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Background: Vasomotor symptoms (VMS) affect 70% of menopausal women and are considered as hallmark symptoms of the menopausal transition experienced by over three quarters of women and severely by 25% of women. Estrogen withdrawal alone is not fully responsible for the onset of the menopausal vasomotor symptoms and the mechanism of altered thermoregulation appears to be centrally mediated with alterations in hypothalamic neurotransmitters playing a key part. The loss of thermoregulatory control coexists with the altered Kisspeptin- Neurokinin B-Dynorphin-expressing (KNDy) neurons of the arcuate nucleus signaling triggered by menopause., Objective: Aim of the review was to explore evidence-based non-hormonal pharmacological interventions for treating vasomotor symptoms., Methods: Comprehensive overview of relevant literature., Conclusions: In the population where, hormonal options are contraindicated or not preferred by the patient, it is essential to explore evidence-based non-hormonal pharmacological interventions for treating vasomotor symptoms. The 2024 landscape of available treatments has expanded yet again, arming the providers with an even wider range of possibilities to help their patients. Fezolinetant, is the first NK3R antagonist developed for the purpose of treating hot flashes in menopausal women. NK3R antagonists provide a safe and effective treatment option for managing menopausal women with VMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Despite the profound impact of menopausal symptoms on women, treatment utilization is low, and many seek alternative therapies. The REALISE study aimed to evaluate the treatment landscape - that is, pharmacological treatment, lifestyle changes (LC), and use of over-the-counter (OTC) products - for women from six high-income countries experiencing vasomotor symptoms (VMS) and receiving healthcare., Study Design: Analysis of a secondary dataset, the Adelphi Real World Disease Specific Programme™, a large, cross-sectional, point-in-time survey conducted in the United States and five European countries (February-October 2020). Physicians provided demographic, clinical, and treatment data; women were stratified by VMS severity (mild; moderate-severe) and presence of concomitant sleep/mood symptoms. Women completed forms on VMS severity, concomitant symptoms, LC, and OTC product use. Two subgroups were identified: VMS-only and VMS + sleep/mood., Main Outcome Measures: Prescription treatment, LC, and OTC product utilization., Results: Physicians (n = 233) provided data on 1767 women; 825 (46.7 %) completed a self-completion form. Physicians rated 60 % of women with moderate-severe VMS, of whom 709 (66.8 %) were currently prescribed pharmacological treatment; 27.1 % had never been prescribed. Hormone therapy was most frequently prescribed in the moderate-severe group (overall, 49.8 %; VMS-only, 57.4 %; VMS + sleep/mood, 47.3 %), followed by serotonergic antidepressants (15.7 %; 9.7 %; 17.6 %, respectively). Most women (78.3 %) with moderate-severe VMS adopted LC, and 57.6 % used at least one OTC product for VMS relief., Conclusions: Nearly a third of women with moderate-severe VMS had never received treatment despite access to healthcare. This, combined with the prevalent use of LC/OTC products, suggests an unmet need for new treatment options to manage VMS and concomitant sleep/mood symptoms., Competing Interests: Declaration of competing interest S.K. is an employee of University Hospitals Cleveland Medical Center and has received consulting fees or honoraria from: Astellas, Alloy, Bayer, Daré, Freya, Reunion Neuroscience, Materna Medical, Madorra, Ms. Medicine, Mithra, Palatin Technologies, Pfizer, Sprout, Strategic Science Technologies, and Vella; and stock options from Alloy. N.S., C.M., and S.S. are employees of Bayer AG, Germany. C.C. and C.J. are employees of Bayer Consumer Care, Switzerland. M.S. and M.H. are employees of Adelphi Real World, UK. L.H. is an employee of Bayer US. V.B. was an employee of Bayer, UK at the time of the study. R.E.N. has past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, MSD, Palatin Technologies, Pfizer, Procter & Gamble, Teva Women's Health, and Zambon; has ongoing relationships with Abbott, Astellas, Bayer HealthCare, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Novo Nordisk, Organon, Shionogi, Theramex, and Viatris; and serves as President-Elect of the International Menopause Society (IMS)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Women may lack awareness of the existence of Hormone Replacement Therapy (HRT), its benefits, and potential drawbacks. Furthermore, they may be uninformed about the treatability of menopausal symptoms. Consequently, there is a need to evaluate the knowledge, attitudes, and practices related to HRT among menopausal women within the Malaysian population. Presently, no studies have reported on the inside, attitudes, and practices regarding HRT among menopausal women in Kuala Lumpur. This study sought to determine the prevalence, knowledge, attitude, and practice (KAP) towards HRT and its association with socio-demographic characteristics of the study population., Method: A cross-sectional study was conducted among menopausal women (n = 404) living in Kuala Lumpur, Malaysia. Data was collected using convenient sampling. This research consists of 5 major parts which are (A) Socio-demographic characteristics of participants, (B) HRT knowledge among respondents, (C) Attitudes towards HRT, (D) Practice of HRT, and (E) Menopausal symptoms. All appropriate data from the project was analyzed using IBM SPSS Statistics Ver 26., Results: A total of 404 participants were recruited in this survey. Overall, participants had good knowledge (n = 254, 62.9%) and negative attitude (n = 213, 52.7%) towards HRT. The majority of them (83.4%) had never taken HRT. The common menopausal symptoms reported were hot flashes (35.4%), irritability/ mood swings (31.9%), and night sweats (29.2%). There was a significant association between knowledge of menopause and HRT and attitude towards HRT use. Participants (68.7%, n = 103) with poor knowledge of menopause and HRT showed a negative attitude towards HRT (p < 0.01)., Conclusions: Overall, the prevalence of HRT use among the respondents is low. 83.4% of them have never taken HRT before. There was a positive correlation between knowledge and attitude towards HRT use. Healthcare systems should educate the public using various educational tools and social media., (© 2024. The Author(s).)

Objective: Among postmenopausal women, oral, ultra-low-dose continuous combined estradiol (E0.5 mg) plus dydrogesterone (D2.5 mg) reduces vasomotor symptoms (VMS)., Methods: This study was a post hoc analysis of data from two phase 3, double-blind studies. Postmenopausal women were randomized 2:1:2 to receive E0.5 mg/D2.5 mg, E1 mg/D5 mg (not included in this analysis) or placebo for 13 weeks (European study), or randomized 1:1 to receive E0.5 mg/D2.5 mg or placebo for 12 weeks (Chinese study). Endpoints assessed in ethnicity subgroups (European and Chinese) included changes from baseline in number of hot flushes, number of moderate-to-severe hot flushes and Menopause Rating Scale (MRS) score., Results: Overall, 579 women were included in the analysis (E0.5 mg/D2.5 mg, n  = 288; placebo, n  = 291). European and Chinese women receiving E0.5 mg/D2.5 mg experienced greater reductions from baseline in mean daily number of hot flushes and mean daily number of moderate-to-severe hot flushes at week 4, week 8 and end of treatment versus those receiving placebo. Significant improvements in the 'hot flushes, sweating' MRS item score were reported in both European and Chinese women., Conclusion: Oral, ultra-low-dose continuous combined 0.5 mg 17β-estradiol and 2.5 mg dydrogesterone improved VMS compared with placebo in European and Chinese postmenopausal women, with a positive impact on health-related quality of life.

Managing menopause symptoms is challenging for women unable or unwilling to take hormone therapy. All nonhormone options thus far have shown less overall efficacy compared with hormone therapy and significant adverse events that limit their use. New science has identified the source of vasomotor symptoms, achieving relief of these bothersome symptoms by directly targeting the neurokinin 3 receptor and its related pathways. This Practice Pearl reviews the clinical data available on neurokinin receptor antagonists., (Copyright © 2024 by The Menopause Society.)

