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Your anticipatory guidance and counseling can make the years between reproductive capability and menopause a more natural transition. Assess and address each woman's health risks and identify her attitudes toward menopause as you continually revisit the advisability of HRT or other option [ABSTRACT FROM AUTHOR]

A commentary is presented on a study published within the issue about the impact of hormone therapy (HT) on long-term all-cause mortality in women. A brief overview of the study is offered, which founds no association between menopausal HT and overall mortality for women initiating HT. The author states that the findings confirm recommendations about the safety and efficacy of HT for the treatment of menopausal symptoms.

Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed., Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms., Design, Setting, and Participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023)., Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks., Main Outcomes and Measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12., Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable., Conclusions and Relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS., Trial Registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

Objective: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS., Methods: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development., Results: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women., Conclusions: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials., Competing Interests: Financial disclosure/conflicts of interest: JoAnn V. Pinkerton serves as principal investigator at University of Virginia for the multicenter Bayer OASIS 2 trial, the fees from the trial are to the University of Virginia, currently serves on the Editorial Board of OBG Management, and is a contributor to Merck Manuals and Up to Date. Nick Panay has lectured and acted in an advisory capacity for Abbott, Bayer, Besins, Gedeon Richter, Mithra, Novo Nordisk, SeCur, Theramex, and Viatris. James Simon has grant/research support from AbbVie, Inc, Bayer Healthcare LLC, Daré Bioscience, Ipsen, Mylan/Viatris Inc, Myovant Sciences, and Sebela Pharmaceuticals Inc; serves as a consultant/is on advisory boards for Bayer HealthCare Pharmaceuticals Inc, Besins Healthcare, California Institute of Integral Studies (CIIS), Daré Bioscience, Femasys Inc, Khyria, Madorra Pty Ltd, Mayne Pharma, Inc, and Vella Bioscience Inc; serves on speaker's bureaus of Astellas Pharma, Inc, Mayne Pharma, Inc, Myovant Sciences, Inc, Pfizer Inc, Pharmavite LLC, and Scynexis Inc; is a stockholder (direct purchase) of Sermonix Pharmaceuticals. Lineke Zuurman and Cecilia Caetano are employees of Bayer CC AG. Christian Seitz, Susanne Parke, Uwe Mellinger, Claudia Haberland, Cornelia Holz, Sven Nisius, and Matthias Schaefers are employees of Bayer AG. Nazanin Haseli Mashhadi is an employee of Bayer PLC. Gordana Atanackovic and Marina Morrison are employees of Bayer US LLC. Guangping Mao is an employee of Bayer Healthcare Co Ltd., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Genitourinary syndrome of menopause is a common, under-reported, and undertreated chronic progressive condition requiring long-term treatment. Hypoestrogenism in the urogenital tissues is associated with bothersome dyspareunia, vulvovaginal symptoms, overactive bladder, and frequent urinary tract infections. Vaginal hormone therapies, including vaginal estrogen and intravaginal dehydroepiandrostenedione, are safe and effective and improve symptoms and clinical findings. Systemic hormone therapy treats vulvovaginal atrophy less effectively than vaginal hormone therapies with increased stress and urge urinary incontinence. Oral ospemifene effectively treats vaginal dryness and dyspareunia. Clinicians need to ask about symptoms of genitourinary syndrome of menopause, confirm the diagnosis, and suggest appropriate treatment options., Competing Interests: J.V.P. Bayer Pharmaceuticals Multicenter Research Trial; Fees to the University of Virginia; A.M.K. serves on an Advisory Board for Sumitomo Pharma America and The University of Florida College of Medicine receives research funding from Bayer, Merck, and Mylan for ongoing clinical trials. M.L.K. declares no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This proceeding summarizes a symposium on multidisciplinary management of menopause held on July 30, 2021 as part of the Health of Women 2021 conference. The workshop featured presentations by national experts who provided insights into multidisciplinary approaches to the management of menopause, vasomotor symptoms and genitourinary syndrome of menopause, bone health (including osteoporosis, muscular strength, and mobility), as well as sexual and psychological health during menopause. In this study, we highlight the major points of each presentation and the resultant discussion.

