ANNALS O F CLINICAL AND LABORATORY SCIENCE, Vol. 15, No. 5 Copyright © 1985, Institute for Clinical Science, Inc. Development of the Reproductive Organs BERNARD GONDOS, M.D. Department of Pathology, University of Connecticut, Farmington, CT 06032 ABSTRACT Understanding of the development of the reproductive organs is essen­ tial to the evaluation of abnormalities in sexual differentiation. Recent advances resulting from application of genetic, biochemical, and ultra- structural techniques have helped to clarify the mechanisms regulating gonadal and reproductive tract development. The present review consid­ ers the major processes of sexual differentiation, development of the female reproductive system and development of the male reproductive system with emphasis on current understanding of basic regulatory mech­ anisms involved in normal and abnormal development of the reproductive organs. Introduction development, however, there is an indif­ ferent stage in which the gonadal anlagen and other structural primordia appear The reproductive organs in each sex identical in male and female embryos. consist of gonads, an internal duct sys­ The process of sexual differentiation is tem, and external genitalia. During the initial event imposed on these prim­ development this basic organ system is itive structures. Subsequently, the male adapted to the different functional needs and female systems develop along sepa­ of the two sexes. Development of the rate pathways, but clearcut homologies reproductive organs involves complex remain as a result of their common or­ interaction of genetic, biochemical, mor­ igin. phologic, and hormonal factors. This Understanding of the development of intricate coordination leads to the estab­ the reproductive organs requires consid­ lishment of structural and functional eration of three main processes: (1 ) estab­ adaptations required for gamete matu­ lishment of sexual differentiation; (2 ) ration, sex hormone secretion, and development of the female reproductive reproduction. system; and (3) development of the male The reproductive system is the prin­ reproductive system. The purpose of the cipal site of divergent differentiation in present report is to provide an overview the two sexes, resulting in the formation of current knowledge in these areas. Par­ of separate male and female reproductive ticular emphasis is given to recent structures and distinctive types and pat­ advances in understanding of major reg­ terns of hormonal activity. Early in ulatory aspects. 363 0091-7370/85/0900-0363 $01.80 © Institute for Clinical Science, Inc. 364 GONDOS Sexual Differentiation lated more closely with testicular differ­ entiation than the presence of a Y chro­ The development of the reproductive mosome suggesting an inductive effect organs proceeds from an indifferent stage on the indifferent gonad. However, there in which gonadal sex is not yet deter­ have been sufficient problems in repro- mined and the internal duct systems of ducibly characterizing this association in mesonephric (Wolffian) and parameso- certain conditions to cast some doubt on nephric (Mullerian) origin are both pres­ its significance. 15 ent (table I). Genetically, however, the A finding that has been well estab­ sex of the embryo is determined at the lished is that sex chromatin bodies rep­ time of fertilization, depending on the resenting inactivated X chromosomes are presence or absence of a Y chromosome. present in all individuals with more than one such structure . 24 The inactivation S e x C h r o m o s o m e E x p r e s s io n occurs early in embryonic development prior to the establishment of gonadal sex The precise mechanism of sex chro­ differentiation. Identification of sex chro­ mosome expression is not clear. Under matin bodies is useful both in determin­ normal circumstances, there is direct ing normal genotypic sex and in charac­ correlation of the presence of a Y chro­ terizing various types of abnormalities. mosome and male phenotypic differen­ However, structural abnormalities of the tiation, as has been shown by procedures X chromosome may escape detection by for Y chromosome fluorescence. How­ this method and therefore karyotype ever, analysis of various types of clinical analysis is needed to indicate structural disorders has demonstrated that genes features. essential for normal male development Further understanding of the site and are also located on the X chromosome action of sex-determining genes will and genes involved in the development depend on refinements in genetic, bio­ of both male and female phenotypes are chemical and immunologic techniques. 32 found on autosomes. 40 At present, the variety of abnormalities Recently it has been proposed that H- in sex differentiation related to structural Y antigen, a histocompatibility antigen and functional chromosome defects only linked to a gene on the Y chromosome, underscores the need for additional may be the key sex-determining factor. 