Fibromyalgia (FM) and climacteric conditions share common epidemiological and clinical features, with FM symptoms often beginning during menopause. Musculoskeletal pain, arthralgia, myalgia and other symptoms are frequently seen in both conditions. Some research suggests a link between the cessation of sex hormones and FM symptoms. Women with FM tend to experience more severe symptoms after menopause, and the severity of FM symptoms can worsen in women who have had a hysterectomy with or without oophorectomy. Despite these similarities, it is essential to treat FM and climacteric conditions separately and follow established guidelines for management. However, it is also important to recognize that both conditions can coexist in the same patient. It is crucial to note that there is limited evidence supporting the effectiveness of menopausal hormone therapy for primary FM management. Therefore, menopausal hormone therapy should not be recommended for FM unless the patient also has climacteric syndrome.

Objective: This study aimed to investigate the effectiveness, tolerability and application of estradiol metered-dose transdermal spray (EMDTS) in postmenopausal women during real-world use., Methods: This was a prospective, non-interventional, multicenter, observational phase IV cohort study. The Menopause Rating Scale II (MRS II) was used to assess symptoms and clinical response. Safety was assessed by the occurrence of adverse events and adverse drug reactions (ADRs)., Results: A total of 451 postmenopausal women were enrolled at 52 gynecological practices across Germany; 383 patients were evaluated for effectiveness and 430 patients for safety. Mean age was 54.3 ± 7.4 years. In total, 228 patients (59.5%) received EMDTS monotherapy and 155 patients (40.5%) received EMDTS plus progestogens. Significant improvements ( p  < 0.0001) from baseline in symptom severity were recorded for all 11 items of the MRS II at 3, 6 and 12 months of treatment. At 12 months, 81.4% of patients reported improvement in hot flushes/sweating. At final visit, 73% of patients and 77% of physicians were 'satisfied/very pleased' with EMDTS. Most common ADRs were headache ( n  = 6), nausea ( n  = 4), dizziness ( n  = 4) and pruritus ( n  = 3)., Conclusions: EMDTS is an effective, well tolerated and easily applied hormone replacement therapy for women experiencing postmenopausal symptoms.

Background: Vasomotor symptoms (VMS), such as hot flashes and night sweats, are highly prevalent and burdensome for women experiencing menopausal transition. Fezolinetant, a selective neurokinin 3 receptor (NK3R) antagonist, is a potential therapeutic option for mitigating VMS., Objectives: Our aim is to assess the efficacy and evaluate the safety profile of fezolinetant compared with placebo in post-menopausal women suffering from VMS, by pooling all the relevant data and reflecting the most current evidence., Search Strategy/selection Criteria: An extensive literature search was performed in the PubMed, Medline and Cochrane Library databases from inception until June 2023 to identify relevant trials., Data Collection and Analysis: Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for continuous outcomes. Risk ratios (RRs) were calculated for dichotomous outcomes. All statistical analyses were performed using R Statistical Software., Main Results: A total of six randomized controlled trials were added. For the frequency of daily VMS, the combined pooled result favored the fezolinetant group over placebo (MD -2.38, 95% CI -2.64 to -2.12; P < 0.001, I 2  = 0%). For the severity of daily VMS, fezolinetant was again found to be superior to the placebo group (MD -0.40, 95% CI -0.51 to -0.29; P < 0.001, I 2  = 70%). Fezolinetant (120 mg) consistently demonstrated a significant reduction in the severity of daily moderate/severe VMS compared with other doses at both 4 and 12 weeks. Patient-reported outcomes (PROs) of Greene Climacteric Scale (GCS), PROMIS the Sleep Disturbance Short Form 8b and Menopause-Specific Quality of Life (MENQoL) scores indicated significant improvement with fezolinetant. No significant difference in efficacy of fezolinetant at 4 and 12 weeks were observed in any outcome. As for safety, no significant differences in the treatment emergent adverse events at 12 weeks were found between fezolinetant and placebo., Conclusions: Our study significantly favors fezolinetant over placebo regarding the primary efficacy outcomes of daily moderate to severe VMS frequency and severity, including PROs, while both the groups are comparable in terms of treatment emergent adverse events. Further studies are needed to confirm these findings., (© 2024 International Federation of Gynecology and Obstetrics.)

