The U.S. Department of Health and Human Services announced today that the Food and Drug Administration will remove so-called “black box” labels from hormone replacement therapy (HRT) medications. menopause. The move reverses a decision made in the early 2000s after research at the time found the treatments increased the risk of breast cancer, heart disease and stroke in some women.
A black box warning is the most serious notice of drug safety concerns and typically applies to an entire class of treatments based on how they affect the body. FDA Commissioner Marty Macari called the use of “black box” warning labels for HRT for menopause “unscientific” in press conference about the ad.
Experts say the FDA's decision could make hormone therapy more accessible to people with menopausal symptoms, which include hot flashes and night sweats. After the FDA added warning labels in 2003, studies suggested that the risks of cancer and metabolic diseases were overestimated and that this could discourage both hormone therapy users and providers. But experts also warn that the FDA's new announcement in turn exaggerated the therapy's benefits for other conditions.
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“I think overall this is a good thing,” says Nanette Santoro, an obstetrician-gynecologist at the University of Colorado Anschutz and lead investigator for the Women's Health Initiative, the research group that originally described the link between HRT and breast cancer. Since 1991, the Women's Health Initiative has conducted several long-term studies of cardiovascular disease, cancer, and osteoporosis in postmenopausal women. Major funding for the initiative came from the National Institutes of Health. “There is a growing awareness that women are undertreated with hormones… and too many women are suffering in silence,” Santoro says.
However, today's announcement may lead to confusion. Health and Human Services Undersecretary Jim O'Neill said, “Many women can reduce their risk of fractures, heart disease, and immune and cognitive decline while prolonging their energy.”
And the FDA's Macari and HHS chief Robert F. Kennedy Jr. pointed to several studies that have shown clear benefits of hormone therapy in reducing mortality overall, as well as in reducing the risk of heart disease, Alzheimer's disease and bone fractures. However, Santoro says the evidence doesn't really support these benefits.
The focus on HRT comes at a time when Macari and Kennedy have been critical of FDA decisions, including those related to vaccines, for years. In response, a panel of experts met in July to review the scientific evidence on the risks and benefits of HRT for menopause.
However, today's decision does not apply to all hormone replacement medications. Some estrogen-only treatments will still carry labels that share the risk of endometrial or uterine cancer, an important risk that has previously received less attention, says gynecologic oncologist Kemi Doll of the University of Washington.
Menopause is primarily caused by decreased levels of estrogen, a hormone that affects sexual and reproductive health, and is usually characterized by the absence of menstruation for 12 months. Hormone therapy has been shown to relieve hot flashes, night sweats and mood changes by administering synthetic versions of hormones—usually either estrogen or a combination of estrogen and progesterone, another sex hormone. Therapy may be administered through oral tablets, patches or gels on the skin, or vaginal rings. Research in the 1960s suggested that hormone therapy was an effective treatment for menopausal and perimenopausal symptoms, and doctors rushed to prescribe it to many women, especially in the 1990s. This was based on studies that showed that hormone therapy reduced the risk of osteoporosis. But in the early 2000s, research from the Women's Health Initiative found an increased risk of breast cancer, heart disease and stroke in some women taking hormone therapy. Shortly after these reports, the FDA added a black box warning to all hormonal treatments prescribed for menopausal symptoms. The number of women taking these treatments has dropped sharply.
Makary, along with Kennedy and a panel of FDA experts, largely criticized these Women's Health Initiative findings. The risks were generally observed in women aged 70 years who were taking older drugs. Subsequent follow-up studies found no significant risks or benefits, Santoro said. “There's not much of a signal anyway—no big harm and no big health benefit” when it comes to older formulations, she says.
At the press conference, FDA experts noted that form The method of delivery of therapy may play a role in the risks and benefits for certain people. For example, vaginal forms generally carry much lower risk than tablet forms that are metabolized by the liver, but both have a black box warning. A 2019 study found that the longer people took menopausal hormone therapy, the higher their risk of breast cancer.
The agency also announced that it recently approved two new drugs to treat menopause: a generic version of the oral hormone therapy pills Premarin, which uses a mixture of estrogen hormones, and Bayer's Lynkuet, a non-hormonal treatment that can treat menopausal symptoms such as hot flashes. Hormone therapy does carry real, albeit small, risks. People who have or have had reproductive cancers, such as breast or ovarian cancer, or those with a history of blood clots should not take them, Santoro said. Doll also emphasizes that people who have a uterus should be well aware of the risks of endometrial cancer from estrogen-only treatment. “It's too much estrogen stimulation,” Doll says. “We're starting to see women with endometrial cancer that was completely preventable because they took high doses of estrogen without progesterone.”
There are alternative treatments available to address specific symptoms such as insomnia.
For others, especially people over 50, the benefits may outweigh the risks, and label changes could make drugs more affordable.
Doll says criticism of past HRT research, such as the Women's Health Initiative study, also stems from a lack of new research in general. “I don't like the idea that we're still relying on the same couple of studies when in fact we need a lot of new cohorts and new questions that are relevant to women today,” she says.
At this time, the evidence does not support the bold claims made by Macari and others about hormone therapy. “I don’t believe it’s the elixir of youth,” Santoro says.
