May 13, 2026
AHRQ- Draft Comment Form for Improving the Management of Menopausal Symptoms in Perimenopausal and Early Postmenopausal Women: A Systematic Review
Introduction comments: We disagree with the decision to omit most of the Women’s Health Initiative (WHI) findings. While we acknowledge the limitations of data based on a sample with a mean age of 63 years. The WHI studies are still important as the most comprehensive sources of long-term randomized evidence regarding hormone therapy-associated risks, including stroke, cardiovascular disease, venous thromboembolism, breast cancer, ovarian cancer, and dementia. The trial included more than 8,000 women in their 50s, making it one of the largest randomized hormone therapy studies conducted in this age group. Although hormonal treatments have changed since the WHI was started, the WHI results showing increased risks and lack of benefits that had directly contradicted observational and self-reported clinician-driven data based on those same hormonal treatments have important implications for more recent studies that are also based on observational and self-reported data. The WHI’s randomized clinical trial design provided substantially stronger evidence regarding long-term safety outcomes and challenged assumptions derived from observational studies, particularly regarding cardiovascular disease prevention. Those findings are still important today. The research protocol should acknowledge that important questions remain about whether younger women experience different levels of risk from hormone therapy when discussing the overall risks and benefits of long-term systemic hormone therapy.
Research clearly suggests important differences between local vaginal estrogen therapies and systemic menopausal hormone therapy (MHT), and these therapies should not be discussed as interchangeable with respect to risks, benefits, or long-term safety evidence. Randomized trials and observational studies have demonstrated increased risks of stroke, venous thromboembolism, breast cancer, and probable dementia associated with systemic hormone therapy in some populations. In contrast, available evidence suggests that low-dose vaginal estrogen therapies may have lower systemic absorption and potentially different risk profiles. It is important to note, however, that studies of vaginal estrogen lack information about the frequency of use per year or the number of years it was used at the time that data were collected regarding the women’s health outcomes. In addition, long-term data are unavailable/inadequate for women at elevated risk for breast cancer or cardiovascular disease (National Center for Health Research, Hormone Therapy and Menopause: Facts and Fiction). The protocol should therefore more clearly distinguish systemic hormone therapy from local vaginal estrogen therapies when discussing comparative effectiveness and long-term safety outcomes. The protocol should also more clearly distinguish FDA-approved hormone products from compounded “bioidentical” hormone therapies, which do not undergo the same review for safety, effectiveness, quality, or dosing consistency.
We recommend that the discussion of nonhormonal therapies include additional context regarding limitations in effectiveness, safety concerns, and controversies surrounding some FDA-approved products marketed for menopausal symptoms. For example, low-dose paroxetine mesylate 7.5 mg (Brisdelle), a popular antidepressant (Paxil) with well-established risks, was approved for vasomotor symptoms despite relatively modest reductions in hot flash frequency compared with placebo in Phase 2 and Phase 3 randomized trials for menopausal vasomotor symptoms (Simon et al., 2013). FDA review documents noted substantial placebo responses across trials, a limited magnitude of treatment benefit, and concerns regarding the overall clinical significance of observed improvements. The FDA review also discussed antidepressant-related adverse effects and class warnings, including suicidal ideation warnings, substantial rebounding difficulties upon discontinuation, drug interactions, serotonin syndrome risk, and CYP2D6 inhibition that may interfere with tamoxifen metabolism (FDA Center for Drug Evaluation and Research, 2013). The FDA advisory committee voted against approval because of concerns regarding the magnitude of benefit relative to risks and adverse effects, and although the FDA usually agrees with its Advisory Committee, the FDA approved the product anyway.
Similarly, research on newer nonhormonal therapies such as fezolinetant (Veozah), a neurokinin 3 receptor antagonist approved for moderate-to-severe vasomotor symptoms, also raises important questions regarding long-term safety and real-world benefits. Phase 3 trials demonstrated major reductions in daily hot flash frequency in the placebo group, and a small but statistically significant additional reduction in hot flash frequency and severity in the Veozah group compared with placebo. The investigators noted that further research is needed regarding effects on mood, sleep, sexual well-being, and broader quality-of-life outcomes (Lederman et al., 2023). A review published in 2024 emphasized the need for additional prospective research evaluating long-term efficacy, recurrence rates, cardiovascular safety, and use in patients with comorbidities or hormone-sensitive cancers (Rani et al., 2024). That same year, the FDA added a Boxed Warning regarding a rare but serious hepatotoxicity associated with fezolinetant and now recommends baseline and serial liver function monitoring during treatment (FDA Drug Safety Communication, 2024).
The research protocol should also acknowledge that many women use behavioral and lifestyle approaches for symptom management. For example, Kaiser Permanente guidance emphasizes that lifestyle changes such as eating more plant-based foods, engaging in regular physical activity (including walking and strengthening exercises), adequate restful sleep, practicing stress reduction, and connecting with supportive communities may help reduce menopausal symptoms, particularly mood changes, stress, weight gain, and difficulties with memory or concentration. It also recommends practical symptom-management strategies such as avoiding triggers such as caffeine, alcohol, spicy foods, and hot beverages; dressing in layers; lowering room temperature; using fans; and practicing relaxation and stress reduction techniques to help manage hot flashes and night sweats. They also recommend keeping a lighter blanket or a change of clothes nearby and adjusting the room temperature as needed (Kaiser Permanente).
