U.S. health officials have announced the first steps to remove the black box warning on estrogen products prescribed to treat symptoms of menopause.
The warning was added to the products in 2003 when data from a large government study on women’s health, known as the Women’s Health initiative (WHI), showed that the hormone therapy was linked to an increased risk of a number of conditions, including breast cancer, heart disease, blood clots, and potentially dementia.
Women’s health experts say the risks were misinterpreted, and did not properly reflect the data from the study. The result—in the following years, many women, and the doctors caring for them, avoided hormone therapy to treat menopause symptoms such as hot flashes, night sweats and mood changes.
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Dr. Marty Makary, commissioner of the U.S. Food and Drug Administration (FDA) said that the agency convened an expert panel in July to review and provide recommendations on the warning label. The FDA’s internal experts on the subject then considered the expert opinions and decided to remove the black box warning. Makers of estrogen products will now reprint labels for their products.
Many women’s health experts have long supported the removal of the black box warning, specifically for certain forms of estrogen. Vaginal estrogen products, prescribed for women who experience vaginal dryness following menopause that can increase the risk of urinary tract infections, are applied topically and urologists have maintained that the risk described in the black box warning was less applicable to these forms.
“Globally I would say that the removal of the black box warning on the label is long overdue,” says Dr. Kathleen Jordan, chief medical officer at Midi Health, a virtual health care company that provides services for 20,000 women weekly who are at midlife. “Experts agree that it over states the risk of estrogen, and especially for low dose vaginal estrogen which has negligible systemic absorption and minimal to any risks associated with it.”
Experts at the American College of Obstetrics and Gynecology (ACOG) say that other forms of hormone therapy, such as the patch or pill, lead to different exposures in the body and therefore come with different risk profiles and therefore the risk-benefit discussion for these forms should be different.
“ACOG guidelines are not changing based on removal of the black box warning,” says Dr. Stella Dantas, immediate past president of ACOG and an obstetrician-gynecologist at Northwest Kaiser Permanente. The group still recommends that if women between ages 50 and 59 are having menopause symptoms such as hot flashes or night sweats, vaginal dryness or difficulty sleeping, they should talk to their physician about whether hormone therapy makes sense.
That conversation should include consideration of a woman’s family and personal history of breast cancer and other health factors. “We know that hormone therapy can really help and benefit women in addressing symptoms,” says Dantas. “However, it also depends on a woman’s personal history and family history how we counsel them and come to shared decision-making on the whether the benefits outweigh the risks.”
The hormone therapy available to women today is different in many ways from the therapy studied in the WHI. In the WHI, women received oral estrogen and synthetic progestin, while today most doctors start with an estrogen patch and use a different form of progesterone that more closely resembles the naturally occurring hormone and are more “breast neutral,” says Jordan.
Dantas says that the population of women in the WHI study were also very different from those who would typically get hormone treatments today. The WHI included women who were on average older, and about a decade past menopause. “They weren’t being treated for menopause symptoms, and were past menopause, so the negative effects of dipping estrogen levels on their arteries and other systems had already started happening,” she says. “Whereas now we are talking about treating women for menopause symptoms and we are now using medications that don’t show the same risk profiles.”
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Dantas, however, says that how the hormone therapy is delivered—by pill or patch—matters, and could lead to different levels of exposure, and risk, in the body. While most experts agree that vaginal estrogen doesn’t warrant the black box warning—the FDA’s strongest warning—oral and patch versions of estrogen are designed to disperse more widely throughout the body, and therefore pose a different level of risk.
“If I had a wish list, it would include a bigger review process to re-evaluate what the labelling of systemic estrogen therapy should be,” she says. “I think taking the black box warning off vaginal creams and rings is different than taking it off more systemic therapies like oral estrogen, because they have a different risk profile, but are being conflated. I think there is data now so we should be able to extrapolate and show whether there is a difference between the transdermal patch and vaginal estrogen, and see what would be the best warning for patients.”
Experts also caution that beyond menopause symptoms, it is not clear what benefits hormone therapy might have. Makary noted that hormone therapy could help women address a number of other health conditions associated with post-menopause, including heart disease and osteoporosis. “There are now profound long term health benefits that few people, even physicians, know about,” he said. “With few exceptions, there may be no other medication in the modern era that improves the health outcomes of women at the population level than hormone therapy.”
While there is promising data suggesting that women taking hormone therapy can reduce their risk of bone fractures and heart disease in particular, the evidence isn’t robust enough for women to lean on hormones as their primary strategy in addressing these health conditions. “There are other medications for osteoporosis, and other medications to control cholesterol,” says Dantas. “Hormone therapy should not be a primary treatment for other diseases or conditions. It’s really to address menopause symptoms.”
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While a welcome step in better informing women about the risks and benefits of hormone therapy, the removal of the black box shouldn’t be interpreted as an indication that the treatments are risk-free. And, says Dantas, women shouldn’t assume that all forms of the hormone therapy are alike. She encourages women experiencing menopause symptoms to have a conversation with their doctors about how the hormone therapy could help them, and what the potential risks might be for them individually.
