An FDA expert panel convened to challenge the current boxed warning labels on menopausal hormone therapy (HT), with multiple specialists arguing that existing warnings overstate risks and fail to reflect the totality of scientific evidence. The meeting, organized by FDA Commissioner Marty Makary and moderated by Principal Deputy Commissioner Sara Brenner, focused on reassessing safety labeling and addressing critical education gaps in menopause care.
Current Warning Labels Under Scrutiny
The existing boxed warnings for menopausal HT stem from the 2002 Women's Health Initiative (WHI) study published in JAMA, which found women receiving estrogen plus progestin had significantly increased risk for total cardiovascular disease, stroke and pulmonary embolism, and a nominally increased risk for breast cancer. The trial was stopped early due to "health risks that exceeded health benefits over an average follow-up of 5.2 years," leading to a dramatic decrease in HT use among women.
However, panel members presented compelling evidence challenging these broad warnings. Howard N. Hodis, the Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology at University of Southern California Keck School of Medicine, emphasized the importance of considering all available data spanning five decades. "We have 50 years of data," Hodis stated during the panel. "These data should be followed. Not just the data that gives us these particular outcomes that we want to believe but look at all of the data."
Vaginal vs. Systemic Therapy Safety Profiles
A significant focus of the panel discussion centered on the disparate safety profiles between vaginal and systemic HT, despite both carrying identical boxed warnings due to class labeling regulations. James Simon, clinical professor at George Washington University and founder of IntimMedicine Specialists, highlighted this regulatory inconsistency using the example of 4 μg Imvexxy (Mayne Pharma), a vaginal soft gel estradiol.
"The label for 4 μg Imvexxy and all estrogen products include warnings about increased risk for stroke, dementia, myocardial infarction, breast cancer, pulmonary embolism and endometrial cancer," Simon explained. However, he argued that vaginal estrogens, by means of their delivery mechanism, should be unable to affect other organs. Simon noted that 4 μg Imvexxy delivers similar estradiol levels to prasterone (Intrarosa, AMAG Pharmaceuticals), which does not include many of the same label warnings.
JoAnn Pinkerton, professor of obstetrics and gynecology at University of Virginia Health System, presented data from a systematic review and meta-analysis published in the American Journal of Obstetrics and Gynecology in 2025 showing that women who had breast cancer using vaginal HT had no increased risk for cancer recurrence compared with controls.
"The boxed warning is not supported by science," Pinkerton stated. "It harms women. It reflects a class labeling which was extrapolated from [the WHI trial]. It overstates risk. There is an absence of a randomized clinical trial or consistent observational evidence linking vaginal estrogen for [genitourinary syndrome of menopause] to cancer, heart disease, dementia, blood clots or stroke."
Reanalysis of WHI Data Reveals Favorable Outcomes
Multiple panel members presented reanalyzed data from the WHI study that challenges the original conclusions. Pinkerton presented data showing that among women aged 50 to 59 years, women receiving estrogen alone had more favorable outcomes than women receiving estrogen plus progestin. Additionally, estrogen alone was linked with a significant reduction in breast cancer incidence and mortality over long-term follow-up.
The data showed women aged 50 to 59 years in the study had low absolute risks of less than 1 per 1,000 women per year for coronary heart disease, stroke, pulmonary embolism, colorectal cancer, hip fracture and all-cause mortality.
Hodis presented additional WHI data indicating that the only adverse outcome with an absolute risk of 10 events per 10,000 women per year was deep vein thrombosis among women receiving estrogen plus progestin. Importantly, all-cause mortality was significantly lower with both estrogen and estrogen plus progestin compared with placebo. Alzheimer's disease was also significantly lower among women receiving estrogen alone versus placebo.
Regarding the original breast cancer findings, Hodis noted that while the original WHI paper showed elevated risk for "nominal statistical significance" for breast cancer with estrogen plus progestin, further adjustments for multiple statistical testing, sequential monitoring and confounding bias showed the association was not significant.
Critical Education Gaps in Healthcare
The panel identified significant deficiencies in menopause education among healthcare professionals as a major barrier to appropriate HT utilization. Mary Jane Minkin, clinical professor at Yale University School of Medicine, presented data published in Menopause in 2023 showing that only 31.3% of residency programs in the U.S. had a standardized menopause program and 29.3% had time dedicated to a menopause clinic.
Heather Hirsch, a board-certified internist and founder of Health by Heather Hirsch MD Collaborative, emphasized the inadequacy of current training, noting that clinicians may receive as little as one hour of menopause training, sometimes in the form of a voluntary lunch session during medical school.
"I do think that the American College of Graduate Medical Education must place more emphasis on teaching all clinicians and health care professionals starting in medical school, through their residency training," Hirsch stated. "Even if a clinician is not going to be the prescriber per se, if there is a clear consensus for who should or could have a consultation for HT, I do think that's really important."
Osteoporosis Prevention and Testosterone Access
The panel also addressed the underutilization of estrogen for osteoporosis prevention. Vonda Wright, an orthopedic surgeon and professor at the University of Central Florida, noted that approximately 70% of hip fractures occur in women, with 30% being fatal within one year after surgery. According to the NIH consensus statement and the European Foundation for Osteoporosis and Bone Disease, estrogen is the only well-established intervention to reduce osteoporosis fracture frequency in postmenopausal women by 30 to 50%.
Despite FDA approval of estrogen to treat osteoporosis, only 4% of women in the United States currently take it for that purpose due to fear of the warning label.
Kelly Casperson, a board-certified urologist, addressed the lack of access to testosterone therapy as part of hormone replacement regimens. "The FDA is failing women by denying access to a hormone their bodies naturally produce," Casperson stated, noting that higher testosterone levels in the brain correlated with lower levels of dementia and that testosterone and estrogen may allow women to discontinue SSRIs.
Moving Forward with Evidence-Based Labeling
Stephanie S. Faubion, professor and chair in the department of medicine at Mayo Clinic and Medical Director of The Menopause Society, told Healio that boxed warning changes for systemic HT are needed. "It is problematic and is a deterrent for many women who are good candidates for the use of systemic HT," Faubion stated. "[The boxed warning] should not be on low-dose vaginal products, as the risks are not the same."
Barbara Levy, clinical professor at George Washington University School of Medicine, acknowledged that another randomized clinical trial is unlikely to be funded and suggested combining data from randomized controlled trials with real-world evidence. "What we have to do is get bigger thinking and combine data from [randomized controlled trials] from Cochrane with real-world data," Levy stated.
The FDA plans to open a public comment period through the Federal Register as early as next week, allowing broader stakeholder input on potential labeling changes for menopausal hormone therapy.
