Direct Agonist/Antagonist Functions of Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) exhibits peak adrenal se- cretion in the fetus at term and around age 30 yr in the adult. Levels then progressively decline, which is associated with decreased levels of testosterone, dihydrotestosterone, and es- trogen in peripheral tissues. DHEA supplementation in post- menopausal women increases bone formation and density, an effect mainly attributed to peripheral conversion to sex hor- mones. In this study, we tested DHEA for direct effects on the androgen (AR) and estrogen (ER) receptors. DHEA bound to AR with aK i of 1M, which was associated with AR transcrip- tional antagonism on both the mouse mammary tumor virus andprostate-specificantigenpromoters,muchliketheeffects of bicalutamide. Unlike bicalutamide, DHEA stimulated, rather than inhibited, LNCaP cell growth, suggesting possible interaction with other hormone receptors. Indeed DHEA bound to ER and ER, with Ki values of 1.1 and 0.5 M, re- spectively. Despite the similar binding affinities, DHEA showed preferential agonism of ER with an EC50 of approx- imately 200 nM and maximal activation at 1 M. With ER we found 30-70% agonism at 5 M, depending on the assay. Phys- iological levels of DHEA are approximately 30 nM and up to 90 nM in the prostate. DHEA at 30 nM is actually sufficient to activate ER transcription to the same degree as estrogen at its circulating concentration, and additive effects are seen when the two were combined. Taken together, DHEA has the potential for physiologically relevant direct activation of ER. With peak levels at term and age 30 yr, there is also a potential for antagonist effects on AR and partial agonism of ER .( Endocrinology 146: 4568-4576, 2005)