38 information to clarify the mechanisms In various types of intersex conditions, involved in sex chromosome expression. the presence of H-Y antigen has corre- G o n a d a l D ifferentiation T A B L E I Differentiation of Reproductive Structures The genital ridges arise as thickenings on the medial aspects of the coelomic M a jo r cavity adjacent to the mesonephros. At E lem en ts O r i g i n Differentiated Structures four to five weeks gestational age, G o n a d s G enital ridge O v a ry gonadal outgrowths composed of coe­ T e s t i s lomic epithelium and underlying mes­ I n t e r n a l d u c t s M üllerian ducts Tubes, uterus, vagina enchyme gradually develop projecting W olffian ducts Epididymis, vas, seminal v e s i c l e s into the future peritoneal cavity. Initially, E x t e r n a l the gonadal primordia are composed only genitalia Urogenital sinus Labia, clitoris, accessory g l a n d s of epithelial and mesenchymal cells of Scrotum, penis, accessory g l a n d s mesodermal origin. Soon, primitive germ cells, large spherical to ovoid cells, DEVELOPMENT OF THE REPRODUCTIVE ORGANS 365 begin to appear in the gonad. These cells the cloaca. Connections are established are morphologically characteristic and between the cranial portions of the ducts histochemically distinctive because of and the gonadal outgrowths through their high alkaline phosphatase and gly­ mesonephric tubules. The latter join cogen content. The germ cells have been with cords of cells from the gonads com­ shown to originate extragonadally in the prising the rete system. wall of the yolk sac from where they mi­ The Mullerian ducts arise as invagi­ grate to the developing gonads. 43 nations of the coelomic epithelium at five The gonads of the two sexes remain weeks gestational age. They extend cau­ morphologically indistinguishable until dally lateral and parallel to the meso­ six weeks of age, when the first evidence nephric ducts. At their caudal ends, they of testicular differentiation is seen. cross the mesonephric ducts ventrally to Aggregates of germ cells and somatic fuse in the urogenital septum. The fused cells bounded by a basal lamina, repre­ portion eventually comes in contact with senting the primitive spermatogenic the urogenital sinus to form the Mulle­ cords, begin to form. In addition, a dis­ rian tubercle. tinct tunica albuginea appears beneath The external genitalia take their origin the coelomic (surface) epithelium. The from protuberances of the cloacal mem­ presumptive ovary shows no specific brane in association with the urogenital changes at this time and retains an undif­ sinus. The genital tubercle is located ferentiated appearance until the onset of anteriorly flanked on either side by the meiosis at the end of the first trimester. genital swellings. At about five weeks of The mechanisms responsible for go­ age, a urethral plate develops from the nadal sex differentiation are unknown. cloacal epithelium in association with the Since it is characteristic of mammalian developing phallic tubercle and subse­ species that testicular differentiation pre­ quently develops an opening, the ure­ cedes that of the ovary, a specific induc­ thral groove. The latter forms in two tive factor in the male would appear stages, the deeper part being endoder- likely. However, the identity of such a mal in origin and the superficial part factor, or factors, remains elusive. communicating with the urogenital ori­ fice of ectodermal origin. Up to 10 to 11 D ifferentiation o f R eproductive T r a c t s weeks, the external genitalia in the two sexes are essentially similar. Two sets of paired ducts, the Wolffian and Mullerian ducts, are responsible for Female Reproductive System giving rise to major portions of the male and female reproductive tracts. In the Major events affecting the function of male, the Wolffian ducts undergo exten­ the female reproductive organs occur sive development to form the internal during fetal development. These include genital structures while the Mullerian differentiation and growth of the ovaries, ducts regress. In the female, only por­ formation of the tubal and uterine struc­ tions of the mesonephric or Wolffian tures from the Mullerian ducts, estab­ duct system persist while the Mullerian lishment of the cervicovaginal canal by ducts undergo profound developmental contributions from the Mullerian ducts, changes to give rise to principal repro­ and urogenital sinus and formation of the ductive structures. female external genitalia. These events Initially, the mesonephric ducts ap­ are generally paralleled by correspond­ pear as elongated structures in the ing changes in the male reproductive sys­ nephrogenic cord extending caudally to tem. However, a notable difference is 366 GONDOS that oogenesis is initiated early in fetal meiosis early in ovarian development, development, while male germ cells do while this process is inhibited in the not enter spermatogenesis until the time developing testis. Recently, it has been of puberty. The early maturation of the demonstrated that a meiosis-inducing ovarian germ cells indicates the impor­ substance (MIS) and a meiosis-prevent- tance of changes occurring in the fetal ing substance (MPS) produced by cells ovary for later reproductive function.