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. derived from mesonephric structures adjacent to the gonad are involved in reg
O v a r ia n D e v e l o p m e n t ulating ovarian and testicular germ cell differentiation . 2 The balance between The basic structural and functional these two substances varies in the two unit of the adult ovary is the follicle, con sexes at different stages of development sisting of an oocyte surrounded by gran with MIS predominating in the fetal ulosa and theca cells. During early devel ovary and MPS in the fetal testis. Fur opment, referred to as the prefollicular ther work on factors involved in meiotic stage, the ovarian cortex is characterized regulation represents an area of active by germ cells and granulosa cells current investigation. arranged in cords and sheets without Although significant changes affecting specific organization. 10 This arrangement germ cell differentiation occur in the persists until mid-gestation when follicle fetal ovary, hormonal activity appears to formation begins. be limited during this time. According to The first distinctive change in the fetal the early studies of Jost, 21 ovarian hor ovary is the onset of meiosis, which mone production is not required for the occurs at 11 to 12 weeks gestation. 14 This differentiation of the female reproductive is preceded by a period of differentiation tract while in contrast endocrine activity of primitive germ cells into groups of in the fetal testis plays a major role in actively dividing cells, the oogonia. The organizing the differentiation of the male mitotic divisions of oogonia are associ reproductive system. This concept has ated with incomplete separation at telo been generally borne out by ultrastruc- phase, leaving the daughter cells con tural studies which have shown no spe nected by intercellular bridges. This cific changes in fetal granulosa cells asso pattern recurs in subsequent divisions, ciated with steroid hormone secretion, so that groups of germ cells remain inter such as are seen in fetal Leydig cells. connected and, therefore, behave in a Furthermore, theca cells, which play an synchronous manner. essential role in steroid synthesis in the Following a series of mitotic divisions, adult ovary, do not appear until late in there is progressive entry into meiosis by gestation and retain a relatively undiffer the cell groups beginning in the inner entiated appearance during the devel most cortex and gradually extending to opmental period. the periphery . 36 The cells, now desig Nevertheless, some lines of evidence nated as oocytes, pass through the var suggest a possible role for steroid hor ious stages of the first meiotic prophase mones in early differentiation. Intersti and by late gestation all of the oocytes tial cells with characteristic ultrastruc- have advanced to the diplotene stage. tural features of steroid-secreting cells Differentiation is then arrested and does are present in the fetal ovary during the not resume until the time of ovulation. prefollicular period . 13 Biochemical stud An important unresolved problem in ies have shown that human fetal ovarian reproductive biology concerns the mech tissue is capable of converting testoster anisms responsible for the initiation of one to estradiol at this time . 8 Moreover, DEVELOPMENT OF THE REPRODUCTIVE ORGANS 367 acquisition of the capacity for key enzy U t e r o t u b a l S t r u c t u r e s matic conversions involved in steroido genesis takes place at the same time in The tubes and uterus are derived from the fetal ovary and testis . 33 Ovarian ste the paired Mullerian ducts. Each duct is roidogenic activity, however, remains at composed of a cranial longitudinal por a relatively low level during fetal devel tion, an intermediate transverse portion, opment, and a specific role for estrogens and a caudal longitudinal portion. The has not been defined. first two become the tubes while the In regard to possible effects of fetal fused caudal segments give rise to the gonadotropins, pituitary gonadotropin uterovaginal canal. The latter contributes production begins as early as 1 0 weeks to the vagina as well as the uterus, but with peak levels occurring at mid-ges the vaginal epithelium is principally of tation . 23 It is of interest that pituitary fol extramiillerian origin. licle stimulating hormone (FSH) is The uterine portion of the uterovaginal higher in female than in male fetuses at canal becomes separated from the vagi mid-gestation. However, while gonado nal portion at mid-gestation. A slight cur tropins have a major influence on follic vature develops at the junction between ular development in the adult ovary, evi the future cervical and fundal parts of the dence for a similar function in the fetus uterus at this time with a second more is lacking. 