Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

256 Section II • Clinical Endocrinology

concept views the fate of the bipotential gonad as balanced between opposing forces and SRY as the key factor. In XY gonads, SRY induces SOX9 and tips differentiation toward testis development, and in XX gonads lacking SRY, other genes combine to repress SOX9 and promote ovary development. 21,50 Germ Cell Sex Differentiation In human embryos, gonadal development begins during the 5th week of gestation as a protuberance overlying the meso nephric ducts, known as the genital or gonadal ridge. The primordial germ cells do not arise within but migrate into the developing gonads between 4 and 6 weeks of gestation, pro liferating as they go (Figure 8.3) . At least in the mouse, their survival during migration appears to depend on an interac tion between the cell surface tyrosine kinase receptor, c -KIT, and a ligand produced by surrounding tissues, called stem cell factor. 51 At this stage of development, the gonads are identi cal in males and females, indifferent and bipotential, capable of differentiating into either testes or ovaries in response to inductive signals. Although germ cells do not induce gonadal development, they play a more active role in females than in males. In the genetic or pharmacologically induced absence of germ cells, testis cords (the embryonic precur sor to seminiferous tubules in the adult testis) can develop, but in females, ovary differentiation fails altogether 52,53 ;

soon after Sry is expressed. 39 Deletion of Fgf9 does not prevent initial expression of Sry or Sox9 in Sertoli cell precursors, but Sox9 expression is a prerequisite for Fgf9 expression, and without it, Sox9 expression cannot be sus tained. 40 FGF9 also appears to actively repress genes that promote ovary differentiation, such as Wnt4 . 39 Whereas ovarian differentiation has long been considered the “default” pathway of sex determination—the automatic result in the absence of a testis-determining factor—recent evidence challenges that traditional concept. In mice, inac tivating mutations in genes such as Wnt4 , 39,41 Rspo1 , 42–44 and Foxl2 45–47 result in partial or complete XX male sex reversal, and activating mutations in β -catenin or Dax1 result in XY female sex reversal. 32,48,49 Rspo1 is required for Wnt4 expression and activates β -catenin, which, like Foxl2, down-regulates Sox9 expression. 21 Dax1 acts as a dominant negative regulator of transcription of other nuclear recep tors, including SF1, and thus may repress Sry expression. 32 Taken together, these observations suggest strongly that ovarian development results from the active repression of one or more genes in the testis pathway, rather than from a developmental default mechanism. It now appears that both testis and ovary differentiation require dominantly acting genes, with SRY inducing testis development via up-regulation of SOX9 and with other genes, primarily WNT4 and RSPO1, teaming to pro mote ovary development via repression of SOX9. The new

9–12 weeks Internal genitalia (epididymis, vas deferens, seminal vesicles) develop under paracrine T influence

8–9 weeks Mullerian tract regresses Leydig cells form and make T

6–7 weeks Sertoli cells form and make AMH

9–14 weeks Prostate and external genitalia develop under T & DHT influence

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4–6 weeks PGCs migrate to gonadal ridge to form bipotential gonads

16 weeks Uterine and vaginal development is complete

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10 weeks Mullerian ducts meet Wollffian ducts degenerate

20 weeks Female external genitalia develops

FIGURE 8.3