ELITE Trial Supports 'Timing Hypothesis' for Estrogen Therapy

JoAnn E. Manson, MD, DrPH


January 07, 2015

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Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I'd like to talk with you today about a recent study that provides further support for the timing hypothesis, or the critical window-of-opportunity hypothesis, for hormone therapy to slow atherosclerosis progression.

The study is the ELITE trial, the Early Vs Late Intervention Trial with Estradiol. Preliminary results were reported at the American Heart Association meeting this past November by Dr Howard Hodis and colleagues.[1]

The ELITE trial included 643 postmenopausal women who had prior hysterectomy. About half were close to the onset of menopause, less than 6 years, and about half were more distant from menopause, at least 10 years. The mean age of the first group was 55 years and the mean age of the second group was 65 years.

The women were randomized to 17 beta-estradiol, 1 mg given orally each day, versus placebo. The women who had an intact uterus also received 10 days of micronized progesterone gel vaginally. The outcome measure was the carotid intima-media thickness (IMT) measured by ultrasound.

Over a period of up to 6 years, the women who were randomized to estradiol, if they were in early menopause, overall had slower progression of atherosclerosis measured by carotid IMT than the women randomized to placebo. However, the older women did not show those differences. Overall there was a significant interaction by age group, with the younger age group women closer to the onset of menopause showing slowing of atherosclerosis with estradiol, but not the older women. The P value for interaction was .007. It was a significant interaction.

Other evidence for the timing hypothesis comes from the observational studies, which tended to include women who were close to the onset of menopause when they initiated hormone therapy. Subgroup analyses in the Women's Health initiative, especially the estrogen-alone trial, showed that women in their 50's tended to do better for heart disease and all-cause mortality and global index than women who were older.[2] There are some other smaller-scale randomized trials that also provide some support for the timing hypothesis.

This provides reassuring news for women in early menopause who are considering hormone therapy for management of menopausal vasomotor symptoms. However, it really shouldn't be used as a rationale for long-term use of hormone therapy for chronic disease prevention, because there are other considerations, including the potential for increased risk for stroke, venous thrombosis, and gallbladder disease, and with estrogen plus progestin there is an increased risk for breast cancer.

The evidence does support the timing hypothesis. We need more research using other formulations of hormone therapy, such as transdermal estradiol, and lower doses of hormones. We look forward to additional research in those areas as well as seeing the final results of the ELITE trial.

Thank you so much for your attention. I look forward to your comments, and I wish you a happy New Year.


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