1 pronounced curvature between the cer Once follicle formation begins at 18 to vix and vagina. The endometrial and 2 0 weeks gestation, the process contin endocervical linings derive from the ues throughout the remainder of fetal Mullerian duct epithelium, while the development. By the late fetal and early stromal and muscular layers are formed neonatal period all of the surviving from the mesenchyme surrounding the oocytes have become surrounded by ducts. The basic structure of the uterus adjacent granulosa cells, and oocyte and is established early in development. follicle growth are well established. However, the cervical portion is larger Many oocytes undergo degeneration than the body throughout fetal develop prior to incorporation in follicles. Nev ment and the fundus to cervix proportion ertheless, a pool of several hundred characteristic of the adult appears only thousand follicles is present in the new after the early postnatal period. born ovary. Stimulation of Mullerian duct devel Follicle growth takes place throughout opment has not been shown to be under infancy and childhood . 27 During this hormonal control. However, clinical evi time, a gradual rise in estrogen and dence of uterine anomalies after prenatal gonadotropin levels occurs. There is exposure to diethylstilbestrol (DES ) 18 increasing asymmetry in the two ovaries and experimental studies in animals which are filled with follicles of varying treated with DES or estradiol7 during size, including preantral and antral folli early development suggest that estro cles. However, it is only at the time of gens may be involved. An interesting puberty that the cyclic changes involving observation in this regard is that differ ovulation and luteinization are initiated. entiation of the uterine epithelium is The precise mechanisms responsible for controlled by the associated mesen the initiation of these major events chym e. 4 Therefore, hormonal effects on remain to be determined, but recent early uterine development would have to studies suggest that changing levels of be mediated through the Mullerian duct estradiol and luteinizing hormone (LH) mesenchyme. are of critical importance . 39 The proliferation of the Mullerian 368 GONDOS ducts is accompanied by a corresponding E x t e r n a l G e n i t a l i a degeneration of the mesonephric ducts. The mesonephric tubules associated with After its establishment, the urogenital the cranial portion of the mesonephric sinus is divided into an upper pelvic por duct generally remain to form connec tion and a lower phallic portion related tions with the rete ovarii. These struc to the base of the genital tubercle and tures persist throughout adult life as the separated from the ectodermal cloaca by epoophoron. The caudal part of the duct the urogenital membrane. may also persist as Gartner’s duct. Epithelial buds arise from the primi tive urethra and the adjacent pelvic part of the urogenital sinus at about 12 to 14 weeks gestation to give rise, respec
C e r v ix a n d V a g i n a tively, to the urethral and paraurethral glands of Skene. The two sets of glands While the vagina and ectocervix (por- together constitute the female homo- tio vaginalis) develop from the Mullerian logue of the prostate. duct system as the caudal portion of the During approximately the same pe uterovaginal canal, their epithelial lining riod, the genital tubercle becomes bent is derived in large part from the endo- caudally and can be recognized as the cli dermal urogenital sinus and the ectoder toris. The lateral portions of the genital mal cloaca. Since the Mullerian ducts are swellings enlarge to form the labia of mesodermal origin, it is evident that majora, while the urethral folds flanking all three germ layers are involved in the urogenital orifice persist as the labia cervicovaginal differentiation. Recent minora. Bartholin’s glands and the lesser reviews on the development of the vestibular glands arise from the vestibule vagina indicate that there is still not into which the vagina and urethra open. general agreement regarding the rela The general pattern of differentiation of tive contributions of these different the external genitalia is well established sources. 25,40 by mid-gestation. During the early development of the The extent to which hormonal factors uterovaginal canal, a cord-like separa influence these changes is unclear. Infor tion, the vaginal plate, forms between its mation from animal studies indicates that lower portion and the cranial portion of removal of the fetal ovaries does not the urogenital sinus. At this time, the affect the differentiation of the female developing vagina has a cuboidal lining. genitalia, implying that ovarian hor Subsequently, after fusion between the mones are not required . 