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Importance and Objectives: Sleep disturbance is one of the most common and debilitating symptoms experienced by women during the menopause transition. However, there are currently no therapies specifically approved for sleep disturbance associated with the menopause. Here, we consider how to characterize sleep disturbance associated with the menopause and discuss its etiology, including the latest advances in our understanding of the neuronal circuits that regulate reproduction, body temperature, sleep, and mood; and reflect on its impact on women's health and well-being. We also examine the current treatment landscape and look to the future of treatment for this condition., Methods: We conducted a review of the literature and combined this with discussion with experts in the fields of sleep and menopause as well as experiences from our own clinical practices., Discussion and Conclusions: Sleep disturbance associated with the menopause is characterized by frequent night-time awakenings and increased awake time after sleep onset. Its impacts are wide-ranging, negatively affecting health as well as personal and social relationships, productivity, and work performance. There is currently an unmet need for effective, safe, and well-tolerated treatments to address this important symptom, and wider recognition of the association between sleep disturbances and the menopause is needed. Sleep disturbances associated with the menopause can result from hormone changes as well as vasomotor and mood symptoms. Growing research has contributed to our knowledge of the role of hypothalamic estrogen-sensitive kisspeptin/neurokinin B/dynorphin neurons. These neurons are thought to integrate the gonadotropin-releasing hormone pathway and the pathways responsible for the homeostatic control of body temperature and the circadian regulation of sleep-wake cycles. Understanding these neurons offers the potential to create treatments that target a key cause of sleep disturbance associated with the menopause. Further research to understand their etiology and characterize the neuronal circuits responsible could benefit the development of these targeted treatment approaches., Competing Interests: Financial disclosure/conflicts of interest: Pauline Maki has received compensation as a member of the scientific advisory board of Astellas, Bayer, and Johnson & Johnson. She has received compensation from Pfizer for consulting. She serves as a member of the scientific advisory board and has/had equity in Alloy, Estrigenix, and MidiHealth. She has received speaking fees and travel support from Mithra. All her research is supported by the NIH. Nick Panay has undertaken speaker's bureau work for: Abbott, Bayer, Besins, Gedeon Richter, Kora, Meda, MSD, Mylan, Novo Nordisk, SeCur, Shionogi, Theramex, and Viatris and participated in advisory committees for: Abbott, Astellas, Bayer, Besins, Gedeon Richter, LivBio, Meda, Mithra, MSD, Mylan, Novo Nordisk, Kora, SeCur, Serelys, Shionogi, and Viatris. James A. Simon has received grant/research support: AbbVie, Inc, Bayer Healthcare LLC., Dare´ Bioscience, Ipsen, Mylan/Viatris Inc, Myovant Sciences, and Sebela Pharmaceuticals Inc, participated as a consultant or in advisory boards for: Bayer HealthCare Pharmaceuticals Inc, Besins Healthcare, Biote Medical, LLC, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc, Khyria, Madorra Pty Ltd., Mayne Pharma, Inc, Pfizer Inc, and Vella Bioscience Inc, has undertaken speaker's bureau work for: Astellas Pharma, Inc, Mayne Pharma, Inc, Myovant Sciences, Inc, Pfizer Inc, Pharmavite LLC., and Scynexis Inc, and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Objective: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects., Methods: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome., Results: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice., Conclusions: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes., Competing Interests: Financial disclosure/conflicts of interest: M.G. received past funding from Effik SA. M.P. received institutional funding from University of Melbourne (Internal Grant Schemes), Royal Women's Hospital (Internal grant scheme), and Cancer Council NSW Project Grant RG 21-06, Centre for Research Excellence in Women's Health in Reproductive Life (CREWHiRL) Seed Funding and Project Support Grant, NHMRC (APP1163202), and Royal Children's Hospital Foundation. She received past funding from FertilityIQ webinar honorarium. She has received fee registration fees as an invited speaker by the Pacific Society of Reproductive Medicine 2023 Conference and had subsidized flights and accommodations as an invited speaker for the European Society of Human Reproduction and Embryology 2022 Conference. She was also given free registration as an invited speaker for the Annual Scientific Meeting of Breast Cancer Trials 2021. D.A. has consulted for Evestra, Exeltis, Lupin, Mithra, ObsEva, and TherapeuticsMD, received industry support for research from AbbVie, Mithra, Myovant, and ObsEva, and has stock holdings in Agile Therapeutics and InnovaGyn, Inc. R.B. was named CI on two grants to Monash University, one from the National Health and Medical Research Council of Australia and one from the Medical Research Future Fund for work not related to the current publication. M.C. has been paid for developing and delivering educational presentations for AllianceChicago, wrote a White Paper on GSM for Materna (no financial reimbursement), and is a member of The Menopause Society Board of Trustees, FDA BRUDAC Committee, and Grand Rounds Presenter University of Indians. S.R.D. reports honoraria from BesinsHealthcare, Mayne Pharma, Health Ed, BioSyent, Lawley Pharmaceuticals, Abbott Laboratories, and Que Oncology. She has served on advisory boards for Mayne Pharm, Astellas Pharmaceuticals, Theramex, Abbott Laboratories, and Gedeon Richterand and has been an institutional investigator for QueOncology and Ovoca Bio. L.K. has lectured and/or acted in an advisory capacity for Gedeon Richter, Dr. KADE Besins and Mithra. C.M.M. has served as a consultant for Scynexis and Ferring Pharmaceuticals, receives research funding from Scynexis, and receives Royalties from UpToDate. R.E.N. has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Shionogi Limited, Theramex, and Viatris. N.P. has lectured and/or acted in an advisory capacity for Abbott, Bayer, Besins, Gedeon Richter, Kora, Lawley, Mithra, Mylan, Novo Nordisk, Roche Diagnostics, SeCur, Shionogi, Theramex, and Viatris. S.R. has lectured and/or acted in an advisory capacity or conducted studies for Abbott, Bayer, Gedeon Richter, Mylan, Amgen, UCB, Theramex, and Viatris. J.S. receives grant/research support from AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience, Ipsen, Mylan/Viatris Inc., Myovant Sciences, and Sebela Pharmaceuticals Inc. He acts as a consultant is on advisory boards for Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., and Vella Bioscience Inc. He serves on speaker's bureaus for Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., and Scynexis Inc. He is a stockholder (direct purchase) of Sermonix Pharmaceuticals. P.S. has received fees for giving educational presentations, and participating in advisory boards and conducting research by Besins Healthcare, Astellas, Mylan, Labatec, Exeltis, Effik, Theramex, and Gedeon-Richter. A.J.V. has received fees for presentations and participation in an advisory board from Besins and Theramex. W.W. has received institutional support with an unrestricted grant from Pfizer and sits on the advisory boards of Pfizer, Lupin, and Biosyent. She has received fees for educational presentations for Lupin, Astellas, Bayer and Pfizer, and Biosyent. She is currently president of the Canadian Menopause Society and a Board Member of the International Menopause Society. M.H. has received funding from Madorra for a study of a device to manage GU symptoms. All other authors report no conflicts of interest., (Copyright © 2024 by The Menopause Society.)

