Development of Male and Female Reproductive SystemPetek Korkusuz MD PhD

AimTo learn the development and congenital abnormalities of both male and female genital system

Learning GoalsTo learn the development and congenital abnormalities of testes and the ovariesTo learn the sex determinationTo learn the development and congenital abnormalities of genital ductsTo learn the development and congenital abnormalities of external genitalia

Development of genital systemGenetic sex is established at fertilization by the kind of sperm that fertilizes the ovum The gonads begin to attain sexual characteristics from 7th week. Early genital systems in two sexes are similar; this initial period is called indifferent state of sexual development

Genital SystemGonads (primitive sex glands)Genital ductsExternal genitalia

ndifferent stage

Development of gonads (testes and ovaries)The mesothelium (mesodermal epithelium) lining the posterior abdominal wallThe underlying mesenchyme (embryonic connective tissue)The primordial germ cells

Indifferent gonads During the 5th week a thickened area of mesothelium develops on the medial side of the mesonephros: a pair of gonadal(genital) ridgesFinger-like epithelial cords (gonadal cords) grow into the underlying mesenchyme The indifferent gonad now consists of an external cortex and an internal medulla. If the embryo is XX: cortex will differentiate into an ovary, medulla regressIf the embryo is XY medulla differentiates into a testis, cortex regress except for vestigial remnants

Primordial germ cellsLarge spherical sex cells are visible early in the 4th week among the endodermal cells of the yolk sac near the origin of the allantoisDuring folding of the embryo dorsal part of the yolksac is incorporated into embryo Thus the primordial germ cells migrate along the dorsal mesentery of the hindgut to the gonadal ridgesDuring 6th week primordial germ cells enter the underlying mesenchyme and are incorporated in the gonadal cords.

Sex determinationChromosomal and genetic sex is established at fertilizationThe type of gonads that develop is determined by the sex chromosome complex of the embryo (XX or XY)Before 7th week gonads of 2 sexes are identical (indifferent gonads)Male phenotype requires Y chromosome (SRY-sex determining region on Y gene) for a testis determining factor-TDF. Female phenotype requires two X chromosomes with a number of genesThe Y chromosome has a testis determining effect on the medulla of indifferent cords . TDF (regulated by Y chrom) differentiate the gonadal cords into primordia of seminiferous tubulesAbsence of a Y chromosome (XX sex chrom) results in the formation of the ovaryTypes of present gonads determines the type of sexual differentiation of the genital ducts and external genitalia. Testosterone produced by the fetal testes determines maleness.Primary female sexual differentiation does not depend on hormones; occurs even if the ovaries are absent (depending possibly on an autosomal gene)

Abnormal sex chromosome complexesXXX, XXYNumber of X chromosome appears to be unimportant in sex determinationIf a normal Y chromosome is present the embryo develops as a male. If Y chromosome or its testis determining region is absent female development occurs

Turner syndrome (45X)

Ambiguous genitalia: if there is normalsexual differentiation, int and ext genitalia are consistent with the chromosome complementTrue hermaphroditism: having ovarian and testicular tissue either in the same or opposite gonads (70 % are 46 XX, 20 % 46 XX/46 XY mosaicism, 10 % 46XY) Female pseudohermaphroditism: 46 XX, having ovaries, resulting from the exposure from excessive androgens of female fetus. Virilization of ext genitalia occurs. Common cause is congenital adrenal hyperplasia, rare cause may be maternal masculinizing tumor.Male pseudohermaphroditism: 46XY having testis, with no sex chromatin. Int and ext genitalia are varible caused by inadequate production of testosterone and MIF by testes.Congenital malformations:Determination of fetal sex

Female pseudohermaphroditism (caused by congenital adrenal hyperplasia)

Congenital malformations:Determination of fetal sexAndrogen insensitivity syndrome (testicular feminization): Normal appearing females with the presence of testes and 46XY chromosomes. They are medically and legally female. There is resistambce to the action fo testosterone at the cellular receptorMixed gonadal dysgenesis: very rare, having chromatin negative nuclei (sex chromatin negative), a testis on one side, an undifferentiated gonad on the other side. The int genitalia are female, but may have male derivatives. The ext genitalia may vary from female to male.

