FDA panel calls for label changes, more education on menopausal hormone therapy

Posted on July 21, 2025

Key takeaways:

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.

Members of an FDA expert panel discussed reassessing boxed warnings for menopausal HT and how to better educate patients and health care professionals.

Concerns about menopausal HT stem back to the publication of findings from the Women’s Health Initiative in JAMA in 2002. As Healio previously reported, the 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.

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

During the expert panel, members presented data showing no increased risks for numerous adverse health outcomes for women who used menopausal HT. Howard N. Hodis, MD, 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.

“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 Simon, MD, 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, MSCP, 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. Pinkerton said the label for vaginal HT should be modified based on the evidence.

“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.”

Multiple health care professionals agreed with the panel that the boxed warning for vaginal HT should be modified or removed.

“It is problematic and is a deterrent for many women who are good candidates for the use of systemic HT,” 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. “[The boxed warning] should not be on low-dose vaginal products, as the risks are not the same.”

Holly L. Thacker, MD, FACP, CCD, NCMP, director of the Cleveland Clinic Center for Specialized Women’s Health and professor at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, praised the panel’s discussion and its push to change the boxed warning for vaginal HT.

“I thought it was a solid panel,” Thacker told Healio. “They gave case scenarios, clinical experience and a lot of hardcore data research. The call to take the boxed warning off of vaginal estrogen is so late. It should have been done a long time ago.”

Monica Christmas, MD, FACOG, MSCP, associate medical director for The Menopause Society and the director of the menopause program and center for women's integrated health at The University of Chicago Medicine, described the boxed warning for local estrogen therapy as being “overstated.”

“Local low-dose ET acts locally at the vaginal walls with negligible systemic absorption,” Christmas told Healio. “It is used to manage genitourinary symptoms associated with menopause, like vaginal irritation, itching, pain, dryness that may contribute to pain or bleeding with intercourse and urinary symptoms, such as urinary urgency and frequency. The confusion with the black box warning stems from grouping local low-dose estrogen therapy with higher dose systemic HT, where there is absorption into the blood stream.”

Nanette Santoro, MD, professor and the E. Stewart Taylor Chair of OB/GYN at the University of Colorado School of Medicine, said while no randomized trial has been conducted assessing vaginal HT, observational safety data are robust enough to alleviate any concerns.”

“[The boxed warning] is the same warning used for systemic estrogen and this flies in the face of data that show that with regular use, there is only a trace amount of estradiol that gets into the bloodstream with vaginal estradiol tablets or inserts,” Santoro said.

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.

Barbara DePree, MD, NCMP, MMM, director of the Women’s Midlife Services at Holland Hospital in Michigan, said she was surprised the panel discussion leaned more toward systemic use of menopausal HT and believed that the discussion on WHI data would have benefited from having one of the investigators on the panel.

“Some panelists seemed a bit loose in applying the WHI data, which only included those two hormones [estrogen plus progestin and estrogen alone], as data that would have the same outcome for the more commonly used preparations, transdermal estradiol and micronized progesterone,” DePree told Healio. “Unfortunately, we just don’t have that data with direct comparisons. We have some, but we need to be cautious about making generalizations from product to product.”

DePree also noted the panel lacked an oncologist who would have been able to provide unique insight on breast cancer safety.

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.

“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.

“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.”

Thacker agreed with the panel, stating that many health care professionals have not been properly educated on hormones, leading patients to instead gravitate online and to compounded products.

“My recommendations are that pretty much any physician, unless you’re a pediatrician, should have some basic knowledge in [menopausal HT] or at least get some resources or find out who is someone in your region that you can access,” Thacker said. “There’s not enough and there’s never probably going to be enough highly trained menopause specialists like myself. … People like us have to be reserved for the really complicated patients, the cancer survivor who needs HT, the person with unstable cardiovascular disease, autoimmune disease and organ transplant.”

Christmas said it is essential for health care professionals to have the ability to educate patients about menopausal HT due to the misconceptions many people have about therapy.

“HT is not the magic antidote to aging; however, it is highly effective in treating vasomotor and genitourinary symptoms associated with menopause,” Christmas said. “There can be downstream benefits as well. For example, night sweats may disrupt sleep and impact energy and mood. If we treat the night sweats either with HT or an effective non-hormonal treatment, sleep may improve leading to better mood and less fatigue. For patients that can't be on HT or would prefer a non-hormonal option, there are a number of effective therapeutic options available.”

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.”

Thacker said she is hopeful that the panel discussion will lead to changes in the public’s perception of menopausal HT, better education for health care professionals and potentially increased access for women who may benefit.

“We have a lot of clinicians on the panel with combined hundreds of years of patient experience that the women that take HT generally not only feel better and function better in terms of work productivity — which is important economically and for society — but they have less burden of disease, CVD, diabetes, osteoporosis, psychosexual problems and dementia, which is a huge burden,” Thacker said.

Hirsch 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.

DePree agreed with Faubion and said the decision to use menopausal HT needs to be individualized for each patient.

“We need to discuss with each patient her symptoms, her health concerns, and review current data about what we know and don’t know, and then let the shared decision-making process occur and explore treatment options that meet her needs and expectations,” DePree said. “As mentioned, women aren’t ‘just a breast, or a brain,’ we can help women make the appropriate decision for their own health journey and safely navigate that without introducing any fear factors.”