Dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepiandrosterone (DHEA) that circulates in far greater relative concentrations. The steroid is hormonally inert and is instead an important neurosteroid and neurotrophin. Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepiandrosterone (DHEA) that circulates in far greater relative concentrations. The steroid is hormonally inert and is instead an important neurosteroid and neurotrophin. Similarly to other conjugated steroids, DHEA-S is devoid of hormonal activity, lacking affinity for the steroid hormone receptors. However, DHEA-S retains activity as a neurosteroid and neurotrophin. It has been found to act as a positive allosteric modulator of the NMDA receptor (50 nM–1 µM), negative allosteric modulator of the GABAA and glycine receptors, and weak agonist of the sigma-1 receptor (Kd > 50 µM). In addition, DHEA-S has been found to directly bind to and activate the TrkA and p75NTR – receptors of neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) – with high affinity (around 5 nM). Although DHEA-S itself is hormonally inert, it has been thought that it can be converted back into DHEA, which is weakly androgenic and estrogenic, and that DHEA in turn can be transformed into more potent androgens like testosterone and dihydrotestosterone (DHT) as well as estrogens like estradiol. As such, it has been thought that DHEA-S is a prohormone with the potential for androgenic and estrogenic effects. However, a 2005 study found that DHEA could be converted into DHEA-S but found no evidence of conversion of DHEA-S into DHEA. DHEA-S has also been found to inhibit the TRPV1 and TRPC5 transient receptor potential channels and to inhibit the P2X receptor. DHEA and DHEA-S are produced in the zona reticularis of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH). DHEA is synthesized from cholesterol via the enzymes cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with pregnenolone and 17α-hydroxypregnenolone as intermediates. Then, DHEA-S is formed by sulfation of DHEA at the C3β position via the sulfotransferase enzymes SULT2A1 and to a lesser extent SULT1E1. Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the gonads (10%), DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women. Approximately 10 to 15 mg of DHEA-S is secreted by the adrenal cortex per day in young adults. Unlike DHEA, which is weakly bound to albumin, DHEA-S is strongly bound to albumin (i.e., with very high affinity), and this is the reason for its much longer comparative terminal half-life. In contrast to DHEA, DHEA-S is not bound to any extent to sex hormone-binding globulin (SHBG). Whereas DHEA easily crosses the blood–brain barrier into the central nervous system, DHEA-S poorly crosses the blood–brain barrier. DHEA-S can be converted back into DHEA via steroid sulfatase (STS). In premenopausal women, 40 to 75% of circulating testosterone is derived from peripheral metabolism of DHEA-S, and in postmenopausal women, over 90% of estrogens, mainly estrone, are derived from peripheral metabolism of DHEA-S. A study found that administration of exogenous DHEA-S in women who were pregnant increased circulating levels of estrone and estradiol. DHEA-S serves as a depot for potent androgens like testosterone and dihydrotestosterone in prostate cancer, which fuel the growth of this cancer. The elimination half-life of DHEA-S is 7 to 10 hours, which is far longer than that of DHEA, which has a elimination half-life of only 15 to 30 minutes.