Is estrogen replacement therapy ever safe?

By Eva Martin, MD of Elm Tree Medical, Inc.

After college, I worked full time researching breast cancer. Part of my job was collecting surveys about risk factors from breast cancer patients. Every time someone reported a history of estrogen replacement therapy, we would knowingly raise our eyebrows. “Well, that’s why…” Was this assumption correct? Since the practice-changing Women’s Health Initiative trial, many doctors are reluctant to prescribe hormones to treat menopausal symptoms, fearing that the drugs will increase patients’ risk of breast cancer and heart disease.  Since that time, researchers have developed the “Estrogen Timing Hypothesis” and, now, tested it with the ELITE trial.

The Women’s Health Initiative Studies. At menopause, many women experience side effects like hot flashes and night sweats, as their levels of hormones decrease. To treat these symptoms, doctors can prescribe replacement hormones- estrogen or estrogen + progestin. The Women’s Health Initiative studies, whose principal results were published in 2002, were designed to study long term hormone therapy in postmenopausal women. The women included in the study had an average age of 63, but they represented a broad range of ages and time since onset of menopause. This trial was terminated three years early because researchers saw a small increase in the rate of breast cancer amongst women taking estrogen + progestin. The study also showed that some women taking hormone replacement therapy had an increased risk of heart disease, stroke, and blood clots, and had a decreased risk of colorectal cancer and broken bones. The results left physicians and patients concerned: were they putting women at risk by prescribing hormones? Concerned about the dangers of hormone replacement therapy, prescriptions for hormones for menopausal symptoms plummeted after publication of the Women’s Health Initiative results.

The Estrogen Timing Hypothesis. In the years following, researchers began to wonder, “Does the timing of estrogen therapy matter?” Specifically, does taking hormones affect women in early menopause differently than women in later menopause? Early menopause is defined as within 6 years of the beginning of menopause, and later menopause is at least 10 years after menopause started. Scientists theorized that estrogen has different effects when used in early menopause and may be both effective and safe for treating menopausal symptoms. In fact, the raw data from the Women’s Health Initiative studies seemed to support this hypothesis.

The ELITE Trial. Fast forward to 2016 and we now have a study directly testing the Estrogen Timing Hypothesis. The ELITE trial results, published in the New England Journal of Medicine, focused on the effects of hormone replacement on heart disease. Unfortunately, the study was too small to measure the effects of hormones on clinical endpoints such as stroke or heart attacks. Instead, they used a surrogate marker, a more convenient substitute: CIMT. CIMT is carotid artery intima-media thickness, a measure of atherosclerosis build-up in one of the major arteries in the neck.  It is associated with risk factors for cardiovascular disease. 643 women participated in the ELITE trial and were divided into two groups: early menopause and late menopause. Women within in each group received either fake placebo drugs or hormone replacement therapy for an average of five years. Women in early menopause who received estrogen had slower build-up of atherosclerosis than women who received placebo. Women in later menopause did not have a slowing of atherosclerosis build-up. As a side note, whether women received progestin with the estrogen did not affect the trends.

What are the implications? Most clinicians and scientists agree: The ELITE trial does not prove that estrogen in early menopause reduces risk of heart disease because the trial did not test this outcome. However, the results are reassuring that, with regard to heart disease, hormone replacement in early menopause may be safe. It supports the Estrogen Timing Hypothesis and will hopefully pave the way for a more nuanced exploration of how, when, and for whom hormone replacement therapy is a good choice. We want to hear from you! Would you prescribe hormone replacement therapy for women in early menopause?