Age-specific changes in sex steroid biosynthesis and sex development.

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.

46,XX sex reversal.

In humans, sexual differentiation is directed by SRY, a master regulatory gene located at the Y chromosome. This gene initiates the male pathway or represses the female pathway by regulating the transcription of downstream genes; however, the precise mechanisms by which SRY acts are largely unknown. Moreover, several genes have recently been implicated in the development of the bipotential gonad even before SRY is expressed. In some individuals, the normal process of sexual differentiation is altered and a sex reversal disorder is observed. These subjects present the chromosomes of one sex but the physical attributes of the other. Over the past years, considerable progress has been achieved in the molecular characterization of these disorders by using a combination of strategies including cell biology, animal models, and by studying patients with these pathologic entities.