Abstract
Adrenal steroid biosynthesis and its related pathology are constant evolving disciplines. In this paper, we review classic and current concepts of adrenal steroidogenesis, plus control mechanisms of steroid pathways, distribution of unique enzymes and cofactors, and major steroid families. We highlight the presence of a "mineralocorticoid (MC) pathway of zona fasciculata (ZF)", where most circulating corticosterone and deoxycorticosterone (DOC) originate together with 18OHDOC, under ACTH control, a claim based on functional studies in normal subjects and in patients with 11β-, and 17α-hydroxylase deficiencies. We emphasize key differences between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) and the onset of a hybrid enzyme - CYP11B1/CYP11B2 -, responsible for aldosterone formation in ZF under ACTH control, in "type I familial hyperaldosteronism" (dexamethasone suppressible). In "apparent MC excess syndrome", peripheral conversion of cortisol to cortisone is impaired by lack of 11β-hydroxysteroid dehydrogenase type 2, permitting free cortisol access to MC receptors resulting in severe hypertension. We discuss two novel conditions involving the synthesis of adrenal androgens: the "backdoor pathway", through which dihydrotestosterone is formed directly from androsterone, being relevant for the fetoplacental setting and sexual differentiation of male fetuses, and the rediscovery of C19 11-oxygenated steroids (11-hydroxyandrostenedione and 11-ketotestosterone), active androgens and important markers of virilization in 21-hydroxylase deficiency and polycystic ovaries syndrome. Finally, we underline two enzyme cofactor deficiencies: cytochrome P450 oxidoreductase which partially affects 21- and 17α-hydroxylation, producing a combined clinical/hormonal picture and causing typical skeletal malformations (Antley-Bixler syndrome), and PAPSS2, coupled to SULT2A1, that promotes sulfation of DHEA to DHEAS, preventing active androgens to accumulate. Its deficiency results in reduced DHEAS and elevated DHEA and androgens with virilization. Future and necessary studies will shed light on remaining issues and questions on adrenal steroidogenesis.
Highlights
Synthesis of steroid hormones by the adrenal cortices – as well as by the interstitial cells of the ovaries and testes (Leydig cells), is a complex and dynamic process whose mechanisms are still unclear
Regulation of adrenal steroid biosynthesis is both external – through trophic stimulus by specific secretagogues (e.g. Adrenocortical trophic hormone (ACTH), angiotensin), as well as by innervation from the autonomous nervous system – and internal – via the presence and catalytic activity of several specific steroidogenic enzymes distributed throughout the adrenocortical layers
Steroid synthesis begins with the acceleration of cholesterol flow through the mitochondrial membrane mediated by StAR (5,9)
Summary
Synthesis of steroid hormones by the adrenal cortices – as well as by the interstitial cells of the ovaries (theca cells) and testes (Leydig cells) –, is a complex and dynamic process whose mechanisms are still unclear. This is one possible reason why the study of steroidogenesis has always been involved by a mist of mystery and challenge for the non-specialist. Instead of presenting detailed physiologic and molecular mechanisms of steroidogenesis, we will review helpful concepts aiming at aspects that usually cause doubts and confusion For those interested in a more in-depth reading, we recommend consulting some excellent recent reviews (1-5)
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