Treatment satisfaction, unmet needs, and new treatment expectations for vasomotor symptoms due to menopause: women's and physicians' opinions.

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.

Evaluation of the Potential Beneficial Effects of Ferula communis L. Extract Supplementation in Postmenopausal Discomfort.

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.

The effect of oral capsules containing Ocimum basilicum leaf extract on menopausal symptoms in women: a triple-blind randomized clinical trial.

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.

Management of the Vasomotor Symptoms of Menopause: Twofers in Your Clinical Toolbox.

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.

Fezolinetant: a novel nonhormonal therapy for vasomotor symptoms due 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.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

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.

POESIT recommendations on management of body-identical hormones in menopausal symptoms.

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 17ß-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.

Clinical Evaluation of Effectiveness and Safety of Combined Use of Dietary Supplements Amberen® and Smart B® in Women with Climacteric Syndrome in Perimenopause.

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.

Phase II study of fezolinetant for treatment of vasomotor symptoms associated with menopause in Japan.

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.

Elinzanetant, a new combined neurokinin-1/-3 receptor antagonist for the treatment of postmenopausal vasomotor symptoms.

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.

A prospective, multicenter, randomized, double-blind placebo-controlled trial on purified and specific Cytoplasmic pollen extract for hot flashes in breast cancer survivors.

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.

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT 1 and 2 Data.

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.

The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

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.

Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause.

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.