Objective: To assess treatment satisfaction, unmet treatment needs, and new vasomotor symptom (VMS) treatment expectations among women with moderate to severe VMS and physicians treating women with VMS., Methods: This noninterventional, nonrandomized survey included qualitative interviews and quantitative surveys of women and physicians in the US. Participating women had moderate to severe VMS in the past year and received ≥1 hormone therapy (HT), non-HT, or over-the-counter (OTC) treatment for VMS in the past 3 months. Participating physicians were obstetrician-gynecologists (OB-GYNs) and primary care physicians (PCPs) who treated ≥15 women with VMS in the past 3 months. Two online survey questionnaires were developed using insights from literature, qualitative interviews, and clinical experts. Menopause Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) measured treatment satisfaction. Results were summarized descriptively., Results: Questionnaires were completed by 401 women with VMS and 207 physicians treating VMS. Among women, mean total MS-TSQ score ranges were 62.8-67.3 for HT, 59.8-69.7 for non-HT, and 58.0-64.9 for OTC treatments. Among physicians, mean total MS-TSQ scores were considerably higher for HT than for non-HT and OTC treatments (HT: 73.4-75.6; non-HT: 55.6-62.1; OTC: 49.2-54.7). Women reported "lack of effectiveness" (41.2%), and physicians reported "long-term safety concerns" (56.5%) as main features that do not meet their current treatment expectations. The majority of women and physicians would consider trying a new non-HT treatment for VMS (75.8 and 75.9%, respectively)., Conclusions: Treatment satisfaction and new treatment expectations were similar but with some differences between women and physicians; the need for additional treatments for VMS was identified., Competing Interests: Financial disclosures/conflicts of interest: B. DePree serves on an advisory council for Astellas Pharma, Inc. A. Shiozawa, J. Kim, and S. Mancuso are employees of Astellas Pharma, Inc. Y. Wang and H. Yang are employees of Analysis Group, Inc., which received funding from Astellas Pharma, Inc., for the current study., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Objectives: Evidence suggests ethnicity-specific differences in postmenopausal symptoms, highlighting the need for therapies that are efficacious across different ethnicities. We evaluated the efficacy of an ultra-low dose combination of 0.5 mg estradiol and 0.25 mg dydrogesterone (E 0.5 mg/D 2.5 mg) in alleviating vasomotor symptoms across a multi-ethnic population., Study Design: Data from two controlled trials were pooled to form a dataset of 583 postmenopausal women from across Europe and China. Participants were randomized to receive treatment with E 0.5 mg/D 2.5 mg or placebo for 12 weeks., Main Outcome Measures: The main efficacy variable was absolute change in the number of hot flushes from baseline to end of treatment. Health-related quality of life and safety were also assessed., Results: Change in the number of hot flushes per day was greater with E 0.5 mg/D 2.5 mg versus placebo (mean difference - 1.5, 95 % confidence interval - 2.1, -1.0; p < 0.001). Participants treated with E 0.5 mg/D 2.5 mg reported improvement in health-related quality of life (including psychological symptoms, vaginal dryness), and high amenorrhea rates. Combined E 0.5 mg/D 2.5 mg was well tolerated: there were no differences between groups in the percentage of participants with at least one serious adverse event or treatment-emergent serious adverse events. Analysis of change in body weight indicated no differences between groups., Conclusions: This pooled analysis demonstrates the consistent efficacy of E 0.5 mg/D 2.5 mg in the treatment of menopause-related symptoms across a multi-ethnic population of postmenopausal women., Competing Interests: Declaration of competing interest MR, QY, and TT declare no conflicts of interest. JCS reports having received speaker's honoraria in the past three years from Abbott, Theramex and Viatris; he is also chairman of Women's Health Concern, a trustee of the British Menopause Society and an expert advisor to the National Institute for Health and Care Excellence (UK). EK is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott. MGC is an employee of Abbott Products Operations AG, Allschwil, Switzerland and owns shares in Abbott. REN reports having received a grant from Fidia to her institution, consulting fees from Astellas, Bayer HealthCare AG, Besins Healthcare and Fidia, and speaker's honoraria from Abbott, Bayer HealthCare AG, Gedeon Richter, Merck & Co, Shionogi Limited, Theramex, Viatris and Vichy Laboratories; she is also president elect of the International Menopause Society. VK is an employee of Established Pharmaceuticals Division, Abbott Ukraine LLC, Kyiv, Ukraine. TS reports having received consulting fees in the past three years from Abbott, Actavis, Applied Medical, Astellas, Estetra, Gedeon Richter, Johnson & Johnson, Medtronic, Mitsubishi Tanabe and Sojournix, and speaker's honoraria from Abbott, Applied Medical, Gedeon Richter, Intuitive Surgical, Shionogi and Theramex., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: evaluate the efficacy and tolerability of PureCyTonin against hot flashes (HF) in breast cancer survivors (BCS)., Methods: a prospective, multicenter, randomized, double-blind placebo-controlled trial was conducted in Italy., Interventions: administration of PureCyTonin or placebo, for 3 months. Effectiveness was investigated through the compilation of a daily diary for HF and of validated questionnaires (Menopause Rating Scale (MRS), Pittsburgh Sleep Quality Index (PSQI), Visual Analogical Scales (VAS) for HF, sweating, irritability, fatigue, sleep, quality of life), carried out before starting the treatment (T0), after 1 month (T1) and after 3 months (T2). Any side effects and HF diary were recorded at each visit., Results: 19 women were randomized to receive PureCyTonin and 20 to placebo. At T2 compared to T0, in the PureCyTonin group, we found a reduction in the number of HF ( p  = 0.02) measured by daily diary. An improvement in the subjective perception of women regarding HF intensity ( p  = 0.04), sweat nuisance ( p  = 0.02), irritability ( p  = 0.03) and fatigue ( p  = 0.04) was observed through VAS scale measurement at T2 compared to T0.The total MRS score was significantly better in the PureCyTonin group at T1 ( p  = 0.03) compared to T0., Conclusions: PureCyTonin significantly reduces HF number after 3 months of therapy in BCS and it is well-tolerated.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n  = 736; placebo, n  = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Objective: The phase II STARLIGHT study was conducted to investigate the efficacy/safety of fezolinetant in Japanese women and identify the optimal dose for future evaluation., Method: Participants were perimenopausal/postmenopausal women aged ≥40 to ≤65 years from 36 centers in Japan seeking treatment/relief for vasomotor symptoms (VMS) associated with menopause. After screening, participants were randomized 1:1:1, stratified by menopausal status, to receive fezolinetant 15 or 30 mg or placebo orally once daily for 12 weeks. Participants completed a daily VMS diary. The primary endpoint was mean change in frequency of VMS of any severity from baseline to week 8. Secondary endpoints included mean change in VMS frequency from baseline each week up to week 12 and frequency/severity of adverse events., Results: A total of 147 participants were randomized (placebo, n  = 47; fezolinetant 15 mg, n  = 53; fezolinetant 30 mg, n  = 47). Fezolinetant 15 and 30 mg demonstrated statistically significant reductions in mean VMS frequency at week 8 versus placebo. Least-squares mean estimates of mean change in frequency of VMS from baseline to week 8 were -7.04 for fezolinetant 15mg, -6.31 for fezolinetant 30mg, and -4.55 for placebo. The difference in least-squares mean estimates was -2.50 (95% CI: -4.03, -0.96), p  = 0.002 for fezolinetant 15mg and placebo, and was -1.76 (95% confidence interval [CI]: -3.35, -0.17), p  = 0.030 for fezolinetant 30mg and placebo. Reductions from baseline in mean VMS frequency versus placebo were seen after week 1 of treatment, maintained throughout 12 weeks. Fezolinetant was well tolerated, with no safety signals of concern for either dose to week 12., Conclusion: Oral fezolinetant at once-daily doses of 15 or 30 mg was efficacious and well tolerated for treatment of mild, moderate and severe VMS associated with menopause in this Japanese study.

Introduction: Perimenopause is a time of transition in a woman's life that links her reproductive years to the cessation of ovulation, or menopause. For many women, this time is characterized by a variety of physiological and lifestyle changes, including increasing irregularity in menstrual bleeding, frequency and severity of vasomotor symptoms, etc. Therapies evaluated specifically for the perimenopausal women are very limited. This study aimed to evaluate the effectiveness and safety of Amberen ® (a succinate-based non-hormonal supplement) combined with a Smart B ® (vitamin B) complex in women with typical (without complications) mild to moderate climacteric syndrome during perimenopause., Methods: Women up to 50 years of age, in perimenopause, with vasomotor and psychosomatic symptoms of the climacteric syndrome were enrolled for the study. The trial was randomized, double-blinded, placebo-controlled, comparative, and prospective., Results: A total of 106 participants were enrolled in the trial and, per protocol, 105 completed the trial. We observed statistically significant improvements in most of the Greene Climacteric Scale symptoms, State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS), and Well-being, Activity, and Mood (WAM) scores. The intervention was well tolerated with few adverse effects reported to be mild and transient., Conclusion: The use of this dietary supplement is safe and eliminates or improves vasomotor and psychosomatic symptoms of climacteric symptoms in perimenopausal women: it improves sleep and cognitive abilities, lowers depression and anxiety, improves mood and well-being, and positively affects quality of life., Gov Identifier: NCT03897738., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Many women seek treatment to improve menopausal vasomotor symptoms (VMS). The selection of women most likely to benefit from menopause hormone therapy (MHT) is crucial in clinical practice. There is general agreement that women younger than 60 years or who initiate MHT within the first 10 years of menopause, with no contraindications, have greater benefits considering symptomatic relief and additional advantages. This group may have the advantage of protection from osteoporosis and from other chronic diseases that affect postmenopausal women, namely cardiovascular disease (CVD). Cumulating evidence supports MHT for symptomatic women. However, inadequate use according to the needs of symptomatic women led to a burden of suffering worldwide. In recent years, the emergent use of non-regulated body-identical hormones (non-rBHT) can expose patients to potential harms. These hormone preparations are not regulated through the same tests of safety, efficacy or dosing consistency as regulated-BHT (r-BHT). The POESIT (Portugal + Spain + Italy) recommendations highlight the use of 17β-estradiol (E2) and micronized progesterone (P4) as the real r-BHT. In addition, the group emphasizes as an example the data from the REPLENISH study with 1 mg E2/100 mg P4. The combination of the two hormones in one convenient pill showed a clear reduction or elimination of hot flashes and an improvement in sleep quality and, consequently, quality of life. At the same time, this combination has shown high rates of amenorrhea and no significant impact on lipid, glucose or coagulation parameters. Both the REPLENISH study and a real-life retrospective study pointed to the possibility of a lower risk of venous thromboembolism (VTE) with this formulation than with other combinations.

