ABSTRACT
The molecular mechanisms of action of dehydroepiandrosterone (DHEA) and its sulfated form, dehydroepiandrosterone sulfate (DHEAS), remain unclear despite extensive studies over many decades. The predominant mechanistic hypothesis for the actions of DHEA is that the steroid is metabolized to potent androgens and estrogens, which activate the intracellular estrogen receptors (ERs) and androgen receptors (ARs; Labrie et al. 2005). Additional proposed molecular mechanisms include the activation of (1) other ligand-dependent intracellular receptors (e.g., peroxisome proliferator-activated receptor-α, pregnane X receptor, or an uncharacterized DHEA-speci‰c receptor); (2) other classes of receptors (e.g., sigma-1 receptor); (3) ion channels (e.g., γ-amino butyric acid A receptor chloride channel); or (4) enzymes (e.g., protein kinase C or glucose-6-phosphate dehydrogenase; comprehensively reviewed in a study by Webb et al. [2006]). Additionally, recent studies have focused on plasma membrane-initiated rapid intracellular signaling related to DHEA. Notable in these studies is that binding and signaling are shown to occur at DHEA concentrations that are within or close to the physiological concentration range of circulating DHEA in humans, suggesting that these mechanisms may be active in vivo.
