Experts urge FDA to remove black box warning on low-dose vaginal estrogen

On July 17, 2025, the FDA convened a panel of experts to discuss the use of hormone replacement therapy (HRT) in menopausal women.¹

“Science evolves and so must our warning labels,” said Rachel S. Rubin, MD.

These experts urged the agency to remove the current boxed warning on vaginal estrogen products that says the medication carries a risk of serious adverse effects. The panelists, who were selected by FDA commissioner Marty Makary, MD, MPH, outlined data showing that these risks may be overstated, leading women to avoid estrogen-containing products out of fear of its risks.

Makary, who has voiced support for the use of HRT, began the discussion by highlighting data showing that the benefits of the medication appear to outweigh the risks. In his opening remarks, he cited data from the 1950s showing early heart disease in women who had their ovaries removed, which “[suggests] a powerful and profound cardio-protective effect of estrogen made in the ovaries,” he noted.

He went on to highlight subsequent data showing that “when a woman starts estrogen or estrogen plus progesterone within 10 years of the onset of menopause, there's somewhere between a 25% and 50% reduction in fatal heart attacks and cardiovascular disease. To put that in context, that is comparable to the risk reduction or greater than the risk reduction of a statin.”

Safety of low-dose, local estrogen

The agency then heard remarks from several prominent experts across urology, women’s health, endocrinology, gynecology, and neuroscience, who highlighted the growing consensus among these fields in the benefits of menopausal hormone therapy when used appropriately.

Heather Hirsch, MD, MS, NCMP, a board-certified internist, opened the discussion by emphasizing the importance of distinguishing between systemic and local estrogen.

“Vaginal or local estrogen is categorically safe for all women, period, because it does not travel systemically,” she explained. “What we know is that it does not increase the risks of heart attacks, breast cancers, or strokes—no data shows that. However, there is a boxed warning inappropriately affirming that it does.”

Hirsch argued that misinformation, compounded by a lack of provider education, is actively harming women. She called on the FDA to remove the boxed warning on vaginal estrogen products to help restore clinician confidence in prescribing HRT.

Specifics matter

Barbara Levy, MD, FACOG, FACS, MSCP, a clinical professor of obstetrics and gynecology – George Washington University School of Medicine & Health Sciences, echoed Hirsch’s remarks that the specifics of administration matter—particularly the route of administration and the dose administered.

She pointed out that the hormone products used in the Women’s Health Initiative (WHI) study—which led to the original boxed warning on estrogen products—were highly specific, and their risks should not be applied broadly to all HRT.

“It’s inappropriate scientifically to conflate the results in a study that used conjugated equine estrogen to all forms of hormone therapy,” Levy noted. “That’s a disaster that we’ve been perpetrating for decades now.”

The need for greater education, awareness

Rachel S, Rubin, MD, a board-certified urologist fellowship trained in sexual medicine, called for greater awareness and updated messaging around treatments for women’s urologic health.

“Science evolves and so must our warning labels,” said Rubin. “Local vaginal hormones, estrogen and DHEA, are not only similar to, but actually way better than Viagra, because not only do they help with sex and its urinary symptoms, they prevent urinary tract infections. This guideline-supported fact says that we can prevent more than 50% of people's urinary tract infections with local vaginal hormones, and we have known this for decades. Why haven't you heard of this before? Because your doctor doesn't know this either, and because women's health has a marketing problem.”

Takeaways and next steps

Collectively, the panelists argued that hormone therapy has a strong risk-benefit profile when started appropriately and monitored. Yet many women continue to go without needed care—largely due to gaps in clinician education, confusing regulations, and persistent fears rooted in outdated or overstated risks.

In a unified call to action, the panel urged the FDA to revise or remove the boxed warning on low-dose vaginal estrogen, calling it a critical step toward improving care for menopausal women.

Hirsch concluded, “Women deserve policy that reflects the current evidence and not outdated myths.”

REFERENCE

1. FDA Expert Panel on Menopause and Hormone Replacement Therapy for Women. YouTube: US Food & Drug Administration. July 17, 2025. Accessed July 18, 2025. https://www.youtube.com/watch?v=_2ZRlOivC5M