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Estrogen Signaling in the Adrenal Cortex: Implications for Blood Pressure Sex Differences

Currently, more than a quarter of the female adult world population and 3-fold more of postmenopausal women in the United Sates have arterial hypertension.1,2 Sex differences in blood pressure (BP) and rate of hypertension play an important role in the susceptibility to cardiovascular disease.2–5 Moreover, hypertension is often undiagnosed or inadequately controlled in women, especially after menopause when cardiovascular risk increases.6

Endogenous estrogens are held to contribute to the maintenance of normal BP in premenopausal women, who show lower BP values than age-matched men.3 Estrogens elicit direct vasodilatory effects in vivo, albeit they may affect BP also through other mechanisms, including inhibition of sympathetic tone.3 During the menstrual cycle, BP is inversely related with circulating estrogen concentrations and is lower when 17β-estradiol (E2) levels peak.7 After menopause, both vascular aging, which leads to arterial stiffening, and the cessation of endogenous estrogen production contribute to a raise in BP,2,6 thereby increasing the risk of hypertension, atherosclerotic vascular disease, myocardial infarction, and stroke.2,6,8 Hormone replacement therapy can alleviate the postmenopausal BP increase and can reduce coronary vascular risk and carotid artery subclinical atherosclerosis progression,9–14 but this protective effect is lost in women who are many years after menopause.2,6

The effects of estrogens on other potent pressor mechanisms, and particularly those involving the renin–angiotensin–aldosterone system (RAAS), have received less attention as discussed below. Likely, this can explain why mineralocorticoid receptor antagonists, which entail an effective treatment of resistant/refractory arterial hypertension,15,16 are still underused in postmenopausal women,17 notwithstanding the high rate of resistant hypertension in this population.2

Aldosterone, one of the major effectors of the RAAS, is a major contributor to cardiovascular mortality in patients …