BACKGROUND: Menopausal vasomotor symptoms (VMS) are increasingly emphasized as a potentially important cardiovascular risk factor, but their role is still unclear. We assessed the association between VMS and subclinical atherosclerotic cardiovascular disease in peri- and postmenopausal women.
RESULTS: Using a cross-sectional study design, questionnaire data were collected from a population-based sample of women aged 50 to 64. The questionnaire asked whether menopause was/is associated with bothersome VMS. A 4-point severity scale was used: (1) never, (2) mild, (3) moderate, and (4) severe. The VMS duration and time of onset were also assessed. Associations with subclinical atherosclerotic cardiovascular disease, detected via coronary computed tomography angiography, coronary artery calcium score, and carotid ultrasound were assessed using the outcome variables \"any coronary atherosclerosis,\" \"segmental involvement score >3,\" \"coronary artery calcium score >100,\" and \"any carotid plaque,\" using logistic regression. Covariate adjustments included socioeconomic, lifestyle, and clinical factors. Of 2995 women, 14.2% reported ever severe, 18.1% ever moderate, and 67.7% ever mild/never VMS. Using the latter as reference, ever severe VMS were significantly associated with coronary computed tomography angiography-detected coronary atherosclerosis (multivariable adjusted odds ratio, 1.33 [95% CI, 1.02-1.72]). Corresponding results for ever severe VMS persisting >5 years or beginning before the final menstrual period were 1.50 (95% CI, 1.07-2.11) and 1.66 (95% CI, 1.10-2.50), respectively. No significant association was observed with segmental involvement score >3, coronary artery calcium score >100, or with any carotid plaque.
CONCLUSIONS: Ever occurring severe, but not moderate, VMS were significantly associated with subclinical coronary computed tomography angiography-detected atherosclerosis, independent of a broad range of cardiovascular risk factors and especially in case of long durations or early onset.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

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.

OBJECTIVE: 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.
CONCLUSIONS: 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.

OBJECTIVE: Vasomotor symptoms (VMS), including hot flashes and night sweats, are hallmark symptoms of the menopause transition. Previous research has documented greater frequency, duration, and severity of VMS in Black women compared with women from other racial/ethnic groups, even after accounting for other factors. This analysis examined the association between discrimination and VMS and the extent to which discrimination accounts for the disproportionate burden of VMS in Black women.
METHODS: Using available discrimination and VMS data from the SWAN cohort study (n = 2,377, 48% White, 32% Black, 6% Japanese, 4% Chinese, and 9% Hispanic women) followed approximately yearly in midlife from premenopause (42-52 y) through postmenopause (~20 y), we assessed concurrent associations between discrimination and VMS frequency in the past 2 weeks using weighted generalized mixed models. We also assessed associations between chronic discrimination across first four visits and VMS trajectories from premenopause to postmenopause using weighted multinomial logistic regression. Models were adjusted for known risk factors for VMS.
RESULTS: Higher levels of discrimination were associated with concurrent reporting of any (odds ratio [OR], 1.57 [1.31-1.89]) and frequent (≥6 d) VMS (OR, 1.55 [1.21-1.99]). After adjustment, associations remained significant for any (OR, 1.30 [1.09-1.54]) but not frequent VMS. For any VMS trajectories, chronic discrimination was associated with \"continuously high\" (OR, 1.69 [1.03-2.77]) and \"high pre-FMP-decline post-FMP\" (OR, 1.70 [1.01-2.88]) versus \"FMP-onset low\" trajectories. After adjusting for discrimination, odds of reporting any, frequent, and of being in the \"continuously high\" any VMS trajectory remained elevated for Black versus White women.
CONCLUSIONS: Discrimination is associated with greater concurrent risk of any (but not frequent) VMS, and chronic discrimination is associated with a continuously high reporting of any VMS over time, independent of known risk factors. Adjusting for discrimination attenuates but does not eliminate the increased risk of VMS for Black women.

The menopause transition is associated with weight gain in women. We examined whether changes in vasomotor symptom (VMS) frequency precede weight changes.
This longitudinal retrospective analysis included data from the multisite, multiethnic Study of Women\'s Health Across the Nation. Women in premenopause or perimenopause aged 42 to 52 years at baseline self-reported VMS frequency (hot flashes/night sweats) and sleep problems at up to 10 annual visits. Menopause status, weight, body mass index, and waist circumference were compared across visits. The primary objective was to measure the association between VMS frequency and weight gain using a lagged approach with first-difference regression models. Secondary objectives were to statistically quantify mediation by sleep problems and moderation by menopause status and explore the association between cumulative, 10-year VMS exposure and long-term weight gain.
The primary analysis sample included 2,361 participants (12,030 visits; 1995-2008). Increased VMS frequency across visits was associated with subsequently increased weight (0.24 kg), body mass index (0.08 kg/m 2 ), and waist circumference (0.20 cm). Cumulative exposure to a high frequency of VMS (≥6 d/2 wk) over 10 consecutive annual visits was associated with increases in weight measures, including a 3.0-cm increase in waist circumference. Contemporaneous sleep problems mediated no more than 27% of waist circumference increases. Menopause status was not a consistent moderator.
This study demonstrates that increases in VMS, onset of a high frequency of VMS, and persistent VMS symptoms over time may precede weight gain in women.

We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS).
166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM).
Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT).
VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition.
METHODS: SWAN, the Study of Women\'s Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy.
METHODS: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C).
RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood.
CONCLUSIONS: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

During the menopausal transition, there is a greater likelihood of the prevalence of various bothersome symptoms, including vasomotor symptoms (VMS) and mood symptoms.
To investigate the association among bothersome VMS and symptoms of anxiety and depression in Chinese women during perimenopause and early in menopause.
This study included 430 midlife Chinese women who had experienced natural menopause and were followed up for 10 years. A structured questionnaire was provided annually, comprising the VMS Bother Score (range 1-8) from the Menopause-Specific Quality of Life questionnaire, the Hospital Anxiety and Depression Scale, and other physical and behavioral factors.
Among the 430 women evaluated, 78.8% had experienced VMS during long-term follow-up. The overall level of VMS bother score was relatively low (1.92 ± 1.32). Both anxiety and depressive symptoms were significantly associated with VMS bother. After adjusting for potential covariates, the association between anxiety or depression symptoms and VMS bother remained highly significant. Menopausal stage, body mass index, general health, follicle-stimulating hormone, and estradiol were independent contributors to VMS. In time-lagged (1-year) models, VMS bother scores significantly predicted the risk of symptoms of both anxiety and depression the following year. In contrast, anxiety symptoms, rather than depressive symptoms, could predict VMS bother the following year.
The prevalence of VMS in our cohort was higher than has been previously reported; however, the overall level of bother was relatively low. This study demonstrated a strong relationship between VMS bother and mood symptoms in Chinese women progressing from perimenopause through natural menopause.