Direct Agonist/Antagonist Functions of Dehydroepiandrosterone

Abstract

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 microM, 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 ERalpha and ERbeta, with Ki values of 1.1 and 0.5 microM, respectively. Despite the similar binding affinities, DHEA showed preferential agonism of ERbeta with an EC50 of approximately 200 nm and maximal activation at 1 microM. With ERalpha we found 30-70% agonism at 5 microM, 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 ERbeta 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 ERbeta. With peak levels at term and age 30 yr, there is also a potential for antagonist effects on AR and partial agonism of ERalpha.

Human prostate stromal cells stimulate increased PSA production in DHEA-treated prostate cancer epithelial cells

“…Humans and other primates are unique among animal species in that their adrenal glands secrete large amounts of DHEA and DHEA-S [5,12]. DHEA has been shown to exert many of its effects via the AR and/or estrogen receptor (ER) following its enzymatic conversion to androgen or estrogen [17], although direct effects of DHEA on the AR and ER have also been demonstrated [18][19][20][21]. DHEA can act as a direct ligand for the ERβ [18] [22].…”

“…DHEA has been shown to exert many of its effects via the AR and/or estrogen receptor (ER) following its enzymatic conversion to androgen or estrogen [17], although direct effects of DHEA on the AR and ER have also been demonstrated [18][19][20][21]. DHEA can act as a direct ligand for the ERβ [18] [22]. Moreover, DHEA can act via non-steroid receptor, non-genomic pathways, as shown in vascular endothelial cells [23].…”

Assessing Baseline and Temporal Changes in Cardiometabolic Risk Using Metabolic Syndrome Severity and Common Risk Scores

“…Although these scores were derived specifically for prediction of CVD, they incorporate multiple measures that are also risk factors for T2DM, including obesity status,10, 11 smoking,12 age,10 high‐density lipoprotein (HDL),13 and (in the case of the ASCVD score) race/ethnicity,13 emphasizing substantial overlap in cardiometabolic risk. Thus, there is a clear likelihood for these scores to also correlate with risk for future T2DM, either with or without ultimate CVD.…”

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts

“…Inhibitors of aromatase (Arimidex, 100 nM) and STS (STX64, 100 nM) were included alone or in combination with relevant steroids. Migration was measured at 4,8,12,24, and 48 h in triplicate dishes for each donor. Conditioned medium, collected from dermal fibroblast cultures 24 h after scratching as previously described (37), was also assessed for its effect on the migration of epidermal keratinocytes.…”