Review
Dissecting human adrenal androgen production

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Abstract

The human adrenal cortex produces aldosterone, cortisol and the so-called adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Within the adult adrenal, the zona glomerulosa produces aldosterone, the zona fasciculata cortisol and the zona reticularis both DHEA and DHEAS. The processes regulating aldosterone and cortisol synthesis are well defined; however, the mechanisms regulating the production of DHEA(S) remain elusive. The emphasis of this review is based on increasing evidence that cytochrome b5, DHEA sulfotransferase and 3β-hydroxysteroid dehydrogenase play crucial roles in regulating production of DHEA(S). Insight into the mechanisms that regulate the synthesis of these key components of DHEA(S) synthesis should provide important clues to the regulation of adrenal androgen biosynthesis.

Section snippets

Cytochrome b5 and the 17,20-lyase activity of CYP17

In human adrenal glands, CYP17 is found in both the fasciculata and reticularis zones of the cortex, consistent with its role in both cortisol and DHEA synthesis. After the cloning of human CYP17, the ability of CYP17 to accomplish both 17α-hydroxylase and 17,20-lyase enzymatic activities was demonstrated 10., 11.. However, the mechanisms that enable CYP17 to accomplish the 17α-hydroxylase reaction with diminished 17,20-lyase activity in the adrenal fasciculata, whilst promoting both

DHEA-sulfotransferase

SULT2A1, in addition to CYP11A1 and CYP17, is necessary for the production of DHEAS (Fig. 2). SULT2A1 has a broad substrate specificity, which includes metabolism of pregnenolone, 17α-hydroxypregnenolone and DHEA to their respective sulfated products 28., 29., 30.. Once sulfated by SULT2A1, pregnenolone and 17α-hydroxypregnenolone are no longer available as substrates for HSD3B2. Therefore, SULT2A1 sulfation of pregnenolone and 17α-hydroxypregnenolone removes these substrates from the

3β-hydroxysteroid dehydrogenase type 2

HSD3B2 catalyzes the oxidation and isomerization of 3β-hydroxy-5-ene steroids into 3-keto-4-ene steroids, thus permitting the adrenal gland to synthesize progesterone and 17α-hydroxyprogesterone from their precursors, pregnenolone and 17α-hydroxypregenenolone (Fig. 2) [40]. This enzyme is essential for adrenocortical synthesis of aldosterone and cortisol, but is not directly involved in the synthesis of DHEA(S). However, by virtue of its broad substrate specificity, HSD3B2 will compete with

Conclusions

It is clear that the level of circulating DHEAS follows a trend during development and aging that is distinct from that of other adrenal steroids or gonad-derived estrogens and androgens. The mechanisms that lead to the distinct pattern of DHEAS production (Fig. 1) remain unknown, making DHEAS the least understood of the steroid hormones produced by the adrenal gland. In many regards, the mechanisms regulating DHEAS synthesis continue to represent one of the most intriguing mysteries of

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