FDA to Remove Black Box Warnings From HRT, Debate Ensues

In 2003, the FDA first added a black box warning to hormone replacement therapy (HRT), after findings from the 2002 Women’s Health Initiative (WHI) showed a potential greater risk of breast cancer with the treatment.1 Today, HHS began the process of reversing that decision, announcing that it is initiating the removal of the so-called black box warning for estrogen and estrogen-progesterone replacement and restoring “gold-standard science to women’s health.2

The target patient population is women experiencing menopausal symptoms, with warnings being removed from 4 product classes: all combined estrogen-progestogen, estrogen alone, other estrogen-containing, and progestogen-only.2

Citing extensive collaboration that encompassed a scientific literature review, a public comment period, and a July expert panel, the agency will further team up with affected pharmaceutical manufacturers to remove warning language against elevated risks of cardiovascular disease, breast cancer, and probable dementia. Warnings toward endometrial cancer related to estrogen-alone products will remain.

“Estrogen is a key hormone for women's health. Every single part of a woman's body depends on estrogen to operate at its best—including the brain, bones, heart, and muscles,” said Alicia Jackson, PhD, in a statement. Jackson is director for Advanced Research Projects Agency for Health. “The removal of the black box warning, based on the best science and data, is an incredible step forward to empower millions of women to live longer, healthier lives,” she added.

Black box warnings are being removed from 4 product classes: all combined estrogen-progestogen, estrogen-alone, other estrogen-containing, and progestogen-only. | Image Credit: © Vitalii Vodolazskyi - stock.adobe.com

Both the press release and a viewpoint piece speak to the positive history of HRT for perimenopausal and menopausal women, specifically its long-term benefits.1,2 These benefits include reductions in vasomotor symptoms, fatal cardiovascular events, bone fractures, cognitive decline, and Alzheimer disease. Further, in JAMA, the authors point out that the higher risk attributed to the WHI study has been linked to a medroxyprogesterone acetate, which is a formulation of progesterone “not in common use today for hormone therapy.”

Findings from that therapy alone led to box warnings that include those previously mentioned, as well as thromboembolism. Today’s hormone therapies, FDA Commissioner Marty Makary, MD, MPH, writes, are “available in formulations that do not appear to carry the same increased risk of blood clots or breast cancer that was seen in earlier studies.” He noted that the WHI study “created a fear machine that lingers to this day.”3

On board with the change is the American College of Obstetricians and Gynecologists (ACOG), whose president Steven J. Fleishman, MD, MBA, FACOG, said today, “ACOG has long advocated for removal of the ‘black box warning’ on low-dose vaginal estrogen… By discouraging clinicians from prescribing low-dose vaginal estrogen, the current warning label harms patients by making inaccessible an effective treatment for symptoms that can significantly decrease health-related quality of life. We hope that this regulatory step forward will improve access to this important treatment option.”4

Along with removing the warning against HRT, revised labels will now also see the removal of recommendations to prescribe the lowest effective dose for the shortest duration, as well as the inclusion of tailored safety information, an emphasis on safety data for topical vaginal use, and timing information for systemic treatment.1

Still, the move has received some pushback, chiefly that the negative effects of menopause and the benefits of HRT have been overstated.5 Among these are claims that divorce is related to menopause, that menopause shortens women’s lives, that the lives of all women will be bettered, and that women with breast cancer will live longer. Of this last claim, Adrian Dobs, MD, MHS, professor of medicine and oncology at the Johns Hopkins University School of Medicine’s Division of Endocrinology, Diabetes and Metabolism, said, “We shouldn’t be afraid of it, but I couldn’t make a statement that vaginal estrogen makes women with breast cancer live longer.” She went on to explain that clinicians typically recommend avoidance

References

1. Makary MA, Nguyen CP, Høeg TB, Tidmarsh GF. Updated labeling for menopausal hormone therapy. JAMA. Published online November 10, 2025. doi:10.1001/jama.2025.22259
2. HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. News release. HHS. November 10, 2025. Accessed November 10, 2025. https://www.hhs.gov/press-room/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy.html
3. Santhosh C, Aboulenein A. US FDA to drop black box warnings from menopause hormone therapies. Reuters. November 10, 2025. Accessed November 10, 2025. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-chief-makary-asks-drugmakers-remove-warnings-hormone-therapy-2025-11-10/
4. ACOG president says label change on estrogen will increase access to hormone therapy. American College of Obstetricians and Gynecologists. November 10, 2025. Accessed November 10, 2025. https://www.acog.org/news/news-releases/2025/11/acog-president-says-label-change-on-estrogen-will-increase-access-to-hormone-therapy
5. Butlet K, McShane J. The many problems with the FDA’s Big menopause announcement. MotherJones. November 10, 2025. Accessed November 10, 2025. https://www.motherjones.com/politics/2025/11/the-many-problems-with-the-fdas-big-menopause-announcement/