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What defines our sexuality is a complex interaction between our genetic makeup, environmental stimulus, and cultural influences. The origins of our sexuality occur at the time of conception when the genetic material from two sources of the opposite sex coalesces into a new individual. From that moment, sexual differentiation occurs by a highly organized process. Sex chromosomes and autosomes dictate the development of gonads; the gonads in turn produce hormones, which then direct the development of the internal and external genitalia. Disorders of sex development (DSD) or differentiation arise from abnormalities in chromosomes, gonadal development, or hormonal production/activity.

Patients with DSD become apparent (1) during the newborn period as having ambiguous genitalia or a discordant phenotypic from the genotype found at the time of amniocentesis, (2) as having inappropriate pubertal development, (3) as having delayed pubertal development, or (4) later in life as having infertility.

Chromosomal Sex

The genetic material necessary for the development of the male phenotype is normally located on the short arm of the Y chromosome (Wilson et al, 1981). The critical gene or sex-determining region on the Y chromosome is known as the SRY region. The gene products of the SRY genetic cascade direct the development of the testis by interacting with multiple other genes such as SOX-9 (Conte and Grumbach, 2007). Genetic information that is known to be necessary for male and female development beyond gonadal differentiation is located on the X chromosome and on the autosomes.

Gonadal Differentiation

The gonads develop from the urogenital ridges (Figure 43–1), which are formed during the 4th week of gestation by the proliferation of the coelomic epithelium and condensation of the underlying mesenchyme along the mesonephros. The germ cells, located in the endoderm of the yolk sac, migrate to the genital ridges. At the early stage of development, the gonad is bipotential, capable of forming into either a testis or an ovary. During the 6th–7th week of gestation, at least four different genes, Wilms' tumor suppressor gene (WT-1), Fushi-Tarza Factor-1 (FTZ-F1), steroidogenic Factor-1 (SF-1), and LIM-1, induce the development of the testis. The primordial germ cells differentiate into the Sertoli cells and associated Leydig cells, which aggregate into spermatogenic cords. Loose mesenchymal tissue condenses into a thick layer, the tunica albuginea, which surrounds the testis and separates its connection with the coelomic epithelium, thereby preventing further migration of mesonephric cells into the testis.

Figure 43–1.

Sex-determining genes involved in testes and ovarian development.

Classic teaching is that the female phenotype is the default developmental pathway in the absence of the SRY cascade. It is now known that at least one gene, dosage-sensitive sex reversal (DAX-1), is essential for ovarian development. DAX-1 is located on the ...

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