MALE SEX DETERMINATION: Current Concepts of Male Sexual Differentiation

In order for an infant to develop as a phenotypically complete male or female, a cascade of complex molecular and morphological events must occur at the appropriate time and in the correct sequence during ontogeny. The male embryo's genetic sex is determined by its chromosomal constituents, the most important of which is the sex-determining gene, or testis-determining factor (TDF), on the Y chromosome. Male gonadal sex, or testis formation, is subsequently thought to be determined by this gene and by other secondary pathways. The male gonad, in turn, normally produces hormones such as testosterone and Mullerian inhibiting substance (MIS) that regulate differentiation of the internal and external genitalia, thus determining phenotypic sex. When an abnormality develops in any of the above three processes, an intersex infant with ambiguous genitalia results from the incongruent genetic, gonadal, and phenotypic sex. Clinically, such 46XY males with intersex abnormalities present challenges for gender assignment, timely surgical intervention, and appropriate hormonal therapy.