FDA Removes Most of the Boxed Warning for Menopausal Hormone Therapy

In November 2025 the Food and Drug Administration (FDA) initiated the removal of most of the boxed warning — the most prominent warning the agency can require — from the prescribing information of all menopausal hormone treatments containing estrogen.[1]

The labeling changes follow an “expert panel” meeting on menopause and hormone replacement therapy for women that the FDA convened in July 2025 and the subsequent submission of public comments.[2] The labeling changes reflect the opinion of FDA Commissioner Martin Makary that the boxed warning overstates the risks of hormone replacement therapy for women.[3]

The changes, which will require discussions with the companies that market the products, will take months to fully implement. Notably, the boxed warning about endometrial cancer for systemic estrogen-alone products will be maintained.[4]

For years, Public Citizen’s Health Research Group has advocated for the strong safety warnings for menopausal hormone therapy that are about to be removed. Although we are open to targeted updates to the safety warnings that incorporate recent medical evidence, many of the labeling changes are unsubstantiated. In our September 2025 comments to the FDA, we urged the agency not to update or remove the boxed warnings before additional safety data were obtained and gaps in the understanding of these treatments were addressed.[5]

Rather than advancing women’s health, the FDA’s rushed actions undermine the agency’s credibility. Moreover, the labeling changes may encourage inappropriate off-label prescribing of hormone replacement therapy for unapproved uses, such as preventing cardiovascular disease and cognitive decline.

The FDA also erred in initiating the changes without convening a formal advisory committee meeting, where independent experts would have offered an impartial and rigorous assessment of the available evidence. The FDA’s expert panel meetings are opinion-based and do not follow the rigorous process of advisory committee meetings. Panel members are more likely to offer interest-driven or one-sided views.[6] For instance, the criteria according to which panelists were selected for the menopause expert panel were not made public. At least some panel members had conflicts of interest that were not adequately disclosed and that should have disqualified them from participation.[7]

About menopausal hormone therapy

The FDA has approved the use of standard menopausal hormone therapy — mainly estrogen alone (such as conjugated estrogens [PREMARIN and generics[8]]) and combined estrogen and progestin (such as conjugated estrogens and medroxyprogesterone [PREMPHASE, PREMPRO[9]]) — for the treatment of moderate to severe vasomotor symptoms and moderate to severe vulvar and vaginal atrophy due to menopause. The FDA has also approved some of these medications for the prevention, but not treatment, of postmenopausal osteoporosis (bone thinning), which increases the risk of fractures. The treatments have been available for many years; conjugated estrogens were first approved in 1942.

At present, the prescribing information for all menopausal hormone therapy containing estrogen, regardless of the dose or formulation, includes a boxed warning stating that the therapy may increase the risk of endometrial cancer, cardiovascular disorders, breast cancer and probable dementia. For this reason, the boxed warning also states: “Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.”[10]

The Text Box below summarizes the FDA’s requested changes to the prescribing information.

FDA’s Requested Changes to the Prescribing Information for Menopausal Hormone Therapy[11]

Changes to the boxed warning for all menopausal hormone therapy (systemic and local vaginal products):

• Remove the language related to cardiovascular diseases, breast cancer and probable dementia
• Remove language related to endometrial cancer except for the systemic estrogen-alone drugs
• Remove the recommendation to use the lowest effective dose for the shortest amount of time

Additional changes to the labeling as a whole for systemic products:

• Add consideration of starting hormone therapy for moderate to severe vasomotor symptoms in women younger than 60 years old or less than 10 years from the start of menopause
• Add Women’s Health Initiative data for women 50-59 years old
• Retain the boxed warning about endometrial cancer for systemic estrogen-alone products
• Retain information about cardiovascular diseases and breast cancer warnings

Additional changes for local vaginal estrogen products:

• Condensed safety information, prioritizing the information most relevant for local vaginal formulations

Evidence against the changes to the boxed warning

Menopausal hormone therapy has several documented risks. These differ depending on the patient’s specific health risks (such as a history of cancer or heart disease), age at treatment initiation, dose and type of hormone therapy, and the length of therapy.[12],[13] Unfortunately, high-quality data from randomized controlled trials that could provide clarity on these interdependent risks (and that should have been required prior to removing the boxed warning) are limited, especially for long-term use and newer hormone therapy formulations.

The long-standing boxed warning for menopausal hormone therapy is largely based on the results of the 2002 Women’s Health Initiative trial, a large long-term randomized controlled study with several sub-studies.[14] The boxed warning is supported by more-recent high-quality evidence as well.

For instance, a 2019 meta-analysis showed that the long-term use of all types of hormone therapy (except vaginal estrogen), especially combination (both estrogen and progestin) hormone therapy, is associated with a higher risk of breast cancer.[15] Although this risk was low after less than one year of hormone therapy, there was an increased risk after one to four years of using hormone therapy and progressively greater risks with longer use.

A 2023 systematic review and meta-analysis noted that several observational studies found that menopausal hormone therapy reduced the risk of Alzheimer’s disease and all-cause dementia.[16] However, in randomized controlled trials (which are considered to provide higher-quality evidence than observational studies) of postmenopausal women aged 65 and older, the risk of dementia appeared to be higher with combination hormone therapy than with placebo.