Objectives: To analyse the effect of fezolinetant on patient-reported sleep disturbance and impairment in individuals with vasomotor symptoms (VMS) using pooled data from the SKYLIGHT 1 and 2 studies., Study Design: The SKYLIGHT studies were phase-3, double-blind investigations. Individuals (≥40-≤65 years) who were assigned female at birth and seeking treatment of/relief from moderate-to-severe VMS were enrolled. Participants were randomised to receive placebo, fezolinetant 30 mg, or fezolinetant 45 mg during a 12-week treatment period., Main Outcome Measures: Sleep assessments: Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b), PROMIS Sleep-Related Impairment - Short Form 8a (PROMIS SRI SF 8a), and Patient Global Impression of Change/Severity in SD (PGI-C SD and PGI-S SD). Assessments were completed at baseline (except PGI-C SD), weeks 4 and 12., Results: Overall, 1022 individuals were randomised and took ≥1 dose of study drug. PROMIS SD SF 8b results showed that improvements in sleep disturbance were observed for fezolinetant 30 and 45 mg versus placebo (week 12, least squares [LS] mean differences: -0.6 [95 % confidence interval [CI]: -1.7, 0.4] for 30 mg and -1.5 [-2.5, -0.5] for 45 mg). Similar improvements in sleep impairment were reported using the PROMIS SRI SF 8a (week 12, LS mean differences: -1.1 [95 % CI: -2.1, -0.1] for 30 mg and -1.3 [-2.3, -0.3] for 45 mg). For PGI-C SD at week 12, 33.6 % (98/292 participants) of the placebo group felt much/moderately better versus 40.1 % (110/274) and 51.0 % (154/302) of the fezolinetant 30 mg and 45 mg groups, respectively. For PGI-S SD at week 12, 44.0 % (129/293) of the placebo group had severe/moderate problems versus 41.1 % (113/275) and 36.6 % (111/303) of the fezolinetant 30 mg and 45 mg groups, respectively. The 12-week timeframe for this analysis was limited by the length of the placebo-controlled period., Conclusions: Fezolinetant had a beneficial effect on four measures of sleep disturbance and impairment following treatment for VMS., Competing Interests: Declaration of competing interest Marla Shapiro C.M. has attended advisory boards and/or received consulting fees or honoraria from Aspen, Astellas, Bayer HealthCare, BioSyent, Duchesnay, GSK, Merck, Mithra, Pfizer, Searchlight, Sprout, Sunovion, and Therapeutics MD; and fulfils a leadership or fiduciary role for the International Menopause Society, Research Canada, and Terry Fox Research Institute. Antonio Cano was the past President of the European Menopause and Andropause Society; and is a consultant for Astellas, Theramex, and Viatris. Rossella E. Nappi has past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Exeltis, Novo Nordisk, Palatin Technologies, Pfizer, Procter & Gamble, Teva Women's Health, and Zambon; has ongoing relationships with Abbott, Astellas, Bayer HealthCare, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Organon, Shionogi, and Theramex; and serves as President Elect of the International Menopause Society. Nanette Santoro is a study investigator, member of a scientific advisory board, and consultant for Astellas; a member of a scientific advisory board for Amazon (Project Ember), MenoGeniX, and QUE Oncology; a consultant for Ansh Labs; an Associate Editor for Menopause; and a past President of the Society for Reproductive Investigation. Marci L. English, Shayna Mancuso, Udaya Valluri, and Faith D. Ottery are employees, or former employees, of Astellas Pharma Inc. Antonia Morga and Emad Siddiqui are employees of Astellas Pharma Europe Ltd., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the effect of fezolinetant treatment on health-related quality of life using pooled data from SKYLIGHT 1 and 2 studies., Design: Prespecified pooled analysis., Setting: USA, Canada, Europe; 2019-2021., Population: 1022 women aged ≥40 to ≤65 years with moderate-to-severe vasomotor symptoms (VMS; minimum average seven hot flushes/day), seeking treatment for VMS., Methods: Women were randomised to 12-week double-blind treatment with once-daily placebo or fezolinetant 30 or 45 mg. Completers entered a 40-week, active extension (those receiving fezolinetant continued that dose; those receiving placebo re-randomised to fezolinetant received 30 or 45 mg)., Main Outcome Measures: Mean changes from baseline to weeks 4 and 12 on Menopause-Specific Quality of Life (MENQoL) total and domain scores, Work Productivity and Activity Impairment questionnaire specific to VMS (WPAI-VMS) domain scores, Patient Global Impression of Change in VMS (PGI-C VMS); percentages achieving PGI-C VMS of 'much better' (PGI-C VMS responders). Mean reduction was estimated using mixed model repeated measures analysis of covariance., Results: Fezolinetant 45 mg mean reduction over placebo in MENQoL total score was -0.57 (95% confidence interval [CI] -0.75 to -0.39) at week 4 and -0.47 (95% CI -0.66 to -0.28) at week 12. Reductions were similar for 30 mg. MENQoL domain scores were also reduced and WPAI-VMS scores improved. Twice as many women receiving fezolinetant reported VMS were 'much better' than placebo based on PGI-C VMS assessment., Conclusions: Fezolinetant treatment was associated with improvement in overall QoL, measured by MENQoL, and work productivity, measured by WPAI-VMS. A high proportion receiving fezolinetant felt VMS were 'much better' based on PGI-C VMS responder analysis., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared. Refer to the online supplementary files to view the ICMJE form(s).

Background: Menopause, characterized by various physical and mental changes, is primarily caused by hormonal fluctuations, resulting in numerous complications. Recently, herbal treatments have gained significant attention for their minimal side effects compared to chemical drugs. This study aimed to investigate the effects of oral capsules containing Ocimum basilicum leaf extract (OBLE) on menopausal symptoms., Methods: This placebo-controlled clinical trial study was conducted in 2020. The research focused on 60 menopausal women referred to Mashhad health centers. Eligible participants were administered either an OBLE 500 mg capsule or a placebo daily for 1 month. Menopause symptoms were evaluated using the Menopause Rating Scale (MRS) before, two weeks, and one month after the intervention. Data were analyzed using SPSS21, independent t, Mann-Whitney, and Friedman tests. A significance level of p < 0.05 was considered significant., Results: The independent t-test indicated that the mean (SD) scores of menopausal symptoms in both the OBLE and placebo groups were initially similar before the intervention (P = 0.141). Two weeks after the intervention, the menopausal symptom scores were 9.5 ± 3.5 and 11.2 ± 5.6 in the OBLE and placebo groups, respectively (P = 0.163, df = 58, t = 1.4). After one month, the menopausal symptom scores were 6.9 ± 0.3 in the OBLE group and 11.26 ± 0.6 in the placebo group (P = 0.001, df = 58, t = 3.4). This indicates a significant difference between the two groups one month after the intervention, compared to before and two weeks after the intervention. Additionally, there was a significant difference in the scores of the physical and somato-vegetative dimension between the intervention and placebo groups two weeks and one month after the intervention (P < 0.05)., Conclusion: The study results suggested that taking OBLE capsules led to a decrease in the scores of menopausal symptoms. This indicates that OBLE can be considered as a safe and cost-effective medicinal plant for alleviating menopausal symptoms among women., (© 2024. The Author(s).)

