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Human sexual development is a sequential process that involves the establishment of chromosomal and genetic sex in the zygote at conception, the formation of the bipotential gonads into testes or ovaries (sex determination), and the development of phenotypic sex (sex differentiation) of the genital tract and external genitalia. Divergent differentiation from the chromosomal sex is possible at each level of sexual development. In addition, gender identity may be established later in life and can be influenced by several prenatal and postnatal factors.

Outside of sexual development, prenatal diagnosis of chromosomal sex is particularly important to identify X-linked disorders. Preimplantation sex determination exists for in vitro fertilization, but mistakes occur in sex assignment in about 1% of cases. Chorionic villus sampling allows for identification of X-linked and other genetic disorders during the first trimester but is associated with an increased risk of fetal loss. Ultrasound and amniocentesis allow for determination of sex in the second trimester. Newer techniques that measure maternal plasma cell-free fetal nucleic acids (DNA and RNA), such as sex-determining region (SRY) gene amplification, allow noninvasive and reliable determination of sex early in the first trimester.


Chromosomal Sex

Genetic or chromosomal sex is determined at fertilization. In humans, males normally have XY sex chromosomes and females have XX chromosomes. A single Y chromosome is usually sufficient to activate and initiate the development of testes, even in the presence of multiple X chromosomes. By contrast, in the absence of a Y chromosome or the translocation of the sex-determining region on Y (SRY), the presence of a single X chromosome can lead to ovarian organogenesis. However, in general, 2 X chromosomes are needed for the survival of oocytes and the development of a normal ovary at birth. Problems with sex development from alterations in sex chromosomes are discussed in a later chapter.

Gonadal Sex

A bipotential gonad arises from the medioventral region of the urogenital ridge and usually occurs at the end of the fifth week of gestation. At this stage, the gonad is colonized by primordial germ cells that migrate from stem cells in the yolk sac. Many genes, including those for the transcriptional regulators, WT1 and SF1, lead to the differentiation of the urogenital ridge into the bipotential primordial gonad (Fig. 531-1). For formation of testes, the SRY gene, located on the distal short arm of the Y chromosome, is an important determinant of testicular organogenesis by about week 6. The SRY protein influences the transcription of downstream genes, including SOX9 (SRY-box 9, coded on chromosome 17), which leads to the differentiation of Sertoli cells and marks testicular differentiation. Deletions or point mutations in the SRY gene can result in complete gonadal dysgenesis and female phenotype in 46,XY individuals.

Figure 531-1

Major genes ...

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