INTRAUTERINE GONADAL DEVELOPMENT*

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FERTILITY AND STERILITY Copyright @ 1976 The American Fertility Society Vol. 27, No.5, May 1976 Printed in U.SA. INTRAUTERINE GONADAL DEVELOPMENT* HANNAH PETERS, M.D. The Finsen Laboratory, The Finsen Institute,Copenhagen, Denmark This review article summarizes the intrauterine gonadal development of both male and female human embryos and fetuses.

1 FERTILITY AND STERILITY 1976 The American Fertility Society Vol. 27, No.5, May 1976 Printed in U.SA. INTRAUTERINE GONADAL DEVELOPMENT* HANNAH PETERS, M.D. The Finsen Laboratory, The Finsen Institute,Copenhagen, Denmark This review article summarizes the intrauterine gonadal development of both male and female human embryos and fetuses. It describes in detail (1) the organization of the indifferent gonad and its seeding by the extragonadal germ cells, (2) the development of the duct systems before sex differentiation, and (3) the controlling mechanism of differentiation of the ovaries and testes. Timetables for the development and differentiation of the human male and fe male reproductive systems have been compiled from the literature. The reproductive organs consist of a gonad, an internal duct system, and external genitalia. The origin of the gonad is common for both sexes, whereas the duct systems that develop into the excretory pathways of the gametes come from two different duct syster.:ls, both of which are present in the early embryos before sexual differentiation takes place. THE INDIFFERENT GONAD The gonad is derived from three different components: (1) the celomic epithelium, (2) the subjacent mesenchyme of a limited part of the mesonephric ridge, and (3) of the primordial germ cells. Primordia of sex glands appear in human embryos 4 to 5 mm long! as a thickening of the celomic epithelium on the medial aspect of the mesonephros. The mesonephros projects into the celomic cavity and has a thick mesentery. The whole mass, the mesentery, the mesonephros, and the celomic covering, makes Accepted December 18, *Presented in part at a symposium, "The Hypothala.!nic-Pituitary-Gonadal Axis," held at the Royal Society of Medicine, February 25 and 26, 1975, London, England. 493 up the urogenital ridge. The primordial germ cells arise outside the urogenital ridge in the dorsal endoderm of the yolk sac. They migrate via the mesentery of the gut into the primordial gonad.2, 3 During their migration the germ cells multiply by mitosis. At this time no morphologically distinguishable features characterize them as male or female germ cells. As they enter the germinal ridge, they apparently carry with them some of the cells from the celomic epithelium into the primitive gonad. That this can happen was shown experimentally by EvereW in the mouse and has recently been reaffirmed by Gondos4 in the rabbit. Before differentiation, then, the early gonad consists mainly of a proliferating celomic epithelium and a mesenchymal cell mass on the urogenital ridge which contains some mesonephric components and primordial germ cells that have recently colonized the organ. THE DUCT SYSTEMS BEFORE SEX DIFFERENTIATION The duct systems that later form the male or the female excretory pathways

The mesonephros consists essentially of a group of tubules, the mesonephric tubules, which empty into a common duct, the mesonephric duct, which in turn ends in the cloaca.

2 PETERS 494 for the gametes differ in origm in the two sexes. Two paired duct systems are present in the early embryo: the mesonephric, or Wolffian, ducts and the paramesonephric, or Mullerian, ducts, which form laterally and separately from the Wolffian ducts. The mesonephros consists essentially of a group of tubules, the mesonephric tubules, which empty into a common duct, the mesonephric duct, which in turn ends in the cloaca. In the male only the mesonephric duct system persists after sex differentiation. In the female the paramesonephric duct persists and most of the mesonephric duct system regresses. Before sexual differentiation takes place we find in the embryo an undifferentiated gonad and two sets of welldefined ducts. During male differentiation the gonad is organized into a testis, the Wolffian duct is transformed into the epididymis, the ductus deferens, and the seminal vesicles; the Mullerian ducts disappear and the male external genitalia form. During female differentiation the gonad is organized and forms the ovary, the Mullerian ducts develop into the oviducts, the uterus and part of the vagina, and the Wolffian ducts regress except for some of the mesonephric tubules from which the rete ovarii develop. Sexual differentiation starts somewhat earlier in the male than in the female. MALE DIFFERENTIATION The first somatic signs of sex differentiation appear in those embryos that carry the Y chromosome. However, for the complete expression of maleness, in addition to the Y chromosome, a gene on the X chromosome responsive to testosterone 5 is necessary. The combined action of testosterone and the product of the gene results in the activation or derepression of all genes required for male differentiation. May 1976 FIG. 1. Early seminiferous cord organization (arrows) in a 12-day-old mouse embryo (x 475). Testis Formation. The differentiation of the testis includes the formation of the seminiferous cords that contain the genn cells and the Sertoli cells, the formation of the Leydig cells, and the incorporation of the rete testis. The first process in the testicular development is the differentiation of the Sertoli cells. It was formerly believed that the seminiferous cords are formed by down growth from the surface epithelium. However, Jost et al. 6 have recently defined the sequence of differentiation. The Sertoli cells within the gonad enlarge, make contact with each other, and engulf the germ cells, thus forming the seminiferous cords (Fig. 1). The process of testicular organization begins near the mesonephric tubules, which, in rats, were found to disintegrate and release granules. 6 Thus J ost et al. infer that the organization of the seminiferous cord is induced by some substance given off by the mesonephric tubules. The same process can also be seen in the mouse (Fig. 2). Simultaneously, a scarcity of r

