Sexual differentiation is a sequential process that begins at fertilization with the establishment of chromosomal sex, continues with the determination of gonadal sex, and culminates in the development of secondary sexual characteristics that comprise the male and female phenotypes. This basic paradigm was formulated by Alfred Jost to explain the results of castration experiments in fetal rabbits. If the gonads (ovaries or testes) were removed before sexual differentiation, female sexual differentiation inevitably ensued. The male pathway could be partly restored by testosterone implants, suggesting that hormones produced by the testes mediate male sexual development. Thus, the concept arose that the testes induce a male pattern of differentiation on an embryo that otherwise would follow the female pathway. Cytogenetic studies shortly thereafter showed that the critical genetic determinant of sex is the presence or absence of the Y chromosome, leading to the proposal that the Y chromosome directs the gonad to differentiate into a testis, which then produces hormone(s) that cause male sexual differentiation. The chromosomal sex of the embryo generally corresponds to its phenotypic sex. Occasionally, however, the process of sexual differentiation goes awry, resulting in individuals with disorders of sexual differentiation (DSD). Clinically recognized disorders of sexual development occur at many levels, ranging from relatively common disorders in the terminal steps of male differentiation (e.g., testicular descent, growth of the penis) to more fundamental abnormalities that lead to varying degrees of ambiguity of phenotypic sex. Although most of these abnormalities impair reproduction, they usually are not life threatening. Thus, humans and experimental animals with naturally occurring defects in sexual differentiation survive to reach the attention of physicians and scientists. This chapter reviews the sequence of events in normal sexual development and describes disorders of this process — many of which result from single-gene mutations — that have provided valuable insights into the mechanisms of sexual differentiation. Normally, human somatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes.
A Young Male with Female Reproductive System
