Ultra-low dose estradiol and dydrogesterone for the treatment of menopausal symptoms in a pooled, multi-ethnic population.

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.

Non-hormonal pharmacological interventions for managing vasomotor symptoms-how can we help: 2024 landscape.

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.

Cooling the flames: Navigating menopausal vasomotor symptoms with nonhormone medications.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: While the gold standard for vasomotor symptoms remains hormone therapy, prescription menopause therapies are significantly underutilized. Nonhormone therapies represent an alternative treatment modality that may improve access to care for patients who cannot or choose not to take hormones. This review aims to update pharmacists on the evidence behind new-to-market fezolinetant and all other nonhormone prescription treatment options for menopausal vasomotor symptoms. SUMMARY: Prescription nonhormone therapy options for vasomotor symptoms include selective serotonin reuptake inhibitors, including Food and Drug Administration-approved low-dose paroxetine, serotonin-norepinephrine reuptake inhibitors, gabapentin, pregabalin, oxybutynin, and fezolinetant. Evidence supporting the use of these options is summarized in this review. All have an important place in treatment for those unable to take the gold standard of hormone therapy; however, most offer only mild to moderate improvement in symptoms. Fezolinetant has been shown to result in a significant reduction in vasomotor symptom frequency when compared to other nonhormone therapies and was not different when compared to hormone therapies. However, additional studies and efforts to address the affordability of fezolinetant and head-to-head comparisons with other agents are needed. CONCLUSION: Vasomotor symptoms of menopause can severely impact the health and well-being of individuals. However, treatment of these symptoms is underutilized due to real and perceived drawbacks of therapy. Pharmacists are ideally suited to bridge this gap, but first it is important for pharmacists to be knowledgeable about and comfortable with the evidence supporting all treatment options.

A 2-year follow-up to a randomized controlled trial on resistance training in postmenopausal women: vasomotor symptoms, quality of life and cardiovascular risk markers.

BACKGROUND: Most women experience vasomotor symptoms (VMS) during the menopausal transition. A 15-week resistance training intervention (RTI) significantly reduced moderate-to-severe VMS (MS-VMS) and improved health-related quality of life (HRQoL) and cardiovascular risk markers in postmenopausal women. Whether a short RTI could have long-term effects is unknown. We aimed to investigate whether there were intervention-dependent effects two years after a 15-week RTI on MS-VMS frequency, HRQoL, and cardiovascular risk markers in postmenopausal women. METHODS: This observational prospective cohort study is a follow-up to a randomized controlled trial (RCT) on a 15-week RTI in postmenopausal women (n = 57). The control group had unchanged low physical activity during these first 15 weeks. At the follow-up contact two years post-intervention, 35 women agreed to participate in an additional physical visit at the clinic with clinical testing, blood sampling, and magnetic resonance imaging, identical to the protocol at the baseline visit at the start of the RCT. RESULTS: Although all women showed reduced MS-VMS and increased moderate-to-vigorous physical activity (MVPA) over the 2-year follow-up compared to baseline, the groups from the original RCT (intervention group; IG, control group; CG) changed differently over time (p < 0.001 and p = 0.006, respectively) regarding MS-VMS. The IG maintained a significantly lower MS-VMS frequency than the CG at the 6-month follow-up. At the 2-year follow-up, there was no significant difference between the original RCT groups. No significant changes over time or differences between groups were found in HRQoL or cardiovascular risk markers. However, significant interactions between original RCT groups and time were found for visceral adipose tissue (p = 0.041), ferritin (p = 0.045), and testosterone (p = 0.010). CONCLUSIONS: A 15-week resistance training intervention reduced MS-VMS frequency up to six months post-intervention compared to a CG, but the effect was not maintained after two years. The RTI did neither contribute to preserved improvements of cardiovascular risk markers nor improved HRQoL after two years compared to a CG. TRIAL REGISTRATION: Clinical trials.gov registered ID: NCT01987778, trial registration date 2013-11-19.

Real-world evaluation of treatment utilization by women experiencing vasomotor symptoms associated with menopause in the United States and Europe: Findings from the REALISE study.

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.

Comprehensive Management of Menopausal Symptoms.

Menopause is an inevitable physiologic process that typically occurs in women between the ages of 45 and 56 years old. It involves the permanent cessation of ovarian function and is recognized to have occurred when there has been no menstrual cycle for 12 consecutive months without another cause. Vasomotor symptoms, such as hot flushes and night sweats, and genitourinary syndrome of menopause, which includes symptoms of vaginal dryness, dyspareunia, and urinary incontinence, are common symptoms of menopause. Symptoms range from mild to severe, and for those interested in treating their symptoms, there are hormonal and nonhormonal options available. Choosing appropriate therapies is based on each individual's health history and personal preferences. Because menopause can affect mental, physical, and emotional health, it is critical for nurses to recognize the changes that occur in menopause so that they can make appropriate inquiries to elicit symptom information. Nurses play an important role in counseling and supporting individuals through the menopause transition with evidence-based guidance.