22 H ow ever, two structures occurs, stratified squa from clinical observations it is known that mous epithelium from the urogenital high levels of maternal steroid hormones sinus extends upward to line the vagina which cross the placental barrier will and ectocervix. This process begins in cause abnormal development of the the late first and early second trimester external genitalia. but is not completed until late in fetal development. It is during this period Male Reproductive System that changes in maternal hormone expo sure, such as DES administration, may Since both male and female reproduc be particularly important in affecting epi tive systems develop from similar ori thelial differentiation in the vagina and gins, parallel patterns of differentiation cervix. 31 are evident. However, there are two DEVELOPMENT OF THE REPRODUCTIVE ORGANS 369 striking differences related to the major formed into cell cords, the seminiferous functions of gamete production and sex cords, and the gonocytes begin to move hormone secretion. Development of tes to the periphery where they become sit ticular germ cells is characterized by a uated along the basal lamina. These cells, delay in maturation so that spermatogen the prespermatogonia, are
T e s t i c u l a r D e v e l o p m e n t into spermatocytes, which undergo two successive meiotic divisions, followed by The basic structural unit of the adult the formation of spermatids and sper testis is the seminiferous tubule contain matozoa. Important events associated ing large numbers of germ cells involved with the initial spermatogenic cycle are in spermatogenesis and Sertoli cells. The the development of a lumen within the fetal and postnatal period of testicular seminiferous tubules and the formation development prior to the onset of sper of a blood-testis barrier by occlusive Ser matogenesis is referred to as the pre- toli cell junctions . 3 spermatogenic stage. Limited numbers The stimulus for the initiation of sper of germ cells of relatively undifferen matogenesis is not definitely known, but tiated type are present throughout this several lines of evidence point to testos period. terone as the key factor. For example, in Initially, groups of primitive germ cells precocious puberty associated with ele and differentiating Sertoli cells become vated testosterone levels, testicular surrounded by a basal lamina within the biopsy characteristically shows prema fetal testis. An early plate-like arrange ture spermatogenesis . 35 Normally, the ment of the cellular aggregates is dem initiation of spermatogenesis is associ onstrated by stereological techniques ated with a rise in testosterone from pre such as scanning electron microscopy. At pubertal baseline levels. It is likely that this time the germ cells, referred to as this is a result of maturation of the hypo gonocytes, are randomly distributed thalamic-pituitary axis and specifically among the more numerous Sertoli changes in LH activity in response to cells. 12 gonadotropin releasing hormone stimu Subsequently the plates are trans lation . 29 370 GONDOS
Endocrine activity in the developing sis by the testis is evident, with activity testis has been carefully studied, and it first noted at eight weeks, peak levels at is now clear that there are two main 12 to 13 weeks and a steady decline after types of hormones produced by the fetal 17 w eeks. 30 Relatively low levels of tes testis: testosterone, which is required for tosterone are produced in the second half differentiation of Wolffian duct structures of gestation and postnatally up to the and development of the external geni time of puberty, except for a transient talia; and a nonsteroidal hormone, known rise in the neonatal period. as Mullerian inhibiting substance or anti- During the latter part of gestation, the Miillerian hormone (AMH), which is testis completes its descent into the scro responsible for regression of the Mulle tum. At approximately the seventh rian ducts (table II). month, the processus vaginalis grows Secretion of anti-Mullerian hormone rapidly and the inguinal canal increases by the fetal testis is a relatively recently in diameter. Descent occurs as a result described phenomenon . 6,20 This finding of degeneration of the portion of the gu- has helped to clarify the regression of the bernaculum in contact with the epidid Mullerian ducts in the male fetus as well ymis and testis allowing both to move as certain related clinical abnormalities. 34 through the dilated inguinal canal into Anti-Mxillerian hormone has been found the scrotum. Numerous studies on to be a glycoprotein produced by the experimental cryptorchidism in animals fetal Sertoli cells beginning shortly after and observations on clinical material testicular differentiation. A monoclonal have been evaluated in an attempt to antibody to AMH is now available define the precise functions of androgens enabling further studies in this area . 37 and gonadotropins in testicular descent, Such studies may help to explain the but a clear picture is yet to emerge and mechanisms by which the Sertoli cells consequently there is still considerable become active in producing this sub controversy on this subject. 28 stance so early in development.
