The US Food and Drug Administration intends to remove most black box warnings from products containing estrogen and progestogen. The decision, announced Monday, is part of a campaign to promote wider use of hormone replacement therapies (HRT) for older women. 

FDA Commissioner Marty Makary, MD, and other agency officials outlined the plans for the label changes in a November 10 article in JAMA and discussed the move at a press conference Monday at the Department of Health and Human Services in Washington, DC. 

Makary said menopause can trigger profound changes in women’s lives, including “mood swings, night sweats, weight gain, hot flashes, divorce.” 

He told attendees, “HRT has saved marriages, rescued women from depression, prevented children from going without a mother.” 

Makary also argued that use of HRT can help women reduce their risk for cardiovascular diseases, Alzheimer’s disease, and skeletal fractures. 

“Currently, there are more than 20 estrogen-alone and combined estrogen-progestogen products in various doses and formulations,” Makary said. “With the exception of antibiotics and vaccines, there may be no medication in the modern world that can improve the health outcomes of older women on a population level more than hormone therapy.” 

At a press conference, Makary said he expects the companies that make HRT products to welcome the agency’s request for label changes. 

“Companies are, generally speaking, very excited when the FDA tells them you can remove a scary warning on your product,” Makary said. 

A spokesperson for Pfizer, which manufactures many HRT products, said the company welcomes the FDA's decision to update labeling for HRT.

The move "marks an important step in destigmatizing this critical treatment option that can help millions of women seeking to manage select menopause symptoms," the spokesperson wrote in a statement to Medscape Medical News.

Novo Nordisk, another manufacturer, declined to comment. 

In the JAMA article, Makary and FDA staff detailed the changes they are seeking. Information about adverse events tied to these drugs will remain on the label, they wrote. 

But a boxed warning will remain on systemic estrogen labels for risk for endometrial cancer with unopposed estrogen in women with a uterus, to remind clinicians and patients that this serious risk can be mitigated by adding a progestogen, the FDA officials wrote. 

But the FDA wants to remove the boxed warnings about risk for cardiovascular disease, stroke, breast cancer, and probable dementia. The agency also wants labels to drop the recommendation to prescribe hormone therapy at the lowest effective dose for the shortest duration. Instead, treatment decisions should be individualized and fall within clinical judgment in discussion with a patient, the FDA staff wrote. 

“Instead of applying identical class-based language across all hormone therapy labels, safety data will be revised to reflect risks most relevant to each specific type of hormone therapy product (eg, combined estrogen plus progestogen vs estrogen alone),” Makary and his co-authors wrote. 

For the topical vaginal estrogen-only products, the label should focus on the safety findings most relevant to topical vaginal use and not the broader warnings associated with systemic exposure. 

Labels should include updated guidance on initiating treatment in women younger than 60 years or within 10 years of the onset of menopause to optimize the balance between risks and benefits, Makary and his co-authors wrote. 

Makary and other physicians have for years sought to counter what they describe as harmful misinterpretation of findings from the Women’s Health Initiative in the early 2000s. Makary’s 2024 book, Blind Spots, has a chapter titled “OMG HRT: The Untold Story of Hormone Replacement Therapy.” In their view, potential signals for an increased risk for breast cancer were overblown but led to warnings for these products that discouraged their use. 

In July, the FDA held a roundtable about the risks and benefits related to hormone therapy for menopausal women. Speakers at the meeting urged the agency to remove warnings that discourage use of vaginal hormone therapies. Among them was Rachel Rubin, MD, who in a September Medscape commentary urged the public to ask the FDA to remove warning labels on vaginal estrogen products. 

“They are sexual health drugs that save lives by preventing urinary tract infections,” Rubin said. “There have even been publications, including some of our own, that show we could save Medicare billions of dollars a year if women were given safe and effective vaginal hormone therapy." 

The American College of Obstetricians and Gynecologists (ACOG) on Monday came out in support of the proposed labeling change. 

“The modifications to certain warning labels for estrogen products are years in the making, reflecting the dedicated advocacy of physicians and patients across the country,” said Steven J. Fleischman, MD, MBA, ACOG’s president, in a statement. 

ACOG has long advocated for removal of the black box warning on low-dose vaginal estrogen, Fleischman said. 

“By discouraging clinicians from prescribing low-dose vaginal estrogen, the current warning label harms patients by making inaccessible an effective treatment for symptoms that can significantly decrease health-related quality of life,” Fleischman said. “We hope that this regulatory step forward will improve access to this important treatment option.” 

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research who has studied the FDA for many years, questioned how regulators reached their decision. 

The FDA should have sought the feedback of its Obstetrics, Reproductive and Urologic Drugs Advisory Committee, Zuckerman said in an email to Medscape. 

Zuckerman said Makary had acknowledged the risks of some types of hormone therapy for some women. Still, his “claim that hormones for menopause is the best way to improve the health of women sounds like a PR statement, not a scientific one,” Zuckerman wrote. 

“There are many better ways to reduce the chances of osteoporosis, heart disease, and dementia,” Zuckerman noted. “By making this announcement on TV and then to the rest of the media, rather than having scientists scrutinize the research at a public FDA scientific meeting, Commissioner Makary is undermining the credibility of the FDA.” 

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.