Treatment utilization and non-drug interventions for vasomotor symptoms in breast cancer survivors taking endocrine therapy: Real-world findings from the United States and Europe.

OBJECTIVES: Vasomotor symptoms induced by endocrine therapy are common in breast cancer survivors and a risk factor for therapy discontinuation and lower quality of life. The REALISE study evaluated the real-world treatment landscape in breast cancer survivors with vasomotor symptoms taking endocrine therapy, including pharmaceuticals, lifestyle changes, and over-the-counter products. STUDY DESIGN: Secondary analysis of the Adelphi Vasomotor Disease Specific Programme™, a large cross-sectional point-in-time survey and chart review conducted in the US and five European countries (February-October 2020). Oncologists provided demographic, clinical, and treatment data for adult breast cancer survivors with induced vasomotor symptoms taking endocrine therapy (tamoxifen or aromatase inhibitors); patients voluntarily completed self-report surveys on their symptom severity, concomitant sleep and/or mood symptoms, lifestyle changes, and use of over-the-counter products. MAIN OUTCOME MEASURES: Patient characteristics; vasomotor symptom severity; use of pharmaceuticals, lifestyle changes, and over-the-counter products (from pre-defined lists); lines of treatment. RESULTS: Overall, 77 oncologists reported data for 618 breast cancer survivors, of whom 183 (29.6 %) completed self-report forms. Physicians classified 420 (68.0 %) women as experiencing moderate-severe vasomotor symptoms, of whom 66.9 % were receiving treatment. In total, 15.2 % of all breast cancer survivors were prescribed systemic hormone therapy. Venlafaxine (24.7 %), citalopram (16.5 %), and paroxetine (13.6 %) were the most commonly prescribed nonhormonal medications. Lifestyle changes (77.8 %) and over-the-counter products (61.6 %) were common, especially in patients with concomitant sleep and/or mood symptoms. CONCLUSIONS: Despite contraindications, a relatively large proportion of treatment-seeking breast cancer survivors with vasomotor symptoms were prescribed systemic hormone therapy. This, combined with high patient-reported use of lifestyle changes and over-the-counter products, suggests a need for symptomatic relief and demand for new nonhormonal alternatives with established safety profiles in this population.

Ultra-low-dose estradiol and dydrogesterone for treatment of vasomotor symptoms in Europe and China.

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 17ß-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.

The prevalence and severity of vasomotor and sexual symptoms among refugee women in Australia.

OBJECTIVE: This study aimed to document the prevalence and severity of vasomotor symptoms (VMS) and sexual symptoms among refugee women in Melbourne, Australia. METHODS: This cross-sectional study included refugee women, aged 18-63 years, recruited from community centers and social media between February and July 2023. The Menopause-specific Quality of Life (MENQOL) questionnaire measured VMS and sexual symptoms. The scores were compared between different menopausal states. RESULTS: Of 333 participants, 62.8% were premenopausal, 8.0% perimenopausal and 29.2% postmenopausal, with a median age of 40 years (range 18-63 years). Moderate-severe VMS was most prevalent amongst perimenopausal (20.8%; 95% confidence interval [CI]: 8.9-41.4%) versus postmenopausal (9.5%; 95% CI: 5.0-17.3%) and premenopausal (0%) women. Moderate-severe sexual symptoms affected 15.8% (95% CI: 5.2-39.3%) of perimenopausal and 16.9% (95% CI: 10.4-26.1%) of postmenopausal women versus 1.4% (95% CI: 0.3-5.3%) of premenopausal women. Perimenopausal and postmenopausal women had higher VMS and sexual symptom scores than premenopausal women (both p < 0.0001); the scores were also higher in perimenopausal women than postmenopausal women (p = 0.016 and p = 0.013, respectively). CONCLUSION: While perimenopausal and postmenopausal VMS and sexual symptoms are not uncommon amongst refugee women, these symptoms were less prevalent in postmenopausal refugees than in the non-refugee population. Further research is warranted to confirm and expand on these findings.

Hot flashes and sleep disruption in a randomized trial in menopausal women.

