ELITE Provides Reassurance About Estrogen in Early Menopause

JoAnn E. Manson, MD, DrPH


April 06, 2016

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This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I would like to talk about the Early vs. Late Intervention Trial with Estradiol (ELITE), which directly tested the timing hypothesis for estrogen in cardiovascular disease. The ELITE trial results were recently published in the New England Journal of Medicine.[1] The trial included 643 women, about half of whom were in early menopause (within 6 years of onset) with a mean age of 55 years. Half of the women were in later menopause (at least a decade since onset) and had a mean age of 63 years. Of interest, that was the same mean age of women in the Women's Health Initiative hormone therapy trials at the time of randomization.[2]

The ELITE trial tested oral estradiol, using 17 beta-estradiol at a dose of 1 mg/day. Women with an intact uterus were also given progesterone vaginal gel. The outcome used in the trial was carotid intima medial thickness (IMT) progression over 5 years of treatment. The results were compared between the estradiol and placebo arms. In the younger women, there was slowing of atherosclerosis progression, as measured by carotid IMT in the estradiol arm compared with the placebo arm, and the differences were statistically significant. In the older age group, there were no differences in carotid IMT progression rates between the estradiol and the placebo arms. Both progressed at a similar rate.

There are several cautions and caveats. Although it is biologically plausible that estrogen would reduce progression of atherosclerosis in early but not later menopause, we know that the estrogen receptors are more functional in early menopause. There is evidence from animal studies and observational studies—even the age-stratified analyses in the Women's Health Initiative hormone trials—to support more favorable results in younger vs older women in terms of coronary disease. The ELITE trial used the surrogate endpoint of carotid IMT progression. ELITE did not look at clinical heart attack events, because it was not large enough to have clinical events. Many pathways are relevant to myocardial infarction and coronary events. In addition to atherosclerosis, there can be plaque rupture and thrombotic occlusion of the blood vessel. We cannot say definitively that estradiol was preventing heart attacks in these women, but there was evidence for slowing of atherosclerosis in the younger women.

In terms of the clinical implications, based on this trial we can't say that hormone therapy should now be used for prevention of heart disease and other chronic disease events in younger women, because the trial used a surrogate endpoint and there could be other effects of hormone therapy. There is a very complex balance of benefits and risks in terms of venous thrombosis, stroke, breast cancer, and other outcomes.

However, this trial does provide further reassurance about the use of estrogen for the treatment of moderate to severe hot flashes, night sweats, and other menopausal symptoms in early menopause, as well as further evidence that concerns about coronary risk should not be used as a reason for denying hormone therapy treatment to women in early menopause who have these symptoms and are otherwise appropriate candidates for treatment. Thank you for your attention. This is JoAnn Manson.


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