Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress

Endothelial function declines progressively across stages of the menopause transition; however, the mechanisms contributing to this decline are unknown. We hypothesized that differences in endothelial function among pre-, peri, and postmenopausal women are related to differences in estradiol and oxidative stress. Brachial artery flow-mediated dilation (FMD) was measured in 87 healthy women categorized by menopause stage (24 premenopausal, 17 early and 21 late perimenopausal, and 25 postmenopausal) before and after 3 days of ovarian hormone suppression (gonadotropin releasing hormone antagonist [GnRH(ant)]) alone, and an additional 3 days of GnRH(ant)with concurrent transdermal estradiol or placebo add-back treatment. In 82 women, FMD during acute vitamin C (antioxidant) infusion was measured before and after GnRH(ant)+ add-back. Before GnRH(ant), FMD was different among groups (p< 0.005; reduced across stages of menopause). Vitamin C increased FMD in late peri- and post- (p< 0.005) but not pre- or early perimenopausal women (p> 0.54). After GnRH(ant)alone, FMD decreased in pre- and peri- (p< 0.01), but not postmenopausal women, and was restored to premenopausal levels by estradiol add-back in the pre- and perimenopausal groups. Vitamin C improved FMD in pre-, peri-, and postmenopausal women on GnRH(ant)+ placebo. There was no effect of vitamin C on FMD in women on GnRH(ant)+ estradiol. These observations support the concept that the decline in endothelial function across the menopause transition is related to the loss of ovarian estradiol. The decline in estradiol may alter redox balance, thereby increasing oxidative stress and impairing endothelial function.