Modern management of the menopause: Are we measuring what matters?

Introduction Vasomotor symptoms (VMS) and genitourinary symptoms are common over the menopause transition and may profoundly impact quality of life. To promote consistency and ensure research outcomes reflect what matters most to women with lived experience, the Core Outcomes in Menopause (COMMA) initiative developed core outcome sets (COS) for these symptoms (published 2021). Methods We explored uptake of these COS in three ways. First, we reviewed outcome reporting in historical randomised trials identified through existing systematic reviews. Second, we examine recently registered trials to see whether awareness of the COS is beginning to translate into practice. Finally, we consider how frontline treatments— menopause hormone therapy (MHT) for VMS and vaginal estrogen for genitourinary symptoms—have been evaluated against the two COS. Results Overall, alignment of outcome reporting against the COS was moderate and appears to have increased after publication of the COS. While reporting of the distress, bother or interference caused by these symptoms has historically been rare (2% of trials), 62% of registered clinical trials are now capturing this outcome. Common treatments for VMS and genitourinary symptoms, MHT and vaginal estrogen, have not been evaluated for all core outcomes, with treatment satisfaction and dysuria reported in only 9% of studies. Conclusion Despite strong endorsement and improvement in capture of symptom experience and impact, uptake of the full COMMA COS is limited. We call on the menopause research community to prioritise reporting of these outcomes that reflect people’s lived experience, so that future evidence is more meaningful, comparable, and patient-centred. Modern management of the menopause: Are we measuring what matters? Authors: Joscelyn Gan 1, Michelle Steeper 2, Tim Hillard 3, Monica Christmas 4, Jan Shifren 5, Nick Panay 6, Martha Hickey 2, Sarah Lensen 2 1. Melbourne Medical School, University of Melbourne, Melbourne, Australia 2. Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, Australia 3. Department of Obstetrics and Gynaecology, University Hospitals Dorset NHS Trust, Poole, Dorset, UK 4. Department of Obstetrics and Gynaecology, University of Chicago, Chicago, IL 5. Midlife Women’s Health Center, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 1 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 6. Queen Charlotte’s and Chelsea Hospital, Imperial College London, London, UK Corresponding author: Sarah Lensen (https://orcid.org/0000-0002-1694-1142) Funding statement: No financial support was received for the study reported in this publication Conflicts of interest: MC is Associate Medical Director of The Menopause Society. TH has received honoraria for speaking engagements and participation in advisory boards from Astellas and Besins. MH is funded by an Australian National Health and Medical Research Society Investigator Grant and by the Medical Research Future Fund of Australia. She is also funded by the Medical Research Council of the UK and has provided expert advice to NICE and the World Health Organisation. NP has lectured and acted in an advisory capacity for: Abbott, Astellas, Bayer, Besins, Gedeon Richter, Mithra, Novo Nordisk, SeCur, Theramex, and Viatris. JG, JS, MS and SL have nothing to declare. Ethics Approval Statement: Not applicable Patient Consent Statement: Not applicable Data Availability Statement: The data that support the findings of this study are openly available in the attached supplementary files

Introduction Vasomotor symptoms (VMS) and genitourinary symptoms are common over the menopause transition and may profoundly impact quality of life. To promote consistency and ensure research outcomes reflect what matters most to women with lived experience, the Core Outcomes in Menopause (COMMA) initiative developed core outcome sets (COS) for these symptoms (published 2021).

We explored uptake of these COS in three ways. First, we reviewed outcome reporting in historical ran- domised trials identified through existing systematic reviews. Second, we examine recently registered trials to see whether awareness of the COS is beginning to translate into practice. Finally, we consider how frontline treatments—menopause hormone therapy (MHT) for VMS and vaginal estrogen for genitourinary symptoms—have been evaluated against the two COS.

Overall, alignment of outcome reporting against the COS was moderate and appears to have increased after publication of the COS. While reporting of the distress, bother or interference caused by these symptoms has historically been rare (2% of trials), 62% of registered clinical trials are now capturing this outcome. Common treatments for VMS and genitourinary symptoms, MHT and vaginal estrogen, have not been evaluated for all core outcomes, with treatment satisfaction and dysuria reported in only 9% of studies.