The number of midlife women transitioning into menopause is substantial, with more than 1 million women in the United States entering menopause each year. Vasomotor symptoms (VMS), mood and sleep disturbances, and sexual problems are common during the menopause transition yet often go untreated. Menopausal hormone therapy is the most effective treatment of VMS, and the benefits typically outweigh the risks for women without contraindications who are younger than 60 years or within 10 years from menopause onset. For women who cannot or choose not to use hormone therapy, nonhormone prescription options exist to treat VMS. Many of these therapies have secondary benefits beyond VMS relief. For example, whereas paroxetine is Food and Drug Administration approved to treat VMS, it can also help with depressive and anxiety symptoms. The aim of this paper is to summarize prescription treatments of VMS and their secondary benefits for other common symptoms experienced by midlife women. The tools presented will help clinicians caring for midlife women provide individualized, comprehensive care with the goal of improving their quality of life during the menopause transition and beyond., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin 3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data., Methods: This analysis pooled data from two identical phase 3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30 mg, 45 mg, or placebo (SKYLIGHT 1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks 4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better.", Results: In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week 4 and - 6.20 (5.18) at week 12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week 4 (odds ratio range 2.48-2.91; P < 0.001) and week 12 (odds ratio range 1.908-2.68; P < 0.001)., Conclusion: PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week 12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option., Trial Registration Number: NCT04003155 and NCT04003142., (© 2024. The Author(s).)

Hormonal changes during the menopause transition may lead to vasomotor symptoms, including hot flashes (HFs) and neuropsychiatric symptoms such as anxiety and irritability. We hypothesized that the effects of cassis polyphenol (CaP) to improve microcirculation and vasorelaxation may alleviate menopausal symptoms. We performed a randomized, double-blind, parallel-group, placebo-controlled trial involving 59 healthy women (mean [standard deviation] age, 51.3 [4.3] years; body mass index, 20.8 [2.6] kg/m 2 ). Participants experiencing subjective menopausal symptoms consumed CaP tablets (400 mg/d, CaP group) or placebo tablets (placebo group) for 4 weeks. Participants were evaluated using questionnaires at baseline, during the 4-week intervention period, and during a 2-week postinterventional observation period. The primary objective was to evaluate the effects of supplementation with CaP on HFs in healthy Japanese women with menopausal symptoms. Additional assessments included the modified Kupperman menopausal index, World Health Organization-5 Well-Being Index, World Health Organization quality-of-life 26-item index, State-Trait Anxiety Inventory (anxiety and trait components), and Oguri-Shirakawa-Azumi sleep inventory (middle-aged and elderly versions). During the 4-week intervention period, no significant between-group differences were detected in the HF frequency, HF score, sweating frequency, menopausal symptoms, quality of life, anxiety, or sleep. During the 2-week postintervention observational period, the HF score and sweating frequency were significantly decreased in the CaP group compared with the placebo group. These findings suggest that twice daily intake of CaP for 4 weeks does not alleviate menopause symptoms, but the improvement observed in the CaP intake group during the postintervention period warrants confirmation through further large-scale studies., Competing Interests: Author Declarations M. O., K. M., T. Y., S. O., A. S., and M. H. are employees of the Kao Corporation, which is the study funder and a chemical, cosmetic, and food company headquartered in Tokyo, Japan. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

Objective: To determine the effect of oral Lavandula angustifolia Mill. essential oil (LEO) on menopausal symptoms, serum cortisol level, and lipid profile in postmenopausal women., Methods: This was a triple-blind parallel-armed randomized trial. Seventy-two postmenopausal women aged 50-65 years referring to healthcare centers in Tabriz, Iran with a score of 15-42 on the Green scale were included from May 10, 2022 to May 22, 2023. The participants were randomly assigned to two groups with a 1:1 ratio and using four and six blocks. One group received LEO soft gel 80 mg per day, and another group received a similar placebo for 60 days. A demographic questionnaire and a Greene menopause symptom scale were used for data collection. The lipid profile (total cholesterol, triglyceride, LDL, HDL) and the serum levels of cortisol were measured using biochemical methods. Chi-square, Fisher's exact tests, Independent samples t-test, Analysis of Covariance (ANCOVA), Repeated measure ANOVA, and Paired sample t-test were utilized for analyses. A p-value less than 0.05 was considered statistically significant., Results: The demographic and personal characteristics of the participants were similar. After two months of intervention, all symptoms in psychological, physical, vasomotor, anxiety, depression, and sexual dysfunction domains were significantly relieved (decreased) among both groups (p < 0.003), except for sexual dysfunction, the reduction of which was not significant in the placebo group (p = 0.317). The mean (SD) total score of menopausal symptoms reduced from 27.4 (6.3) at baseline to 17.7 (4.9) at the end of the study in the LEO group (p < 0.001). It also decreased from 27.4 (7.1) to 17.6 (5.1) in the placebo group (p < 0.001). However, between-group analyses revealed that this reduction was significantly greater in the LEO group compared to the placebo group only in the sexual dysfunction (Mean (SD): 1.3 (0.6) vs. 1.0 (0.5); adjusted mean difference (95% confidence interval); p: - 0.35 (-0.67 to -0.02); 0.039). No significant within-group changes or between-group differences were observed (p > 0.05) in terms of studied serum markers., Conclusion: The oral LEO exhibited a significant enhancement in sexual dysfunction among postmenopausal women. Therefore, it can be used alongside other therapies to improve sexual dysfunction during menopause. LEO did not affect lipid profile and serum cortisol level in this study., Competing Interests: Declaration of Competing Interest There is no conflict of interest in this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Objective: Vasomotor symptoms (VMS) are the most common symptoms during menopause including hot flushes and night sweats. They are highly disruptive to the quality of life. Fezolinetant is an FDA-approved non-hormonal selective neurokinin3 receptor antagonist for the treatment of VMS. In this study, we aim to assess the efficacy and safety of fezolinetant for VMS associated with menopause., Methods: Databases were searched until September 2023 for relevant studies comparing fezolinetant against placebo. Data was extracted into an online form and analyzed using RevMan (Version 5.4.1). The GRADE approach was conducted to evaluate the quality of evidence regarding efficacy outcomes. We included randomized controlled trials (RCTs) comparing fezolinetant to placebo in postmenopausal women experiencing VMS. Exclusion criteria comprised studies involving participants with contraindications to fezolinetant or those evaluating its efficacy for indications other than VMS associated with menopause., Results: Six studies were included in this study involving 3301 patients. Compared to placebo, fezolinetant reduced the frequency of VMS episodes from baseline (SMD = -0.64, 95 % CI [-0.77, -0.5]) and (SMD = -0.63, 95 % CI [-0.72, -0.53] at weeks 4 and 12 respectively. Additionally, fezolinetant reduced VMS severity score (SMD = -0.59, 95 %CI [-0.77, -0.42]) and (SMD = -0.4, 95 % CI [-0.54, -0.27]) at weeks 4 at 12 respectively. These reductions were positively reflected on Menopause specific quality of life score (SMD = -0.46, 95 %CI [-57, -0.34]), (SMD = -0.37, 95 %CI [-0.48, -0.25]) at weeks 4 and 12 respectively. Regarding safety analysis, fezolinetant showed increased risk for drug-related TEAEs (RR = 1.47, 95 %CI [1.06,2.04]), serious TEAEs (RR = 1.67, 95 %CI [1.09,2.55]), fatigue (RR = 4.05, 95 %CI [1.27,12.88]), arthralgia (RR = 2.83, 95 %CI [1.02,7.8]) and ALT or AST > 3 times (RR = 2, 95 %CI [1.12,3.57]), with no other statistically significant difference regarding other safety terms., Conclusion: Fezolinetant has demonstrated efficacy in reducing the frequency and severity of VMS in postmenopausal women, leading to an improvement in their quality of life. These findings suggest that Fezolinetant may serve as a viable alternative to hormonal therapy for managing VMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The aims of the study were to further characterize the efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) due to menopause using responder analysis and to investigate whether efficacy, not adjusted for placebo, resulted in clinically meaningful within-patient change., Methods: This prespecified analysis used pooled data from two phase 3, randomized, double-blind, placebo-controlled studies (SKYLIGHT 1 and 2). Responders were those experiencing ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. Responder analysis was performed for patient-reported outcome (PRO) measures to evaluate participants achieving a clinically meaningful within-patient change (not placebo adjusted) at week 4 and 12 versus baseline. Single responders were based on outcomes of VMS frequency, Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b Total Score, Menopause-Specific Quality of Life (MENQoL) Total Score, and MENQoL VMS Domain Score. Double and triple responder analyses combined VMS frequency plus one or more of the PRO. Patient Global Impression of Change VMS was deemed a suitable anchor measure for meaningful within-patient change in VMS frequency., Results: A greater proportion of fezolinetant-treated versus placebo-treated participants had ≥50%, ≥75%, ≥90%, or 100% reduction in VMS frequency from baseline to weeks 4 and 12. A greater proportion of responders were observed in the fezolinetant groups versus placebo at week 12 in all four single responder analyses. In the double and triple responder analyses, odds ratios were supportive of a beneficial effect for both doses of fezolinetant versus placebo., Conclusions: Fezolinetant was associated with significantly higher within-patient clinically meaningful improvement in important PRO, including VMS frequency, PROMIS SD SF 8b Total Score, MENQoL Total Score, and MENQoL VMS Domain Score., Competing Interests: Financial disclosure/conflicts of interest: R.E.N. reports past financial relationships (lecturer, member of advisory boards and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Exeltis, Novo Nordisk, Palatin Technologies, Pfizer, Procter & Gamble, Teva Women's Health and Zambon; ongoing relationships with Abbott, Astellas, Bayer HealthCare, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Organon, Shionogi, Theramex and Viatris; serving as President elect of the International Menopause Society; and is a member of the Fezolinetant Scientific Steering Committee. K.A.J. reports being a study investigator and consultant for Astellas and a study investigator for iResearch Atlanta. P.S. reports being a consultant for Astellas; a board member for DMG and EMAS; President of the SGEM; speaker's fees for Theramex, Exeltis, Gedeon Richter, Besins Healthcare, and Jenapharm; and a member of the Fezolinetant Scientific Steering Committee. M.B., M.E., L.S. and F.D.O. are employees of Astellas Pharma Inc. A.M. and E.S. are employees of Astellas Pharma Europe Ltd., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

