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  • Male differentiation in humans is determined by the testis-determining gene, SRY, which is located on the short arm of the Y chromosome adjacent to the pseudoautosomal region.

  • Cytogenetic studies of infertile males have revealed rare individuals with an apparently normal 46,XX karyotype. The majority of these sex-reversed XX males have inherited a small fragment of the Y chromosome, which includes SRY, transferred to the short arm of one of their X chromosomes.

  • SRY mutations are found in 15 percent of XY females with pure gonadal dysgenesis.

  • SRY induces the differentiation of Sertoli cells in the developing gonad. Sertoli cells produce anti-Mullerian hormone, which causes regression of the female internal genitalia; they also induce Leydig cells to secrete the androgens necessary for the development of male internal and external genitalia. Any genetic or environmental factor that prevents testis differentiation in 46,XY embryos leads to the development of a sex-reversed XY female.

  • This chapter reviews the role of SRY in primary sex-reversal syndromes.


In all mammals, sexual differentiation in the early embryo is a consequence of the development of the gonadal ridge into either a testis or an ovary. A central role for the testis in sex determination was established in the 1940s by the embryonic castration experiments of Jost, who showed that removal of the undifferentiated gonads before a critical stage in male rabbit embryos led to female differentiation of the internal and external genitalia.1 Unilateral castration of male embryos led to ipsilateral female differentiation of the genital ducts and male differentiation of the ducts contralaterally. This indicated the local action of androgenic hormones secreted by each testis.

The first signs of testicular differentiation occur in the supporting cell lineage of the embryonic gonad, which surrounds the incoming germ cells.2 These cells enlarge into Sertoli cells, which organize to form tubular structures within the gonad. In addition to providing sustenance to the maturing germ cells, the Sertoli cells secrete anti-Mullerian hormone (AMH, also known as Mullerian-inhibiting hormone), which causes regression of the Mullerian ducts (the anlage of the uterus, fallopian tubes, and upper vagina).3 Sertoli cells also may induce the embryonic interstitial (Leydig) cells to secrete the androgens that stimulate the mesonephric (Wolffian) ducts to differentiate into seminal vesicles, vasa deferentia, and epididymes. The production of androgens also masculinizes the external genitalia. Another function of Sertoli cells is to inhibit meiosis in spermatogonia until puberty, when a further wave of differentiation in both cell types is initiated by the hypothalamus through the anterior pituitary. Testis differentiation occurs in the absence of germ cells, emphasizing the critical role of the Sertoli cell in male differentiation.4

Jost’s studies revealed that the ovaries develop later than the testes. In the absence of Sertoli-cell differentiation, the supporting cell lineage of the undifferentiated gonad become follicular cells that surround the incoming oogonia to form primordial follicles. The oogonia ...

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