Androgen insensitivity syndrome (testicular feminization):46XY

Development of testesTDF induces the gonadal cords (seminiferous cords) to condense and extend into the medulla of the indifferent gonad; where they branch and anastamose to form the rete testis. A dense layer of fibrous CT (tunica albuginea) separates the testis cords from the surface epitheliumIn the 4th month testis cords become horseshoe shaped; their extremities are continous with those of the rete testisTestis cords are now composed of primitive germ cells and sustentacular cells of Sertoli derived from the surface epithelium of the gland

Development of testesInterstitial cells of Leydig derived from the original mesenchyme of the gonadal ridge begin development shortly after onset of differention of these cordsLeydig cells lie between the testis cords and begin testosterone production by 8th week of gestationThus the testis is able to influence sexual differentiation of the genital ducts and ext genitalia.

Development of testesTestis cords remain solid untill puberty; when they are canalyzed forming seminiferous tubulesThus they join rete testis tubules, which in turn enter the ductuli efferentes which are the remaining parts of the excretory tubules of the mesonephric systemThey link the rete testis and the mesonephric or wolffian duct which becomes ductus defferens

Development of ovariesGonadal development occurs slowly in femaleIn XX embryo primitive sex cords dissociate into irregular cell clusters containing groups of primitive germ cells in the medullary part of ovaryLater they disappear and are replaced by a vascular stroma thet forms the ovarian medulla

Development of ovariesSurface epithelium of the female gonad (unlike that of the male) continues to proliferate giving rise to a second generation of cords (cortical cords) in the 7th week.Cortical cords penetrate the underlying mesenchyme but remain close to the surfaceIn the 4th month cortical cords split into isolated cell clusters with each surrounding one or more primitive germ cellsGerm cells develop into oogonia, surrounding epithelial cells, descendants of the surface epithelium form follicular cells.

Development of genital ducts: Indifferent stageAt the begining both male and female embryos have 2 pairs of genital ducts:Mesonephric (wolffian) ducts Paramesonephric (mlerian) ducts arising as a longitudinal invagination of the epithelium on the antlat surface of the urohenital ridgeTwo ducts are separated by a septum but later fuse to form the uterine canalThe caudal tip of the combined ducts projects into the posterior wall of the urogenital sinus causing a swelling (paramesonephric/mllerian tubercle)The mesonephric ducts open into the urogenital sinus an either side of the mllerian tubercle

Development of genital ducts: Indifferent stage7th week9th week

Molecular regulation of male genital duct developmentSRY is a transcription factor and the master gene for testes development; possibly acting in conjunction with the autosomal gene SOX9 a transcription regulator also inducing testes differentiationSOX9 binds the promoter region of the gene for antimullerian hormone/mullerian inhibiting substance (AMH, MIH) regulating this genes expressionAt the begining SRY and/or SOX9 induce the testes to secrete FGF-9 acting as a chemotactic factor that causes tubules from the mesonephric duct to penetrate the gonadal ridge.Without penetration by these tubules differentiation of the testes does not continue. Next SRY directly or indirectly through SOX9 upregulates production of stetoidogenesis factor-1 (SF-1) that stimulates differention of Sertoli and Leydig cells. SF1 with SOX9 increase AMH leading to regression of the paramesonephric (mullerian)ducts. SF1 upregulates the genes for enzymes that synthesize testosterone

SRYSOX9SF1Other genesTestes

Molecular regulation of female genital duct developmentWNT4 is the ovary determining gene; upregulating DAX1 which is a member of the nuclear hormone receptor family DAX1 inhibits the function of SOX9WNT regulates expression of other genes (TAFII105....TATA binding protein for RNA polimerase in ovarian follicular cells) responsible for ovarian differentiation Mice that do not synthesize that subunit do not form ovariesEstrogens are involves in sexual differentiation; under their influence paramesonephric (mullerian) ducts are stimulated to form ext genitaliaWNT4DAX1Other genesTAFII 105Ovaries

Genital duct development in maleMesonephros regress; a few excretory tubules (epigenital tubules) establish contact with cords of the rete testis and finally form efferent ductules of the testis.Excretory tubules along the caudal pole of the testis (paragenital tubules) do not join the cords of the rete testis; their vestiges are named paradidymis.

