Assessing the Impact of Postmenopausal Hormone Therapy on Cardiovascular Health

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Hormone replacement therapy within a few years after menopause could decrease the risk for heart disease.
Hormone replacement therapy within a few years after menopause could decrease the risk for heart disease.

Introduction

Over the last 4 decades, research has produced a sizable, though not entirely consistent, body of data regarding the association between hormone replacement therapy and cardiovascular (CV) health in postmenopausal women.

In the 1980s, observational studies revealed that postmenopausal women receiving hormone replacement had a lower risk of coronary heart disease (CHD) and death from all causes;1 however, these findings were later overshadowed by the results of randomized trials, including the Women's Health Initiative (WHI), which failed to support the suggestion that hormone therapy after menopause protects against heart disease.2-4 

Further research and analysis — along with the recognition that the mean age in the WHI trials was 63 years compared with observational studies that included mainly younger women — suggested that the timing of hormone therapy with respect to menopause onset, and the age of the woman at the start of therapy, might help explain the seemingly inconsistent results of those earlier studies.

This explanation, now known as the “timing hypothesis,” asserts that the initiation of hormone replacement therapy within a few years after menopause — when women's hearts are younger and their coronary arteries are more receptive to the beneficial effects of estrogen — could decrease the risk for heart disease. However,  the initiation of therapy later in menopause, when women tend to be older, may have no CV benefit and may even be harmful.5-7

The ELITE Trial

The timing hypothesis was tested by Howard Hodis, MD, of the Atherosclerosis Research Unit at the Keck School of Medicine at the University of Southern California in Los Angeles, and colleagues in the Early vs Late Intervention Trial with Estradiol (ELITE), a single-center, randomized, double-blind, placebo-controlled trial funded by the National Institute on Aging.

The trial demonstrated that women who received estradiol, rather than placebo, had lower rates of subclinical atherosclerosis progression, but only when therapy was started within 6 years after menopause. Results were published in a 2016 issue of The New England Journal of Medicine.6

Healthy postmenopausal women without diabetes or clinical evidence of cardiovascular disease (CVD; n=643) participated in the ELITE study. The women had not had a regular menses for at least 6 months or had undergone surgically-induced menopause, and also had serum estradiol levels of <25 pg/ml (92 pmol/L).6 

In a 1:1 ratio, the women were randomly assigned to receive either oral 17-beta-estradiol or placebo. The estradiol group received 1 mg per day; women with an intact uterus also received 45 mg of progesterone as a 4% vaginal gel, administered sequentially (ie, once a day for 10 days of each 30-day cycle). In a similar regimen, the non-estradiol group received oral placebo and placebo vaginal gel, instead of oral estradiol and vaginal progesterone.6

At the time of randomization, the women were stratified into 2 groups based on their number of postmenopausal years. The early postmenopause group consisted of women who had reached menopause <6 years before (median time since menopause: 3.5 years and median age: 55.4 years at enrollment). Women who were postmenopausal for ≥10 years were stratified to the late postmenopause group *(median time since menopause: 14.3 years and median age: 63.6 years).6 

Randomization stratification factors also included baseline carotid-artery intima-media thickness (CIMT; <0.75 mm or ≥0.75 mm) and history of hysterectomy. Mean CIMT was 0.75 mm in the “early” stratum and 0.79 mm in the “late” stratum.6 

The rate of change in CIMT, measured in the far wall of right distal common carotid artery, was the trial's primary outcome. CIMT was assessed twice at baseline and averaged, and then every 6 months during follow-up for a median of 5 years, using computer image processing of B-mode ultrasonograms. The degree of coronary atherosclerosis measured by cardiac computer tomography (CT) upon completion of the assigned regimen was a secondary end point.6  

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