US health officials announced first steps to remove the black box warning on estrogen products prescribed to treat menopausal symptoms.
There was a warning added to products in 2003 when data from a large government study of women's health known as the Women's Health Initiative (WHI) showed that hormone therapy was associated with an increased risk of a number of diseases, including breast cancer, heart disease, blood clots and possibly dementia.
Women's health experts say the risks were misinterpreted and did not properly reflect the study data. As a result, in subsequent years, many women and their doctors avoided hormone therapy to treat menopausal symptoms such as hot flashes, night sweats, and mood changes.
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Dr. Marty Macari, commissioner of the U.S. Food and Drug Administration (FDA), said the agency convened a panel of experts in July to review and make recommendations on the warning label. The FDA's internal experts on the subject then reviewed the experts' opinions and decided to remove the black box warning. Manufacturers of estrogen products will now reprint labels for their products.
Many women's health experts have long supported eliminating the black box warning, especially for certain forms of estrogen. Vaginal estrogen preparations prescribed to women experiencing vaginal dryness after menopause, which can increase the risk of urinary tract infections, are used topically, and urologists say the risk described in the black box warning is less applicable to these forms.
“On a global scale, I would say that removing the black box warning on the label is long overdue,” says Dr. Kathleen Jordan, chief medical officer of Midi Health, a virtual health company that provides services to 20,000 middle-aged women each week. “Experts agree that this overstates the risk of estrogen use, especially low-dose vaginal estrogen, which has negligible systemic absorption and is minimal compared 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 patches or pills, result in different effects on the body and therefore have different risk profiles, and so the risk-benefit discussion for these forms should be different.
“ACOG guidelines do not change with the removal of the black box warning,” says Dr. Stella Dantas, former ACOG president and an OB-GYN at Northwest Kaiser Permanente. The group still recommends that if women aged 50 to 59 experience menopausal symptoms such as hot flashes or night sweats, vaginal dryness or trouble sleeping, they should talk to their doctor about whether hormone therapy makes sense.
This conversation should include consideration of the 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 managing their symptoms,” Dantas says. “However, how we counsel them and come to shared decisions about whether the benefits outweigh the risks also depends on the woman's personal and family history.”
The hormone therapy available to women today differs in many ways from the therapy studied at WHI. At WHI, women received oral estrogen and a synthetic progestin, whereas today most doctors start with estrogen patches and use a different form of progesterone that is more similar to the natural hormone and more “breast-neutral,” Jordan says.
Dantas says the population of women in the WHI study was also very different from those typically receiving hormonal treatment today. The WHI included women who were, on average, older and had reached menopause approximately ten years ago. “They were not treated for menopausal symptoms, and menopause had already passed, so the negative effects of falling estrogen levels on their arteries and other systems had already begun to occur,” she says. “Whereas now we talk about treating women for menopausal symptoms, we're using medications that don't have the same risk profile.”
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Dantas, however, says that how hormone therapy is administered—pills or patches—makes a difference and can result in different levels of exposure and risk to the body. While most experts agree that vaginal estrogen does not merit a black box warning (the FDA's strictest warning), oral versions of estrogen and patches are designed to be distributed more widely throughout the body and therefore pose a different level of risk.
“If I had a wish list, it would include a more extensive review process to re-evaluate what the labeling for systemic estrogen therapy should be,” she says. “I think lifting the black box warning for vaginal creams and rings is different than lifting more systemic treatments like oral estrogen because they have a different risk profile, but they are combined. I think the data is there 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 warn that beyond menopausal symptoms, it is unclear what benefits hormone therapy might have. Makary noted that hormone therapy can help women cope with a number of other conditions associated with postmenopause, including heart disease and osteoporosis. “There are profound long-term health benefits now that few people, even doctors, know about,” he said. “With some exceptions, in the modern era there may be no other drug that improves women's health at the population level than hormone therapy.”
Although there is promising evidence that women taking hormone therapy may reduce their risk of bone fractures and heart disease in particular, the evidence is not strong enough for women to rely on hormones as a primary strategy in treating these conditions. “There are other medications for osteoporosis, as well as medications to control cholesterol,” Dantas says. “Hormonal therapy should not be the primary treatment for other diseases or conditions. It is actually intended to address menopausal symptoms.”
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While removing the black box is a welcome step in better informing women about the risks and benefits of hormone therapy, it should not be interpreted as indicating that the treatment is risk-free. And, Dantas says, women shouldn't assume that all forms of hormone therapy are the same. She encourages women experiencing menopausal symptoms to talk to their doctors about how hormone therapy can help them and what the potential risks may be for them individually.
