Androgen synthesis in adrenarche

Abstract

The enzymes and pathways of steroidogenesis are central to an understanding of adrenarche. The quantitative regulation of steroidogenesis occurs at the first step, the conversion of cholesterol to pregnenolone. Chronic quantitative regulation is principally at the level of transcription of the CYP11A1 gene encoding P450scc, which is the enzymatically rate-limiting step. Acute regulation is mediated by the steroidogenic acute regulatory protein (StAR), which facilitates the rapid influx of cholesterol into mitochondria, where P450scc resides. Qualitative regulation, which determines the type of steroid produced in a cell, is principally at the level of P450c17 (CYP17). In the absence of P450c17 in the zona glomerulosa, C21 deoxy steroids are produced, leading to the mineralocorticoid, aldosterone. In the presence of the 17alpha-hydroxylase but not the 17,20 lyase activity of P450c17 in the zona fasciculata, C21, 17-hydroxy steroids are produced, leading to the glucocorticoid, cortisol. When both the 17alpha-hydroxylase and 17,20 lyase activities of P450c17 are present in the zona reticularis, the androgen precursor DHEA is produced. The discrimination between 17alpha-hydroxylase and 17,20 lyase activities is regulated by two post-translational events, the serine phosphorylation of P450c17 and the allosteric action of cytochrome b5, both of which act to optimize the interaction of P450c17 with its obligatory electron donor, P450 oxidoreductase. In the adrenal zona reticularis, the abundant expression of P450 oxidoreductase and cytochrome b5, and the low expression of 3beta-hydroxysteroid dehydrogenase (HSD3B2) result in the production of the large amounts of DHEA that characterize adrenarche.