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 for menopause. The move reverses a decision that came down in the early 2000s, after research at the time found that the therapies increased the risk of breast cancer, heart disease and stroke in some women.
A black box warning is the most severe notification of safety issues on a medication and is typically applied to an entire class of treatments based on how they work in the body. The FDA’s commissioner Marty Makary called the use of black box warning labels for HRT for menopause “unscientific” in a press conference about the announcement.
Experts say the FDA’s decision might make hormonal therapies more accessible to people with menopausal symptoms, which include hot flashes and night sweats. After the FDA added warning labels in 2003, research showed that the risks of cancer and metabolic disease were overstated and that this may have deterred both hormone therapy users and providers. But experts also caution that FDA’s new announcement, in turn, exaggerated the therapies’ benefits for other conditions.
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“I think, overall, it’s a good thing,” says Nanette Santoro, an ob-gyn at the University of Colorado Anschutz and a lead researcher with the Women’s Health Initiative, the research group that had initially described the connection between HRT and breast cancer. Starting in 1991, the Women’s Health Initiative has been carrying out several long-term studies on heart disease, cancer and osteoporosis in postmenopausal women. The initiative’s main funding has come from the National Institutes of Health. “There’s been a growing appreciation that women are undertreated with hormones…, and there are too many women who suffer in silence,” Santoro says.
But today’s announcement may lead to confusion. Deputy Secretary of Health and Human Services Jim O’Neill said, “Many more women can reduce their risk of fracture, heart disease, and immune and cognitive decline while extending their vigor.”
And the FDA’s Makary and HHS’s chief Robert F. Kennedy, Jr., pointed to several studies that showed apparent benefits of hormone therapy for reducing mortality in general, as well as for reducing the risk of cardiovascular disease, Alzheimer’s disease and bone fractures. Yet Santoro says the evidence doesn’t really support these benefits.
The attention to HRT comes at a time when Makary and Kennedy are turning a critical eye to FDA decisions over the years, including those around vaccines. In response, a panel of experts convened in July to review scientific evidence on the risks and benefits of HRT for menopause.
Today’s decision doesn’t cover all hormone replacements, however. Certain estrogen-only therapies will still carry labels that share the risk of endometrial or uterine cancer—an important risk that has previously gotten less attention, says gynecologic oncologist Kemi Doll of the University of Washington.
Menopause is primarily driven by decreases in estrogen, a hormone that influences sexual and reproductive health, and generally marked by the absence of a period for 12 months. Hormone therapy has been shown to alleviate hot flashes, night sweats and mood changes by delivering synthetic versions of hormones—usually either estrogen or a combination of estrogen and progesterone, another sex hormone. Therapies can be given through oral pills, patches or gels on the skin or vaginal rings. Studies in the 1960s suggested that hormone therapy was an effective treatment for symptoms of menopause and perimenopause, and doctors rushed to prescribe it to many women, especially during the 1990s. This was based on research that suggested hormone therapy reduced the risk of osteoporosis. But in the early 2000s, Women’s Health Initiative studies found an increased risk of breast cancer, heart disease and stroke in some women taking hormone therapy. Shortly after those reports, the FDA added a black box warning to all hormone therapies prescribed for menopause symptoms. The number of women taking these therapies plummeted.
Makary, alongside Kennedy and the FDA’s panel of experts, largely criticized these findings from the Women’s Health Initiative. The risks were generally seen in women in their 70s who were taking an older formulation of the drugs. Subsequent follow-up studies failed to show either substantial risks or benefits, according to Santoro. “There’s no big signal either way—there’s no big harm, and there’s no big health benefit” when it comes to those older formulations, she says.
At the press conference, the FDA’s experts noted that the form of the therapy’s delivery method could play a role in risks and benefits for certain people. The vaginal formulations, for example, generally carry much lower risks than the pill forms, which are metabolized in the liver, yet both came with a black box warning. Research from 2019 suggests that the longer people took hormone therapy for menopause, the higher the risk of breast cancer was.
The agency also announced that it has recently approved two new drugs for menopause: a generic version of the oral hormone therapy tablet Premarin, which uses a mixture of estrogen hormones, and Bayer’s Lynkuet, a nonhormonal treatment that can treat menopausal symptoms such as hot flashes. Hormone therapies do carry real, albeit small, risks. People who have or have had reproductive cancers, such as breast cancer or ovarian cancer, and those who have a history of blood clots should not take them, Santoro says. Doll also emphasizes that people who have a uterus should be highly aware of the risks of endometrial cancer from estrogen-only treatments. “It’s too much estrogen stimulation,” Doll says. “We’re starting to see women with endometrial cancers that were totally preventable coming in because they have been on massive doses of estrogen with no progesterone.”
Alternative therapies exist to address specific symptoms, such as sleeplessness.
For others, particularly people in their 50s, the benefits may outweigh the risks, and this label change could make the drugs more accessible.
Doll says that criticism of past HRT research, such as the Women’s Health Initiative studies, has also been fueled by a lack of new research overall. “I don’t like the idea that we still are kind of pulling from the same couple of studies when what we really need is a lot of new cohorts and new questions that are relevant to women today,” she says.
As of now, the evidence doesn’t support the bold claims Makary and others are making about hormone therapy. “I do not believe that it is the elixir of youth,” Santoro says.
