US health leaders hailed the benefits of hormone therapy for menopause. Doctors are pushing for balance
On Monday, US Health and Human Services Secretary Robert F. Kennedy Jr. and US Food and Drug Administration Commissioner Dr. Marty Makary announced that after 20 years, they were righting a medical wrong — what Makary has called “maybe one of the greatest screw-ups of modern medicine” — by pushing to remove the “black box” warning on hormone therapy for menopause symptoms.
By dismissing the classwide boxed warning that flagged risks of heart disease, breast cancer and potentially dementia from estrogen-containing products, the FDA expects to open access to a therapy that Makary said was so impactful, it ranks near antibiotics and vaccines.
Makary blamed the broad 22-year-old warning on flawed, misrepresented research he said became dogma and “medical groupthink” that spread fear and dismissal of women’s menopausal “mood swings, night sweats, weight gain, hot flashes, divorce.” He hailed the “profound long-term health benefits that few people, even physicians, know about.”
“HRT has saved marriages, rescued women from depression, prevented children from going without a mother,” Makary said.
Kennedy, addressing an audience that included his wife and two daughters, described how prescription pills, creams, sprays, patches and injections that deliver estrogen or a combination of estrogen and progesterone could dramatically cut a woman’s risk of heart disease and dementia and even extend life an additional decade.
Physicians who treat women applauded parts of the decision but said they worry that the benefits of hormones might be oversold based on outdated or cherry-picked data. Some said the removal of the black box warning from all forms of hormone therapy — particularly pills, which deliver estrogen to the entire body — isn’t scientifically justified and downplays evidence of real risks of longer-term use.
They’re not miracle drugs, they say, and benefits and risks will vary from woman to woman.
“I really worry about this overwhelming embrace of hormone replacement therapy without understanding the data,” said Dr. Leslie Cho, an interventional cardiologist and director of the Cleveland Clinic’s Women’s Cardiovascular Center. Cho was the lead author of a comprehensive research review published in 2023 that detailed the risks and benefits of hormone therapy for women of various ages and health histories.
Cho and other experts say that what’s needed now is better balance. They are asking FDA officials and doctors to treat hormone therapy like any other drug that has both benefits and risks, and remember that hormones aren’t the only options for treating menopausal symptoms anymore.
After extolling the benefits of hormones, Makary emphasized that doctors and patients would decide what treatments to use and for how long. The government, he said, is not the doctor.
“We want people to talk to their doctors,” he said, “and we want doctors to have the right information, and part of that means removing these scary black box warnings and putting the nuanced discussion in the package insert of the medications.”
In 2002, a large government-funded randomized controlled trial called the Women’s Health Initiative was stopped early by an outside panel of experts who were monitoring the results in real time. The panel, called the data safety monitoring board, had determined that the risks of taking a combination of estrogen and progesterone outweighed the benefits to study participants.
After analyzing the results of the study in detail, the FDA determined in 2003 that women should be informed of the risks of estrogen-containing therapies and ordered that those risks be prominently featured on the product labels as a boxed warning.
Women stopped using hormones in droves.
“Basically, we went from everybody wanting to put estrogen in the water to prevent heart disease, to then this black box label where you wouldn’t dare use it,” said Dr. Marcia Stefanick, a professor of medicine at the Stanford Prevention Researcher Center, who was one of the original investigators on the Women’s Health Initiative study.
“And now we’re going back to ‘Let’s remove the black box label,’ so it feels like we really have come full circle.’”
Newer evidence suggests that hormones applied to the skin aren’t metabolized by the body the same way as bodywide estrogen therapies and thus may have lower risks. Women’s health advocates have argued for years that these blanket warnings have unfairly lumped estrogen applied to the skin and the lining of the vaginal canal with estrogen pills and injections that raise estrogen levels in the blood.
Makary said this week that the FDA’s decision to ditch most of the black box warning — it will still caution women who have a uterus not take estrogen alone, since that increases the risk of endometrial cancer — was based on an expert panel discussion held earlier this year and the agency’s own “robust review of the latest scientific evidence.”
Makary said that the FDA’s staff scientists enthusiastically recommended the move and that their evidence review would be published at a later date.
