The steroid metabolome of adrenarche

Abstract

Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). The timing of adrenarche varies between primates, but in humans, serum levels of DHEAS are seen to increase around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis (ZR) of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which, have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occurs during the process of adrenarche.

PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

“…Soon after birth, the outer definitive zone differentiates into zG and zF, while the inner fetal zone undergoes a marked involution with a corresponding decrease in adrenal androgen levels. Subsequently, at around 6-8 years of age, the emergence of zR at the corticomedullary junction heralds the onset of adrenarche and the return of adrenal androgen production, including DHEA/DHEAS and androstenedione, leading to axillary and pubic hair development and possibly brain maturation (3,4). While both the zF and zR express CYP17, the zR expresses high levels of the allosteric regulator cytochrome b5 (CYB5) rather than HSD3B2, which favors its 17,20-lyase activity leading to DHEA synthesis.…”

Regulation of Human 3β-Hydroxysteroid Dehydrogenase Type 2 by Adrenal Corticosteroids and Product-Feedback by Androstenedione in Human Adrenarche

“…Adrenarche is associated with a major expansion of the zona reticularis, which expresses high levels of cytochrome b 5 , leading to selective stimulation of the 17,20-lyase activity of the bifunctional cytochrome P450 c17 to produce DHEA in preference to 17a-hydroxypregnenolone. The zona reticularis also expresses high levels of DHEA-sulfotransferase (SULT2A1) and low levels of both 3bHSD2 mRNA (Rege et al, 2014) and protein (Rainey et al, 2002;Rege and Rainey, 2012). Our inhibition data now suggest that the 3bHSD2 product steroid, androstenedione, may be a key player in limiting the metabolism of DHEA by 3bHSD2 in the zona fasciculata and reticularis during adrenarche.…”

Novel mechanisms for DHEA action

“…The physiological role of circulation DHEA and DHEA-S as sources of bulk androgen cannot be overlooked (Rainey et al 2004, Rainey & Nakamura 2008, Rege & Rainey 2012, because a source of androgen is required to rapidly produce the sex-related hormones during adrenarche and parturition. Our studies of DHEA metabolism and the biological action of DHEA and its metabolites on hepatic metabolism have provided evidence that induction of the enzymes normally involved in foreign compound metabolism by DHEA is common to those induced by drugs and chemical toxicants (Webb et al 2006).…”