Objective: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects., Methods: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome., Results: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice., Conclusions: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes., Competing Interests: Financial disclosure/conflicts of interest: V.P. received past funding from Sigvaris AG. M.P. received institutional funding from University of Melbourne (Internal Grant Schemes), Royal Women's Hospital (Internal grant scheme), and Cancer Council NSW Project Grant RG 21-06, Centre for Research Excellence in Women's Health in Reproductive Life (CREWHiRL) Seed Funding and Project Support Grant, NHMRC (APP1163202), and Royal Children's Hospital Foundation. She received past funding from FertilityIQ webinar honorarium. She has received fee registration fees as an invited speaker by the Pacific Society of Reproductive Medicine 2023 Conference and had subsidized flights and accommodations as an invited speaker for the European Society of Human Reproduction and Embryology 2022 Conference. She was also given free registration as an invited speaker for the Annual Scientific Meeting of Breast Cancer Trials 2021. D.A. has consulted for Evestra, Exeltis, Lupin, Mithra, ObsEva, and TherapeuticsMD, received industry support for research from AbbVie, Mithra, Myovant, and ObsEva, and has stock holdings in Agile Therapeutics, InnovaGyn, Inc. N.A. receives ongoing institutional funding from the National Cancer Institute. J.C. is owner of JSCarpenter, LLC which received scale licensing fees from Mapi Research Trust (2022), consulting fees from the University of Wisconsin (spring 2022), and consulting fees from Simumetrix SMX Health (spring 2022). M.C. has been paid for developing and delivering educational presentations for Alliance Chicago, received fees for an educational video and speaking engagements with Fertility IQ, wrote a White Paper on GSM for Materna (no financial reimbursement), and is a member of The Menopause Society Board of Trustees. M.D. receives current institutional funding from National Institute of Health Research. She serves as a chief investigator on POISE study (research relevant to HRT) and a chief investigator for BLUSH study (research on treatment of menopause). She received past institutional funding from Best Practice & Research Clinical Obstetrics & Gynaecology as editor of volume on menopause management published 2022. She is an elected member of the Medical Advisory Council of the British Menopause Society, is a member of the ESHRE guideline update group on Premature Ovarian Insufficiency, is a member of the British Endocrine Society working group producing clinical guidelines on estrogen treatment, and is a member of the British Gynaecological Cancer Society working group producing clinical guidelines on HRT. T.H. received past funding from Besins and Astellas. M.H. receives ongoing funding from Rightsteps and current funding from Hello Therapeutics. L.K. has lectured and/or acted in an advisory capacity for Gedeon Richter, Dr. KADE Besins and Mithra. P.M. has received compensation as a member of the scientific advisory board of Astellas, Bayer, and Johnson & Johnson; compensation from AbbVie and Pfizer for consulting; and serves as a member of the scientific advisory board and has/had equity in Alloy, Estrigenix, and MidiHealth. She has received speaking fees and travel support from Mithra. R.E.N. has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Shionogi Limited, Theramex, and Viatris. N.P. has lectured and/or acted in an advisory capacity for Abbott, Lawley, Mithra, Novo, SeCur, and Viatris. S.R. has lectured and/or acted in an advisory capacity or conducted studies for Abbott, Bayer, Gedeon Richter, Mylan, Amgen, UCB, Theramex, and Viatris. J.S. receives grant/research support from AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience; Ipsen, Mylan/Viatris Inc., Myovant Sciences, Sebela Pharmaceuticals Inc. He acts as a consultant is on advisory boards for Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., and Vella Bioscience Inc. He serves on speaker's bureaus for Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., Scynexis Inc. He is a stockholder (direct purchase) of Sermonix Pharmaceuticals. P.S. has received fees for giving educational presentations, participating in advisory boards and conducting research by Besins Healthcare, Astellas, Mylan, Labatec, Exeltis, Effik, Theramex, and Gedeon-Richter. A.J.V. has received fees for presentations and participation in an advisory board from Besins and Theramex. W.W. has received institutional support with an unrestricted grant from Pfizer and sits on the advisory boards of Pfizer, Lupin, and Biosyent. She has received fees for educational presentations for Lupin, Astellas, Bayer and Pfizer, and Biosyent. She is a board member of the International Menopause Society and the President of the Canadian Menopause Society. M.H. has received funding from Madorra for a study of a device to manage GU symptoms and is a clinical expert for the NICE Menopause Guidelines. J.T.G. is a speaker for NurtureMed Pharma, Bayer Phils, Corbridge Phils, and Zuellig Pharma. P.S. has a research consultancy relationship with Chugai Pharmaceuticals. H.J. receives grant funding from the National Institutes of Health, Merck, and Pfizer and is a consultant to Bayer, Merck, and Hello Therapeutics. She receives in kind support from Sage to her institution (drug provided to support NIH-funded trial), funds from Bayer support a pilot grant program she lead within an NIH-funded Center grant. Her spouse is employed by Arsenal Biosciences and receives equity from Merck Research Labs. N.J. is on the advisory board of Vira Health, UK. All other authors report no conflicts of interest., (Copyright © 2024 by The North American Menopause Society.)

Objective: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause., Methods: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test., Results: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred., Conclusions: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause., Competing Interests: Financial disclosures/conflicts of interest: R.K. has been a consultant for Astellas, Amgen (no longer active), Pfizer, and TherapeuticsMD (no longer active); has been on the advisory board for Astellas, Pfizer, and Pharmavite (no longer active); has been on speaker's bureau for Astellas, Pfizer, and TherapeuticsMD (no longer active); has been a medical advisor for Carrot Fertility and Lisa Health; and Data Monitoring Committee for Astellas. J.A.S. receives grant/research support from AbbVie, Bayer Healthcare, Daré Bioscience, Enteris BioPharma, ylan/Viatris, Myovant Sciences, ObsEva, Pfizer, Inc, and Viveve Medical; serves on consulting/advisory boards of Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies (CIIS), Daré Bioscience, DEKA M.E.L.A S.r.l., Femasys, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mitsubishi Tanabe Pharma Development America, Pfizer, Inc, QUE Oncology, Scynexis Inc, Sprout Pharmaceuticals, and Vella Bioscience; serves on speaker's bureaus of: Ascend Therapeutics, Astellas Pharma, Inc, Mayne Pharma, Myovant Sciences, Pfizer, Pharmavite, and Scynexis; is a stockholder (direct purchase) in Sermonix Pharmaceuticals. Dr. Goldstein was a consultant for Astellas, Bayer, Cook OB/GYN, Cooper Surgical, Mylan, and Pfizer. B.S.K. and S.N.J. are consultants for Sermonix. D.J.P. is an employee and stockholder of Sermonix; his spouse is also an employee and stockholder of Sermonix., (Copyright © 2024 by The Menopause Society.)