This systematic review and meta-analysis investigated the efficacy and safety of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) associated with menopause. PubMed, Cochrane Library, Embase and Web of Science were searched for randomized controlled trials (RCTs) published from inception to June 2023, comparing fezolinetant to placebo in postmenopausal women suffering from moderate-to-severe VMS. The mean difference and risk ratio were calculated for continuous and binary outcomes, respectively. R software was used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. We performed subgroup analysis based on different dosing regimens. Five RCTs comprising 3302 patients were included. Compared with placebo, at 12-week follow-up, fezolinetant significantly reduced the daily frequency of moderate-to-severe VMS (weighted mean difference [WMD] - 2.36; 95% confidence interval [CI] - 2.92, -1.81) and daily severity of moderate-to-severe VMS (WMD -0.22; 95% CI -0.31, -0.13). Also, fezolinetant significantly improved the quality of life (WMD -0.42; 95% CI -0.58, -0.26) and sleep disturbance (WMD -1.10; 95% CI -1.96, -0.24). There were no significant differences between groups in adverse events. These findings support the efficacy and safety of fezolinetant for the treatment of VMS related to menopause.

Introduction: During menopause, the majority of women experience vasomotor symptoms which may lead to several untoward effects and negatively impact quality of life. Fezolinetant, a novel agent directly targeting the underlying pathophysiology of menopause-associated vasomotor symptoms, offers an alternative to hormonal therapies for which many patients have a contraindication or unwillingness to take due to safety concerns., Areas Covered: This review summarizes key pharmacologic, pharmacokinetic, and pharmacodynamic parameters of fezolinetant along with efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications evaluating the efficacy and safety of fezolinetant was conducted using PubMed and EMBASE databases. A review of registered trials in clinicaltrials.gov was evaluated to identify ongoing studies., Expert Opinion: Placebo-controlled studies demonstrated that fezolinetant led to a statistically significant reduction in vasomotor symptom frequency and severity among patients with moderate-to-severe vasomotor symptoms. The most common adverse event is headache (5-10%) and no serious safety signals have been noted. Direct head-to-head comparison with hormonal therapies and nonhormonal therapies for vasomotor symptoms, assessment of sleep outcomes, and evaluation of efficacy and safety beyond 1 year are key areas where additional data are still needed.

Hormone replacement therapy (HRT) is considered the gold standard for management of vasomotor and vaginal symptoms of menopause. Vasomotor symptoms of menopause may include hot flashes and diaphoresis that vary in intensity and duration. Other symptoms of menopause can include vaginal atrophy and dryness, leading to dyspareunia and increased risk of infection. These symptoms can be impactful on a woman's life and HRT has data to support its efficacy, however, HRT carries significant risks that are generally well known, including risk of stroke, cardiovascular disease, breast cancer, and venous thromboembolism. These risks were most well characterized by several landmark trials published in the early 2000s. There are several nuances to prescribing HRT that can make doing so complex. These include consideration of cyclic vs continuous administration and of tapering therapy. Additionally, estrogen is available in a variety of dosage forms including injections and transdermal formulations. However, for women with an intact uterus, estrogen will need to be combined with progestin or bazedoxifene (a selective estrogen receptor modulator - SERM), both once daily oral formulations, in order to minimize malignancy risk. Though product preference and considerations of dosing may vary depending on practitioner preference, this brief report aims to clarify some nuances to prescribing or recommending HRT., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years., Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up., Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Objective: We aimed to assess long-term safety and tolerability of fezolinetant, a nonhormonal neurokinin 3 receptor antagonist, among Chinese women with vasomotor symptoms associated with menopause participating in the MOONLIGHT 3 trial., Methods: In this phase 3 open-label study, women in menopause aged 40-65 years received fezolinetant 30 mg once daily for 52 weeks. The primary endpoint was frequency and severity of treatment-emergent adverse events (TEAEs), assessed at every visit through week 52 and one follow-up visit at week 55., Results: Overall, 150 women were enrolled (mean age, 54 years) and 105 completed treatment. The frequency of TEAEs was 88.7%. Most TEAEs were mild (63.3%) or moderate (22.7%). The most common TEAE was upper respiratory tract infection (16.0%), followed by dizziness, headache, and protein urine present (10.7% each). There was no clinically relevant change (mean ± standard deviation) in endometrial thickness (baseline, 2.95 ± 1.11 mm; week 52, 2.94 ± 1.18 mm). Alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of normal were reported in 1.4% of women; no Hy's Law cases occurred., Conclusions: Fezolinetant 30 mg once daily was generally safe and well tolerated over a 52-week period among women in China with vasomotor symptoms associated with menopause. ClinicalTrials.gov Identifier: NCT04451226., Competing Interests: Declaration of conflicting interestsWeizhong He was an employee of Astellas Pharma Global Development, Inc., at the time of the study. Kentaro Miyazaki is an employee of Astellas Pharma, Inc., Xuegong Wang is an employee of Astellas Pharma Global Development, Inc., and Xiao Ma is an employee of Astellas (China) Investment Co, Ltd. The remaining authors have no conflicts of interest to disclose.