Despite strong endorsement and improvement in capture of symptom experience and impact, uptake of the full COMMA COS is limited. We call on the menopause research community to prioritise reporting of these outcomes that reflect people’s lived experience, so that future evidence is more meaningful, comparable, and patient-centred.

Vasomotor symptoms (VMS), including hot flushes and night sweats, affect approximately 50 – 75% of women during the menopausal transition, and more than 50% of women experience genitourinary symptoms (1). Both VMS and genitourinary symptoms significantly impair quality of life (2, 3). 2 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. Systematic reviews have consistently demonstrated considerable heterogeneity in how clinical trials define and measure outcomes related to menopausal symptom management. This inconsistency hampers the conduct of robust meta-analyses and limits comparability across studies (4, 5). In response, the Core Outcomes in Menopause (COMMA) initiative convened an international collaboration of 227 clinicians, researchers, and people with lived experience to develop standardised, patient-centred core outcome sets (COS) for VMS and genitourinary symptoms (Table 1, 2) (6, 7). The list of COMMA core outcomes was published in 2021 (6, 7), and the recommended measurement instruments were published in 2024 (8, 9). These COS are intended to improve consistency and comparability across trials while ensur- ing that the outcomes assessed reflect those of greatest relevance to individuals experiencing menopausal symptoms. With the exception of side-effects, all selected core outcomes are patient reported – reported directly by the individual without interpretation by clinicians or others (10). This reflects the strong views of people with lived experience, researchers and clinicians that outcomes should be measured in ways that are meaningful to people and reflect their lived experience, rather than objective or biological measures that may or may not correlate with symptom experience. Where validated instruments are available, COMMA also recommends specific patient-reported outcome measures (PROMs) for each outcome (Table 1, 2) (8, 9). These COMMA COS are recognized and endorsed by National of Health and Care Excellence (NICE) (11), the Agency for Healthcare Research and Quality (AHRQ) (12), and more than 50 women’s health journals within the CROWN (CoRe Outcomes in WomeN’s health) initiative (13). The COMMA COS represent the outcomes that matter the most. In this manuscript we assess how well relevant trials have measured these core outcomes, both before and after the introduction of COMMA COS. We also assess two front-line treatments for these symptoms, MHT and vaginal estrogen, for how well they have been evaluated against these critical outcomes. Adherence of existing trials to the COMMA COS We drew on existing systematic reviews of randomised controlled trials evaluating treatments for VMS and genitourinary symptoms, undertaken during the development of these COS, to assess the extent to which outcome reporting in previous trials aligned with the respective COMMA COS domains (4-8). The COMMA core outcomes were published in 2021. This assessment examined whether these outcomes were already being reported in randomised trials conducted prior to 2021 (search dates of the two systematic reviews were May and December 2018). Trials were assessed for reporting of each core outcome with attention to whether these outcomes were explicitly listed as patient-reported and whether they used the COMMA-recommended PROM tools (Table 1, 2). Notably, the systematic review of VMS trials included only the primary trial outcomes, which limits comparability of these data with outcomes from more recently registered trials. Overall, existing trials have poor to moderate compliance with the COMMA COS, and there is marked variation across core outcomes (1% to 72% reporting) (Table 1, 2; Figure 1, 2). Among trials of treatments for genitourinary symptoms, most (72%) trials reported vulvovaginal dryness, compared to only 2% measuring distress, bother or interference of these symptoms. None of the trials utilised the endorsed PROMs (Day- to-Day Impact of Vaginal Aging (DIVA)(14), PROMIS ® Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity) (15) (Table 2). Vulvovaginal dryness is the only outcome that could be measured using either patient- or clinician-reported measures. Of the 78 