Importance: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA)., Objective: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe., Evidence Review: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses., Findings: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment., Conclusions and Relevance: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe., Competing Interests: Financial disclosure/conflicts of interest: C.B. is a partner at PeriPharm, Inc, and A.C. and C.R. are employees at PeriPharm, Inc, a company that has served as a consultant to Duchesnay, Inc, and has received funding from Duchesnay, Inc. A.F. and D.B. have served as consultants for Duchesnay, Inc. D.B. currently receives funding from AbbVie, Bayer, BioSyent, Duchesnay, Merck, Organon, Pfizer, and Searchlight. R.M. is an employee at Duchesnay, Inc. J.A.S. receives grant/research support from the following: AbbVie, Bayer Healthcare, Dare Bioscience, Enteris BioPharma, Mylan/Viatris, Myovant Sciences, ObsEva, and Viveve Medical; is on consulting/advisory boards of the following: Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies (CIIS), Dare Bioscience, DEKA M.E.L.A S.r.l., Duchesnay, Inc, Femasys, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mitsubishi Tanabe Pharma Development America, QUE Oncology, Scynexis, Inc, Sprout Pharmaceuticals, Vella Bioscience; serves on the speaker's bureaus of the following: Mayne Pharma, Myovant Sciences, Pfizer, Pharmavite, Scynexis, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life., Methods: Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life., Results: Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: -3.93 [SE, 1.02], P < 0.001; week 12: -2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (-2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated., Conclusions: Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS., Competing Interests: Financial disclosure/conflicts of interest: C.C. and L.Z. are employees of Bayer CC AG. C.S. is an employee of Bayer AG. M.K., S.P., E.B., S.S., and M.T. are employees of NeRRe Therapeutics. J.B., as an employee of Cytel Inc, was a paid statistical consultant on this trial. R.A.A. has undertaken consultancy work for NeRRe Therapeutics and Sojournix Inc. J.A.S. has grant/research support from AbbVie, Inc, Bayer Healthcare LLC, Daré Bioscience, Ipsen, Mylan/Viatris Inc, Myovant Sciences, ObsEva SA, Sebela Pharmaceuticals Inc, and Viveve Medical; has been a consultant/advisory boards of Bayer HealthCare Pharmaceuticals Inc, Besins Healthcare, California Institute of Integral Studies, Camargo Pharmaceutical Services, LLC, Covance Inc, Daré Bioscience, DEKA M.E.L.A. S.r.l., Femasys Inc, KaNDy/NeRRe Therapeutics Ltd, Khyria, Madorra Pty Ltd, Mitsubishi Tanabe Pharma Development America, Inc, QUE Oncology Pty, Limited, Scynexis Inc, Sebela Pharmaceuticals, Inc, Sprout Pharmaceuticals, Inc, and Vella Bioscience Inc; has served on the Speaker's bureaus of Mayne Pharma, Inc, Myovant Sciences, Inc, Pfizer Inc, Pharmavite LLC, Scynexis Inc, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals. N.P. has undertaken consultancy and speaker's bureau work for a number of pharmaceutical companies including Bayer AG. H.J. has received grant funding from National Institutes of Health, Merck, Pfizer, and Hello Therapeutics; has undertaken consultancy work for Bayer, Jazz, and Eisai; and her spouse is an employee at Arsenal Biosciences and has equity at Merck., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: To evaluate endometrial progesterone receptor (PGR) expression in menopausal women who used vaginal 4-μg and 10-μg estradiol (E2) inserts or placebo., Methods: REJOICE was a randomized, placebo-controlled trial investigating vaginal E2 inserts in women with moderate to severe dyspareunia due to menopause. In this post hoc analysis, 25 eligible women with endometrial biopsies were randomly selected from each treatment group (4-μg and 10-μg E2 vaginal inserts and placebo). Endometrial biopsy sections were immunostained using an anti-PR (A and B) monoclonal antibody. Cell staining was quantified using an artificial intelligence feature-recognition algorithm. Mean PGR expression levels were analyzed between baseline and week 12., Results: PGR expression results were available for 22 women in the 4-μg E2 group, and 25 women each for the 10-μg E2 and placebo groups. Similar PGR expression levels were observed at baseline (0.301-0.470 pmol/mg) and after 12 weeks of treatment (0.312-0.432 pmol/mg) for all treatment groups, with no significant differences between baseline and week 12., Conclusions: No meaningful differences in endometrial PGR expression were observed with the vaginal E2 (4- and 10-μg) inserts at week 12 from baseline, supporting the hypothesis that local exposure to E2 from a low-dose, vaginal insert placed near the vaginal introitus will not be sufficient to upregulate endometrial PGR expression. Coupled with the lack of histologic changes and systemic absorption, our data suggest that these softgel vaginal E2 inserts would not be expected to stimulate endometrial hyperplasia leading to a potential endometrial safety issue in postmenopausal women with moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy. Further study on the endometrial safety of softgel vaginal E2 inserts is under way., Competing Interests: Financial disclosure/conflicts of interest: J.A.S. (within the past year, or current) has grant/research support from: AbbVie, Inc., Bayer Healthcare LLC., Endoceutics, Inc., Ipsen, Myovant Sciences, ObsEva SA, TherapeuticsMD, Viveve Medical; has been a consultant/advisory boards of: Allergan, AbbVie, Inc., AMAG Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals Inc., Camargo Pharmaceutical Services, LLC, CEEK Enterprises, LLC., Covance Inc., Dare’ Bioscience, Duchesnay USA, Hologic Inc., KaNDy/NeRRe Therapeutics Ltd., Madorra Pty Ltd., Mitsubishi Tanabe Pharma Development America, Inc., Sebela Pharmaceuticals Inc., Shionogi Inc., Sprout2 Inc., TherapeuticsMD; has served on the Speaker's bureaus of: AMAG Pharmaceuticals, Inc., Duchesnay USA, TherapeuticsMD; and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals. J.H.L. consults for Allergan, AMAG, Bayer Healthcare, Daré, Ferring, Lupin, Mitsubishi-Tanabe, Sebela, and TherapeuticsMD and has received research support for clinical trials (paid to UH Cleveland Medical Center) from AbbVie, Allergan, Bayer Healthcare, Femasys, Ferring, and Palatin Technologies. D.F.A. has served as a consultant to AbbVie, Agile Therapeutics, Bayer Healthcare, Endoceutics, Evestra, Exeltis, InnovaGyn, Lupin, Mithra, OvsEva and TherapeuticsMD; and has received research support from Actavis, Bayer Healthcare, Endoceutics, Mithra, Myovant, ObsEva and TherapeuticsMD. He has stock in InnovaGyn and stock options from Agile Therapeutics. B.K. has served as a consultant for TherapeuticsMD and Sermonix. B.B., S.G., and S.M. are employees of TherapeuticsMD with stock/stock options. P.D.C. has nothing to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Objective: Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause., Methods: We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings., Results: A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment., Conclusion: These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women., (Copyright © 2021 by The North American Menopause Society.)

Objective: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS., Methods: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS., Results: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment., Conclusion: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS., Competing Interests: Financial disclosure/conflicts of interest: S.L., S.I., M.C., R.B., H.R., K.G., U.J., S.K., B.V.K., J.S., and M.S.H. declare no disclosures/conflicts of interest., (Copyright © 2021 by The North American Menopause Society.)

Objective: The aim of the study was to evaluate the clinically meaningful effect of oral TX-001HR (17β-estradiol [E2]/progesterone [P4]) capsules on hot flushes severity (vasomotor symptoms [VMS] severity scale) using the patient-reported Clinical Global Impression (CGI)., Methods: REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR in postmenopausal women (40-65 y) with a uterus. Those with frequent moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized in a VMS substudy to daily E2/P4 (1/100, 0.5/100, 0.5/50, or 0.25/50 mg/mg), or placebo. Patients rated VMS severity from 1 (mild) to 3 (severe) and symptom improvements with the CGI. CGI results were an anchor in a nonparametric discriminant analysis to define clinically important differences (CIDs) and minimal CID in VMS severity at weeks 4 and 12., Results: In the VMS substudy (n = 726), determined CID and minimal CID severity thresholds were reductions of 0.525 and 0.350 points at week 4, respectively, and 0.775 and 0.225 points at week 12. Significantly more women taking the two highest E2/P4 doses (1/100 and 0.5/100) versus placebo met CID severity thresholds at weeks 4 (40% and 44% vs 17%; P < 0.05) and 12 (56% and 48% vs 29%; P < 0.05)., Conclusion: REPLENISH trial data demonstrated that E2/P4 1/100 and 0.5/100 provided clinically meaningful improvements in hot flushes severity in postmenopausal women. In conjunction with previously demonstrated clinically meaningful VMS frequency improvements, these data support oral E2/P4 1/100 and 0.5/100 for postmenopausal women with a uterus seeking treatment for moderate to severe VMS.

The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop.

