Mutation of HSD3B2 Gene and Fate of Dehydroepiandrosterone.

3ßHSD2 enzyme is crucial for adrenal and gonad steroid biosynthesis. In enzyme deficiency states, due to recessive loss-of-function HSD3B2 mutations, steroid flux is altered and clinical manifestations result. Deficiency of 3ßHSD2 activity in the adrenals precludes normal aldosterone and cortisol synthesis and the alternative backdoor and 11-oxygenated C19 steroid pathways and the flooding of cortisol precursors along the Δ5 pathway with a marked rise in DHEA and DHEAS production. In gonads, it precludes normal T and estrogen synthesis. Here, we review androgen-dependent male differentiation of the external genitalia in humans and link this to female development and steroidogenesis in the developing adrenal cortex. The molecular mechanisms governing postnatal adrenal cortex zonation and ZR development were also revised. This chapter will review relevant clinical, hormonal, and genetic aspects of 3ßHSD2 deficiency with emphasis on the significance of alternate fates encountered by steroid hormone precursors in the adrenal gland and gonads. Our current knowledge of the process of steroidogenesis and steroid action is derived from pathological conditions. In humans the 3ßHSD2 deficiency represents a model of nature that reinforces our knowledge about the role of the steroidogenic alternative pathway in sex differentiation in both sexes. However, the physiological role of the high serum DHEAS levels in fetal life as well as after adrenarche remains to be elucidated.