Rethinking Menopausal Hormone Therapy: Experts Urge FDA to Revise Outdated Warnings

Menopause marks a significant milestone in a woman’s life, accompanied by a variety of physical and emotional changes. Among the most effective tools for managing its symptoms and potential health risks is menopausal hormone therapy (MHT). Yet, for decades, millions of women have been denied this option—or have avoided it themselves—due to lingering fears fueled by outdated safety warnings on medication labels. Now, leading medical experts are calling on the US Food and Drug Administration (FDA) to update its guidance, particularly regarding low-dose vaginal estrogen, based on mounting evidence that these warnings are not only unsupported by current science but are actively harming women’s health.

Historical Context: The Shadow of the WHI

The story of hormone therapy is, in many ways, a cautionary tale about how science and public health policy can become misaligned. In the early 2000s, the Women’s Health Initiative (WHI)—a massive, federally funded study—sent shockwaves through the medical community with findings suggesting hormone therapy increased the risk of breast cancer, heart disease, and stroke. The FDA responded by mandating boxed (“black box”) warnings on all estrogen-containing products, a signal to clinicians and patients of potentially severe risks.

Dr. Marty Makary, FDA Commissioner, recently revisited this history at a high-level roundtable at the FDA’s Silver Spring headquarters. He noted that the WHI’s findings were often misinterpreted and overgeneralized, neglecting nuances in the data. “As a result of the fear of breast cancer, 50 million plus women have not been offered the incredible potential health benefits of hormone replacement therapy,” Makary said.

Scientific and Clinical Evidence: What the Data Tell Us

The WHI was a landmark trial, but its participants were, on average, older than the typical woman starting hormone therapy—most were in their 60s, rather than in their 50s, when menopause usually begins. Subsequent analyses and follow-up studies have made several crucial clarifications:

• For women who start hormone therapy within 10 years of menopause, there is a 25% to 50% reduction in fatal heart attacks and cardiovascular disease—a benefit comparable to or greater than statin therapy.
• Estrogen-alone therapy in women aged 50 to 59 reduces all-cause mortality, heart events, and even breast cancer incidence.
• Most risks identified in the WHI (heart attacks, clots, strokes) were statistically rare and largely confined to older women or those starting therapy well after menopause.

Dr. JoAnn V. Pinkerton, presenting on behalf of Dr. JoAnn Manson, emphasized: “If women are between 50 and 59, the outcomes are more favorable.”

Systemic vs. Local Estrogen: A Critical Distinction

The boxed warning does not differentiate between systemic hormone therapy (oral or transdermal, affecting the whole body) and local (vaginal) estrogen, which is used in much lower doses to treat symptoms like vaginal dryness, irritation, and recurrent urinary tract infections. Dr. Heather Hirsch, a menopause specialist, stated bluntly, “Vaginal or local estrogen is categorically safe for all women—period—because it does not travel systemically.”

Dr. James A. Simon expanded: “You cannot measure [systemic levels] in the blood” after using low-dose vaginal estrogen. “So, you cannot interpret the delivery of low-dose vaginal estrogens as causing all these things that are horrible, painful, that keep patients from using the products.”

Case Vignette: Mary’s Dilemma

Mary Johnson, a 54-year-old librarian, suffered from severe vaginal dryness and frequent urinary tract infections after menopause. When her primary care doctor suggested a low-dose vaginal estrogen cream, Mary hesitated. She had read the boxed warning and feared increasing her risk of breast cancer or stroke. After much anxiety, she refused treatment, only to end up in the emergency room months later with a serious urinary infection. Mary’s story is echoed in clinics nationwide—and highlights the real-world harm of unclear labeling.

Misconceptions and Harmful Behaviors

The legacy of the WHI and the FDA’s boxed warnings has fostered persistent myths and led to widespread underuse of hormone therapy:

• Many women and clinicians believe all forms of hormone therapy carry the same risks, regardless of dose or delivery method.
• Fear of breast cancer remains high, despite evidence showing no significant increase in breast cancer mortality in estrogen-alone users, and even a reduced incidence in some groups.
• Medical training on menopause has lagged; fewer than 30% of residency programs include menopause-specific education, according to Dr. Mary Jane Minkin.

