Changes to ‘black box’ warning on hormone therapy for menopause symptoms expected soon, FDA chief says

By Brenda Goodman, CNN

(CNN) — The US Food and Drug Administration plans to make changes soon to the lengthy black box warning on many hormone replacement products for women with menopause symptoms, Commissioner Dr. Martin Makary said.

“We are in serious discussions now about what to do about the black box warning, and I think you’ll hear something on it very soon,” Makary told CNN Chief Medical Correspondent Dr. Sanjay Gupta in the “Chasing Life” podcast.

The black box warning is the strongest type of alert the FDA puts on a drug label. Since 2003, labels of menopause treatments that contain estrogen – including pills, patches, sprays and creams – have warned that their use can increase the risk of uterine and breast cancers, as well as strokes and blood clots. The labels also warn about an increased risk of dementia for women over the age of 65.

The warning was added after a large government-funded study found that women taking estrogen pills after menopause had higher risks for some kinds of cancers, heart disease and stroke compared with women who took a placebo. The study participants had an average age of 63, so many were past menopause when they started the therapy.

After the study and the label change, prescriptions for hormone replacement therapy drugs for women dropped by more than 70%, and doctors became reluctant to prescribe them.

“It’s really a tragedy. It’s maybe one of the greatest screw-ups of modern medicine,” Makary said. “It’s resulted in 50 million women being denied this incredible therapy.”

The result has been undertreatment of symptoms that can be debilitating for women in midlife. In the late 1990s, more than 1 in 4 postmenopausal women were taking hormones to manage symptoms such as hot flashes, mood swings and night sweats. By 2020, that number had dropped to about 1 in 25, one study found.

Newer analyses of the original study, called the Women’s Health Initiative, have since found that hormone therapy started in women younger than 60, or within 10 years of starting menopause, may safely help manage menopausal symptoms such as hot flashes and poor sleep as long as the women don’t have specific contraindications such as a history of hormone-sensitive breast or uterine cancer.

Makary also said hormone replacement therapy may also have important benefits like reducing bone loss, heart disease risk and memory loss,

“Women live longer and feel better on hormone replacement therapy when started before age 60,” Makary told Gupta.

The potential change follows a July meeting of experts, convened by the FDA, to discuss the benefits and risks of hormone replacement therapy for women. The panelists urged the agency to remove the warning label.

“I am begging the FDA, and all of us are begging, please remove the box label,” said Dr. JoAnn Pinkerton, a professor of obstetrics and gynecology at the University of Virginia School of Medicine. “And please stop harming women.”

Some women’s health experts say the FDA overstepped when it applied the boxed warning to all forms of estrogen replacement.

“That is a real mistake,” said Dr. JoAnn Manson, a professor at Harvard Medical School and one of the principal investigators of the Women’s Health Initiative study.

Some forms don’t raise estrogen levels in the blood, so they aren’t likely to raise a woman’s cancer risk. For example, studies have found that low doses of estrogen delivered by tablets, creams or rings in the vagina can safely treat symptoms of dryness, painful sex and urinary tract infections in postmenopausal women, Manson said.

The black box warning, though, may stop women from using them.

“It scares them away. And even after they purchase the product, they just don’t take it,” Manson said.

“This is really where women are being tremendously undertreated and are suffering unnecessarily due to a boxed warning that is just class labeling. All hormone therapy products get exactly the same boxed warning, and it is really harming women,” said Manson, who is chief of the Division of Preventive Medicine at Brigham and Women’s Hospital.

Manson said it would also be reasonable for the FDA to consider removing the warnings on estrogen-containing therapies that are delivered through the skin in patches, sprays or creams to relieve the symptoms of menopause like hot flashes and night sweats. Those deliver hormones into the bloodstream, but observational studies suggest that they have a more favorable balance of risks and benefits than pills, she said.

Manson feels less certain about removing the boxed warning from estrogen-containing pills that are taken by mouth, however.

“I think that’s where it’s evidence-based and justified,” she said.

A 2022 review by the US Preventive Services Task Force concluded that, in women who are past menopause, there was no net benefit to taking either estrogen alone – prescribed for women who’ve had their uterus removed – or a combination of estrogen and progestin – which is typically prescribed for women who still have their uterus – to prevent chronic health conditions such as heart disease and dementia.

What’s less clear is whether a woman who starts hormone therapies in perimenopause need to stay on them long-term to get memory, heart and bone benefits.

“It’s a very good question,” said Dr. Roberta Diaz Brinton, a neuroscientist who studies estrogen’s effects on the brain at the University of Arizona. “We need to answer that.”

Other experts say there’s not enough scientific evidence to support long-term use of hormones to prevent heart disease, Alzheimer’s disease or osteoporosis.

Four medical societies — the American College of Obstetricians and Gynecologists, the Menopause Society, the Endocrine Society, and the American Association of Clinical Endocrinology — support the use hormones to alleviate menopausal symptoms, but they don’t recommend continued use for preventing chronic conditions like heart disease.

Dr. Leslie Cho, who runs Cleveland Clinic’s Women’s Cardiovascular Center, said she’s supportive of the idea of lifting the warning from vaginal estrogen cream. “It’s never made sense on the cream,” she said.

But Cho said she’s worried that some of the benefits being discussed are drawn from after-the-fact analyses of studies that weren’t designed to look at those outcomes in the first place.

“I’m so glad to hear the FDA chair talk about this, because then, if that’s the case, they should do a study. They should fund a study,” she said.

In a world where people can get hormones prescribed over the internet, Cho said she worries too many women could start taking hormones when they have risks like high blood pressure, obesity or high cholesterol that could overshadow the benefits. Even in younger women, studies show hormones may increase the risk of dangerous blood clots, she said.

“Women have to talk to their physicians about hormone replacement therapy before they believe in all the hype that’s currently ongoing, because so much of it is hype,” she said.

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