Genital duct development in maleMesonephric ducts persist and form the main genital ducts except for the most cranial portion (appendix epididymis)Mesonephric duct elongate, become highly convoluted forming the ductus epididymis immediately below the entrance of the efferent ductulesMesonephric ducts obtain a thick muscular coat and form ductus deferens (from the tail of the epididymis to the outbudding of the seminal vesicle) The region of the ducts beyond the seminal vesicles is the ejaculatorius duct.The paramesonephric ducts degenerate except for a small portion at their cranial ends (appendix testis)

Female ducts in malesIf testes fail to develop (agonadal males), similar development of mesonephric ducts occurs in males, because of the absence of MIS

Development of male genital glandsA lateral outgrowth from th caudal end of each mesonephric duct gives rise to seminal vesicle/glandMultiple endodermal outgrowths arising from the prostatic part of urethra grow into the surrounding mesenchyme and differentiate into prostate glandular epithelium; mesenchyme differntiate into prostatic stromaBulbourethral glands develop from paired outhgrowths from the spongy part of urethra

Genital duct development in femaleParamesonephric ducts develop into the main genital ducts Initially 3 parts can be recognized in each duct:Cranial vertical portion that opens into the abdominal cavity....develop into uterine tubeHorizontal part that crosses the mesonephric duct...develop into uterine tubeCaudal vertical part that fuses with its partner from the opposite side...fuse to form uterine canal

Genital duct development in femaleSecond part of the paramesonephric ducts move medio-caudally; urogenital ridges gradually come to lie in a transvers plane The ducts fuse in the midline; a broad transverse pelvic fold (broad ligament of uterus) is established. The uterine tube lies in its upper border and the ovary lies on its posterior surfaceUterus and broad ligs divide the pelvic cavity into uterorectal pouch and the uterovesical pouchFused paramesonephric ducts differentiate into corpus and cervix of the uterus. They are surrounded by a layer of mesenchyme that forms the myometrium and the perimetrium

Early development of uterus and the ovaries

Development of vaginaAfter the solid tip of the mesonephric ucts reaches the urogenital sinus; two solid evaginations (sinovaginal bulbs) grow out from the pelvic part of the sinus.Sinovaginal bulbs proliferate and form a solid vaginal plate.Proliferation continues at the cranial end of the plate; increasing the distance between the uterus and the urogenital sinus.By the 5th month vaginal outgrowth is entirely canalized. Vaginal fornices (wing-like expansions of the vagina around the end of uterus) are of paramesonephric origin

Development of vaginaThus the vagina has two origines:upper portion derived from the uterine canallower portion derived from the urogenital sinusLumen of the vagina remains separated from that of the urogenital sinus by a thin tissue plate; the hymenHymen consists of epithelial lining of the sinus and a thin layer of vaginal cells. It usualy develops an opening during perinatal life

Remnants of the ducts in femaleRemnants of the cranial and caudal excretory tubules in the mesovarium form the epoophoron and paroophoron respectivelyMesonephric duct disappear except for a small cranial portion found in the epoophoron and a small caudal portion in the wall of uterus or vagina (Gartners cyst)

Double uterus (uterus didelphys): results from failure of fusion of the inferior parts of the paramesonephric ducts. It may be associated with double or single vagina.Bicornuate uterus: One paramesonephric duct is retarded in its growth and does not fuse with other one. Bicornuate uterus with rudimentary horn: the rudimentary horn may not communicate with uterine cavityUnicornuate uterus: One paramesonephric duct fails to develop; resulting in a uterus with one uterine tube. Absence of vagina and uterus: Reslts from the failure of sinovaginal bulbs to develop. Vaginal atresia: Failure of the canalization of the vaginal plate. Imperforate hymen: Failure of perforation of the inferior end of the vaginal plateCongenital anomalies of uterus and vagina

