Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction.

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After the unexpected findings of the Women's Health Initiative trial, indicating that traditional cardiovascular risk markers fail to predict the effects of hormone replacement therapy, it is of interest to characterize how steroids act on vascular cells. This is particularly important for tissue-specific drugs such as tibolone, whose actions may differ from other preparations. Because nitric oxide (NO) is a key regulator of vascular tone and atherogenesis, we studied its regulation by tibolone and its metabolites on human endothelial cells. Tibolone and its estrogenic metabolites (3alpha- and 3beta-OH tibolone) activate NO synthesis by recruiting functional estrogen receptors, whereas the progestogenic/androgenic metabolite (Delta(4) isomer) has no effect. During prolonged exposures, tibolone and the estrogenic compounds enhance the expression of endothelial NO synthase (eNOS). In addition, tibolone is able to induce rapid activation of eNOS, leading to rapid increases in the release of NO. Relevant for its clinical effects, the sulfated metabolites of tibolone are also effective in activating eNOS. Different from estrogen, rapid activation of eNOS does not rely on recruitment of phosphatidylinositol-3 kinase but rather on MAPK-dependent cascades. These results help to understand the mechanisms of action of tibolone on the cardiovascular system and have relevant clinical implications.

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