Role of estrogen receptors in modulating aldosterone biosynthesis and blood pressure.

Blood pressure is lower in premenopausal women than in age-matched men; after menopause blood pressure values and the prevalence of hypertension show opposite trends indicating that estrogens contribute to maintaining normal blood pressure values in women. In experimental studies menopause increases aldosterone levels, an effect alleviated by estrogen treatment. We have recently discovered a role of estrogen receptors (ER) in controlling aldosterone biosynthesis in the human adrenocortical zona glomerulosa, which expresses both the classical ERα and β receptors and G protein-coupled estrogen receptor (GPER). We have also identified that GPER mediates an aldosterone-induced aldosterone response. We found that 17 β-estradiol exerts a dual effect: it blunts aldosterone production via ERβ, but displays a potent aldosterone secretagogue effect via GPER activation after ERβ blockade. Thus, in premenopausal women high estrogen levels might tonically blunt aldosterone synthesis via ERβ, thereby maintaining normal blood pressure; after menopause loss of this estrogen-mediated inhibition can contribute to increasing blood pressure via GPER-mediated aldosterone release. The additional findings that GPER mediates an aldosterone-induced stimulation of aldosterone biosynthesis and that GPER predominates in aldosterone-producing adenomas strongly involves this receptor in the pathophysiology of primary aldosteronism. Our purpose here was to provide an update on estrogen receptor function in the normal adrenal cortex and its relevance for the sex differences in blood pressure in light of the newly discovered role of GPER in regulating aldosterone synthesis. The implications of the novel knowledge for the treatment of estrogen-dependent malignancies with ER modulators are also discussed.