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Department of Molecular Endocrinology (F.C., K.K., E.B., J.F., H.W., A.S., S.H., L.P.F., A.A.R.), Merck Research Laboratories, West Point, Pennsylvania 19486; and Centro de Investigación Básica (M.M., C.T.M.), Merck, Sharp & Dohme de España, Madrid 28027, Spain
Address all correspondence and requests for reprints to: Fang Chen, Ph.D., Department of Molecular Endocrinology, Merck Research Laboratories, WP26A-1000, Sumneytown Pike, West Point, Pennsylvania 19486. E-mail: fang_chen{at}merck.com.
Dehydroepiandrosterone (DHEA) exhibits peak adrenal secretion 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 estrogen in peripheral tissues. DHEA supplementation in postmenopausal women increases bone formation and density, an effect mainly attributed to peripheral conversion to sex hormones. In this study, we tested DHEA for direct effects on the androgen (AR) and estrogen (ER) receptors. DHEA bound to AR with a Ki of 1 µM, which was associated with AR transcriptional antagonism on both the mouse mammary tumor virus and prostate-specific antigen promoters, much like the effects 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 ERß, with Ki values of 1.1 and 0.5 µM, respectively. Despite the similar binding affinities, DHEA showed preferential agonism of ERß with an EC50 of approximately 200 nM and maximal activation at 1 µM. With ER we found 30–70% agonism at 5 µM, depending on the assay. Physiological levels of DHEA are approximately 30 nM and up to 90 nM in the prostate. DHEA at 30 nM is actually sufficient to activate ERß 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 ERß. With peak levels at term and age 30 yr, there is also a potential for antagonist effects on AR and partial agonism of ER.
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