Experts urge FDA to revise boxed warnings on hormone therapies for menopause

Experts urge FDA to revise boxed warnings on hormone therapies for menopause | Image credit: Contemporary OB/GYN

A high-level roundtable convened by the US Food and Drug Administration (FDA) highlighted growing consensus among clinicians and researchers that current boxed warnings on menopausal hormone therapies, particularly low-dose vaginal estrogen, are outdated and not supported by current evidence. Held at the FDA's White Oak campus, the session featured prominent experts in women’s health, endocrinology, gynecology, urology, and neuroscience, who called for regulatory reform to remove what they described as medically inaccurate and harmful labeling.

Historical context and clinical consequences

FDA Commissioner Marty Makary, MD, MPH, opened the meeting by referencing historical data from the 1950s showing early heart disease in women whose ovaries were removed at a young age. “That suggested a powerful and profound cardioprotective effect of estrogen,” he said, citing further studies that show a 25% to 50% reduction in fatal heart attacks and cardiovascular disease when hormone therapy is started within 10 years of menopause. “That is comparable to the risk reduction, or greater than the risk reduction of a statin,” he added.

Makary also noted that after the 2002 publication of the Women’s Health Initiative (WHI), clinicians and patients reacted with widespread fear over a perceived breast cancer risk, despite the WHI not showing a statistically significant increase in breast cancer mortality. “As a result of the fear of breast cancer, 50 million plus women have not been offered the incredible potential health benefits of hormone replacement therapy,” he said.

Clarifying safety: Systemic vs local estrogen

Panelists emphasized the importance of distinguishing between systemic and local (vaginal) estrogen. Heather Hirsch, MD, MS, NCMP, board-certified internist, accredited menopause specialist, founder of the menopause clinic at Brigham and Women's Hospital, stated, “Vaginal or local estrogen is categorically safe for all women—period—because it does not travel systemically.” She added that current boxed warnings on these products are not supported by evidence, noting, “There again, are no increased risks of heart attacks, clots or strokes, and the black box warning is wrong and should be removed.”

James A. Simon, MD, CCD, NCMP, IF, clinical professor at George Washington University, founder and medical director of IntimMedicine Specialists, echoed this, stating, “You cannot measure [systemic levels] in the blood” after using low-dose vaginal estrogen. “So, you cannot interpret the delivery of low-dose vaginal estrogens as causing all these things that are horrible, painful, that keep patients from using the products.”

WHI data reexamined

JoAnn V. Pinkerton, MD, FACOG, MSCP, professor of obstetrics and gynecology at the University of Virginia Health System, presenting data on behalf of JoAnn Manson, MD, MPH, DrPH, emphasized the age-dependent outcomes in the WHI. For women aged 50 to 59 years, conjugated estrogen alone led to reductions in all-cause mortality, heart events, and breast cancer incidence. “What we’re telling you is that if women are between 50 and 59, the outcomes are more favorable,” Pinkerton said.

Howard N. Hodis, MD, expanded on this by presenting WHI data showing rare and statistically nonsignificant adverse events in younger women, and a significant reduction in mortality with conjugated estrogen alone. “On scientific grounds, the claim that WHI demonstrates an increased risk of breast cancer is not justified by the published data,” Hodis said.

Hodis holds the Harry J. Bauer and Dorothy Bauer Rawlins Professorship in Cardiology, is a professor of medicine and population and public health sciences, molecular pharmacology and toxicology, and director of the Atherosclerosis Research Unit in the Division of Cardiovascular Medicine at the Keck School of Medicine at the University of Southern California.

Implications for training and access

Multiple speakers addressed the lack of provider education following the 2002 WHI publication. Mary Jane Minkin, MD, clinical professor, Department of Obstetrics and Gynecology, and Reproductive Sciences, Yale University School of Medicine, noted, “Menopause education stopped on July 9, 2002,” and cited surveys showing that fewer than 30% of residency programs provide menopause-specific training.

Barriers to access were also highlighted. Rachel S. Rubin, MD, urologist and sexual medicine specialist, and assistant clinical professor in Urology at Georgetown University Hospital, described how the boxed warning prevented ICU clinicians from restarting her mother’s home dose of vaginal estrogen, despite a UTI risk. “Your label tried to kill my mother,” she told the FDA.

Testosterone: Another gap

The absence of an FDA-approved, female-specific testosterone formulation was raised by Kelly Casperson, MD, board-certified urologist and expert and advocate for sexuality and hormones. “One in 5 men are diagnosed with hypogonadism… nearly all women experience the same hormone decline when they live long enough,” she said. Casperson argued that this represents a regulatory and equity failure, given that trans men receive doses 10 times higher than what would be needed for women.

Clinical implications and next steps

The roundtable underscored the broad clinical benefits of hormone therapy when initiated appropriately, including reductions in cardiovascular events, cognitive decline, osteoporosis-related fractures, and genitourinary symptoms. Vonda Wright, MD, MD, orthopaedic surgeon, associate professor of orthopaedic surgery at the University of Central Florida and founder and CEO of Precision Longevity, emphasized, “It is estimated that estrogen must be used 10 years to change the outcome of fracture, and that once you stop estrogen… your bone will rapidly decline as if you’d never had it at all.”

Roberta Diaz Brinton, PhD, director of the Center for Innovation in Brain Science in the College of Medicine at the University of Arizona-Tucson. presented imaging and mechanistic research linking the menopausal transition to early Alzheimer’s disease pathology and emphasized the importance of timely initiation of hormone therapy to mitigate neurologic risk.

Panelists collectively urged the FDA to remove or revise boxed warnings for low-dose vaginal estrogen and to support regulatory pathways for female-specific testosterone products. Hirsch concluded, “Women deserve policy that reflects the current evidence and not outdated myths.”

Reference:

FDA. FDA Expert Panel on Menopause and Hormone Replacement Therapy for Women. Panel Discussion. July 17, 2025. Accessed July 18, 2025. https://www.youtube.com/live/_2ZRlOivC5M