Approximately 50% of postmenopausal women experience vulvovaginal symptoms associated with genitourinary syndrome of menopause (GSM). GSM is a chronic and progressive condition with a well-defined treatment algorithm. Analysis of the MsFLASH Vaginal Health Trial data produced two main conclusions, which were that prescribed vaginal 10 μg estradiol tablet and over-the-counter (OTC) vaginal moisturizer did not provide additional benefit over placebo vaginal tablet and placebo gel in reducing postmenopausal vulvovaginal symptoms; or increasing the proportions of women reporting sexual activity or improving pain scores with sexual activity. These treatment conclusions are contrary to all prior robust clinical trial data for dyspareunia and vaginal dryness, and not in line with the good clinical practice for GSM management presented by the American College of Obstetricians and Gynecologists, The North American Menopause Society, and the Endocrine Society. Overall, the flaws of the MsFLASH Vaginal Health Trial were to incorrectly identify the therapeutic outcomes of most interest using metrics that exhibit high degrees of placebo bias; and to utilize low statistical power with which to appreciate any significant differences between groups.

Objective: TX-004HR is a low-dose estradiol (E2) softgel vaginal insert designed to be rapidly dissolving and mucoadhesive. This report describes the physical attributes and pharmacokinetic parameters of the softgel vaginal insert evaluated for the treatment of moderate to severe dyspareunia due to menopausal vulvar and vaginal atrophy., Methods: In vitro dissolution studies with 25-μg E2 inserts were performed and media samples were analyzed for E2 by high-performance liquid chromatography. Effects of body position on E2 bioavailability were assessed in a phase 1, randomized trial of the 25-μg softgel capsule versus a reference product in which women remained supine after dosing (n = 16), and in a substudy (n = 16) in which women were ambulatory or seated after dosing. Estradiol C max, AUC0-24, and t max were measured by high-performance liquid chromatography-tandem mass spectroscopy. A phase 2, randomized study (n = 50) of 10-μg E2 versus placebo inserts assessed timing of capsule disintegration at days 1 and 15., Results: In vitro testing detected more than 80% of E2 in the dissolution medium by 15 minutes (first time point measured). In the phase 1 studies, baseline-corrected E2 plasma levels were not significantly different regardless of supine versus ambulatory/seated position after dosing: C max, 24.1 versus 34.3 pg/mL; AUC0-24, 77.6 versus 93.7 h · pg/mL; and t max, 2.1 versus 1.9 hours, respectively. In the phase 2 study, no remnants of the softgel capsule were found at day 1 (6 hours) after dosing and day 15. Vaginal discharge was minimal (1/48 women; 2.1%)., Conclusions: The presented data support rapid dissolution of the softgel capsule and similar E2 pharmacokinetic parameters regardless of body position after dosing.

Objective: To prospectively evaluate the effects of ospemifene on the vulva and vagina in postmenopausal women using vulvar-vestibular photography and direct visual assessments., Methods: Postmenopausal women (aged 40-80 years) with moderate to severe vaginal dryness as their most bothersome symptom (MBS) were randomized to daily ospemifene 60 mg or placebo in this 12-week, multicenter, double-blind, phase 3 study. Vulvar-vestibular photographic images were captured at baseline and week 12 and were independently assessed with the Vulvar Imaging Assessment Scale (VIAS). Changes from baseline in Vaginal and Vulvar Health Indices (VHI and VuHI) with ospemifene versus placebo were analyzed at weeks 4, 8, and 12. Correlations between VIAS, VHI, and VuHI, with vaginal dryness severity and the Female Sexual Function Index (FSFI) scores were also assessed., Results: In all, 631 eligible participants were randomized (ospemifene 316, placebo 315) and included in the intention-to-treat population. Compared with placebo, ospemifene significantly improved total scores for VIAS (P = 0.0154), VHI (P < 0.0001), and VuHI (P < 0.0001) from baseline to week 12; significant VHI (P < 0.0001) and VuHI (P = 0.002) improvements were observed at week 4. Most VHI and VuHI individual items were significantly better with ospemifene versus placebo at week 12 (P < 0.05). Most correlations between the vulvovaginal assessment total scores versus vaginal dryness severity and FSFI scores were significant (P < 0.05)., Conclusion: Improvements observed in vulvovaginal health with ospemifene assessed by prospective vulvar-vestibular photography and other direct visual assessments support its efficacy in addition to the treatment of moderate to severe vaginal dryness due to menopause and the use of photographic and direct visual evaluations in future clinical trials., Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A415.

Objective: The aim of the study was to describe the effects of TX-001HR (17β-estradiol [E2] and natural progesterone [P4] in a single oral capsule) on menopause-specific quality of life in women with moderate to severe vasomotor symptoms (VMS)., Methods: The REPLENISH study (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial which evaluated four E2/P4 doses in postmenopausal women with VMS and a uterus. Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were included in a VMS substudy. Participants self-administered the Menopause-Specific Quality of Life (MENQOL) questionnaire. Baseline changes in MENQOL overall and domains were determined as well as correlations between changes in MENQOL scores and VMS frequency or severity., Results: In the VMS substudy, women treated with E2/P4 had significantly greater improvements from baseline in their MENQOL overall score at week 12, and months 6 and 12, compared with placebo (all, P < 0.05, except the lowest E2/P4 dose at months 6 and 12). Improvements from baseline for the MENQOL vasomotor domain score were significantly greater with TX-001HR doses versus placebo at all time points (all, P < 0.01). Changes in MENQOL vasomotor scores moderately correlated with changes in VMS frequency (r = 0.56, P < 0.0001) and severity (r = 0.55, P < 0.0001)., Conclusion: In the REPLENISH trial, women with moderate to severe VMS treated with most E2/P4 doses reported significant improvements in quality of life from baseline to 12 weeks compared with placebo, which were maintained up to 12 months. TX-001HR, if approved, may provide the first oral hormone therapy formulation in a single capsule containing E2 and P4 for the treatment of VMS in postmenopausal women with a uterus.

Objective: The aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus., Methods: In the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (≥7/d or ≥50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17β-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods., Results: In the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression-based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥25 moderate to severe VMS: 82-88% vs 69%; all, P < 0.05) and CID (weekly reduction of ≥39 VMS: 68%-73% vs 52%; all, P < 0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life-based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of ≥34 VMS: 74%-81% vs 55%; all, P < 0.01) and CID (weekly reduction of ≥44 VMS: 61%-69% vs 42%; all, P < 0.01) at week 12., Conclusions: TX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.

Objective: This study describes women's experiences of the genitourinary syndrome of menopause (GSM) elicited through focus groups and cognitive debriefing sessions during development of a novel patient-reported outcome measure (PROM) designed for use in both clinical care and research., Methods: A draft questionnaire to identify and assess bothersome genitourinary symptoms associated with estrogen deficiency in menopausal women was developed in five discrete phases from multiple sources of information in accordance with standards for PROM development. GSM was confirmed by report of symptoms in conjunction with a confirmatory pelvic examination and laboratory assessments., Results: Qualitative content interviews were completed in 36 menopausal women with GSM. Cognitive testing of draft PROM items was performed in nine focus groups, including 26 menopausal women with and 15 without GSM. Participants reported a range of symptoms and described associated impacts on more than 15 quality-of-life domains. The majority of women reported that their symptoms impacted their sexual functioning and had a negative effect on their overall quality of life. GSM affected many aspects of menopausal women's lives beyond sexual function, with descriptions of pain when walking, urinating, wearing tight clothes, and with other activities of daily living., Conclusions: Women's own words methodically recorded and analyzed during qualitative interviews and cognitive debriefing focus groups illuminate the subjective experience of women with GSM. It is hoped that the PROM currently in development will provide an effective tool for increasing our understanding of the prevalence, predictors, and impact of GSM in menopausal women's lives.

Objective: To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA)., Methods: This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies., Results: Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed., Conclusions: Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.

