Ontogeny of adrenal steroid biosynthesis: why girls will be girls

Abstract

Male and female external genitalia appear identical early in gestation. Testosterone exposure at 8-12 weeks' gestation causes male differentiation. Female fetuses virilize if their adrenals secrete excessive levels of androgens, as occurs in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This can be ameliorated by administering dexamethasone to the mother. A study by Goto et al. in this issue of the JCI provides a rationale for this treatment by demonstrating that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate (see the related article beginning on page 953). Dexamethasone suppresses this axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not virilize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization.

Figure 1. Steroid biosynthesis and metabolism during gestation.

Conversions within the fetal adrenal cortex, fetal liver, male (i.e., testosterone-exposed) genital skin, and placenta are denoted by arrows; the enzyme mediating each conversion is also shown. Relative amounts of cortisol and DHEAS secreted by the fetal adrenal cortex are regulated by expression of HSD3B2, which is labeled in red. ARSC1, arylsulfatase; SRD5A2, steroid 5α-reductase type 2; SULT2A1, steroid sulfotransferase.

Figure 2. Relative levels of cortisol and DHEAS secretion by the fetal adrenal cortex during gestation as well as postnatally.

Approximate times of several events are shown (see “Endocrinology of human pregnancy”). The existence of the first peak of cortisol secretion at 8–10 wpc was demonstrated in this issue by Goto et al. (1). Vertical axis is logarithmic, but values are approximate. Horizontal axis is not to scale.