No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies

Abstract

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS inter-convert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependent conversion of DHEA (0.1-2 mum) to DHEAS but no conversion of DHEAS (0.1-2 mum). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.

Premature adrenarche: novel lessons from early onset androgen excess

“…Accordingly, DHEAS was found to serve as a circulating storage pool for the generation of DHEA in peripheral target tissues of sex steroid action. However, while exogenous administration of DHEA in humans yields ample generation of both active sex steroids and DHEAS (20), we have previously shown that the administration of DHEAS does not result in appreciable levels of DHEA or active sex steroids (146,147). This suggests that DHEA sulphation is a permanent inactivating step and that the reverse reaction, cleavage of DHEAS to DHEA by STS, does not have a major impact on circulating steroid concentrations.…”

Dehydroepiandrosterone-induces miR-21 transcription in HepG2 cells through estrogen receptor β and androgen receptor

“…T is metabolized to E 2 by aromatase (CYP19). In humans, DHEA levels peaks in the morning (Hammer et al, 2005). DHEA-S levels are reduced in patients with advanced nonalcoholic fatty liver disease (NAFLD) (Charlton et al, 2008; Tokushige et al, 2013).…”

PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

“…It was previously assumed that DHEA and DHEAS are continuously interconverted, with DHEAS serving as a circulating pool for reactivation to DHEA, and ultimately sex steroids. However, this concept was called into question by studies suggesting that DHEA sulfation by the enzyme DHEA sulfotransferase, SULT2A1, is the predominant reaction, and the conversion back to DHEA through the enzyme steroid sulfatase is only a rare occurrence (1, 2), except for distinct tissues with ample steroid sulfatase activity, such as placenta and cancers of prostate, breast, endometrium, and colon (3). …”