studies evaluating vulvovaginal dryness, 9 (11.5%) utilised patient-reported outcome measures only, 11 (14.1%) used clinician-reported tools only, whilst 58 (74.4%) incorporated both types of assessments. Does the future look brighter? Adherence of new clinical trials To evaluate implementation of the COMMA COS in research conducted after its publication, we searched the International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for trials of interventions 3 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. for VMS or genitourinary symptoms registered between January 1, 2023, and May 15, 2025 (search strategy: Supplementary File 1; data: Supplementary File 2, 3). Among 49 VMS and 59 genitourinary symptom trials, reporting of COMMA core outcomes has increased since publication of the COS (2021), particularly for distress, bother, or interference, which were captured in 61% and 34% of registered trials compared with only 2% of historical trials (Table 1, 2; Figure 1, 2). How well have front-line treatments been assessed against outcomes that matter? In addition to assessing overall compliance of trials with the COMMA COS, we examined the extent to which existing first-line treatments for these symptoms have been evaluated against the COS domains. We identified trials from existing systematic reviews of menopause hormone therapy (MHT) for VMS and vaginal estrogen for genitourinary symptoms (data: Supplementary File 4, 5) (16-18). Among 35 trials evaluating MHT for VMS in postmenopausal women, most reported outcomes on VMS frequency (97%) and severity (94%) as well as side effects (83%); however, only one trial assessed the impact of MHT on distress, bother, or interference associated with VMS (Table 1, Figure 3). Among 49 trials investigating vaginal estrogen for genitourinary symptoms, most reported vulvovaginal dryness (70%) and side effects (83%) while only 9% reported discomfort or pain when urinating or satisfaction with treatment (Table 2, Figure 4).

The COMMA COS for VMS and genitourinary symptoms aim to address the observed heterogeneity in outcome reporting by promoting the use of patient-centred measures that reflect the priorities of people with lived experience of these symptoms (6-9). Our findings show a clear improvement in alignment with the COS over time, with newly registered trials de- monstrating substantially greater adherence than previously published studies. Notably, key patient-reported domains including impact on sleep, and distress, bother, or interference of symptoms demonstrate a major improvement in reporting. This likely reflects a global shift in recognition of the importance of symptom experience and impact over objective clinical and laboratory-based measures which provide biological infor- mation but may not correlate with how people actually experience their symptoms. Despite this, few trials plan to use the COMMA-recommended PROMs to capture these outcomes (e.g., The Hot Flash Related Daily Interference Scale (HFRDIS), DIVA, or the PROMIS Vaginal Discomfort with Sexual Activity). Despite promising focus on patient-centred outcomes, compliance with the full COS remains limited with poor capture of specific outcomes such as satisfaction with treatment. MHT and vaginal estrogen, the most common treatments for VMS and genitourinary symptoms, have seldom been assessed for core outcomes such as treatment satisfaction or the distress, bother, and interference caused by symptoms. Evidence on these patient-centred domains remains limited, leaving major gaps in understanding how well these therapies address the real-world impact of menopause on daily life. While somewhat disappointing, these findings are similar to COS uptake in other areas of women’s health including infertility (19) and polycystic ovarian syndrome (20), and uptake may be slow and steady as was observed for the COS in rheumatoid arthritis (21). Promisingly, more recent trials evaluating neurokinin 3 receptor antagonists for VMS show higher uptake of the COS, with the exception of ‘satisfaction with treatment’ (22, 23). The COMMA COS were identified through rigorous consensus methods and prioritised as critical by clini- cians, researchers, and—most importantly— people with lived experience. Failure to consistently measure and report them risks perpetuating the same heterogeneity and evidence gaps that the COS was designed to address. Regulatory guidance, particularly from the United States Food and Drug