On Tuesday, a person with direct knowledge of the FDA’s plans said Makary was referring to a Viewpoint article co-authored by Makary and three other FDA officials in the medical journal JAMA. (In the conflicts of interest section, the article notes that Makary receives royalties from sales of his 2024 book, “Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health,” which devotes a chapter to hormone therapy.)
“The JAMA article was essentially that. The FDA conducted their comprehensive review,” said the person, who asked not to be named because they weren’t authorized to share the information with the media.
But the JAMA Viewpoint is not the detailed study of studies that researchers and regulators typically undertake when trying to assess the benefits and risks of a treatment. Instead, it is a position statement that cited selected studies to support its points.
During Monday’s announcement, for example, Makary held up a study he said was “from the journal Cancer” in 2023 that “concluded that more than 40 observational studies show a consistent 30% to 50% reduction in coronary heart disease.” The study Makary referenced was not from Cancer, a highly cited medical journal published by the American Cancer Society, but from a lesser-known publication called The Cancer Journal.
Makary also didn’t mention the sentence in that paper that said randomized controlled trials “have shown a null effect of [hormone replacement therapy] on [coronary heart disease] in analyses of women over all ages, typically 45–90 years old when randomized to HRT versus placebo” — meaning studies that have compared women taking estrogen-containing hormone therapies with those on a placebo have found no net benefit for heart disease.
Other studies cited in an HHS fact sheet on the decision – including one to support the claim that hormone therapy can cut a woman’s risk of heart disease by 50% – come from research reviews that are decades old and don’t include more recent scientific findings. A citation to support the claim that hormone therapy can cut a woman’s risk of dementia by 65% comes from an older, relatively small Danish study of 343 women published in 2005.
The type of evidence, as well as the breadth of evidence the FDA uses to make its regulatory decisions, matters, experts said.
Dr. Rebecca Thurston, the assistant dean of women’s health research at the University of Pittsburgh School of Medicine, noted that the FDA’s decision to remove the boxed warning “was a deviation from the typical process.”
In the past, the agency has followed a very different protocol when considering the removal of black box warnings from drugs like the diabetes treatment Avandia, which had a warning removed in 2013. The agency followed similar steps, including the review of new data and convening of an advisory committee, when it removed the boxed warning from the smoking cessation drug Chantix in 2016.
Asked Monday why the FDA had not convened an advisory committee to review all the data on hormone therapy and make recommendations to the agency, Makary said it was because such committees are “are bureaucratic, long, often conflicted and very expensive, so we can have an active, robust discussion as a group of medical experts spontaneously.”
In July, at the FDA’s panel on hormone therapy, many of the experts were there to champion the removal of the warning from a specific group of hormone products: vaginal estrogens.
Medical groups including the American College of Obstetricians and Gynecologists and the Menopause Society had advocated to remove the warning from those products for nearly a decade. The FDA had rejected a petition to remove the boxed warning from the vaginal estrogen products in 2018, citing a lack of evidence on their safety.
Vaginal estrogens prevent thinning and drying of the tissues that line the vaginal walls, which can lead to painful sex and urinary tract infections. Estrogens inserted into the vagina stay in the tissues there and don’t seem to affect blood levels, said Dr. JoAnn Manson, chief of preventive medicine at Brigham and Women’s Hospital.
“The boxed warning for local vaginal estrogen was inappropriate. It was not evidence-based, and it was leading to many women not benefiting from a safe and effective medication for a common debilitating condition,” Manson said.
Four major medical societies that have established guidelines on the use of hormone therapy to relieve menopause symptoms — the American College of Obstetricians and Gynecologists, the Menopause Society, the American Association of Clinical Endocrinology and the Endocrine Society — told CNN that the FDA did not reach out to them before making the new decision to lift the boxed warning on estrogen-containing products.
This week, some experts said they felt that the FDA was going too far in removing the warning from systemic therapies — such as pills or injections that don’t just stay in one area but travel around the body — especially in the absence of any new clinical trial evidence.
“HHS and the FDA have claimed that the removal of the boxed warning for hormone replacement therapy will ‘restore gold-standard science to women’s health.’ In fact, the opposite is true. These treatments have well-documented cardiovascular, cognitive and cancer safety risks,” Nina Zeldes, a health researcher at Public Citizen’s Health Research Group, said in a statement Monday.
Zeldes pointed out that claims that hormones could lengthen life and prevent dementia and heart disease go beyond what these products are approved for: treating menopausal symptoms and prevention of bone loss in osteoporosis.
