Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

Abstract

BACKGROUND Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested. METHODS A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima– media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen. RESULTS After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P = 0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P = 0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P = 0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum. CONCLUSIONS Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.)

Early Postmenopausal Phase Is Associated With Reduced Prostacyclin-Induced Vasodilation That Is Reversed by Exercise Training

“…Along these lines, the beneficial effects of estrogen supplementation in terms of atherosclerosis and cardiovascular disease are most pronounced during the peri-and early postmenopausal years when estrogen receptors (ERs) or other compensatory mechanisms may function. 17,18 To what extent the beneficial effects of exercise training on vascular function are preserved in the early postmenopausal phase is currently not known.…”

“…17,18 Hence, the vasculature could also be more responsive to exercise training during this period. In support of this suggestion, the vascular response to infusion of epoprostenol and acetylcholine increased with exercise training in the postmenopausal women and this effect of training was not different from that of the premenopausal women.…”

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

“…63 More recently, the ELITE trial (Early vs Late Intervention Trial With Estradiol) was designed to address this hypothesis and stratified effects of HRT based on years since menopause when HRT was commenced and examined carotid intimamedial thickness and CAC. 37 The trial showed that women Figure 6. Effects of estrogen receptor (ER) silencing on β-estradiol (E2)-stimulated mineralization and calcification marker expression in cultured human coronary artery smooth muscle cell (HCASMC).…”

MECHANISMS IN ENDOCRINOLOGY: Aging and anti-aging: a Combo-Endocrinology overview

“…Women starting MHT within the first decade following the menopausal transition had up to 48% decrease in the incidence of CHD and up to 30% reduction in mortality (110, 111). In support of these findings, the ELITE randomized-controlled trial (Early vs Late Intervention Trial with Estradiol) showed that estradiol therapy slowed the progression of subclinical atherosclerosis as compared to placebo, when administered in early but not in late postmenopausal women (menopausal age <6 years vs ≥10 years) (112). The individualization of MHT in the context of IHD is presented in Table 1.…”