3 Vol. 27, No.5 INTRAUTERINE GONADAL DEVELOPMENT 495 FIG. 3. Testis of a 15-day-old mouse embryo. The gonocytes lie in the center of the seminiferous cords, and the Sertoli cells occupy the periphery (X 120). FIG. 2. Mesonephric tubules (mt) with granules close to seminiferous cord (s) in a 12-day-old male mouse embryo (x475). cells in the surface of the gonad develops, a characteristic condition in the early embryonic testis (the tunica albuguinea). The male germ. cells become completely enveloped in the seminiferous cords where they continue to divide mitotically for a short time. The gonocytes stop dividing temporarily when the Sertoli cells are arranged in palisade fashion around the periphery of the cords, and the gonocytes come to lie centrally without apparent contact with the basement membrane 7 (Fig. 3). The germ cells begin to divide again after birth, after having migrated to the basement membrane. Almost simultaneously with the organization of the seminiferous cords, Leydig cells are recognizable. 6 Somewhat later, the rete testis, arising from the mesonephric. tubules, makes contact with the seminiferous cords. 8 Male Duct Differentiation. With the organization of the testis male sex differentiation is not complete. The excretory ducts through which the gametes escape from the testis have yet to be formed. This is accomplished by the transformation of the W olffian duct and the mesonephric tubules into the epididymis, ductus deferens, and seminal vesicles. During the time the male duct system is formed from the Wolffian duct, the paramesonephric Mullerian duct disappears. The question arises what controls the differentiation of the Wolffian duct and the regression of the Mullerian duct in the male fetus. The organization of the Wolffian duct is dependen~ on androgen produced, by the Leydig cells, and the regression of the Mullerian duct is dependent on a factor or hormone produced by the Sertoli cells of the fetal testis. The crucial role of the fetal testis in male sex differentiation was defined by Jost. 9 He showed that the fetal testis is necessary for the masculinization of the external genitalia, the maintenance of the Wolff-