“Unsubstantiated claims by senior FDA officials about the effectiveness of hormone replacement therapy for unapproved indications undermines public trust in the agency’s decision-making,” Zeldes said.
Dr. Steven Fleischman, president of the American College of Obstetricians and Gynecologists, said the group was supportive of the FDA’s decision to remove the boxed warning since it would surely encourage more conversations between women and their doctors about using hormone therapy.
Fleishman cautioned, though, that not all hormone therapy products carry the same risks.
“It is important to distinguish that systemic estrogen products — such as oral estrogen and transdermal patches, gels, and sprays — have a different safety profile than low-dose vaginal estrogen. Like all medications, systemic estrogen products are not without risk, and their use should be based on an individualized conversation between patients and their clinicians,” he said in a statement.
All things considered, experts say, there’s still not enough evidence that taking hormones long-term can prevent chronic diseases of aging.
“Most women who are post-menopausal can probably take hormone replacement therapy,” said the Cleveland Clinic’s Cho. “However, what we now know from many, many years of hormone replacement trials is that there are women in whom we should really have sort of careful discussion, risk-benefit analysis before starting hormone replacement therapy.
“If women have high blood pressure, they have high cholesterol, they are overweight, we should really pause before we start hormone replacement therapy and discuss the pros and cons.”
There is good evidence that some types of hormone therapy reduce the risk for hip fracture, which many older adults struggle to recover from. The FDA approved hormone therapy for osteoporosis in 1988. One study estimated that each year of hormone therapy decreased the risk of hip fracture by about 6% per year of use, and data from the Framingham heart study found that the risk of hip fracture was reduced by 65% in current users of hormone therapy and about 30% in former users.
But hormone therapy isn’t the only drug that treats bone health, so experts say women should weigh all their options with their doctors before making their decision.
Some worry that the FDA overshot the mark by removing the warning from all types of hormone therapies, especially pills, which expose the entire body to hormones and may increase a person’s risk for dangerous blood clots as much as fivefold.
“I would prefer a more nuanced change of the labeling if it was for systemic therapies,” said Dr. Cynthia Stuenkel, a clinical professor of medicine at the University of California at San Diego.
“I think that there are estrogen preparations, particularly oral ones, that the black box warning is still relevant for, and I think for the combinations of hormone therapy that were used in the [Women’s Health Initiative], I think those warnings are relevant. That’s where these data came from.”
Transdermal, or through-the-skin, estrogen creams, gels, patches and sprays don’t seem to be metabolized by the liver the same way pills are. As a result, there’s some evidence that transdermal forms of estrogen may not raise blood clot risk the same way pills do, she said.
“I think if it was just the vaginal preparations, a lot of us have been saying for a long time that this would make sense,” Stuenkel said.
Other experts are worried that doctors and patients will misread the FDA’s action as a green light to use hormones in all women.
Already, says Dr. Stephanie Faubion, a physician at the Mayo Clinic who is medical director of the Menopause Society, says she’s had patients well past the age of menopause come in and ask to take estrogen. One wanted to know whether she should take it for tinnitus, or ringing in the ears, and to improve markers of heart health like homocysteine and cholesterol.
“It’s a weird place to be in,” Faubion said. “With every patient, and I’m like, ‘All right, which side are we on?’”
Invariably, Faubion finds herself having one of two very different kinds of conversations with patients about hormone therapy: Either “it’s not an anti-aging drug. You shouldn’t take it for everything” or “it’s not going to kill you, really. I promise it’s a safe therapy, and you can use it for your hot flashes,” she said. “But it’s one or the other.”
In a recent viewpoint published in the journal JAMA Internal Medicine, Thurston, at the University of Pittsburgh, said she hopes this time that women and their doctors won’t treat hormone therapy like a miracle drug, but with the same consideration they’d give any other medication.
“It has risks, it has benefits, it has indications, it has contraindications, but it is neither a panacea nor poison,” Thurston said.
Every woman is different, and every woman’s needs during perimenopause and menopause will be unique. In recent years, the FDA has even approved two nonhormonal drugs that can help women manage their hot flashes, Veozah and Lynkuet.
She said patients and their doctors should carefully consider their choices.
“And really, women deserve a range of different options,” Thurston said.