Introduction: In many postmenopausal women, quality of life is decreased due to vasomotor symptoms. Efficient and well-tolerated non-hormonal treatment options are needed., Areas Covered: The present review summarizes what is known about the etiology of postmenopausal vasomotor symptoms as a rationale for the mechanism of action of Elinzanetant, a new neurokinin (NK)-1/-3 receptor antagonist, as well as its efficacy and side effect profile., Expert Opinion: Elinzanetant likely exerts an antagonistic effect on the NK-3 receptor in the preoptic thermoregulatory zone, but also an additional antagonistic effect on the NK-1 receptor possibly leading to a reduction in vasodilatation and heat-sensing neuro-activity. Elinzanetant's reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours. Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses. There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity. Overall, Elinzanetant seems to be well-tolerated. In the SWITCH-1 study, the 120 mg/day and 160 mg/day regimen showed good efficacy for the treatment of vasomotor symptoms and led to significant improvements in quality of life. Thus, 120 mg oral Elinzanetant/day was used in phase III trials, whose results have not yet been published.

Objective: To evaluate the efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms (VMS) associated with menopause in East Asian women., Methods: In this phase 3, randomized, double-blind study, postmenopausal women with moderate to severe VMS (minimum average frequency in the 10 days before randomization, ≥7/day or 50/week) received fezolinetant 30 mg/day or placebo (weeks 1-12), followed by an open-label extension phase with fezolinetant 30 mg/day (weeks 13-24). The co-primary endpoints were the mean changes in the daily frequency and severity of VMS at weeks 4 and 12., Results: Among 301 participants, the difference in the least squares mean change (95% confidence interval) from baseline in the daily frequency of moderate to severe VMS versus placebo was -0.65 (-1.41 to 0.12) at week 4 and -0.55 (-1.35 to 0.26) at week 12. The differences in the least squares mean change from baseline in the VMS severity score versus placebo were -0.06 (-0.14 to 0.03) and -0.13 (-0.27 to 0.01) at weeks 4 and 12, respectively. Serious adverse events occurred in 0.7% of participants receiving fezolinetant in weeks 1 to 12, compared with 1.3% of those receiving placebo., Conclusions: Fezolinetant was generally safe but did not reduce the frequency or severity of VMS versus placebo in postmenopausal women in this study. ClinicalTrials.Gov Identifier: NCT04234204., Competing Interests: Declaration of conflicting interestsWeizhong He was an employee of Astellas Pharma Global Development, Inc., at the time of the study. Kentaro Miyazaki is an employee of Astellas Pharma, Inc., Xuegong Wang is an employee of Astellas Pharma Global Development, Inc., and Xiao Ma and Nan Song are employees of Astellas (China) Investment Co, Ltd. The remaining authors have no conflicts of interest to disclose.

Objective: The present study aimed to determine the efficacy of EstroG-100 herbal extract on hot flashes in postmenopausal women., Material and Methods: This randomized, double-blind, placebo-controlled trial was performed on postmenopausal women recruited from two university hospitals complaining of hot flashes. The intervention group received two extract capsules (daily for 12 weeks), and the control group received two placebo capsules (daily for 12 weeks). Finally, the frequency and severity of hot flashes (F&S) were subjectively reported and compared weekly during the treatment for 12 weeks., Results: Out of 120 randomized participants, 35 entered the final analysis for each group. In the third week, participants of the control group significantly reported more moderate hot flashes than other group (MD=1.00, P = 0.004). However, in terms of mild (MD=0.74, P = 0.057) and severe (MD=0.60, P = 0.064) hot flashes, the groups did not differ. In the sixth week, mild (MD=1.51, P<0.001), moderate (MD=1.54, P<0.001), and severe (MD=1.22, P<0.001) hot flashes were significantly reported more in the control group compared with another group., Conclusion: The present study revealed that EstroG-100 herbal extract could improve hot flashes in postmenopausal women., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Menopausal and postmenopausal women experience many physical and psychological symptoms. The positive effects of aromatherapy sessions with different oils on menopausal symptoms are well known. The aim of this study was to investigate the effect of an aromatherapy massage with peppermint and lemon essential oil on menopausal symptoms., Methods: Total 63 menopausal and postmenopausal women were included in this study. Participants were randomly divided into three groups: Menta peppermint (n = 21), Citrus lemon (n = 21), and Placebo (n = 21). The peppermint and lemon essential oils of the intervention groups were diluted with 1.5 % sweet almond oil. Pure sweet almond oil was used in the placebo group. Each participant in the massage groups received a hand and arm massage with the selected oil twice a week for 4 weeks in 30-min sessions. Participants' menopausal symptoms were assessed before and after application using the Menopause Symptoms Rating Scale (MRS)., Results: When the differences in the treatment groups according to time were examined, it was found that there were statistically significant differences in lemon (F = 9.561, p = 0.003, η 2  = 0.139) and peppermint essential oil (F = 15.687, p = 0.001, η 2  = 0.210) groups according to time. The peppermint essential oil group was more effective than the lemon group. In addition, both peppermint and lemon essential oils were effective for somatic symptoms (p < 0.05). For psychological symptoms, only the lemon oil (p = 0.011) proved effective, and for urogenital symptoms, only the peppermint essential oil (p = 0.001)., Conclusion: The study found that aromatherapy massage with peppermint and lemon essential oil effectively reduced menopausal symptoms. Peppermint essential oil was more effective than lemon essential oil in reducing the menopausal symptoms., The Clinical Trial Registration Number: NCT05677698., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Hormonal changes physiologically occurring in menopausal women may increase the risk of developing metabolic and vasomotor disturbances, which contribute to increase the risk of developing other concomitant pathologies, such as metabolic syndrome (MetS). Materials and Methods: Retrospective data from 200 menopausal women with MetS and vasomotor symptoms taking one sachet per day of the dietary supplement INOFOLIC ® NRT (Farmares srl, Rome, Italy) were collected. Each sachet consisted of myo-Inositol (2000 mg), cocoa polyphenols (30 mg), and soy isoflavones (80 mg, of which 50 mg is genistin). Patients recorded their symptoms through a medical questionnaire at the beginning of the administration (T0) and after 6 months (T1). Results: We observed an improvement in both the frequency and the severity of hot flushes: increased percentage of 2-3 hot flushes (28 at T0 vs. 65% at T1, p value < 0.001) and decreased percentage of 4-9 hot flushes (54% at T0 vs. 18% at T1, p value < 0.001). Moreover, symptoms of depression improved after supplementation (87% at T0 vs. 56% at T1 of patients reported moderate depression symptoms, p value < 0.001). Regarding metabolic profile, women improved body mass index and waist circumference with a reduction in the percentage of overweight and obesity women (88% at T0 vs. 51% at T1, p value = 0.01; 14% at T0 vs. 9% at T1, p value = 0.04). In addition, the number of women suffering from non-insulin dependent diabetes reduced (26% at T0 vs. 16% at T1, p value = 0.04). Conclusions: These data corroborate previously observed beneficial effects of the oral administration of myo-Inositol, cocoa polyphenols, and soy isoflavones against menopausal symptoms in the study population. Considering the promising results of the present study, further prospective controlled clinical trials are needed to deeply understand and support the efficacy of these natural compounds for the management of menopausal symptoms.