Testosterone production by the fetal I n t e r n a l G e n i t a l S t r u c t u r e s testis is associated with the differentia tion of Leydig cells in the testicular inter- Establishment of male internal repro stitium. Leydig cells begin to appear at ductive structures involves the regres eight weeks gestation, are particularly sion of the Mullerian ducts and differ prominent during the third and fourth entiation of the Wolffian duct system. months, and then undergo involutional The first of these events, correspond changes at mid-gestation . 26 A c o rre ing to the early secretion of AMH, is the sponding pattern of testosterone synthe- regression of the paramesonephric ducts. Beginning at seven to eight weeks, the
T ABLE I I ducts undergo degenerative changes and lose their communications with the coe- Fetal Testicular Hormones lomic cavity. The cranial portion of each duct persists to form the appendix testis, Testosterone Produced by Leydig cells but the remainder disappears entirely Peak secretion during 3rd and 4th m o n th s with the possible exception of contribu Stim ulates W olffian duct tions from the caudal end to the prostatic differentiation A ntim iillerian utricle. hormone Produced by Sertoli cells The Wolffian ducts begin to grow and Peak activity at 7 to 10 weeks Causes M tillerian duct regression differentiate at nine to 10 weeks. The cranial part of each duct becomes con DEVELOPMENT OF THE REPRODUCTIVE ORGANS 371 nected to the testicular cords through two lateral, in accordance with the major some of the mesonephric tubules, which lobes of the adult prostate. give rise to the efferent ductules, and the At the end of the third month, the gen rete testis. The adjacent portion of the ital tubercle becomes elongated and is duct undergoes extensive lengthening transformed into the cylindrical phallus. and convolution to form the epididymis. The genital swellings develop into the Later the distal segment develops a thick scrotal folds which become rounded, muscular layer and becomes the ductus migrate caudally and fuse below the base or vas deferens. Close to the junction of the penis. The definitive urethral with the urogenital sinus, a glandular groove extends forward on the ventral diverticulum subsequently arises to form aspect of the phallus so that the lining of the seminal vesicle. The part of each the penile urethra is derived principally mesonephric duct between the seminal from the endodermal urogenital sinus. vesicle and the urethra becomes the ejac- Fusion of the urethral folds results in the ulatory duct. formation of the perineal raphe. The primary role of testosterone in Subsequently, there is a proliferation mediating these events is now well estab of ectodermal surface epithelium into the lished on the basis of experimental stud glans penis to meet the distal extremity ies and clinical observations. 42 The latter of the urethral plate. The prepuce starts include cases of defective testosterone developing at about the same time from synthesis40 and abnormalities in andro structures related to the urethral folds gen receptor function . 16 In either and the bulbourethral glands arise from instance, failure of normal differentiation a portion of the penile urethra as endo of Wolffian duct structures occurs, indi dermal derivatives. Connective tissue cating the dependence of male reproduc surrounding the urethra becomes con tive tract formation on testosterone densed to form the corpus cavernosum action. in which numerous convoluted blood vessels with arteriovenous anastomoses
E x t e r n a l G e n i t a l i a arise. Development of the prostate and As in the female, the external genitalia external genitalia from the urogenital in the male arise in relation to the phallic sinus has been shown by Wilson and col portion of the definitive urogenital sinus. leagues to be under the direct influence The prostate gland also develops in con of dihydrotestosterone . 17,41 Thus, while junction with the urogenital sinus includ testosterone produced by the fetal testis ing contributions from the primitive ure is responsible for the differentiation of thra and the pelvic portion of the the epididymis, vas deferens and seminal urogenital sinus. vesicles from the Wolffian ducts, it is the Mesenchymal influences have been reduced form of the hormone, DHT, shown to have an important inductive which controls the differentiation of effect on the differentiation of the pros structures derived from the urogenital tatic epithelium . 5 Endodermal buds arise sinus, genital tubercle and genital swell from the urethra at 1 1 to 1 2 weeks ges ings. This has been demonstrated both tation and extend into the surrounding in animal experiments and in clinical mesenchyme which differentiates into studies on several pedigrees of families the fibromuscular component of the with 5a-reductase deficiency. 19,42 Devel gland. The epithelial buds which grow opment of the male reproductive tract is out from the urethra are arranged into evidently influenced by a number of five groups, anterior, middle, dorsal, and gene-regulated enzymatic conversions in 372 GONDOS the steroidogenic pathway related to tes 3. Camatim, M., Franchi, E ., and d e C urtis, I.: Differentiation of inter-Sertoli junctions in tosterone and dihydrotestosterone for human testes. Cell Biol. Int. Rep. 5:109—110, mation. Specific genetic defects have 1981. been identified at several different levels 4. C unha, G. R. and L ung, B.: The importance of stroma in morphogenesis and functional activity in this process to account for various of urogenital epithelium. 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