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.

The Conserved Rieske Oxygenase DAF-36/Neverland Is a Novel Cholesterol-metabolizing Enzyme

“…Cholesterol and other sterol(s) serve as indispensable precursors for the biosynthesis of steroid hormones, and the conversion of cholesterol to the next specific intermediate is a crucial biochemical step across species (1)(2)(3)(4). In the biosynthesis of vertebrate steroid hormones, cholesterol is commonly converted to pregnenolone by side-chain cleavage catalyzed by the cytochrome P450 monooxygenase P450scc/CYP11A1 (2).…”

“…In the biosynthesis of vertebrate steroid hormones, cholesterol is commonly converted to pregnenolone by side-chain cleavage catalyzed by the cytochrome P450 monooxygenase P450scc/CYP11A1 (2). The step catalyzed by CYP11A1 is the key rate-limiting step in the synthesis of all vertebrate steroids, and it thus is controlled by numerous physiological responses throughout the life cycle (2,5).…”

DHEA-Bodipy—A functional fluorescent DHEA analog for live cell imaging

“…However, because DHEA-Bodipy is not converted to androstenediol-Bodipy and activates the ERα to the same extent as DHEA, it seems likely that the ERα might be activated also by DHEA itself. Some of the steroidogenic enzymes reside in mitochondria, most of them in the endoplasmic reticulum (Miller, 2008). Therefore, the staining of the endoplasmic reticulum and mitochondria following incubation of SK-ERα cells with DHEA-Bodipy could reflect the binding of DHEA-Bodipy and its unknown fluorescent metabolites to steroidogenic enzymes.…”

Multilevel regulation of steroid synthesis and metabolism in the bovine placenta

“…None of these has been evaluated in the context of bovine placental androgen and oestrogen synthesis, however. As the P450c17 enzyme plays a crucial role in the control of steroid synthesis, changes in the factors that regulate the ratio of the two activities of this enzyme obviously affect the ratio of different steroids synthesized (Miller, 2009).…”