No evidence for hepatic conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA – in vivo and in vitro studies

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA, the mandatory precursor of human sex steroid biosynthesis. It is generally accepted that DHEA and DHEAS interconvert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted intracellularly toward sex steroids. We sought to analyze DHEA/DHEAS interconversion in healthy young and elderly men (n=8 in each group; ages 23–29 and 52–66yrs, BMI 20–26 and 23–28kg/m2). They were studied with frequent serum sampling (0830h-1500h) on three occasions: at baseline, after oral administration of 100mg DHEA at 0900h and after i.v. administration of 25mg DHEAS at 0900h. DHEA 100mg orally and DHEAS 25mg i.v. resulted in similar longstanding increases in serum DHEAS (oral DHEA vs. i.v. DHEAS: AUC0–6h 98±9 vs. 95±7µmol/lxh, n.s.). Oral DHEA also led to a significant increase in serum DHEA (AUC0–6h 400+32 vs. 263+20 nmol/lxh at baseline, p<0.05). However, surprisingly, DHEAS i.v. did not result in a significant DHEA increase (AUC0–6h 295+20 vs. 263+20 nmol/lxh, n.s.). Analysis of downstream conversion revealed a similar pattern with a significant increase in androstenedione after oral DHEA (AUC0–6h 84+4 vs. 53+4 nmol/lxh at baseline, p<0.05) but not after DHEAS i.v. (AUC0–6h 59+6 vs. 53+4 nmol/lxh, n.s.). Similarly, androstanediol glucoronide, a marker of peripheral androgen synthesis, increased after oral DHEA (AUC0–6h 156+14 vs. 117+11 nmol/lxh at baseline, p<0.05) but not after DHEAS i.v. (AUC0–6h 120+10 vs. 117+11 nmol/lxh, n.s.) The striking absence of significant conversion from DHEAS to DHEA was mirrored by our in vitro findings in HepG2 human hepatoma cells, revealing ample conversion of DHEA (100nM-10µM) to DHEAS while DHEAS (100pM-10µM) was not converted at all. Thus there seems to be no hepatic conversion of DHEAS to DHEA, challenging the previous view of free interconversion of DHEA and DHEAS.