Abstract

Context: The Early versus Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced progression of atherosclerosis when initiated in early but not in late postmenopause.Objective: This post-trial analysis determined the association between plasma estradiol (E2) levels and atherosclerosis determined by rate of change in carotid artery intima-media thickness (CIMT) and tested whether this association is equally evident in early (<6 years) compared with late (=10 years) postmenopause.Design: Randomized controlled trial stratified by time since menopause (ClinicalTrials.gov number NCT00114517). Mixed-effects linear models tested the association of E2 levels with CIMT rate of change.Setting: Los Angeles, California, USA.Participants: Healthy postmenopausal women.Intervention: Oral E2 with/without cyclic vaginal progesterone.Main outcome measures: Plasma E2 levels and CIMT assessed every 6 months over an average 4.8 years.Results: Among 596 postmenopausal women, higher E2 was inversely associated with CIMT progression in early-postmenopausal women (p=0.041) and positively associated with CIMT progression in late-postmenopausal women (p=0.006) (p-for-interaction<0.001). CIMT progression rate for the lowest versus highest quartiles of E2 levels among early-postmenopausal women was 8.5 mum/yr and 7.2 mum/yr, while among late-postmenopausal women was 9.8 mum/yr and 11.7 mum/yr, respectively.Conclusion: E2 levels are differentially associated with atherosclerosis progression according to timing of hormone therapy initiation. With higher E2 levels, CIMT progression rate is decreased among early-postmenopausal women, but increased among late-postmenopausal women. These results support the timing hypothesis of HT initiation on cardiovascular benefit, with reduced atherosclerosis progression for initiation during early postmenopause.

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