Testing the menopausal hormone therapy timing hypothesis: The early versus late intervention trial with estradiol

Abstract The Early versus Late Intervention Trial with Estradiol (ELITE) is a 2x2, double-blinded, placebo-controlled trial specifically designed to determine whether menopausal hormone therapy (HT) has a differential effect on slowing the progression of subclinical atherosclerosis according to time-since-menopause when HT is initiated. The ELITE cohort is comprised of 643 healthy postmenopausal (>6 months) women without clinical evidence of cardiovascular disease (CVD) or diabetes mellitus who were randomized according to their time-since-menopause (<6 years, n=271 or >10 years, n=372). The primary trial end point is progression of carotid artery intima media thickness (CIMT) by high resolution B-mode ultrasound measured at baseline and every 6 months for up to 6 years. Women with a median (interquartile range) of 3.5 (1.9,5.0) and 14.3 (11.4,18.6) years-since-menopause were randomized to oral 17β-estradiol 1 mg daily with (uterine intact) or without (hysterectomy) vaginal micronized progesterone gel 4% (45 mg) 10 days per month versus placebos. Baseline CVD risk factors differed across the early (<6 years-since-menopause) and late (>10 years-since-menopause) postmenopausal strata as reflected by the mean CIMT (0.748 and 0.787 mm) and mean ages of the women (55.4 versus 65.4 years), respectively, whereas baseline risk factors were comparable among randomized treatment groups within each respective strata. Compliance with study products was greater than 90% and serum estradiol levels and CVD risk factors changed in the expected directions with HT relative to placebo in both strata. However, the rate of CIMT progression was significantly reduced with HT relative to placebo in the early postmenopausal group but not in the late postmenopausal group; the HT effect on CIMT progression significantly differed between the early versus late postmenopausal groups (p-value for interaction = 0.007). In conclusion, the results from ELITE support the cumulative literature that suggests that when HT is initiated at the time of menopause or early (within 6 years) after menopause that there is a significant reduction in CVD relative to no effect when initiated late (>10 years) after the menopause.