Methods section comments: Several methodological choices raise serious concerns. Most notably, the research protocol applies publication date restrictions that appear to be specifically aimed at limiting or excluding foundational evidence from the Women’s Health Initiative (WHI), without adequately providing clear methodological justifications for those decisions. As noted earlier, we strongly disagree with those varying decisions to restrict inclusion to studies published after 2002, 2009, or 2014, and believe it weakens the final evidence review for the workshop because the WHI is central to the questions that still need to be answered regarding long-term hormone therapy risks and benefits, regarding cardiovascular disease, stroke, venous thromboembolism, breast cancer, dementia, and other long-term safety outcomes associated with systemic hormone therapy.
We note that the research protocol emphasizes limited evidence regarding harms in perimenopausal and early postmenopausal women while minimizing or excluding the largest federally funded randomized hormone therapy trials ever conducted, including thousands of women in their 50s. Even acknowledging population differences, WHI remains one of the most rigorous and informative sources of long-term safety data available. Excluding or minimizing these data risks creates an incomplete and potentially misleading evidence review, and raises questions about the possible interference of former Commissioner Makary and other officials.
Given the continuing controversies and unanswered questions about the risks and benefits of hormonal therapy for menopause, the methods should more clearly explain how conflicting findings from randomized clinical trials, observational studies, clinician experience, and self-reported data will be interpreted and weighted, particularly for long-term outcomes.
Additionally, several tables and analytic frameworks are difficult to interpret and would benefit from substantial simplification and clarification. In their current form, some tables appear overly dense, schematic, and insufficiently reader-friendly, making it difficult to understand how studies and outcomes will ultimately be categorized and synthesized.
Discussion and conclusion comments: The final review informing the ‘NIH Pathways to Prevention Workshop on Improving the Management of Menopausal Symptoms’ should be revised to avoid broad or generalized statements regarding the safety of menopausal hormone therapy, particularly given important differences across formulations, routes of administration, dosing, duration of use, timing of initiation, and patient populations. The final review should emphasize individualized, patient-centered care and be revised to avoid overstating the safety, effectiveness, or long-term benefits of either hormonal or nonhormonal therapies where evidence remains limited, inconsistent, or conflicting. The final review should also more clearly acknowledge the limitations of the current evidence base, particularly regarding long-term safety outcomes in younger symptomatic women, and should transparently address areas where randomized trial data and observational or self-reported findings differ. In addition, the discussion should acknowledge the real-world challenges many patients face in accessing balanced counseling, evidence-based care, and clear communication regarding the risks, benefits, and uncertainties associated with menopause treatments.
Does this report describe both the problem and the evidence in a way that you could understand? The narrative text is understandable, but the conclusions are misleading because of the lack of transparency and scrutiny regarding the interpretation and weighting of long-term safety evidence, including WHI findings. In addition, several tables and analytic frameworks are difficult to interpret and would benefit from simplification and clearer presentation.
Could you find and understand the results and conclusions? As this is a research protocol rather than a final review, complete results and conclusions are not yet available. However, the proposed methods and evidence framework requires additional clarification regarding study inclusion criteria, interpretation of conflicting evidence, and handling of long-term safety outcomes.
References:
- National Center for Health Research, Hormone Therapy and Menopause: Facts and Fiction https://www.center4research.org/hormone-therapy-and-menopause-facts-and-fiction/
- https://www.center4research.org/nchr-fda-comment-hormones-for-menopause/
- https://www.center4research.org/brisdelle-paxil-hot-flashes-not-great-idea/
- https://www.center4research.org/fda-hot-flashes-veozah-menopause/
- Simon, J. A., Portman, D. J., Kaunitz, A. M., Mekonnen, H., Kazempour, K., Bhaskar, S., & Lippman, J. (2013). Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause (New York, N.Y.), 20(10), 1027–1035. https://doi.org/10.1097/GME.0b013e3182a66aa7
- FDA Center for Drug Evaluation and Research, 2013: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204516Orig1s000CrossR.pdf
- Lederman, S., Ottery, F. D., Cano, A., Santoro, N., Shapiro, M., Stute, P., … & Neal-Perry, G. (2023). Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. The Lancet, 401(10382), 1091-1102.
- Rani, P., Zehra, D., Mansoor, M., & Rani, P. (2024). FDA approved fezolinetant (Veozah): a critical evaluation of its efficacy and safety for menopausal vasomotor symptoms, calling for prospective research. Archives of women’s mental health, 27(6), 943–946. https://doi.org/10.1007/s00737-024-01456-y
- https://www.fda.gov/safety/medical-product-safety-information/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due
- Kaiser Permanente: Lifestyle, Mind-Body, and Complementary Care for Menopausal Symptoms
https://mydoctor.kaiserpermanente.org/ncal/structured-content/lifestyle-mind-body-and-complementary-care-for-menopausal-symptoms-2209783/overview