Does DHEA Exert Direct Effects on Androgen and Estrogen Receptors, and Does It Promote or Prevent Prostate Cancer?

Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Serum levels of DHEA and its sulfated conjugation product, DHEA sulfate (DHEAS), peak in men and women in the third decade and decrease progressively and profoundly with age (1). In the United States, DHEA is widely available as an over-the-counter dietary supplement and is increasingly self-prescribed for its alleged anabolic and antiaging effects, with unsubstantiated claims of beneficial effects on body composition, cardiometabolic, immune, and neurobiological functions, as well as uncertain long-term safety, in the elderly (2). Humans and other primates are unique among animal species in that their adrenal glands secrete large amounts of DHEA and DHEAS (3). To date, no cognate nuclear or membrane receptor for DHEA has been identified, and its mechanisms of action remain a subject of active investigation. DHEA has been shown to exert many of its effects via the androgen receptor (AR) and/or estrogen receptor (ER) after its enzymatic conversion to androgen or estrogen (4), although direct effects of DHEA on the AR and ER have also been demonstrated (5, 6). Moreover, DHEA can act via non-steroid-receptor nongenomic pathways, as shown in vascular endothelial cells (7). In aged adults, the use of DHEA as a dietary supplement is of potential concern in that its androgenic or estrogenic actions may stimulate proliferation of, and other adverse effects on, cancer cells within the prostate or breast. Controversy remains as to whether DHEA enhances or reduces the risk of prostate and breast cancer (8).