58:195, 1936. 30. PINKERTON, J. H. M., McKAY, D. G., ADAMS, E. C" and HERTIG, A. T. Development of the human ovary: A study using histochemical technics. Obstet Gynec 18: 152, 1961. 31. POTTER, E. L. "The Ovary in Infancy and Childhood." In The Ovary, Grady, H. G., Ed. International Academy of Pathology Monograph 3. Williams & Wilkins, Baltimore, 1963, p. 11. 32. REMBOLD, H. Die Kastenentstehung bei der Honigbiene, Apis mellifica L. Naturwissenschaften 51:49, 1964. 33. REMBOLD, H., and HANSER, G. Ueber den Weiselzellenfuttersaft der Honigbiene: VIII. Nachweis des determinierenden Prinzips im Futtersaft der Koniginnenlarven. Hoppe Seyler Z Physiol Chem 339:251, 1964. 34. RIDDLE, 0., and BATES, W. "The Preparation, Assay and Actions of Lactogenic Hormone." In Sex and Internal Secretions, Allen, E., Ed. Williams & Wilkins, Baltimore, 1939. 35. RILEY, G. M., and WITscm, E. Unpublished experiments. 36. SEGAL, S. J., and WITSCHI, E. The specificity of the weaver finch test for the luteinizing gonadotrophins (LH and CGH). ] Clin Endocr 15:880, 1955. 37. TAKEWAKI, K. Some experiments on the control of hypophysealgonadal system in the rat. Gen Comp Endocr (Suppl. 1) :309,1962. 38. TIETZE, C. Pregnancy rates and birth rates. Populatiof,l Studies 16:31, 1962. 39. VAN WAGENEN, G., and SIMPSON, M. E. Embryology of the Ovary and Testis, Homo sapiens and Macaca mulatta. Yale Univ. Press, New Haven, 1965. 40. WITscm, E. Development of Vertebrates. Saunders, Philadelphia, 1956. 41. WITscm, E. "Sex and Secondary Sexual Characters." In Biology and Comparative Physiology of Birds (Vol. II), Marshall, A. J., Ed. Acad. Press, New York, 1961,
p.115.
42. WITscm, E. "Embryology of the Ovary." In The Ovary, Grady,' H. G., Ed. International Academy of Pathology Monograph 3. Williams & Wilkins, Baltimore, 1963, p. 1. 43. WITscm, E. "Grundlagen der sexuellen Differenzierung." In Gyniikologie und Geburtshilfe (Bd. I), Kaeser, E., et al. Eds. Thieme, Stuttgart. In press. 44. WITscm, E., and LAGUENS, R. Chromosomal aberrations in embryos from overripe eggs. Develop Biol 7:605, 1963. 45. WITscm, E., and MUNEMITSU, S. Fetal stage of a male pseudohermaphrodite. Rev Suisse Zool71:287, 1964. 46. WITscm, E., and PFEIFFER, C. A. The hormonal control of oestrus, ovulation and mating in the female rat. Anat Reo 64:85, 1935.