Abstract: Following the release of the Women's Health Initiative data, women began to use compounded bioidentical hormone therapy (cBHT) in the misguided belief of greater safety and efficacy than traditional hormone therapy. New guidelines recommend government-approved hormone therapy for symptomatic healthy menopausal women younger than 60 years or within 10 years of menopause at the time of initiation. For women requesting bioidentical hormones, those similar to the hormones present before menopause, there are many government-approved hormone therapies with extensive pharmacokinetic, safety, and efficacy data provided with package inserts delineating efficacy, safety, and potential risks. For women requesting non-Food and Drug Administration-approved (cBHT), these cBHTs lack data on pharmacokinetics, safety, and efficacy and are not provided a label detailing risk. Their use should be restricted to women with allergies or dosing or formulations not available in government-approved therapies. Pellet therapy providing women with supraphysiologic hormone dosing raises even more safety concerns., Competing Interests: Conflicts of Interest and Source of Funding: The author has disclosed that she has no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Selective estrogen receptor (ER) modulators have variable tissue specific estrogen agonist and antagonist activities. Tamoxifen is approved for treatment and prevention of breast cancer; acts as an endometrial estrogen agonist. Raloxifene is approved for prevention and treatment of osteoporosis and prevention of breast cancer. The selective ER modulators bazedoxifene paired with conjugated estrogens relieves vasomotor symptoms and prevents bone loss with neutral effects on breast and amenorrhea similar to placebo. Ospemifene is approved to treat dyspareunia. Lasofoxifene is in development for resistant ER positive breast cancer. Estetrol (E4), synthesized by human fetal liver, has dual weak-estrogenic/antiestrogenic features, now approved as a contraceptive., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Transdermal testosterone therapy, dosed within premenopausal physiologic testosterone ranges, used alone or with menopausal hormone therapy for postmenopausal hypoactive sexual desire disorder, has shown short-term efficacy, with few androgenic side effects. After natural or surgical menopause, meaningful improvements include an additional satisfying sexual episode per month; improvement in desire, arousal, orgasm, pleasure, and responsiveness; and a reduction in distress. Long-term data on cardiovascular, cancer, and cognitive safety are lacking. No approved testosterone preparation is available for women. Compounded testosterone creams or reduced dosing of male-approved therapies represent off-label use. Injections or pellets cause supraphysiological testosterone levels and are not recommended., Competing Interests: Disclosure J.V. Pinkerton—none in past 24 months. I. Blackman—no disclosures. E.A. Conner—no disclosures. A.M. Kaunitz: Advisory Boards: Mithra, Pfizer; Clinical trials (financial support to University of Florida): Mithra., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Case and Principles of Management: The case of a symptomatic, postmenopausal woman is presented and a full discussion of the approach to her management is discussed. Pertinent guidelines and scientific evidence are emphasized as support for the recommendations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years., Methods: Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years., Results: In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up., Conclusions: WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

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.

The recent Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) publication calculated the attributable risk of breast cancer from use of estrogen alone and estrogen plus a synthetic progestogen for less than 5 to 15 or more years of use. This CGHFB report calculated attributable risk based on their findings of relative risk from pooled data from 58 studies. Notably, neither the CGHFBC nor other previous studies have examined the effect of underlying risk of breast cancer on attributable risk. This omission prompted us to determine the magnitude of the effect of underlying risk on attributable risk in this perspective. Meaningful communication of the potential risk of menopausal hormonal therapy requires providing women with the estimated risk above their existing underlying risk (ie, attributable risk). Therefore, we have estimated attributable risks from the data published by the CGHFBC, taking into account varying degrees of underlying risk. Based on the Endocrine Society Guideline on Menopausal Hormone Therapy (MHT), we divided groups into 3 categories of risk: low (1.5%), intermediate (3.0%), and high (6.0%) underlying risk of breast cancer over 5 years. In women taking estrogen plus a synthetic progestogen for 5 to 9 years, the attributable risks of MHT increased from 12, to 42, to 85 additional women per 1000 in the low-, intermediate-, and high-risk groups, respectively. The attributable risks for estrogen alone were lower but also increased based on underlying risk. Notably, the attributable risks were amplified with duration of MHT use, which increased both relative risk and breast cancer incidence., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Women with estrogen-sensitive cancer or survivors of these neoplasms are generally not candidates for systemic menopausal hormone therapy or tibolone for the treatment of bothersome vasomotor symptoms (hot flashes or night sweats). However, menopausal symptoms negatively affect quality of life and need to be addressed by clinicians. For mild vasomotor symptoms, optimizing lifestyle changes or mind-brain behavior may be sufficient. For women with moderate to severe vasomotor symptoms unresponsive to these measures, non-hormone pharmacologic therapy may be needed. Randomized controlled trials have shown efficacy for vasomotor symptoms with selective serotonin reuptake inhibitors (paroxetine, citalopram, and escitalopram) and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine), as well as gabapentin, pregabalin, and clonidine. Therapies in development include neurokinin B inhibitors (neurokinin 3 receptor), stellate ganglion blockade, and a natural estrogen, estetrol. Individualizing therapy is important. As the physiology of menopausal hot flashes becomes better understood, it will drive development of future non-hormone pharmacotherapies.

