Sex Hormones as Potential Modulators of Vascular Function in Hypertension

Abstract

Abstract-The greater incidence of hypertension in men and postmenopausal women compared with premenopausal women has suggested gender differences in vascular function. Vascular effects of the female sex hormones estrogen and progesterone and the male hormone testosterone have been described. Sex steroid receptors have been identified in vascular endothelium and smooth muscle. Interaction of sex hormones with cytosolic/nuclear receptors initiates long-term genomic effects that stimulate endothelial cell growth but inhibit smooth muscle proliferation. Activation of sex hormone receptors on the plasma membrane triggers nongenomic effects that stimulate endothelium-dependent vascular relaxation via NO-cGMP, prostacyclin-cAMP, and hyperpolarization pathways. Sex hormones also cause endothelium-independent inhibition of vascular smooth muscle contraction, [Ca 2ϩ ] i , and protein kinase C. These vasorelaxant/vasodilator effects suggested vascular benefits of hormone replacement therapy (HRT) during natural and surgically induced deficiencies of gonadal hormones. Although some clinical trials showed minimal benefits of HRT in postmenopausal hypertension, the lack of effect should not be generalized because it could be related to the type/dose of sex hormone, subjects' age, and other cardiovascular conditions. The prospect of HRT relies on continued investigation of the molecular mechanisms underlying the vascular effects of sex hormones and identification of compounds that specifically target the vascular sex hormone receptors. Naturally occurring hormones and phytoestrogens may be more beneficial HRT than synthesized compounds. Also, the type/dose, time of initiation, and duration of HRT should be customized depending on the subject's age and preexisting cardiovascular condition, and thereby enhance the outlook of sex hormones as potential modulators of vascular function in hypertension.

Race and Sex Differences in Hypertension Control in CKD: Results From the Kidney Early Evaluation Program (KEEP)

“…Estrogens may upregulate production of such vasorelaxant substances as nitric oxide, react directly on vascular smooth muscle cells, and dampen the cardiovascular stress response to adrenergic stimuli. [17][18][19] Conversely, testosterone was shown to increase secretion of such vasoconstrictors as endothelin and stimulates the renin-angiotensin-aldosterone system, leading to inadequate sodium excretion in the setting of increased arterial blood pressure. 18,19 Genetic variability related to the renin-angiotensin-aldosterone system and/or the α-adrenergic receptor also was linked in population-based studies to sex differences in blood pressure in both African Americans 20 and whites.…”

“…[17][18][19] Conversely, testosterone was shown to increase secretion of such vasoconstrictors as endothelin and stimulates the renin-angiotensin-aldosterone system, leading to inadequate sodium excretion in the setting of increased arterial blood pressure. 18,19 Genetic variability related to the renin-angiotensin-aldosterone system and/or the α-adrenergic receptor also was linked in population-based studies to sex differences in blood pressure in both African Americans 20 and whites. 21 However, a primary biological explanation for sex differences in hypertension control would suggest persistently increased blood pressures for both African American and white men relative to women.…”

Association of Plasma Dehydroepiandrosterone-Sulfate Levels with Endothelial Function in Postmenopausal Women with Coronary Risk Factors

“…Testosterone supplementation in men (25,26) and estrogen replacement in postmenopausal women (27,28) improves endothelial vasomotor function. Activation of endothelial nitric oxide synthase and stimulation of nitric oxide production via androgen and estrogen receptors (29) might be attributable to the effect of DHEA(-S) on FMD. For this reason, we added testosterone and estradiol into the analysis.…”

Regulation of adrenomedullin release from human endothelial cells by sex steroids and angiotensin-II

“…Oestradiol has many reported vascular benefits in women, such as improving endothelial-dependent vasodilation (Pinto et al 1997, Virdis et al 2000 and regulation of cell proliferation (Farhat et al 1996). However, clinical trials of oestradiol in postmenopausal women have provided equivocal evidence of benefit (Khalil 2005). Investigations regarding the actions of testosterone have produced contradictory results (Kravariti et al 2005, Rosano et al 2005.…”