In July, an advisory panel urged the United States Food and Drug Administration (FDA) to remove the boxed warnings on labels for vaginal estrogen products and asserted there is a lack of data to support the warnings. Furthermore, they said the warnings wrongly deter patients and providers from using the products.
The panel was convened by FDA Commissioner Marty Makary to discuss hormone therapy for menopausal women, a subject of particular interest to Makary. However, the discussion quickly focused on the black box warning that is included with all menopause treatments containing estrogen.
The warnings indicate an increased risk of breast cancer, blood clots, and strokes for patients using vaginal estrogens. Consequently, many physicians are hesitant to prescribe these treatments. These warnings originated from a 2002 National Institutes of Health (NIH)-sponsored study regarding estrogen use among menopausal women. Members of the panel overwhelmingly advocated for the removal of the warning label.
The goal of the meeting was to “separate medical dogma from evidence,” Makary said. Makary noted that both the North American Menopause Society and the American Society for Obstetrics and Gynecology have called for the removal of these warnings. He stated that “no clinical trials have ever found an association between hormone replacement therapy and an increase in breast cancer mortality.”
Makary also touted the benefits of hormone replacement therapy, and that these benefits can be traced to a 1950 study conducted by the Mayo Clinic. The study found that women who had their ovaries removed in their 20s were at a higher risk of heart attacks. He said that there is a “powerful and profound cardioprotective effect of estrogen on the ovaries.”
Research indicates that studies have shown when a woman begins estrogen therapy within 10 years of menopause onset, there is a 25% to 50% reduction in the risk of fatal heart attacks and cardiovascular disease, he said.
Makary said that when the 2002 study came out, “Doctors called their patients to get off of it immediately. The many benefits of hormone therapy were ignored… Prescriptions for hormone replacement therapy plummeted. Women flushed their pills down the toilet. The amazing thing was that in the 2002 paper, there was no statistically significant increase in breast cancer mortality. Amazing. However, as a result of the fear of breast cancer, 60 million plus women have not been offered the incredible health benefit of hormone replacement therapy. One of those women was my mother, who went through peri-menopause around that time.”
Heather Hirsch, a Physician at the Cleveland Clinic said that “history got it wrong when it comes to menopausal women.” She said that there are no “clear facts” to justify the boxed warnings. She said that these therapies have had a long-term positive impact on women’s health. She added that “vaginal estrogen is important for women, and the black box warning is wrong.”
Hirsch further noted that clinicians receive scant training in menopause education and added that “gaps in training magnify the damage.”
Physician Barbara Levy said that “I have PTSD from the NIH study.” She added that the actions taken as a result of the study had a “devastating” impact on women’s health.
REFERENCE: RAPS Regulatory Focus; 17 JUL 2025; Joanne S. Eglovitch