Vasomotor symptoms (VMS) are associated with adverse health consequences and can cause significant morbidity for postmenopausal women. Although hormone therapy remains the gold standard of VMS treatment in menopausal women, some women have contraindications to or may choose not to take hormone therapy. This article provides an up-to-date overview of the current evidence-based nonhormone therapies available for managing VMS. Evidence supporting various treatment options is reviewed, including lifestyle interventions, mind-body therapies, procedures, pharmacologic agents, and emerging therapies, such as neurokinin-receptor antagonists. The efficacy, safety, and clinical use of these treatments are detailed, offering insights for clinicians to make informed decisions in menopausal VMS management., (Copyright © 2024 The Cleveland Clinic Foundation. All Rights Reserved.)

Importance: Vasomotor symptoms (VMS) affect many postmenopausal persons and impact sleep and quality of life., Objective: This systematic review examines the literature describing the safety and efficacy of neurokinin-3 receptor antagonists approved and in development for postmenopausal persons with VMS., Evidence Review: A search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts was conducted using the search terms and permutations of neurokinin-3 receptor antagonist, elinzanetant, fezolinetant, and osanetant. Inclusion criteria of reporting on efficacy or safety of fezolinetant, elinzanetant, or osanetant; studies in participants identifying as female; full record in English; and primary literature were applied. Abstract-only records were excluded. Extracted data were synthesized to allow comparison of reported study characteristics, efficacy outcomes, and safety events. Eligible records were evaluated for risk of bias via the Cochrane Risk of Bias 2 tool for randomized studies and the Grading of Recommendations Assessment, Development and Evaluation system was used. This study was neither funded nor registered., Findings: The search returned 191 records; 186 were screened after deduplication. Inclusion criteria were met by six randomized controlled trials (RCT), four reported on fezolinetant, and two reported on elinzanetant. One record was a post hoc analysis of a fezolinetant RCT. An additional study was identified outside the database search. Three fezolinetant RCT demonstrated a reduction in VMS frequency/severity, improvement in Menopause-Specific Quality of Life scores, and improvement in sleep quality at weeks 4 and 12 compared with placebo without serious adverse events. The two RCT on elinzanetant also showed improvements in VMS frequency and severity. All eight records evaluated safety through treatment-emergent adverse events; the most common adverse events were COVID-19, headache, somnolence, and gastrointestinal. Each record evaluated had a low risk of bias. There is a strong certainty of evidence as per the Grading of Recommendations Assessment, Development and Evaluation system., Conclusions and Relevance: Because of the high-quality evidence supporting the efficacy of fezolinetant and elinzanetant, these agents may be an effective option with mild adverse events for women seeking nonhormone treatment of VMS., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

Competing Interests: Financial disclosure/conflicts of interest: S.D.R. has ongoing funding from NIH, receives royalties from UpToDate and received research funding from Bayer in the past.

Objective: This study aimed to assess the efficacy of the neurokinin 3 receptor antagonist, fezolinetant, according to several intrinsic (individual related) and extrinsic (external influence) factors that may influence the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) using pooled 12-week data from SKYLIGHT 1 and 2., Methods: SKYLIGHT 1 and 2 were two phase 3, randomized, double-blind studies conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg. After 12 weeks, placebo participants were rerandomized to receive fezolinetant 30 mg or 45 mg, whereas those receiving fezolinetant continued on the same dose. Change in VMS frequency from baseline to week 12 was used to assess efficacy according to several intrinsic and extrinsic factors. Overall efficacy and safety were also investigated., Results: Overall, 1,022 individuals were included. Fezolinetant was efficacious in reducing VMS frequency across all intrinsic and extrinsic factors. Efficacy was most notable for participants who self-identify as Black (least squares mean difference for fezolinetant 45 mg versus placebo, -3.67; 95% CI, -5.32 to -2.01), current smokers (-3.48; -5.19 to -1.77), and current alcohol users (-3.48; -4.42 to -2.54). Overall efficacy was -2.51 (95% CI, -3.20 to -1.82) for fezolinetant 45 mg versus placebo. Similar findings were observed for the fezolinetant 30 mg dose. Comparable incidences of treatment-emergent adverse events were observed for placebo (132 of 342 individuals [38.6%]), fezolinetant 30 mg (132 of 340 individuals [38.8%]), and fezolinetant 45 mg (135 of 340 individuals [39.7%])., Conclusions: None of the intrinsic and extrinsic factors analyzed substantially reduced the efficacy response to fezolinetant in SKYLIGHT 1 and 2. These data provide additional confidence for using fezolinetant in a diverse population of individuals with VMS., Competing Interests: Financial disclosure/conflicts of interest: N.S. is a study investigator, member of a scientific advisory board, and consultant for Astellas; a member of a medical advisory board for Amazon (Project Ember); a member of a scientific advisory board for MenoGeniX and QUE Oncology; a consultant for Ansh Labs; an associate editor for Menopause; and a past president of the Society for Reproductive Investigation. R.E.N. has past financial relationships (lecturer, member of advisory boards, and/or consultant) with Boehringer Ingelheim, Eli Lilly, Endoceutics, Exeltis, Novo Nordisk, Palatin Technologies, Pfizer, Procter & Gamble, Teva Women's Health, and Zambon; has ongoing relationships with Abbott, Astellas, Bayer HealthCare, Fidia, Gedeon Richter, HRA Pharma, Merck & Co, Organon, Shionogi, and Theramex; and serves as president elect of the International Menopause Society. G.N-.P. is a member of a scientific advisory board for Astellas and Ferring Pharmaceuticals; has received research funding from the American Association of Medical Colleges, Merck, and NICHD; is the vice president of Diversity, Equity and Structural Change for the Society for Reproductive Investigation; is the program committee chair for the American Society of Reproductive Medicine; holds committee membership of the Endocrine Society; and is an associate editor for Frontiers in Endocrinology. M.E., D.D.K., Y.Y., and F.D.O. are employees of Astellas Pharma Inc., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Aims: To examine the influence of GED on the gut microbiota and metabolites using a bilateral ovariectomized (OVX) rat model. We tried to elucidate the underlying mechanisms of GED in the treatment of menopausal hot flashes., Methods and Results: 16S rRNA sequencing, metabonomics, molecular biological analysis, and fecal microbiota transplantation (FMT) were conducted to elucidate the mechanisms by which GED regulates the gut microbiota. GED significantly reduced OVX-induced hot flashes and improved disturbances in the gut microbiota metabolites. Moreover, FMT validated that the gut microbiota can trigger hot flashes, while GED can alleviate hot flash symptoms by modulating the composition of the gut microbiota. Specifically, GED upregulated the abundance of Blautia, thereby increasing l(+)-ornithine levels for the treatment of menopausal hot flashes. Additionally, GED affected endothelial nitric oxide synthase and heat shock protein 70 (HSP70) levels in the hypothalamic preoptic area by changing the gut microbiota composition., Conclusions: Our study illuminated the underlying mechanisms by which GED attenuated the hot flashes through modulation of the gut microbiota and explored the regulatory role of the gut microbiota on HSP70 expression in the preoptic anterior hypothalamus, thereby establishing a foundation for further exploration of the role of the gut-brain axis in hot flashes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)