A 2019 systematic evidence review requested by the FDA showed that low-dose vaginal estrogens (without concomitant progestogen) for vulvar and vaginal atrophy in menopausal women did not increase the risk of endometrial cancer.[17] Similarly, a federally funded systematic review published in 2024 comparing hormonal treatments and vaginal moisturizers for vulvar atrophy in postmenopausal women reported a low frequency of serious adverse events with these treatments.[18] However, the authors of both reviews stated that longer-term data is needed to confirm their findings because many of the randomized controlled trials were small and none followed participants for more than one year.

The long-standing boxed warning specifically states that neither estrogen-alone therapy nor estrogen-plus-progestin therapy should be used for the prevention of cardiovascular disease or dementia. This warning is supported by a 2022 review of clinical trials by the U.S. Preventive Services Task Force (USPSTF) — a federally funded, independent, voluntary panel of experts that makes evidence-based recommendations about clinical preventive services.[19] The USPSTF found that although some evidence shows that estrogen-alone therapy lowers the risks of diabetes and fractures, it also increases the risks of gallbladder disease, stroke, blood clots and urinary incontinence. Likewise, the USPSTF found that combined estrogen and progestin therapy lowered the risks of colorectal cancer, diabetes and fractures but increased the risks of invasive breast cancer, gallbladder disease, stroke and blood clots in postmenopausal women. The USPSTF also concluded that estrogen-plus-progestin therapy probably increased the risks of dementia and urinary incontinence.[20] For these reasons, the task force has consistently recommended against hormone replacement therapy (assigning it a grade “D” recommendation) for the prevention of chronic conditions in postmenopausal women.

What You Can Do

Be aware that the FDA’s decision to remove most of the boxed warning for menopausal hormone therapy was based on opinion, not more safety data.

If you experience moderate to severe menopausal symptoms, discuss with your clinician whether menopausal hormone therapy is an option for you. Also discuss with your clinician other potential treatments. If hormone treatment is planned, take these medications for the shortest period necessary to ensure that the treatment’s benefits outweigh the possible risks.

References

[1] The Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies. November 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations. Accessed November 18, 2025.

[2] The Food and Drug Administration. FDA expert panel on menopause and hormone replacement therapy for women. July 17, 2025. https://www.fda.gov/patients/fda-expert-panels/fda-expert-panel-menopause-and-hormone-replacement-therapy-women-07172025. Accessed November 6, 2025.

[3] Rabin RC. F.D.A. panelists call for removal of warnings on menopause treatments. The New York Times. July 17, 2025. https://www.nytimes.com/2025/07/17/health/hormone-therapy-menopause-fda.html. Accessed November 6, 2025.

[4] The Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies. November 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations?utm_medium=email&utm_source=govdelivery. Accessed November 11, 2025.

[5] Zeldes N. Comments regarding the Food and Drug Administration’s expert panel on menopause and hormone replacement therapy for women. September 24, 2025. https://www.citizen.org/article/comments-to-the-fda-on-the-expert-panel-on-menopause-and-hormone-replacement-therapy-for-women/. Accessed November 6, 2025.

[6] Alexander GC. The FDA’s pivot from ad comms to ‘expert’ panels is bad medicine. STAT. September 5, 2025. https://www.statnews.com/2025/09/05/fda-expert-panels-advisory-committees-talc-ssris-formula/. Accessed November 6, 2025.

[7] Let’s Talk Menopause. Our team. https://www.letstalkmenopause.org/our-team. Accessed October 31, 2025.

[8] Pfizer, Inc. Label: Conjugated estrogens (PREMARIN). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/004782s179lbl.pdf. Accessed November 6, 2025.

[9] Pfizer, Inc. Label: conjugated estrogens plus medroxyprogesterone acetate (PREMPHASE). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/020527s067lbl.pdf. Accessed November 6, 2025.

[10] Pfizer, Inc. Label: Conjugated estrogens (PREMARIN). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/004782s179lbl.pdf. Accessed November 6, 2025.

[11] The Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies. November 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations?utm_medium=email&utm_source=govdelivery. Accessed November 11, 2025.

[12] Mayo Clinic. Menopause hormone therapy: Is it right for you? April 18, 2025. https://www.mayoclinic.org/diseases-conditions/menopause/in-depth/hormone-therapy/art-20046372. Accessed November 6, 2025.

[13] The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794.

[14] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-333.

[15] Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168.

[16] Nerattini M, Jett S, Andy C, et al. Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia. Front Aging Neurosci. 2023;15 (October 23):1260427.

[17] Constantine GD, Graham S, Lapane K, et al. Endometrial safety of low-dose vaginal estrogens in menopausal women: a systematic evidence review. Menopause. 2019 Jul;26(7):800-807.

[18] Danan ER, Sowerby C, Ullman KE, et al. Hormonal treatments and vaginal moisturizers for genitourinary syndrome of menopause: A systematic review. Ann Intern Med. 2024 Oct;177(10):1400-1414.

[19] US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(17):1740-1746.

[20] USPSTF reaffirms recommendations against using menopausal hormone therapy to prevent chronic conditions. Worst Pills, Best Pills News. April 2023. https://www.worstpills.org/newsletters/view/1526. Accessed November 6, 2025.