BACKGROUND: Hot flashes, common during menopause, affect up to 80% of the Western menopausal women and are reported to contribute to sleep disturbances in midlife. Few prospective data are available to confirm the specific role of hot flashes in disrupting sleep in midlife women, however, or confirm whether changes in hot flashes in response to clinical therapies result in improvement in sleep. OBJECTIVE: To examine the effects of continuous nitroglycerin therapy on sleep quality in perimenopausal and postmenopausal women with frequent hot flashes (pre-specified secondary trial endpoint) and to examine prospective associations between hot flashes and sleep disruption in this population. STUDY DESIGN: Sleep data were analyzed from a randomized, double-blinded, placebo-controlled trial of continuous transdermal nitroglycerin (NTG) therapy to suppress nitric oxide-mediated vasodilation in perimenopausal or postmenopausal women with hot flashes. Participants were randomized to uninterrupted use of transdermal NTG (0.2-0.6 mg/hour) or placebo for 12 weeks. Nocturnal hot flashes awakening participants from sleep were evaluated using 7-day symptom diaries at baseline, 5 weeks, and 12 weeks. Sleep disruption (wakefulness after sleep onset, WASO) was assessed using validated sleep diaries, and global sleep quality was assessed by the validated Pittsburgh Sleep Quality Index (PSQI: range 0 [best] 21 [worst]) questionnaire. Mixed linear models examined changes in sleep quality and disruption, as well as the strength of associations between nocturnal hot flash frequency and sleep outcomes, over 5 and 12 weeks, adjusting for baseline values, age, race, and ethnicity. RESULTS: Among the 141 participants (70 to NTG and 71 to placebo, mean age 54.6 [±3.9] years), the mean baseline hot flash frequency was 10.8 (±3.5) per day, including 2.6 (±1.7) nocturnal hot flashes awakening participants. At baseline, hot flashes were the most commonly reported reason for nocturnal awakening, with 62.6% of participants reporting waking due to hot flashes at least twice nightly. Over 5 and 12 weeks, mean frequency of nocturnal hot flashes causing awakenings decreased in both groups (NTG: -0.9 episodes/night, placebo: -1.0 episodes/night). Sleep disruption as measured by average nightly WASO also decreased (NTG: -10.1 minutes, placebo: -7.3 minutes), and mean PSQI score improved (NTG: -1.3 points, placebo: -1.2 points). No significant between-group differences in change in sleep outcomes were detected from baseline to 5 and 12 weeks, including PSQI sleep quality score as a prespecified secondary trial endpoint (P≥.05 for all). Greater improvement in nocturnal hot flash frequency over 5 and 12 weeks was associated with greater improvement in PSQI sleep quality score (ß= -0.30, P=.01) and sleep disruption reflected by WASO (ß= -1.88, P=.02) in the combined sample. CONCLUSION: Among menopausal women in a randomized trial of continuous NTG therapy for hot flashes, hot flashes were the most frequently reported cause of nocturnal awakenings. Compared to placebo, continuous NTG therapy did not result in greater improvements in sleep quality from baseline to 5 and 12 weeks. Based on night-by-night symptom diaries and questionnaires, however, greater improvement in nocturnal hot flash frequency in both groups was associated with greater improvement in sleep quality and disruption.

A survey of women diagnosed with breast cancer experiencing oncology treatment-induced hot flushes: identification of specific characteristics as predictors of hot flush occurrence, frequency, and severity.

PURPOSE: More women diagnosed with breast cancer (BC) are living with oncology treatment-induced hot flushes (HFs). This Australian-based survey explores why some women experience more severe or ongoing HF and whether specific population characteristics are predictive of HF occurrence, frequency, and/or severity. METHODS: A non-probabilistic anonymous survey distributed online (Register4) and two Australian hospitals collected demographic and clinical information. Eligibility was consenting Australian-based women, 18 years and over, with a primary BC diagnosis. Analysis included linear and logistic regression models. RESULTS: A total of 324 survey responses were analyzed. Chemotherapy and hormone therapy were each associated with HF occurrence (aOR = 2.92, 95% CI [1.27, 6.70], p = 0.01; and aOR = 7.50, 95% CI [3.02, 18.62], p < 0.001) and in combination (aOR = 5.98, 95% CI [2.61, 13.69], p < 0.001). Increased self-reported anxiety at BC diagnosis was significantly associated with HF frequency and severity scores (aCO = 0.71, 95% CI [0.31, 1.12], p = 0.001; and aCO = 0.44, 95% CI [0.33, 0.55], p < 0.001). Postmenopausal women had significantly lower HF severity and frequency scores than premenopausal women (aCO = -0.93, 95% CI [-1.62, -0.25], p = 0.008; and aCO = -2.62, 95% CI [-5.14, -0.11], p = 0.041). CONCLUSIONS: Women with BC receiving chemotherapy and/or hormone therapy and premenopausal or experiencing elevated anxiety and/or stress will likely experience more severe oncology treatment-related HFs. IMPLICATIONS FOR CANCER SURVIVORS: HFs continue across the BC treatment trajectory with women >5-year survivorship still reporting life impacts, with premenopausal women at the time of BC diagnosis at higher risk of experiencing severe and more frequent oncology treatment-induced HFs than postmenopausal women. Women at high risk require information on methods to moderate HF potential life impacts and maintain treatment compliance.