4 496 PETERS May 1976 ian duct, and the regression of the Mullerian duct. That two different factors must be involved, one in the masculinization and the maintenance of the Wolffian duct, the other in the regression of the Mullerian duct, was shown by Elger.lO He injected the anti androgen cyproterone acetate into pregnant rabbits. All male characteristics were absent. The Mullerian duct was also absent, signifying that the androgen had not been able to inhibit a factor that causes Mullerian duct regression. That the androgen which caused the development of the Wolffian duct was actually produced by the fetal testis was shown in organ culture experiments by PriceY In culture of reproductive tract explants lacking testis, the Wolffian duct retrogressed completely; in that containing testis the Wolffian duct was maintained. That a second factor was responsible for the inhibition of the Mullerian duct in males was recently demonstrated by JOSSO,12 who showed that an anti-mullerian factor was produced by the seminiferous tubules and, more specifically, by the fetal Sertoli cells. 13 Fragments of testicular tissue from human fetuses were explanted in organ culture and submitted to y-radiation to destroy the germ cell population in the seminiferous tubules. The Mullerian-inhibiting activity of the irradiated fetal testis was then tested against Mullerian ducts from 14-day-old embryos and shown still to be active. As germ cells in these specimens were greatly reduced and Sertoli cells had survived, it was reasoned that the source of the anti-mullerian factor was the Sertoli cell. Thus it seems that in males ~ the Y chromosome is responsible for maleness and that secretion of the early mesonephros tubules is probably responsible for induction of the formation of the seminiferous tubules. The Leydig cells secrete androgen, which differentiates and maintains the Wolffian ducts and masculinizes the external genitalia. The Sertoli cells are the source of a factor that causes the Mullerian ducts to regress. FEMALE DIFFERENTIATION The differentiation of the female Includes the organization of the ovary and of the Mullerian duct system, the regression of the W olffian duct, and the differentiation of the external genitalia. Much less is known about the stimuli that produce female sex differentiation. Formation of the Ovary. There is an inherent tendency of the primitive gonad to develop into an ovary, provided that germ cells are present and persist, unless prior testicular differentiation has occurred. The absence of a Y chromosome is necessary for the organization of an ovary, and there is some evidence that a second X chromosome is essential for female sex differentiation.14 It is usually said that ovarian organization begins when the first follicles form in the organ. However, we would like to emphasize that an ovary can be recognized long before this occurs. When germ cells enter meiotic prophase, the gonad is clearly recognizable as female (Fig. 4). The germ cells in the female gonad behave quite differently from those in the male. The female germ cells do not become isolated in the center of sex cords as do those in the male gonad, but rather remain distributed throughout the sex cords which quickly make up the whole mass of the cortex. These cords constitute an irregular, ill-defined, 3-dimensional net which is lined by a basement membrane and contains the germ cells. The germ cells multiply for a time; then at a certain stage of their development they cease to multiply, and enter the long stage of meiotic prophase in which they remain until shortly before they ovulate.

5 Vol. 27, No.5 INTRAUTERINE GONADAL DEVELOPMENT 497 FIG. 4. Ovary of a 13-day-old mouse embryo. Some germ cells have entered meiotic prophase (arrows), which characterizes the early female gonad (x 227). Thus in the female the germ cells stop propagating very early (either during the embryonic period or in the early neonatal period), and the oocyte complement becomes finite. Neoformation of oocytes after this time does not take place, as was convincingly shown in the quantitative studies of Zuckerman 15 and later in the autoradiographic studies that demonstrated that DNA synthesis in the oocyte takes place in the last premeiotic interphase, 16, 17 i.e., during the embryonic or neonatal period. Later DNA synthesis and formation of oocytes does not occur. 18 Unfortunately, misunderstanding still persists in some laboratories. The outer cortex of the ovary remains rich in cells; no tunica albuguinea forms. Two main and opposing opinions concerning the origin of the central area of the organ have been voiced: those which maintain that ((medullary cords" derive from a downgrowth of the lower part of the sex cords, and those which propose that medullary cords are derived from the rete tubules which, in turn; derive from the mesonephric tubules and enter the ovary. Von Winiwarter 19 and later Gillman 20 described the rete as arising from mesonephric tubules. The FIG. 5. Ovary of a newborn cat. The rete cords (r) are in close contact with the sex cords (sc). Meiosis has already started in the germ cells closest to the rete (x 110). rete invades the hilum as a network of bands that later come into contact with the sex cords. The question of the origin of the central part of the ovary has recently been reinvestigated by Byskov, 21 who, after reviewing the development of the ovary in several species, comes to the conclusion that the rete system derives from the mesonephric tubules as a system of cords that enter the ovary and form the rete ovarii, which have an extraovarian part, a connecting part, and an intraovarian part. The rete enters the gonad and comes in contact with the sex cords (Fig. 5). The start of meiosis and the formation of follicles occur first in those areas where the contact between rete and germ cells has been established. The rete cords contain periodic acid-schiff-positive secretions. In transplantation experiments, Byskov22 showed that the onset of meiosis is dependent on the rete ovarii. Meiosis was induced only in those parts of the embryonal gonad that also contained rete, whereas in parts cultured without rete meiosis failed to