Objective: The objective of this consensus document is to broaden the perspective on clinical management of genitourinary syndrome of menopause to include androgens., Methods: A modified Delphi method was used to reach consensus among the 14 international panelists representing multiple disciplines and societies., Results: Menopause-related genitourinary symptoms affect over 50% of midlife and older women. These symptoms have a marked impact on sexual functioning, daily activities, emotional well-being, body image, and interpersonal relations. Tissues in the genitourinary system are both androgen and estrogen-dependent. The clitoris, vestibule, including minor and major vestibular glands, urethra, anterior vaginal wall, periurethral tissue, and pelvic floor are androgen-responsive. Historically, treatment of postmenopausal genitourinary symptoms involved both androgens and estrogens. This subsequently gave rise to predominantly estrogen-based therapies. More recently, double-blind, placebo-controlled clinical trials have demonstrated that local vaginal dehydroepiandrosterone improves symptoms in postmenopausal women, including moderate to severe dyspareunia. Limited data suggest that systemic testosterone treatment may improve vaginal epithelial health and blood flow. Open-label studies that have used high doses of intravaginal testosterone in the presence of aromatase inhibitor therapy for breast cancer have resulted in supraphysiological serum testosterone levels, and have been reported to lower vaginal pH, improve the vaginal maturation index, and reduce dyspareunia., Conclusions: Vaginal dehydroepiandrosterone, hypothesized to enhance local production of both androgen and estrogen, is effective for the management of dyspareunia in menopause. Vaginal testosterone offers potential as a treatment for genitourinary syndrome of menopause, but more studies are needed.

The objective of The North American Menopause Society (NAMS) and The International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel was to create a point of care algorithm for treating genitourinary syndrome of menopause (GSM) in women with or at high risk for breast cancer. The consensus recommendations will assist healthcare providers in managing GSM with a goal of improving the care and quality of life for these women. The Expert Consensus Panel is comprised of a diverse group of 16 multidisciplinary experts well respected in their fields. The panelists individually conducted an evidence-based review of the literature in their respective areas of expertise. They then met to discuss the latest treatment options for genitourinary syndrome of menopause (GSM) in survivors of breast cancer and review management strategies for GSM in women with or at high risk for breast cancer, using a modified Delphi method. This iterative process involved presentations summarizing the current literature, debate, and discussion of divergent opinions concerning GSM assessment and management, leading to the development of consensus recommendations for the clinician.Genitourinary syndrome of menopause is more prevalent in survivors of breast cancer, is commonly undiagnosed and untreated, and may have early onset because of cancer treatments or risk-reducing strategies. The paucity of evidence regarding the safety of vaginal hormone therapies in women with or at high risk for breast cancer has resulted in avoidance of treatment, potentially adversely affecting quality of life and intimate relationships. Factors influencing decision-making regarding treatment for GSM include breast cancer recurrence risk, severity of symptoms, response to prior therapies, and personal preference.We review current evidence for various pharmacologic and nonpharmacologic therapeutic modalities in women with a history of or at high risk for breast cancer and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. Treatment of GSM is individualized, with nonhormone treatments generally being first line in this population. The use of local hormone therapies may be an option for some women who fail nonpharmacologic and nonhormone treatments after a discussion of risks and benefits and review with a woman's oncologist. We provide consensus recommendations for an approach to the management of GSM in specific patient populations, including women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease.

Objective: Clinical trials in menopause have undergone much scrutiny over the years. This has led to significant shifts in the treatment of symptomatic menopause and a substantial impact on women. We aim to delineate the key studies contributing to this controversy and highlight new directions specifically related to menopausal hormone therapy (HT) and vascular disease risk., Methods: We performed a search of sentinel studies delineating the risks and benefits of HT in otherwise healthy postmenopausal women. Using PubMed we input the following search terms: hormone replacement therapy, cardiovascular disease, coronary artery disease, coronary atherosclerosis, myocardial infarction, angina, coronary heart calcification, carotid intimal thickness, lipids, and/or lipoproteins. We included studies of menopausal women (surgical or natural) using combined estrogen/progestogen therapy or estrogen-only therapy that looked at cardiovascular disease risk factors or outcomes. Studies were evaluated for inclusion by the authors; however, this is not intended to be a systematic or an exhaustive analysis., Results: In women close to the time of menopause, there is a decreased risk of subclinical and clinical coronary heart disease with menopausal HT. Additionally, HT confers a significant benefit to vasomotor symptoms of menopause, bone health, and colorectal cancer. There is an increased risk of venous thromboembolism with oral formulations that appears mitigated with transdermal estradiol. Mixed data regarding breast cancer risk are available, with some studies suggesting an increased risk of invasive breast cancer with estrogen/progestogen therapy and a null effect with estrogen-only therapy. Other more long-term epidemiologic studies identify a decreased risk., Conclusions: The available literature suggests that HT is a viable option for the primary prevention of cardiovascular disease in postmenopausal women. Newer trials will likely verify this assessment. If this is enough to change clinical practice, however, remains to be seen given the general fear of HT by many with prescriptive authority, and also the women in our care.

Objective: To evaluate the response of the vaginal mucosa with TX-004HR and its correlation with vulvar and vaginal atrophy (VVA) symptoms, and whether visual examination is a useful measure for assessing VVA., Methods: REJOICE was a 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study of a vaginal, muco-adhesive, 17β-estradiol softgel capsule (TX-004HR 4, 10, and 25 μg) in postmenopausal women with VVA and moderate-to-severe dyspareunia. Treatments were self-administered vaginally once per day for 2 weeks, then twice per week for 10 weeks. The vagina was visually examined at baseline and at weeks 2, 6, 8, and 12; changes were evaluated using a 4-item scale for vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal secretions., Results: Significant improvements were observed with all three TX-004HR doses versus placebo in vaginal color (least square mean score changes of -0.96 to -1.06 for TX-004HR doses vs -0.60 for placebo at week 12), epithelial integrity (-0.97 to -1.07 vs -0.60), epithelial surface thickness (-0.94 to -1.03 vs -0.61), and secretions (-1.01 to -1.06 vs -0.64) (P < 0.001 for all comparisons at all time points). Both Pearson's correlations and logistic regression receiver-operating characteristic curve analyses significantly correlated the sum of the individual visual assessment scores with dyspareunia (P < 0.0001) and vaginal dryness (P < 0.0001) at 12 weeks., Conclusions: Greater improvements in the vaginal mucosa of postmenopausal women with VVA and moderate-to-severe dyspareunia were observed with TX-004HR versus placebo, and vaginal mucosa assessment scores correlated with vaginal symptoms of dyspareunia and dryness. Visual vaginal assessment by healthcare professionals is a useful measure for diagnosing VVA and assessing response to treatment.

Objective: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy., Methods: A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-μg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates., Results: Seventy-two women (mean 59 y) participated. TX-004HR 4 μg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 μg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 μg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 μg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed., Conclusions: Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 μg, and only minor increases were observed with 25 μg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.

Objective: To evaluate the safety and efficacy of TX-004HR vaginal estradiol soft-gel capsules for moderate-to-severe dyspareunia associated with postmenopausal vulvar and vaginal atrophy., Methods: In this randomized, double-blind, placebo-controlled, phase 3 study, postmenopausal women with a self-identified most bothersome symptom of dyspareunia received 4, 10, or 25 μg TX-004HR or placebo for 12 weeks. Four co-primary efficacy endpoints were change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH, and severity of dyspareunia. Secondary endpoints included severity of vaginal dryness and vulvar and/or vaginal itching or irritation. Endometrial histology and adverse events (AEs) were included in the safety endpoints., Results: In all, 764 women were randomized (modified intent-to-treat population, n = 747; mean age 59 y). Compared with placebo, all three doses of TX-004HR significantly improved the four co-primary endpoints (P < 0.0001 for all, except dyspareunia with 4 μg, P = 0.0149). Changes in cytology, pH, and dyspareunia were also significant at weeks 2, 6, and 8. Vaginal dryness and vaginal itching/irritation improved. Sex hormone binding globulin concentrations did not change with treatment. TX-004HR was well-tolerated, with no clinically meaningful differences in treatment-emergent AEs versus placebo, and no treatment-related serious AEs or deaths., Conclusions: TX-004HR (4, 10, and 25 μg) was safe, well-tolerated, and effective for treating moderate-to-severe dyspareunia within 2 weeks with minimal systemic estrogen exposure. This novel product may be a potential new treatment option for women experiencing postmenopausal vulvar and vaginal atrophy.

