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Plasma BDNF levels are influenced by hormonal status. Modifications in BDNF circulating levels during the menstrual cycle suggest a potential role for gonadal sex hormones (E(2) and progesterone) in regulating neurotrophin expression.

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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.

The antiatherogenic effect of estrogen is mediated, in part, by inhibitory effects on endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. To determine the mechanism by which estrogen regulates VCAM-1 expression, we compared the effect of 17beta-estradiol (E(2)) and of the glucocorticoid dexamethasone (Dex) on lipopolysaccharide (LPS)-induced VCAM-1 expression in human endothelial cells. E(2) decreased LPS-induced VCAM-1 mRNA and protein expression to a greater extent than Dex. Dex, but not E(2), stabilized VCAM-1 mRNA. This correlated with inhibition of monocytoid U937 cell adhesion to endothelial cells. Transfection of endothelial cells with a functional VCAM-1 promoter construct showed that E(2) inhibited LPS-induced VCAM-1 gene transcription more potently than did Dex. However, using a truncated construct containing only the nuclear factor-kappaB (NF-kappaB)-responsive elements but lacking the consensus sequences for activator protein-1 (AP-1) and GATA, E(2) and Dex had similar inhibitory effects. Consistently, gel-shift assays showed that E(2) and Dex comparably inhibit LPS-induced activation of NF-kappaB, whereas E(2) inhibited LPS-induced activation of AP-1 and GATA to a greater extent than Dex. E(2) inhibition of NF-kappaB after LPS treatment was associated with decreased inhibitor kappaB (IkappaB) kinase activity and with a stabilization of the NF-kappaB inhibitor IkappaBalpha. These results indicate that E(2) decreases VCAM-1 gene expression through the inhibition of NF-kappaB, AP-1, and GATA and suggest novel mechanisms for the antiatherogenic effect of estrogen on the vascular wall.