Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

254 Section II • Clinical Endocrinology

Genetic sex (XX, XY)

Gonadal sex (testes, ovaries)

Hormone production during fetal development

Sexual differentiation of the brain

Hormone production at puberty

Sexual differentiation of the external genitalia

Secondary sexual development

Sex of assignment and rearing

Gender identity

FIGURE 8.1

at the very distal ends of the short and long arms of the Y. The “pseudoautosomal” region constitutes only approxi mately 5% of the entire Y chromosome and is the only region that normally pairs and recombines during meiosis. 10,12 Most of the remaining 95% of the Y chromosome is unique to the male, containing multiple copies of genes expressed specifically in the testis and encoding proteins with special ized functions. 8 A single copy of the one gene most critical to testis differentiation, SRY (Sex-determining Region on Y), is located on the distal short arm of the Y (Yp11.3), immedi ately adjacent to the pseudoautosomal region. 13 Most of what is known about the genetic basis for sexual differentiation derives from studies of mutations in the mouse and human associated with varying degrees of “sex reversal,” conditions in which the chromosomal sex does not corre late with the gonadal or phenotypic sex. In humans, 46,XX male sex reversal occurs when pairing between the X and Y chromosomes during male meiosis extends abnormally into adjacent nonhomologous regions, allowing inappro priate recombination and transfer of Y-specific DNA onto the X chromosome. Careful analysis of four XX males having a very small piece of translocated Y DNA (60 kb) 14 prompted a search for highly conserved sequences within that region, which led to discovery of the SRY gene. 13 The identification of SRY mutations in three XY females supported the hypothesis that SRY was the critical and long-sought “testis-determin ing factor,” 15,16 but proof derived ultimately from studies in the mouse. First, a deletion in Sry (by convention, mouse gene symbols are italicized and the first letter is in upper case with all the rest in lowercase, human gene symbols are italicized and all letters are in uppercase, mouse and human

protein designations are the same as the gene symbol, but not italicized and all in uppercase) was identified in a line of XY female mice. 17 Second, Sry gene expression in the genital ridge was observed just at the time of testis differen tiation. 18 Third, transgenic XX mice carrying Sry develop as males. 19 SRY now is generally established as the primary genetic signal determining the direction of gonadal dif ferentiation in mammals . 10,20 However, XX hermaphrodites having ovotestes but not SRY have been described, and only a small proportion of phenotypic females with XY gonadal dysgenesis (Swyer syndrome) harbor SRY mutations. These observations indicate clearly that sex determination and sex reversal involve genes other than SRY . 21 Although the mechanisms that regulate SRY expression are still unclear, the nuclear receptor SF1 (Steroidogenic Factor 1) has emerged as a likely and important activator. In the mouse, SF1 binds to and activates the Sry promoter, 22 and heterozygous mutations in the Sf1 gene (resulting in haploinsufficiency) produce XY female sex reversal. 23–25 In humans, SF1 haploinsufficiency is a known cause of XY female sex reversal, 26 and an SF1 polymorphism that reduces transactivation function by approximately 20% is recognized as a susceptibility factor for the development of micropenis and cryptorchidism. 27,28 Evidence indicates that splice variants of WT1 (Wilms tumor 1) and GATA4 (GATA-binding protein 4) also may be involved in the regulation of Sry expression; both are transcription fac tors containing zinc-finger motifs that can interact and synergistically activate the promoter of human SRY . 29 WT1 mutations are associated with gonadal dysgenesis and ambiguous genitalia in males. 30

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