Testosterone treatment increases sexual desire and well-being in women with hypoactive sexual desire disorder; however, many studies have shown only modest benefits limited to moderate doses. Unlike men, available data indicate women show a bell-shaped dose-response curve for testosterone, wherein a threshold dosage of testosterone leads to desirable sexual function effects, but exceeding this threshold results in a lack of further positive sexual effects or may have a negative impact. Emotional and physical side-effects of excess testosterone, including aggression and virilization, may counteract the modest benefits on sexual interaction, providing a possible explanation for a threshold dose of testosterone in women. In this commentary, we will review and critically analyze data supporting a curvilinear dose-response relationship between testosterone treatment and sexual activity in women with low libido, and also explore possible explanations for this observed relationship. Understanding optimal dosing of testosterone unique to women may bring us one step closer to overcoming regulatory barriers in treating female sexual dysfunction.

Objective: The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause., Methods: This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100 mg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment., Results: One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100 mg groups). The response in the 10 mg group was significantly different from placebo at 4 weeks (P = 0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity., Conclusions: Daily treatment with 10 mg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.

Objective: Assess effects of once-daily, extended-release oxybutynin chloride on frequency and severity of vasomotor symptoms in healthy, postmenopausal symptomatic women., Methods: A 12-week, multicenter, double-blind, placebo-controlled, phase 2 clinical trial randomized naturally postmenopausal women experiencing at least seven moderate-to-severe vasomotor symptoms daily to oxybutynin 15 mg once daily (n = 73) or placebo (n = 75). Co-primary outcomes were the change from baseline to week 12 in the frequency and severity of moderate-to-severe vasomotor symptoms., Results: Significant reductions in both frequency and severity of moderate-to-severe vasomotor symptoms in women who received oxybutynin compared with placebo were observed at all weeks of treatment (P ≤ 0.007, all time points) through week 12. Mean changes in frequency in the oxybutynin and placebo groups were -9.48 and -4.69 episodes/d, respectively, at week 12. Mean changes in severity (scale 0-3) in the oxybutynin and placebo groups were -1.27 and -0.30, respectively, at week 12. At the end of treatment, 73% of women in the oxybutynin group and 26.1% in the placebo group rated symptom improvement "much better" (P ≤ 0.001). Women treated with oxybutynin showed significant improvement in sleep quality, sleep disturbance, and the global sleep index on the Pittsburgh Sleep Quality Index (P ≤ 0.023). Dry mouth was reported by 52.1% of participants given oxybutynin and 5.3% of participants given placebo, leading to discontinuation of oxybutynin in 6.8% of participants., Conclusions: Oxybutynin is an effective, nonhormonal therapy for moderate-to-severe vasomotor symptoms in postmenopausal women.

Objective: To evaluate the risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) complications, and assess healthcare costs in menopausal women using an estradiol transdermal system versus oral estrogen therapy (ET)., Methods: Health insurance claims from 60 self-insured US companies from 1999 to 2011 were analyzed. Women at least 50 years of age, newly initiated on transdermal or oral ET, were included. Cohorts were matched 1:1 based on exact factors and propensity score-matching methods. The incidence rate ratios (IRRs) of CVD complications, as well as VTE and other CVD events separately, were assessed through conditional Poisson models. Cohorts were also compared for healthcare costs using linear regression models to assess per-patient per-month cost differences. Confidence intervals (CIs) and P values were determined using a nonparametric method for cost outcomes., Results: From each cohort, 2,551 users were matched to form the study population. A total of 274 transdermal ET users developed CVD complications compared with 316 women in the oral ET cohort (adjusted IRR 0.81; 95% CI, 0.67-0.99). Transdermal ET users also incurred lower adjusted all-cause and VTE/CVD-related healthcare costs relative to oral ET users (all-cause per-patient per-month cost difference [95% CI] = $41 [-34; 137], P = 0.342)., Conclusions: This large matched-cohort study based on real-world data suggests that women receiving transdermal ET have significantly lower incidences of CVD events compared with those receiving oral ET, and that they also incur lower healthcare costs.

Objective: This trial examined diaries of hot flash events reported upon occurrence to assess the test/retest reliability of the diaries and their ability to measure treatment effects on hot flash frequency and severity., Methods: Forty-two postmenopausal women (aged ≥40 y; 5-50 hot flashes/wk) were randomized (3:3:1) to placebo, raloxifene 60 mg, or paroxetine 20 mg daily for 12 weeks. Diaries of hot flash frequency and severity were evaluated at 1-week intervals (twice before study treatment and thrice during study treatment)., Results: Forty-one women were evaluated. Baseline characteristics were similar between groups (eg, mean, 29.8 hot flashes/wk). Concordance correlation coefficients between screening (week -2) and baseline (week -1) measures of hot flash frequency and severity were 0.73 and 0.71, respectively. After 12 weeks, the mean (95% CI) percent changes from baseline in weekly hot flash frequency were as follows: placebo, -37.4% (-60.9 to -14.0); raloxifene, -14.2% (-37.7 to 9.3); paroxetine, -49.8% (-88.6 to -11.0); the mean (95% CI) percent changes in hot flash severity were as follows: placebo, -39.9% (-69.1 to -10.8); raloxifene, -9.6% (-38.8 to 19.6); paroxetine, -36.6% (-84.7 to 11.5). There were no significant differences in hot flash diary results between treatment groups., Conclusions: Measures of hot flash frequency and severity show acceptable test/retest reliability between screening and baseline. Reductions in vasomotor symptoms by raloxifene are numerically less than those seen with placebo, but no statistically significant treatment differences have been documented in this small study. The large effect of placebo and the significant reduction in vasomotor symptoms by paroxetine are consistent with other studies. The diary seems to be suitable for use in hot flash clinical trials.

The author considers hypothetical comparisons between oral conjugated equine estrogens and transdermal estradiol and between oral medroxyprogesterone acetate and oral micronized progesterone for their effects on four primary outcomes of the Women's Health Initiative (WHI): cardiovascular disease risk, cerebrovascular disease risk, venous thromboembolism risk, and breast cancer risk. Although the discussion in this article focuses on transdermal estradiol delivered through patches, gels, or lotions, it could be broadened to include all forms of nonoral estrogen administration. After a brief review of the WHI and a survey of the relevant literature in which the safety of these various hormone therapies is assessed or compared, the author uses statistical methods to ascertain the attributable risk of venous thromboembolism for transdermal estradiol versus oral hormone therapy and imputes those risks into the WHI primary outcomes.