6 498 PETERS May 1976 start. Therefore, it seems that induction of meiosis is dependent on some substance supplied by the rete cells. The stimulus necessary for the regression of the Wolffian duct or the organization of the Mullerian ducts into oviduct, uterus, and vagina are not yet known, although female hormones accelerate the development of Mullerian duct derivatives in female embryos. The idea seems to emerge that the stimulus for the induction of the organization of the gonad in the two sexes comes from the mesonephric tubules: in the male their secretion is involved in stimulating the organization of the seminiferous cords, and in the female the secretion from the rete, which evolves from the mesonephric tubules, is essential for the start of meiosis. SEX DIFFERENTIATION IN THE HUMAN EMBRYO An attempt has been made to summarize the time sequence of development of the human embryo. In the undifferentiated stage (Table 1) the first primordial germ cells become recognizable in the 24-day-old embryo. During the next few days, i.e., during the 4th week, the mesonephric tubules form23 and the Wolffian ducts begin to appear.24 During the 5th week the primordia of the sex glands appear as a thickening of the celomic epithelium20 and the germ cells migrate toward the gonad.3 The Mullerian ducts appear only TABLE 1. Undifferentiated Stage (Human) Age of embryo Reference Stage of development days 24 WitschP First primordial germ cells recognizable Patten 23 Mesonephric tubules form Jirasek24 Primordia of W olffian ducts form Gillman 20 Primordia of sex glands appear as thickening of celomic epithelium Witschi 3 Migration of germ cells to gonadal primordia Jirasek24 Mullerian ducts appear between days 44 and 48,24 just about the time male differentiation begins (Table 2). During the 6th and 7th weeks the seminiferous cords begin to form. 6, 24 Early stages of the rete testis can be seen at 7 weeks 8 and make connection with the seminiferous cord a few days later. 8 Leydig cells and external genitalia begin to differentiate simultaneously at 8 weeks. 6 The Mullerian duct, which was first recognized at about 7 weeks, begins to regress at 81h weeks and completes regression during the 3rd month.24 At 12 weeks a sharp peak in plasma and testicular testosterone takes place. 25 At about the same time the Leydig cells fill the interstitial spaces in the gonad. 6 Their number declines rapidly between the 18th and 20th weeks. 25 This is reflected in the testosterone level, which is low in the embryo at 24 weeks. Differentiation of the reproductive organs starts later in the female embryo than in the male embryo (Table 3). A marked development of the rete cords TABLE 2. Male Differentiation (Human) Age of embryo Reference Stage of development 6-7 wk Jost et a1.,6 Seminiferous cords form Jirasek24 7 wk WilsonS Early stages of rete testis 7'h wk WilsonS First connection between seminiferous cords and rete 8wk Jost et a1.6 Leydig cells appear 8wk Jost et a1.6 External genitalia begin to differentiate 8'h wk Jirasek24 Mullerian ducts begin to regress During Jirasek24 Mullerian ducts regress 3rd mo 12 wk Grumbach Sharp peak in plasma and and testicular Kaplan27 testosterone Early Jost et a1.6 Leydig cells fill 4thmo interstitial spaces wk Grumbach Rapid decline in and number of Leydig cells Kaplan27 24wk Grumbach Testosterone at low level and Kaplan 27

