Estrogen Replacement Therapy Does Not Increase Cardiovascular Risk Except in People 70 Years or Older

In postmenopausal women with vasomotor symptoms, does estrogen replacement therapy, with or without progesterone, affect the likelihood of experiencing a cardiovascular event?

Almost 25 years ago, the results of the Women's Health Initiative study were published. The study was abruptly stopped because of suspicion of increased harm, and it had a chilling effect on the prescribing of postmenopausal estrogen for more than 20 years. A secondary analysis found no increase in cardiovascular risk in women 50 to 59 years of age; an increased risk, but no clear harm, in patients 60 to 69 years of age; and a statistically significant increased risk in patients 70 years and older. Similarly, a long-term study of 876,805 women found no increased mortality with estrogen replacement therapy. The US Food and Drug Administration has removed the boxed warnings for cardiovascular disease, breast cancer, and probable dementia in the labeling of estrogen replacement products. (Level of Evidence = 1b)

The study is a secondary analysis of the Women's Health Initiative study, which was stopped early almost 25 years ago because of a nonsignificant increase in breast cancer rates early in treatment. The study enrolled 27,347 healthy postmenopausal outpatients 50 to 79 years of age who were randomized to receive combined equine estrogen, with or without medroxyprogesterone, or placebo. Over a median follow-up of 5.6 years (estrogen with progesterone) to 7.2 years (estrogen alone), estrogen alone or with progesterone did not increase the overall rate of the composite outcome of nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral artery disease, carotid artery disease, or death from cardiovascular disease.

When patients were analyzed by decade of life, there was a significant increase in the risk of any cardiac outcome in patients 70 years and older treated with estrogen (hazard ratio [HR] = 1.95; 95% CI, 1.06–3.59). This rate translates to 217 excess events per 10,000 person-years. For participants 50 to 59 years of age, the cardiovascular risk was lower with hormone therapy, but not significantly so (HR = 0.85; 95% CI, 0.53–1.35), and for participants 60 to 69 years of age, the risk was higher with hormone therapy, although not significantly so (HR = 1.31; 95% CI, 0.90–1.90). Results were similar in participants treated with combination therapy. The study did not evaluate the effect on overall mortality, cancer, or hip fractures.

Study Design: Randomized controlled trial (double-blinded)

Funding Source: Government

Allocation: Concealed

Setting: Outpatient (any)

Reference: Rossouw JE, Aragaki AK, Manson JE, et al. Menopausal hormone therapy and cardiovascular diseases in women with vasomotor symptoms: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Intern Med. 2025; 185(11): 1330-1339.