Uterine anomaliesNormal uterus and vaginaDouble uterusDouble uterus with single vaginaBicornuate uterusBicornuate uterus with a rudimentary left hornSeptate uterusUnicornuate uterus

Congenital anomalies of hymen

Development of external genitalia: indifferent stageIn the 3th week mesenchyme cells originating in the region of the primitive streak migrate around the cloacal membrane to make a pair of slightly elevated cloacal folds.Cranial to the cloacal membrane, the folds unite to form the genital tubercleCaudally the folds are subdivided into urethral folds anteriorly and anal folds posteriorlyAnother pair of elevations (geniatl swellings) becomes visible on each side of the urethral foldsLater these swellings from the scrotal swellings in male, labia majora in female

Development of external genitalia in maleIs under the influence of androgens from the fetal testesCharacterized by rapid elongation of the genital tubercle (phallus); during which the phallus pulls the urethral folds forward so that thay form the lateral walls of the urethral grooveThe urethral groove does not reach the most distal part (glans)The epithelial lining of the groove which originates in the endoderm, forms the urethral plate

Development of external genitalia in maleAt the end of third month the two urethral folds close over the urethral plate; forming the penile urethraThis canal does not extend to the tip of the phallus This most distal urethra is formed during 4th month when ectodermal cells from the tip of the glans penetrate inward and form an epithelial cord.This cord obtains a lumen and forms the external urethral meatusThe genital/scrotal swellings arise in the inguinal region; move caudally and each one makes up half of the scrotum, separated by scrotal septum.

Hypospadias: most common anomaly of the penis. The external urethral orifice is on the ventral surface of the glans penis (penile hypospadias). Resulting from inadequate production of androgens by the fetal testes/or inadequate receptor sites for the hormoneEpispadias: The urethra opens on the dorsal surface of the penis; often associated with extrophy of the bladder; resulting from inadequate ectodermal-mesodermal interactions during development of genital tubercleAgenesis of external genitalia: Absence of penis or clitoris; resulting from the failure of development of genital tubercle.Bifid penis and double penis: vary rare, often associated with extrophy of the bladder or urinary anomalies; results when two genital tubercles develop.Micropenis: The penis is so small that it is almost hidden by the suprapubic pad of fat. It results from a fetal testicular failure. Congenital anomalies of penis

Hypospadias

Agenesis of external genitalia

Development of external genitalia in femaleStimulated by estrogens, genital tubercle elongates only slightly forming the clitorisUrethral folds do not fuse; develop into labia minoraGenital swellings enlarge and form the labia majoraUrogenital groove is open and forms the vestibuleAlthough the genital tubercle does not elongate extensively in female, its larger than in male during the early stages; resulting in mistakes in identification of the sex by USG examination.

5th week

Development of external genitaliaA-B: 4th-7th weekndifferent stageC, D: 9th weekE, F: 11th weekG, H: 12th week

Descent of the testesTesticular descent is associated with Enlargement of testes and atrophy of mesonephroi (mesonephric kidneys)Atrophy of mesonephric ducts induxed by the MIS Enlargement of processus vaginalis guiding the testis through inguinal canal into scrotumBy 26 weeks have descended retroperitoneally from the posterior abdominal wall to the deep inguinal ringsAndrogens, gubernaculum (a mesenchymal condensation) may guide the descentDescent may take 2-3 days and the inguinal canal contracts after they enter the scrotumAs the testis and the ductus deferens descend they are enshetaed by the facial extensions of the abdominal wall

Cryptorchidism or undescended testis: occurs in 30 % of premature, 3-4% of full-term males. It may be uni or bilateral. Failure of descent in the first year causes atrophy of testes. It may be in the abdominal cavity or anywhere along the descent path, usually in the inguinal canal. It may be caused by teh defficiency of androgen production in testes. Ectopic testes: After traversing the inguinal canal, the testis may deviate from its usual path of descent and lodge in various abnormal locations.

Congenital anomalies of descent of the testes

Descent of the ovariesDescent is considerably less in femaleThe ovaries sttle below the rim of the true pelvisCranial genital ligament forms the suspansory ligament of ovaryCaudal genital ligament forms the ligament of the ovary proper and the round ligament of the uterus

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