Objective: This study aimed to assess the efficacy and safety of flibanserin, a serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in postmenopausal women with hypoactive sexual desire disorder (HSDD)., Methods: Naturally postmenopausal women with HSDD received flibanserin 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co-primary endpoints were changes from baseline to week 24 in the number of satisfying sexual events (SSEs) across 28 days and in the Female Sexual Function Index (FSFI) desire domain score. Secondary endpoints included change from baseline in Female Sexual Distress Scale-Revised (FSDS-R) Item 13 score (which assesses distress due to low sexual desire), FSDS-R total score, and FSFI total score. The Patient Benefit Evaluation was asked on treatment discontinuation., Results: There were significant improvements with flibanserin versus placebo in the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (-0.8 [0.1] vs -0.6 [0.1]), FSDS-R total score (-8.3 [0.6] vs -6.3 [0.6]), and FSFI total score (4.2 [0.4] vs 2.7 [0.4]; all P < 0.01). More women on flibanserin (37.6%) than women on placebo (28.0%) reported experiencing meaningful benefits from the study medication on treatment discontinuation. The most frequent adverse events associated with flibanserin were dizziness, somnolence, nausea, and headache., Conclusions: In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.

Objective: This study aims to determine the emotional and physical impact of vaginal atrophy on North American postmenopausal women and their male partners., Methods: A weighted sample of 1,000 married or cohabiting North American postmenopausal women aged 55 to 65 years with vaginal discomfort and 1,000 male partners of postmenopausal women aged 55 to 65 years who experienced vaginal discomfort participated in the Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) online survey to determine the impact of vaginal discomfort and local estrogen therapy on intimacy, relationships, and women's self-esteem., Results: Vaginal discomfort caused most surveyed North American women to avoid intimacy (58%), experience loss of libido (64%), and experience pain associated with sex (64%). Most surveyed North American men also believed that vaginal discomfort caused their partners to avoid intimacy (78%), experience loss of libido (52%), and find sex painful (59%). Approximately 30% of North American women and men cited vaginal discomfort as the reason they ceased having sex altogether. North American women who used local estrogen therapy to treat their vaginal discomfort reported less painful sex (56%), more satisfying sex (41%), and improved sex life (29%). Most men reported looking forward to having sex (57%) because of their partner's use of local estrogen therapy., Conclusions: Local estrogen therapy ameliorates the negative impact of vaginal atrophy on the intimate relationships of North American postmenopausal women and their male partners. Additional education and awareness efforts about the symptoms of and available treatments for vaginal atrophy may be of further benefit to North American partners.

Objective: The aim of this study was to assess US postmenopausal women's knowledge of and attitudes toward vaginal atrophy, using the Vaginal Health: Insights, Views & Attitudes survey., Methods: Data were obtained from 3,520 postmenopausal women (aged 55-65 y) in the United States, Canada, and Europe using a structured Internet-based questionnaire. Results for US women (n = 500) are presented., Results: Eighty percent of women had finished their menses more than 5 years previously, and 93% had experienced at least one menopausal symptom, although only 63% associated vaginal symptoms with menopause. Of those who had experienced "vaginal discomfort" (48%), vaginal dryness (85%) and pain during intercourse (52%) were most commonly reported. Eighty-two percent of women had experienced vaginal discomfort for 1 year or more. Most women (80%) considered vaginal discomfort to negatively impact their lives, particularly with regard to sexual intimacy (75%), ability to have a loving relationship (33%), and overall quality of life (25%); women also felt that it made them feel old (36%) and affected their self-esteem (26%). Of those with symptoms, 37% did not consult any healthcare professional, and 40% waited 1 year or more before doing so. Although 78% of those with vaginal discomfort used some form of treatment, this consisted mainly of lubricating gels and creams (65%); only 34% of women had used any form of hormone therapy., Conclusions: Vaginal atrophy negatively impacts women's lives, but women lack knowledge of the subject and are hesitant to consult healthcare professionals, who should proactively initiate discussions regarding appropriate treatment options.

Objective: The efficacy and safety of low-dose paroxetine 7.5 mg for the treatment of menopausal vasomotor symptoms were evaluated in two multicenter, double-blind, placebo-controlled, phase 3 studies of 12 and 24 weeks' duration., Methods: Postmenopausal women were randomly assigned 1:1 to receive paroxetine 7.5 mg or placebo once daily. The four primary efficacy endpoints included mean changes in the frequency and severity of moderate to severe vasomotor symptoms on weeks 4 and 12; an additional endpoint was persistence of treatment benefit on week 24., Results: Five hundred ninety-one participants were randomly assigned to treatment with paroxetine 7.5 mg, and 593 participants were randomly assigned to treatment with placebo. All primary endpoints were met in the 24-week study; three of four primary endpoints were met in the 12-week study. In both studies, paroxetine 7.5 mg significantly reduced the mean weekly vasomotor symptom frequency compared with placebo on week 4 (P < 0.0001 for both studies) and week 12 (P = 0.0090, 12-wk study; P = 0.0001, 24-wk study). Mean weekly reduction in vasomotor symptom severity was significantly greater for paroxetine 7.5 mg than for placebo on week 4 (P = 0.0048) in the 12-week study and on week 4 (P = 0.0452) and week 12 (P = 0.0114) in the 24-week study. Persistence of treatment benefit was demonstrated in the 24-week study. Most treatment-emergent adverse events were mild or moderate in severity. No clinically significant changes in laboratory values or vital signs were noted, and no short-term discontinuation of symptoms followed treatment cessation., Conclusions: Paroxetine 7.5 mg is well-tolerated, is effective in reducing the frequency and severity of menopausal vasomotor symptoms, and demonstrates persistence of treatment benefit through 24 weeks of treatment.

Objective: The aim of this work was to study the role of ospemifene, a novel selective estrogen receptor modulator, in the treatment of vulvar and vaginal atrophy in postmenopausal women with moderate to severe dyspareunia and physiological vaginal changes., Methods: This multicenter phase 3 study used a randomized, double-blind, parallel-group design to compare the efficacy, safety, and tolerability of oral ospemifene 60 mg/day versus placebo. A total of 605 women aged 40 to 80 years who self-reported a most bothersome symptom of dyspareunia and had a diagnosis of vulvar and vaginal atrophy were randomized to take a once-daily dose of ospemifene (n = 303) or placebo (n = 302) for 12 weeks., Results: Analysis of the intent-to-treat (n = 605) population found the efficacy of ospemifene to be significantly greater than that of placebo for each of the following coprimary endpoints: percentages of parabasal and superficial cells, vaginal pH, and severity of dyspareunia. With ospemifene, the percentage of parabasal cells and vaginal pH significantly decreased; the percentage of superficial cells significantly increased; and dyspareunia was significantly reduced versus placebo (all P < 0.0001, except for dyspareunia: P = 0.0001). Among the randomized women, 186 (61.4%) in the ospemifene group and 154 (51.0%) in the placebo group reported at least one treatment-emergent adverse event. Hot flushes were the most frequently reported treatment-related adverse event (ospemifene 6.6% vs placebo 3.6%); only one participant discontinued in each group. As determined by the investigators, no serious adverse events related to the study drug were reported., Conclusions: In this study, once-daily oral ospemifene 60 mg was effective for the treatment of vulvar and vaginal atrophy in postmenopausal women with dyspareunia.

Objective: The aim of this study was to assess the safety of ospemifene, a novel selective estrogen receptor modulator, for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus., Methods: In this multicenter, randomized, double-blind, placebo-controlled, long-term safety extension study, nonhysterectomized women aged 40 to 80 years (n = 180) received daily oral doses of placebo, ospemifene 30 mg/day, or ospemifene 60 mg/day for 40 weeks (continued as blinded treatments from the initial 12-week pivotal efficacy study of ospemifene). The total treatment period was 52 weeks. Safety assessments included adverse events, cervical Papanicolaou tests, endometrial histology, endometrial thickness, gynecological examination, breast palpation, mammography, physical examination, and clinical safety laboratory assessments., Results: No clinically significant adverse changes in safety assessments were observed in any treatment group. Most treatment-emergent adverse events were mild or moderate in severity. Hot flushes, the most frequently occurring treatment-emergent adverse event related to the study drug, had a low discontinuation rate (1.6%). No study participants discontinued because of endometrial or cervical pathology; no endometrial findings were clinically meaningful. On week 52, more than 95% of endometrial biopsy samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. There were no treatment-emergent adverse events of pelvic organ prolapse or venous thromboembolism. No cases of endometrial hyperplasia or carcinoma were observed. Only three participants (1.7%) taking ospemifene experienced vaginal bleeding or spotting, which was self-limiting., Conclusions: Daily doses of ospemifene 30 mg and ospemifene 60 mg yielded few treatment-emergent adverse events and demonstrated no significant endometrial changes during the 1-year treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus.