Administration (FDA), strongly shapes outcome reporting in genitourinary trials (24). Many trials captured the Vaginal Maturation Index (VMI) and Vaginal pH, both outlined in FDA draft guidance for assessing vulvovaginal atrophy (24).Yet, neither of these nor any other clinician or laboratory-based measure was considered of sufficient importance 4 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. by stakeholders in the COMMA process. ‘Change in the most bothersome symptom’ is also recommended by the FDA. Despite the FDA’s own guidance on selection of appropriate and validated PROMs (25), it is unclear how this outcome construct was developed, whether people with lived experience were involved, and no validated PROM currently exists to measure this construct. The continued reliance on clinician- and laboratory-reported outcomes, coupled with incomplete uptake of the COS, represents a missed opportunity to capture what people with lived experience consistently identify as most important—their symptom experience and its impact. Despite widespread awareness and endorsement of these COS by organisations such as NICE, AHRQ, and the CROWN initiative, uptake remains only moderate. As one approach to address this, we are initiating a prospective project to notify newly registered clinical trials of the COS and their current level of compliance, with the aim of reaching investigators early in the trial lifecycle, when outcome selection may still be modified to incorporate the COS (26). We call on the menopause research community to champion these COS—through their research, clinical practice, and leadership roles—to ensure future trials deliver evidence that truly reflects the outcomes that matter most to people with lived experience (Box 1). Disclosure of interests MC is Associate Medical Director of The Menopause Society. TH has received honoraria for speaking en- gagements and participation in advisory boards from Astellas and Besins. MH is funded by an Australian National Health and Medical Research Society Investigator Grant and by the Medical Research Future Fund of Australia. She is also funded by the Medical Research Council of the UK and has provided expert advice to NICE and the World Health Organisation. NP has lectured and acted in an advisory capacity for: Abbott, Astellas, Bayer, Besins, Gedeon Richter, Mithra, Novo Nordisk, SeCur, Theramex, and Viatris. JG, JS, MS and SL have nothing to declare.

1. Crandall CJ, Mehta JM, Manson JE. Management of Menopausal Symptoms: A Review. JAMA. 2023;329(5):405–20. 2. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assess- ment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009;62(2):153–9. 3. Nappi RE, Siddiqui E, Todorova L, Rea C, Gemmen E, Schultz NM. Prevalence and quality-of-life burden of vasomotor symptoms associated with menopause: A European cross-sectional survey. Maturitas. 2023;167:66– 74. 4. Christmas MM, Song B, Bell RJ, Iliodromiti S, Mitchell C, Hickey M. Variation in outcome reporting and measurement tools in clinical trials of treatments for genitourinary symptoms in peri- and postmenopausal women: a systematic review. Menopause. 2020;27(9). 5. Iliodromiti S, Wang W, Lumsden MA, Hunter MS, Bell R, Mishra G, et al. Variation in menopausal vasomotor symptoms outcomes in clinical trials: a systematic review. BJOG: An International Journal of Obstetrics & Gynaecology. 2020;127(3):320–33. 6. Lensen S, Archer D, Bell RJ, Carpenter JS, Christmas M, Davis SR, et al. A core outcome set for vaso- motor symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative. Menopause. 2021;28(8). 7. Lensen S, Bell RJ, Carpenter JS, Christmas M, Davis SR, Giblin K, et al. A core outcome set for genitourinary symptoms associated with menopause: the COMMA (Core Outcomes in Menopause) global initiative. Menopause. 2021;28(8). 8. Lensen S, Paramanandam VS, Gabes M, Kann G, Donhauser T, Waters NF, et al. Recommended mea- surement instruments for menopausal vasomotor symptoms: the COMMA (Core Outcomes in Menopause) 5 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. consortium. Menopause. 2024;31(7). 9. Paramanandam VS, Lensen S, Gabes M, Kann G, Donhauser T, Waters NF, et al. Recommended measu- rement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium. Menopause. 2024;31(7). 10. Powers JH, III, Patrick DL, Walton MK, Marquis P, Cano S, Hobart J, et al. Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force. Value in Health. 2017;20(1):2–14. 