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

Abstract

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.

Keywords: Aging; Menopause; Sex hormones; Vascular biology; Women.

Fig. 1

Ovarian hormone suppression decreased endothelial function in premenopausal and perimenopausal women. a Brachial artery FMD and b nitroglycerine (GTN)-mediated vasodilation before (black bars) and following GnRH antagonist (GnRHant) treatment (gray bars). Data are means ± SE. *p < 0.01 vs. premenopausal women under the same condition; ^†p < 0.05 vs. baseline condition early perimenopausal; ^‡p < 0.01 vs. baseline condition of the same group. In the subsample of women (N = 45; Pre, premenopausal, N = 15; Early Peri, early perimenopausal, N = 8; Late Peri, late perimenopausal, N = 9; Post, postmenopausal, N = 23) who had GTN-mediated dilation performed, there was a significant main effect of time with all groups decreasing after GnRH_ant; p < 0.005)

Fig. 2

The change in endothelial function (brachial artery FMD) following GnRH antagonist treatment was dependent on menopausal state. Data are means ± SE. ^*p < 0.01 vs. premenopausal women; ^†p < 0.05 vs. early perimenopausal women

Fig. 3

Estradiol add-back treatment reversed the impairment in endothelial function with ovarian suppression alone in premenopausal women and increased endothelial function in perimenopausal and postmenopausal women to normal premenopausal levels. Brachial artery FMD before and following GnRH antagonist (GnRH_ant) alone and with placebo or estradiol add-back treatment. Data are means ± SE. ^*p < 0.01 vs. baseline of the same group; ^†p < 0.05 vs. GnRH antagonist alone condition of the same group; ^‡p < 0.01 vs. baseline condition of the same group; ^‖p < 0.001 vs. placebo add-back condition of the same group

Fig. 4

Acute antioxidant vitamin C infusion increased endothelial function in late perimenopausal and postmenopausal women. Baseline a brachial artery FMD and b nitroglycerine (GTN)-mediated vasodilation before (black bars) and following acute vitamin C infusion (hatched bars). Data are means ± SE (N = 82; Pre, premenopausal, N = 22; Early Peri, early perimenopausal, N = 16; Late Peri, late perimenopausal, N = 21; Post, postmenopausal, N = 23). ^*p < 0.01 vs. premenopausal women under the same condition; ^†p < 0.05 vs. baseline condition early perimenopausal; ^‡p < 0.01 vs. baseline condition of the same group. For GTN, there was a significant main effect of the time (N = 39; Pre = 11, Early Peri = 7, Late Peri = 11, Post = 10; p = 0.004)

Fig. 5

Acute vitamin C treatment reversed the effect of ovarian suppression in placebo-treated women but had no effect in estradiol-treated women. Brachial artery FMD during saline (solid bars) and vitamin C infusion (hatched bars) before (black bars) and following GnRH antagonist (gray bars) plus placebo or estradiol treatment in a premenopausal, b perimenopausal, and c postmenopausal women. Data are means ± SE. ^*p < 0.01 vs. baseline saline of the same group; ^†p < 0.05 vs. GnRH antagonist plus add-back saline of the same group