Objective: The aim of this study was to report the effects of denosumab on radius cortical and trabecular bone density, mass, and strength, and wrist fracture incidence in the FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months) study., Methods: In the FREEDOM study, postmenopausal women with osteoporosis (N = 7,808) received placebo or 60 mg of denosumab every 6 months for 36 months. Radius bone mineral density (BMD), bone mineral content, and strength (polar moment of inertia) were evaluated in two prespecified substudies using dual-energy x-ray absorptiometry (placebo, n = 209; denosumab, n = 232) or quantitative CT (placebo, n = 48; denosumab, n = 62). Prespecified analysis assessed wrist fracture incidence in all FREEDOM participants (placebo, N = 3,906; denosumab, N = 3,902), and post hoc subgroup analyses evaluated those with higher fracture risk (baseline femoral neck T-score ≤-2.5; placebo, N = 1,406; denosumab, N = 1,384)., Results: Denosumab significantly increased areal BMD (assessed by dual-energy x-ray absorptiometry) and volumetric BMD, bone mineral content, and polar moment of inertia (assessed by quantitative CT), compared with placebo, in radius cortical and trabecular bone at all time points evaluated (all P < 0.05). Wrist fracture incidence was 2.9% for placebo and 2.5% for denosumab (relative risk reduction, 16%; P = 0.21) on month 36. Participants with a femoral neck T-score of -2.5 or lower were at increased risk for wrist fracture, and denosumab significantly reduced wrist fracture incidence compared with placebo (placebo, 4.0%; denosumab, 2.4%; relative risk reduction, 40%; absolute risk reduction, 1.6%; P = 0.03)., Conclusions: Denosumab significantly improves radius bone density, mass, and strength compared with placebo. In higher-risk women, denosumab significantly reduces wrist fracture risk.

Objective: The aim of this study was to assess the effects of zoledronic acid and raloxifene on bone turnover markers., Methods: This multicenter, randomized, double-blind study involved 110 postmenopausal women with low bone mineral density who received either a single intravenous infusion of zoledronic acid 5 mg or 6 months of daily oral raloxifene 60 mg. The primary efficacy variable was change from baseline in the bone resorption marker urine N-telopeptide of type I collagen. The secondary efficacy variable was change from baseline in the bone formation marker serum bone-specific alkaline phosphatase. Analysis time points were at 2, 4, and 6 (primary) months., Results: At 6 months, zoledronic acid produced a significantly greater reduction than did raloxifene in urine N-telopeptide of type I collagen (P < 0.001). Zoledronic acid also yielded significantly greater decreases in urine N-telopeptide of type I collagen at 2 and 4 months and in serum bone-specific alkaline phosphatase at all time points (P < 0.001 vs raloxifene for all comparisons). Both treatments were well tolerated. More adverse events occurred in the zoledronic acid group; these were primarily transient postdose symptoms that occurred within the first 3 days after the infusion., Conclusions: Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass.

New therapies for abnormal uterine bleeding have been slow to reach the marketplace for a variety of reasons. These reasons include the availability of cost-effective therapies already available and the extraordinarily difficult and expensive regulatory barriers emphasizing long-term safety. Common comorbidities like bleeding diatheses, adenomyosis, and leiomyomata further complicate clinical development, necessitating large study samples and making it more expensive. Even the accurate measurement of menstrual blood loss adds an additional hindrance to novel drug development. These obstacles and the currently available therapies will be reviewed in the context of developing new methods for approaching this complicated and prevalent clinical problem., (© 2011 by The North American Menopause Society)

Contemporary women have long life expectancy (81 y, United States), especially relative to the age at menopause (51 y, United States). Menopause is a consequence of reproductive aging and follicular depletion (ovarian failure), yielding very low circulating estrogen serum concentrations and biologically disadvantageous metabolic alterations. Stated in terms of antagonistic pleiotropy, the ongoing hypoestrogenic endocrine environment, beneficial during lactation, results in acceleration of several age-related illnesses after menopause (ie, late postmenopausal osteoporosis, cardiovascular disease, and cognitive decline). Specifically, the similar hypoestrogenic hormonal milieu present during postpartum lactation provides biologic advantages (fitness) to both mother and newborn. These precepts of evolutionary medicine encourage a reassessment of hormone therapy, and on the basis of data presented the authors propose additional opportunities for disease prevention and morbidity reduction in postmenopausal women.

Objective: To assess how menopause affects the lives of busy female executives by evaluating how they view their overall health and how specific symptoms affect their lives and to gain insight into their knowledge and general perspective of hormone therapy as treatment for menopause-related symptoms., Design: In this survey, 961 members of the National Association of Female Executives aged 35 years and older completed an Internet survey about the impact of menopausal symptoms and general knowledge and understanding of hormone therapy. Subgroups within this survey included women who were premenopausal (n = 118), perimenopausal (n = 239), menopausal (n = 297), and postmenopausal (n = 307)., Results: A majority of women surveyed (88%) had personal experience with menopause, 95% reported physical symptoms, and 79% reported emotional symptoms. Among women reporting symptoms, 40% found symptoms to be problematic in at least one area of their lives. Of the 41% of respondents who had used hormone therapy to treat their menopausal symptoms, 57% reported continued use at the time of the survey. Among those who discontinued hormone therapy, 39% cited the Women's Health Initiative results as one of the reasons. The survey also found substantial gaps in the knowledge and understanding of hormone therapy by the survey responders., Conclusions: The majority of menopausal women surveyed experience physical and/or emotional symptoms. For many women, symptoms related to menopause significantly affect their daily personal, professional, and social lives. Educating patients about scientific findings, current treatment options, and the associated risks and benefits is critical to providing effective, individualized care to improve quality of life.

Objective: This study describes age-related changes in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in a 5-year prospective study of reproductive aging., Design: Participants (n = 156 college-educated, white, US women; 25 to 58 y) were recruited from the TREMIN Research Program on Women's Health. They collected daily urine specimens for 6 months in each of 5 consecutive years. Specimens were assayed for LH and FSH. Aggregate changes were calculated in LH and FSH with age, and multilevel models were used to estimate individual hormone trajectories and within-woman and between-woman variances by age., Results: Aggregate LH levels increased beginning after age 45; FSH increased at all ages, accelerating after age 45. Individual-level patterns with age included the following: reproductive-age LH and FSH levels, with increasing FSH and increasing or decreasing LH (ages 20 to 49); rapidly increasing LH and FSH (ages 40 to 59); and increasing or steady postmenopausal LH and FSH (ages 46 to 62). FSH levels were consistently high in the latter category, but LH levels overlapped with levels found in younger women (<45 y). Individual LH patterns showed more variability (5% to 35% of total variance) than FSH (3% to 22% of total variance). Both hormones had relatively low variation within individuals compared with between-woman differences (65% to 97% of total variance)., Conclusions: Aggregate-level data do not reflect differences across women and oversimplify the age-related increases and variability in LH and FSH. Individual FSH levels are not distinguishable from reproductive-age levels until after rapid perimenopausal increases in FSH occur; individuals vary in whether their postmenopausal LH levels are distinguishable from reproductive-age levels.