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.

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.

Development and application of a weighted change score to evaluate interventions for vasomotor symptoms in patients with breast cancer using regression trees: a cohort study.

PURPOSE: Vasomotor symptoms (VMS) are common among individuals with breast cancer (BC) and poorly managed symptoms are associated with reduced quality of life, treatment discontinuation, and poorer breast cancer outcomes. Direct comparisons among therapies are limited, as prior studies evaluating VMS interventions have utilized heterogeneous change measures which may not fully assess the perceived impact of change in VMS severity. METHODS: We performed a prospective study where BC patients chose one of four categories of interventions to manage VMS. Change in VMS severity at 6 weeks was assessed using the validated Hot Flush Rating Scale (HFRS). A novel weighted change score integrating baseline symptom severity and directionality of change was computed to maximize the correlation between the change score and a perceived treatment effectiveness score. Variables influencing change in VMS severity were included in a regression tree to model factors influencing the weighted change score. RESULTS: 100 baseline and follow-up questionnaires assessing VMS were completed by 88 patients. Correlations between treatment effectiveness and VMS outcomes strengthened following adjustment for baseline symptoms. Patients with low VMS severity at baseline did not perceive change in treatment effectiveness. Intervention category was predictive of change in HFRS at 6 weeks. CONCLUSION: Baseline symptom severity and the directionality of change (improvement or deterioration of symptoms) influenced the perception of clinically meaningful change in VMS severity. Future interventional studies utilizing the weighted change score should target moderate-high baseline severity patients.

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.

Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial.

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.

Real-world clinical evaluation of natural and induced vasomotor symptoms in the USA and Europe.

OBJECTIVE: This study aimed to examine physicians' and patients' perceptions regarding symptom burden and impact in women experiencing natural vasomotor symptoms (nVMS) or vasomotor symptoms induced by endocrine therapy for breast cancer (iVMS). METHODS: The cross-sectional survey based on real-world clinical consultations was conducted in the USA and five European countries. Obstetrician-gynecologists, primary-care physicians and oncologists provided demographic and symptom data for patients experiencing VMS; patients optionally self-reported their experiences via questionnaires, including their symptom profile and work/activity burden through the Menopause Quality of Life (MENQOL) and Work Productivity and Activity Impairment (WPAI) tools. RESULTS: Physicians completed survey forms on 2451 consulting patients; patients completed 1029 questionnaires. nVMS and iVMS severity was significantly associated with the severity of mood symptoms and sleep disturbances (p < 0.0001). However, around half of the patients with mild nVMS/iVMS also experienced moderate-severe mood changes (55.4%/43.7%) or sleep disturbances (42.4%/40.4%). Presence of mood/sleep disturbances alongside nVMS increased MENQOL vasomotor scores (p = 0.004/p < 0.001). Presence of sleep disturbances increased WPAI activity impairment (p < 0.001) but mood changes did not. Similar findings were reported for iVMS patients. CONCLUSION: Significant burden from the triad of natural or induced menopausal symptoms, sleep disturbances and mood changes affected women's daily activities, work and quality of life more than vasomotor symptoms alone.

Summary of the 2023 Thai Menopause Society Clinical Practice Guideline on Menopausal Hormone Therapy.

The Thai Menopause Society is an academic organization consisting of healthcare professionals engaged in menopause medicine. The position statement was first issued in 1994 and updated in 2003 and 2023. Herein, we reviewed the important updates of the 2023 position statement on menopausal hormone therapy (MHT) as an international reference for healthcare professionals in Thailand. An advisory panel of clinicians and research experts in the field of menopause reviewed the recommendation of published International Consensus Statements and updated the evidence using the MEDLINE database through PubMed. The evidence-based information and relevant publications were assessed, and a consensus on recommendations was subsequently achieved using the level of evidence to determine the recommendation strength and evidence quality. MHT remains the most effective treatment for vasomotor symptoms and genitourinary syndromes of menopause even after 20 years. Additionally, it is effective in preventing bone loss and fractures in postmenopausal women. The cardiovascular risk of MHT increased in women who initiated MHT after 60 years of age. Hormone therapy should be individualized following the hormone type, dose, administration route, use duration, and progestogen inclusion. The necessary pretreatment evaluation and appropriate follow-up recommendations were added for improved MHT standard care. The updated 2023 Clinical Practice Guideline on MHT is useful for gynecologists, general physicians, endocrinologists, and other healthcare professionals in treating menopausal women receiving hormone therapy in Thailand.

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.