Hormone therapy remains the most effective treatment for menopausal symptoms but decisions are complex, requiring an assessment of benefits and risks and determination of best treatment type, dose, and duration. Benefits exceed risks for most women with bothersome menopausal symptoms or high risk for fracture if initiated under age 60 years or within 10 years since menopause. Long-term mortality and safety data from the Women's Health Initiative is reassuring, with no increase in deaths from cardiovascular disease or cancer compared with placebo after 18 years of follow-up and a trend towards less mortality in those who initiate hormone therapy ages 50 to 59 years.

Background: Although sexual health can be considered a vital sign for overall health, several barriers prevent women from receiving proper medical counseling, support, and/or care for their sexual health needs and concerns., Methods: Experts in sexual health compiled research and experience on the impediments to women receiving adequate assessment and treatment for their sexual health. Specific solutions and a roadmap for overcoming such barriers and improving patient-clinician communication are presented., Results: Social stigma around female sexuality remains in Western culture and as a result, women often avoid and/or are embarrassed to discuss their sexual health with their health care professionals (HCPs). Moreover, midlife women are typically unaware or have misconceptions about conditions that may adversely impact their sexual life, such as genitourinary syndrome of menopause and hypoactive sexual desire disorder. Without understanding there may be underlying medical conditions, there is also a lack of awareness that safe and effective treatments are available. Lack of training, tools, time, and limited treatment options impede HCPs from providing women with necessary sexual health support. Educating women, training HCPs, and providing communication tools to HCPs can facilitate effective dialog between patients and HCPs. More specifically, HCPs can be trained to initiate and maintain a sexual health conversation in a manner that is comfortable for women to convey sexual health needs and concerns, and for HCPs to correctly identify, diagnose, and treat the sexual problems of their female patients., Conclusions: Solutions exist to address the barriers currently impeding patient-clinician interactions around sexual health.

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.

Objective: Hormone therapy (HT) prescription patterns have varied enormously over time and across specialties. The present study attempts to look at practice variation in specific controversial scenarios and to determine if attendance at The North American Menopause Society (NAMS) 2016 Annual Meeting, where the draft of the 2017 NAMS HT Position Statement was presented, had any impact on members' HT prescribing patterns., Methods: An anonymous survey with 11 case scenarios was sent to all NAMS members before and after the 2016 NAMS Annual Meeting. Pre- and postmeeting responses were pooled into a single cohort. For those who responded to both surveys, only the postmeeting survey responses were included in the cohort. The impact of attendance at the 2016 NAMS Annual Meeting was investigated by comparing paired responses with "controversial questions" between pre- and postmeeting surveys in the matched population who either attended the 2016 NAMS Annual Meeting (intervention arm) or did not (control arm). "Controversial questions" were defined as those where 25% to 75% of responders answered "YES" to a question. McNemar's test was applied to analyze paired responses using SAS statistical software, with P ≤ 0.05 being considered statistically significant., Results: A total of 1,786 NAMS members were surveyed before and after the 2016 NAMS meeting, 234 (13%) completed the premeeting survey, 166 (9%) completed the postmeeting survey, and 52 completed both surveys. Of the 52, 27 attended the 2016 NAMS Annual Meeting and 25 did not. The pooled cohort contains 348 responses which represents a 20% response rate. Six complex case scenarios with "controversial questions" were identified from the pooled cohort and reexamined in the intervention and control arm, respectively. In the intervention arm, significant changes toward being more likely to prescribe HT in guideline-consistent cases were noted in four out of six cases, whereas significant changes in HT use were not seen in any of six complex cases in the control arm., Conclusions: NAMS members' prescribing patterns of HT vary in complex clinical scenarios. After the 2016 NAMS Annual Meeting where a draft of the 2017 NAMS HT Position Statement was presented and discussed, in four challenging and complex clinical situations a significant number of practitioners changed their prescription patterns toward prescribing HT which was consistent with the new guideline.

The first approved tissue-selective estrogen complex is a pairing of conjugated estrogen combined with the selective estrogen-receptor modulator, bazedoxifene. Advantages include relief of menopausal symptoms without the increased chance of bleeding or breast tenderness unlike with traditional estrogen-progestin therapy, which is associated with both bleeding and breast tenderness. Tissue-selective estrogen complex effects on relief of vasomotor symptoms, prevention of bone loss, improvement in vaginal symptoms, lack of significant cardiovascular effects beyond the expected 2-fold increase in venous thrombosis, neutral effect on breast, and protective effects on the endometrium are discussed.

The goal of the 2017 North American Menopause Society Hormone Therapy (HT) Position Statement is to remove fear about HT and encourage individualized shared decision making, using best available evidence. Systemic HT is safe and effective for symptomatic menopausal women aged younger than 60 years and within 10 years of menopause. Special populations of early menopause, high risk for fracture, risk of breast or uterine cancer, and extended duration are discussed. With longer duration of use, periodic evaluation and reassessment of health risks are needed. Lowered doses, transdermal therapies or newer options may enhance the benefit:risk ratio for HT.