These misconceptions have led to:

• Unnecessary suffering from genitourinary symptoms of menopause
• Increased rates of osteoporosis, fractures, and cardiovascular disease
• Higher rates of cognitive decline and possible early Alzheimer’s pathology

Correct Health Practices and Practical Recommendations

Leading experts now advocate for:

• Shared decision-making: Discuss the risks and benefits of hormone therapy individually, considering age, time since menopause, and personal risk factors.
• Clear differentiation: Clinicians and patients should understand the vast difference between systemic and local estrogen therapies.
• Updated education: Medical schools and continuing education programs should include up-to-date menopause management curricula.
• Early initiation: When appropriate, start hormone therapy within 10 years of menopause to maximize benefits and minimize risks.

Table: Key Differences Between Systemic and Local (Vaginal) Estrogen

Feature	Systemic Estrogen	Local (Vaginal) Estrogen
Purpose	Hot flashes, night sweats, overall menopausal symptoms	Vaginal dryness, irritation, painful intercourse, recurrent UTIs
Dose	Higher, affects entire body	Low, minimal systemic absorption
Risks	Small increased risk of clots, stroke (mainly in older women)	No significant systemic risks
FDA Boxed Warning	Yes	Yes (but not supported by evidence)

Expert Insights and Commentary

The FDA roundtable brought together prominent voices in women’s health. Dr. Howard N. Hodis summarized the consensus: “On scientific grounds, the claim that WHI demonstrates an increased risk of breast cancer is not justified by the published data.”

Dr. Rachel Rubin, a urologist, underscored the practical consequences: “Your label tried to kill my mother,” she told the FDA, after ICU clinicians refused to allow her mother’s home dose of vaginal estrogen, risking a serious infection.

Another gap highlighted was the absence of FDA-approved, female-specific testosterone formulations. Dr. Kelly Casperson pointed out the inequity: “One in 5 men are diagnosed with hypogonadism…nearly all women experience the same hormone decline when they live long enough.”

Broader Implications: Bone, Brain, and Beyond

Estrogen is not just about hot flashes. Dr. Vonda Wright emphasized, “Estrogen must be used 10 years to change the outcome of fracture, and that once you stop estrogen…your bone will rapidly decline as if you’d never had it at all.” Dr. Roberta Diaz Brinton presented research linking menopause to early Alzheimer’s disease pathology and argued that timely hormone therapy could help protect the aging brain.

Next Steps: Toward Regulatory Reform

The roundtable’s message to the FDA was clear: revise or remove boxed warnings for low-dose vaginal estrogen and support research and approval pathways for female-specific testosterone. Dr. Hirsch concluded, “Women deserve policy that reflects the current evidence and not outdated myths.”

Conclusion

Menopausal hormone therapy, when used appropriately, offers substantial benefits for women’s health and quality of life. The time has come for regulatory messaging—and clinical practice—to catch up with the evidence. Clear, accurate labeling and renewed medical education are critical for empowering women and their clinicians to make informed choices, free from the shadow of outdated fears.

References

1. The 2024 FDA Menopause Roundtable. (2024, March 15). FDA.gov. https://www.fda.gov
2. Manson, J.E., et al. (2017). Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA, 318(10), 927–938.
3. Pinkerton, J.V., & Santoro, N. (2022). Menopausal hormone therapy and risk of cardiovascular disease: Current perspectives. Nature Reviews Cardiology, 19(6), 392–405.
4. Hodis, H.N., & Mack, W.J. (2022). Menopausal hormone therapy and mortality. Climacteric, 25(5), 409–415.
5. North American Menopause Society (NAMS). (2022). The 2022 Hormone Therapy Position Statement. Menopause, 29(7), 767–794.
6. FDA. FDA expert panel on menopause and hormone replacement therapy for women. Panel Discussion. July 17, 2025. Accessed July 18, 2025. https://www.youtube.com/live/_2ZRlOivC5M