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.).

Figure 1. Study Enrollment, Randomization, and Follow-up

Other reasons for a lack of carotid-artery intima–media thickness (CIMT) follow-up were as follows: in the early-postmenopause stratum, estradiol group, 3 participants were too busy, and 1 did not want to take estradiol; in the early-postmenopause stratum, placebo group, 3 participants moved away from the area, 1 was too busy, 1 was called for armed-services duty, 1 had a competing family issue, 1 was counseled by a physician to withdraw, and 1 did not want to take estradiol; in the late-postmenopause stratum, estradiol group, 2 participants moved away from the area, 1 was too busy, 1 was no longer interested, 1 had a weight increase, and 1 had concern about blood clots; in the late-postmenopause stratum, placebo group, 1 participant moved away from the area, 2 were too busy, 1 was called for armed-services duty, 1 had a competing family issue, and 1 received a diagnosis of breast cancer after undergoing baseline mammography. Other reasons for participants not being included in the coronary-artery calcium (CAC) and cardiac computed tomographic angiography (CCTA) analysis were as follows: in the early-postmenopause stratum, placebo group, 1 participant lost contact; in the late-postmenopause stratum, estradiol group, 1 participant was too busy; in the late-postmenopause stratum, placebo group, 1 participant had an incomplete examination and 2 participants lost contact.

Figure 2. CIMT Progression According to Study Group and Postmenopause Stratum

At 5 years, the mean absolute CIMT values were as follows: in the late-postmenopause stratum, placebo group (83 participants), 0.838 mm (95% confidence interval [CI], 0.810 to 0.866), and in the estradiol group (72 participants), 0.831 mm (95% CI, 0.805 to 0.857); in the early-postmenopause stratum, placebo group (65 participants), 0.789 mm (95% CI, 0.763 to 0.814), and in the estradiol group (75 participants), 0.770 mm (95% CI, 0.746 to 0.793). The effect of hormone therapy on the absolute value of CIMT at 5 years differed significantly between the postmenopause strata (P = 0.03 for the interaction). In the early-postmenopause stratum, the mean 5-year CIMT was significantly lower in the estradiol group than in the placebo group (P = 0.04); in the late-postmenopause stratum, the mean 5-year CIMT did not differ significantly between the estradiol and placebo groups. Shown at the bottom of the figure for each time point are the numbers of participants for whom CIMT data were available, participants who had completed or discontinued participation in the study, and participants who were still in the study but did not have CIMT data available.