7 Vol. 27, No.5 INTRAUTERINE GONADAL DEVELOPMENT 499 TABLE 3. Female Differentiation (Human) Age of embryo Reference Stage of development 8lh wk Wilson 8 Marked development of 9wk Matejna26 rete cords Development of vagina begins 9wk Wilson 8 Rete cords form lumen 10wk Jirasek24 Mullerian ducts fuse 10wk Jirasek24 Wolffian duct regression begins 10wk Grumbach Fetal pituitary contains and FSH andlh Kaplan27 12 wk Grumbach FSH in fetal serum and Kaplan27 12wk Jost et a1.6 Rete in center of ovary 3mo Ohno et al.2 8 Meiosis begins End of Jirasek24 W olffian duct regression 3mo complete 4lh mo Gillman20 First follicles form 5mo Grumbach FSH in fetal serum and at peak Kaplan27 5mo Baker29 Peak population of germ 7 mo Baker9 cells Last oogonia enter meiosis at 8% weeks8 and the beginning of the formation of the vagina are noted at 9 weeks.26 The Mullerian ducts fuse in the 10-week-old embry024 at the same age as Wolffian duct regression begins.24 The fetal pituitary contains follicle-stimulating hormone (FSH) and luteinizing hormone (LH) at 10 weeks,27 and FSH appears in the fetal serum 2 weeks later.27 The rete ovarii is in the center of the ovary at 12 weeks,6 and meiosis starts at the same age.28 The first follicles form in the 4%-month-old embryo. 20 The FSH level reaches a peak in the fetal serum at 5 months,27 at the same age when a peak population of germ cells is found in the ovary.29 All oogonia have entered meiotic prophase in the 7 -month-old embryo. REFERENCES 1. Hamilton WJ, Mossman HW: Human Embryology. Baltimore, Williams & Wilkins Co, Everett NB: Observational and experimental evidences relating to the origin and differentiation of the definite germ cells in mice. J Exp Zool 92:49, Witschi W: Migration of the germ cells of human embryos from yolk sac to the primitive gonadal folds. Contrib Embryol 32:67, Gondos B: The ultrastructure of granulosa cells in the newborn rabbit ovary. Anat Rec 165:67, Lyon MF: Role of X and Y chromosomes in mammalian sex determination and differentiation. Helv Paediatr Acta [Suppl] 34:7, Jost A, Vigier B, Prepin J, Perchellet JP: Studies on sex differentiation in mammals. Recent Prog Horm Res 29:1, Peters H: Migration of gonocytes into the mammalian gonad and their differentiation. Philos Trans R Soc Lond [BioI Sci] 259:91, Wilson KM: Origin and development of the rete ovarii and the rete testis in the human ovary. Contrib Embryol 17:69, Jost A: Recherches sur la differentiation sexuelle de l'embryon de lapin. III. Role des gonades foetales dans la differenciation sexuelle somatique. Arch Anat Microsc Morphol Exp 36:271, Elger W: Die Rolle der fetalen Androgene in der Sexualdifferenzierung des Kaninchens und ihre Abgrenzung gegen andere hormonale und somatische Faktoren durch Anwendung eines starken Antiandrogens. Arch Anat Microsc Morphol Exp 55:657, Price D: In vitro studies on differentiation of the reproductive tract. Philos Trans R Soc Lond [BioI Sci] 259:133, Josso N: Activite inhibitrice du testicule de foetus de veau sur Ie canal de Muller de foetus de rat, en culture organotypique: role de tubules se~ini(eres. C R Acad Sci [DJ (Paris) 274:3573, Josso N: Mullerian-inhibiting activity of human fetal testicular tissue deprived of germ cells by in vitro irradiation. Pediatr Res 8:755, Grumbach MM, Barr ML: Cytologic tests of chromosomal sex in relation to sexual anomalies in man. Recent Prog Horm Res 14:255, Zuckerman S: The number of oocytes in the mature ovary. Recent Prog Horm Res 6:63, Peters H, Levy E, Crone M: Deoxyribonucleic acid synthesis in oocytes of mouse embryos. Nature 195:915, Lima-de-Faria A, Borum K: The period of DNA synthesis prior to meiosis in the mouse. J Cell BioI 14:381, Rudkin GT, Griech HA: On the persistence of oocyte nuclei from fetus to maturity in the laboratory mouse. J Cell BioI 12:169, 1962

8 500 PETERS May von Winiwarter H: Recherche sur l'ovogenese et l'organogenese de l'ovaire des mammiferes (lapin et homme). Arch BioI 17:33, Gillman J: The development of the gonads in man, with a consideration of the whole fetal endocrines and the histogenesis of ovarian tumors. Contrib Embryol 32:81, Byskov AG: The role of the rete ovarii in meiosis and follicle formation in the cat, mink and ferret. J Reprod Fertil 45:201, Byskov AG: Does the rete ovarii act as a trigger for the onset of meiosis? Nature 252: 396, Patten BM: Human Embryology. New York, McGraw-Hill, Jirasek JE: Development of the Genital System and Male Pseudohermaphroditism. Baltimore, Johns Hopkins University Press, Grumbach MM, van Wyk JJ: Disorders of sex differentiation. In Textbook of Endocrinology, Fifth Edition. Philadelphia, WB Saunders Co, 1974, p Matejna M: Die Morphogenese der menschlischen Vagina und ihre Gesetzmassigkeiten. Anat Anz 106:20, Grumbach MM, Kaplan SL: Ontogenesis of growth hormone, insulin, prolactin and gonadotropin secretion in the human foetus. Foetal and Neonatal Physiology, Edited by KW Cross, P Nathanielez. Cambridge, Cambridge University Press, 1973, p Ohno S, Klinger HP, Atkin NB: Human oogenesis. Cytogenetics 1:43, Baker TG: A quantitative and cytological study of germ cells in human ovaries. Proc R Soc BioI Lond 158:417, 1963

Growth pattern of the sex ducts in foetal mouse hermaphrodites

/. Embryol. exp. Morph. 73, 59-68, 1983 59 Printed in Great Britain The Company of Biologists Limited 1983 Growth pattern of the sex ducts in foetal mouse hermaphrodites By C. YDING ANDERSEN 1, A. G. BYSKOV