11. National Institute for Health and Care Excellence (NICE). NICE guideline Menopause: Identification and Management. NICE guideline.; 2024 12. Agency for Healthcare Research and Quality (AHRQ). Evidence-based Practice Center Sys- tematic Review Protocol - Improving the Management of Menopausal Symptoms in Peri- menopausal and Early Postmenopausal Women: A Systematic Review 2025 [Available from: https://effectivehealthcare.ahrq.gov/products/menopausal-symptoms/protocol. 13. Khan K. The CROWN Initiative: Journal editors invite researchers to develop core outcomes in women’s health. Best Practice & Research Clinical Obstetrics & Gynaecology. 2019;57:e1–e4. 14. Huang AJ, Gregorich SE, Kuppermann M, Nakagawa S, Van Den Eeden SK, Brown JS, et al. Day-to-Day Impact of Vaginal Aging questionnaire: a multidimensional measure of the impact of vaginal symptoms on functioning and well-being in postmenopausal women. Menopause. 2015;22(2). 15. Weinfurt KP, Lin L, Bruner DW, Cyranowski JM, Dombeck CB, Hahn EA, et al. Development and Initial Validation of the PROMIS® Sexual Function and Satisfaction Measures Version 2.0. The Journal of Sexual Medicine. 2015;12(9):1961–74. 16. Gaudard A, Silva de Souza S, Puga MES, Marjoribanks J, da Silva EMK, Torloni MR. Bioidentical hormones for women with vasomotor symptoms. Cochrane Database of Systematic Reviews. 2016(8). 17. Tang Y, Ma R, Zhang L, Sun X, Wang Y. Effectiveness and safety of hormone replacement therapy in the treatment of menopausal syndrome: a meta-analysis. Am J Transl Res. 2025;17(1):1–15. 18. Agency for Healthcare Research and Quality (AHRQ). Improving the Management of Menopausal Sym- ptoms in Perimenopausal and Early Postmenopausal Women: A Systematic Review (UNPUBLISHED). 2025. 19. Li W, Jia N, Chi H, Zhan S, Zeng L. Assessing the uptake of infertility core outcome set in IVF randomized controlled trials. Human Reproduction. 2025;40(1):85–95. 20. Li W, Li G, Chi H, Wang H, Zeng L. Uptake of the core outcome set on polycystic ovary syndrome before and after its publication. Human Reproduction. 2023;38(9):1816–24. 21. The OMERACT Handbook: For establishing and implementing core outcomes in clinical trials across the spectrum of rheumatologic conditions. 2021. Contract No.: 16 September. 22. Cardoso F, Parke S, Brennan Donal J, Briggs P, Donders G, Panay N, et al. Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer. New England Journal of Medicine. 2025;393(8):753– 63. 23. Johnson KA, Martin N, Nappi RE, Neal-Perry G, Shapiro M, Stute P, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. The Journal of Clinical Endocrinology & Metabolism. 2023;108(8):1981–97. 24. U.S. Food and Drug Administration. Estrogen and Estrogen/Progestin Drug Products to Treat Vaso- motor Symptoms and Vulvar and Vaginal Atrophy Symptoms — Recommendations for Clinical Evaluation. 2003. 6 Posted on 17 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176067563.37235043/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 25. U.S. Food and Drug Administration. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims 2009. 26. Susanto N. COMMA ASSESS: Assessing the Uptake of the COMMA Recommendations in Clinical Trials Investigating Vasomotor Symptoms and Genitourinary Symptoms. OSF. 2025. DOI 10.17605/OSF.IO/75NRF Supplementary file 1 Search Strategy: For VMS trials, search terms included combinations of: (”vasomotor symptoms” OR ”hot flushes” OR ”hot flashes” OR ”night sweats”) AND (”menopause” OR ”menopausal”). For GSM trials, search terms included combinations of: (”genitourinary syndrome of menopause” OR ”vulvovaginal atrophy” OR ”vaginal dryness” OR ”dyspareunia” OR ”vaginal discomfort” OR ”urogenital atrophy”) AND (”menopause” OR ”menopausal”). Supplementary file 2 Table S2. Clinical trials assessing interventions to treat vasomotor symptoms (registered between January 1, 2023, and May 15, 2025) Supplementary file 3 Table S3. Clinical trials assessing interventions to treat genitourinary symptoms (registered between January 1, 2023, and May 15, 2025) Supplementary file 4 Table S4. Included study from existing systematic reviews of vaginal estrogen for genitourinary symptoms Supplementary file 5 Table S5. Included study from existing systematic reviews of menopause hormone therapy (MHT) for vaso- motor symptoms Hosted file COMMA_BJOG_tablesfigs_251007.docx available at https://authorea.com/users/980949/articles/ 1347116-modern-management-of-the-menopause-are-we-measuring-what-matters 7