Key takeaways:
Table of Contents
- The FDA convened an expert panel to discuss the safety and efficacy of menopausal HT.
- Some panel members stated the boxed warning for HT should be changed to better reflect published evidence.
Editor’s note: This is a developing news story. Please check back soon for updates.
Members of an FDA expert panel discussed reassessing boxed warnings for menopausal HT and how to better educate patients and health care professionals.
An FDA panel discussed data regarding benefits and risks of menopausal HT and how to make improvements with education health care professionals about menopause. Image: Adobe Stock
Concerns about menopausal HT stem back to the publication of findings from the Women’s Health Initiative in JAMA in 2002. As Healio previously reportedthe study found women receiving estrogen plus progestin had significantly increased risk for total CVD, 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.” The results of the trial led to a large decrease in the use of HT among women.
During the expert panel, members presented data showing no increased risks for numerous adverse health outcomes for women who used menopausal HT. Howard N. Hodi, 1500; the Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology at University of Southern California Keck School of Medicine, said there are issues with every trial, including the WHI, and emphasized that the medical community should follow all the data when weighing benefits and risks with menopausal HT.
Howard N. Hodis
“We have 50 years of data,” Hodis said 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.”
Safety for vaginal HT
One of the topics discussed was differences in safety outcomes between vaginal and systemic HT. While the boxed warning for the two types of HT is the same due to regulations on class labeling, safety between them differs, panel members said.
James SimonMD, CCD, NCMP, IF, clinical professor at George Washington University and founder and medical director of IntimMedicine Specialists, said the label for 4 µg Imvexxy (Mayne Pharma), a vaginal soft gel estradiol, and all estrogen products include warnings about increased risk for stroke, dementia, myocardial infarction, breast cancer, pulmonary embolism and endometrial cancer. Simon, however, said vaginal estrogens, by means of their delivery, should be unable to affect other organs. Simon added that 4 µg Imvexxy delivers similar estradiol levels to women as prasterone (Intrarosa, AMAG Pharmaceuticals), which does not include many of the same label warnings as Imvexxy.
“The FDA has a very complicated, oftentimes difficult balancing act in constructing a label that’s understandable, that’s straightforward and that carefully and correctly balances risks and the benefits of a given product,” Simon said during the panel. “I believe that in terms of the low-dose vaginal estrogen label, they have failed.”
JoAnn Pinkerton, MD, FACOG, MSCPprofessor 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. Pinkerton said the label for vaginal HT should be modified based on the evidence.
JoAnn Pinkerton
“The boxed warning is not supported by science,” Pinkerton said during the panel. “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.”
Stephanie S. Faubion, MD, MBA, FACP, MSCP, IF, professor and chair in the department of medicine and the Penny and Bill George Director of the Mayo Clinic Center for Women’s Health, and Medical Director of The Menopause Society, told Healio that she agreed boxed warning changes for systemic HT are needed.
Stephanie S. Faubion
“It is problematic and is a deterrent for many women who are good candidates for the use of systemic HT,” Faubion told Healio. “[The boxed warning] should not be on low-dose vaginal products, as the risks are not the same.”
Deeper dive into WHI data
Multiple panel members presented data on menopausal HT safety, including data on the WHI. Pinkerton presented data published from the WHI that showed 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. Pinkerton said 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 also presented data from WHI and stated 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. He added 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 vs. placebo, Hodis said.
Hodis added 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.
“It is past time to stop overstating risks, and promoting fear and confusion about HT, which has been shown to safely offer life-enhancing and lifesaving benefits for countless menopausal women,” Hodis said during the panel.
More education needed
Mary Jane Minkin, MD, clinical professor in the department of obstetrics, gynecology and reproductive sciences at Yale University School of Medicine, said one of the biggest issues surrounding menopausal HT is a lack of education among health care professionals. She discussed data published in Menopause in 2023 which found 31.3% of residency programs in the U.S. had a standardized menopause program and 29.3% had time dedicated to a menopause clinic.
Mary Jane Mink
“We need to start to training people,” Minkin said during the panel. “We need to do what we can, whether it’s reach out through videos or [other methods]. The other thing that’s crucial is we have to train other practitioners. We need to train nurse practitioners, we need to train our [physician assistants]and many of them are tremendously interested in menopause care.”
Heather Hirsch, MD, MS, NCMP, a board-certified internist and founder and CEO of Health by Heather Hirsch MD Collaborative, said a greater emphasis needs to be placed on training health care professionals across all specialties about menopause.
Heather Hirsch
“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 said during the panel. “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.”
Moving forward
Most members of the panel said they favor labeling changes for menopausal HT. When asked what the largest data gaps were on menopausal HT, Simon stated he wants to see the FDA follow the data that have already been published.
Barbara Levy, MD, FACOG, FACS, MSCP, clinical professor of obstetrics and gynecology at George Washington University School of Medicine and Health Science,; voluntary clinical professor in the department of obstetrics, gynecology & reproductive sciences at University of California, San Diego Health Sciences, and Chief Medical Officer at Visana Health, said another randomized clinical trial is unlikely to be funded, so researchers need to find other ways to gather data.
“What we have to do is get bigger thinking and combine data from [randomized controlled trials] from Cochrane with real-world data,” Levy said during the panel. “There’s a lot of real-world data out there.”
vHirsch said the members of the panel didn’t believe HT was “appropriate” for all women, but many women who could benefit from therapy don’t receive it due to health care professionals not being educated about it. Faubion told Healio that health care professionals must take several factors into account when assessing whether a patient would benefit from menopausal HT.
“Calculating an individual woman’s risk-benefit ratio for the use of HT involves a number of factors, including her age, time since menopause onset, estrogen plus progesterone or estrogen alone (eg, presence or absence of a uterus), cardiovascular disease and breast cancer risk factors as well as personal preferences,” Faubion said.
For more information:
Stephanie S. Faubion, MD, MBA, FACP, MSCP, IF can be reached at editor@healio.com.
References:
Allen JT, et al. Menopause. 2023; two: 10.1097/GME.0000000000002234.
Beste Me, et al. Am J Obstet Gynecol. 2025; DOI: 10.1016/J.AJOG.2024.10.054.
Rossouw you, et al. JAMA. 2002; DOI: 10.1001/Jama. 288.3.321.
Sources/Disclosures
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Disclosures:
Simon reports receiving research support from AbbVie, Bayer Healthcare, Mylan/Viatris and Myovant Sciences; consulting or advising for Ascend Therapeutics, Bayer HealthCare Pharmaceuticals, Besins Healthcare, Biote Medical LLC, Cosette Pharmaceuticals, Femasys, Mayne Pharma, Pfizer and Vella Biosciences; speaking for Ascend Therapeutics, Lawley Pharmaceuticals, Mayne Pharma, Myovant Sciences and Pharmavite LLC; and holding stock in Sermonix Pharmaceuticals. Faubion and Hirsch report no relevant financial disclosures. Healio could not confirm relevant financial disclosures for Hodis, Levy, Minkin and Pinkerton prior to publication.
