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Abstract Context Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. Objective We aimed to assess efficacy/safety of fezolinetant for treatment of moderate to severe VMS associated with menopause. Methods In this double-blind, placebo-controlled, 12-week phase 3 trial with a 40-week active treatment extension (NCT04003142; SKYLIGHT 2), women aged 40 to 65 years with minimum average 7 moderate to severe VMS/day were randomized to 12 weeks of once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to week 4 (W4) and W12 in VMS frequency and severity. Safety was also assessed. Results Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, –1.82 (0.46; P < .001); 45 mg, –2.55 (0.46; P < .001); W12: 30 mg, –1.86 (0.55; P < .001); 45 mg, −2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, −0.15 (0.06; P < .05); 45 mg, −0.29 (0.06; P < .001); W12: 30 mg, −0.16 (0.08; P < .05); 45 mg, −0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1 and maintained through W52. Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. Conclusion Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause.

Roger McIntyre and associates1 discuss reciprocal relationships between hormone replacement therapy (HRT) and antidepressant treatment. Although some women experience significant mood changes related to changes in estrogen levels at menopause, I believe there is another obvious explanation for the increase in prescriptions for selective serotonin reuptake inhibitors (SSRIs) after publication of the Women's Health Initiative (WHT) trial.2 As demonstrated by Loprinzi and colleagues,7 breast cancer patients with depression reported a reduction in hot flashes when taking SSRIs. Subsequently, other SSRIs were shown to have similar beneficial effects. However, SSRIs are much less effective in this regard than HRT (which is more than 85% effective).3 1. McIntyre RS, Konarski JZ, Grigoriadis S, Fan NC, Mancini DA, Fulton KA, et al. Hormone replacement therapy and antidepressant prescription patterns: a reciprocal relationship [editorial]. CMAJ 2005;172(1):57-9.

Objective: To determine the normal endometrial thickness (ET) on transvaginal ultrasound (TVUS) of asymptomatic postmenopausal women not on hormone replacement therapy. A subgroup that was determined to be suspicious for having an endometrial polyp was compared with the remainder. Methods: This prospective study selected 1,500 consecutive asymptomatic postmenopausal women receiving TVUS assessment from January to August 2010. ET was recorded. Results were divided into those with a normal-appearing lining (n = 1,399) and those suspicious for polyp (n = 101). Results for the entire sample were obtained and the groups were compared using independent samples t tests. Results: Of 1,500 women aged 45-95 years, 77.1% had an ET of ≤4 mm and 92% were ≤5 mm. Independent samples t tests were performed to compare the mean age and mean ET based on polyp status (i.e. with or without a possible polyp). There was a significant difference in mean age, 67.71 vs. 62.36 years (p < 0.01) and mean ET 8.02 vs. 3.40 mm (p < 0.01) between groups. Conclusions: 92% of asymptomatic postmenopausal women not on hormone replacement therapy had an ET of ≤5 mm. The mean ET was 3.71 ± 1.9 mm. However, a significant group, 6.7%, had an endometrial lining suspicious for polyp. These women had a significant increase in mean age and ET.

Background SKYLIGHT 2 (NCT04003142) investigated safety and efficacy of fezolinetant (a neurokinin-3 receptor antagonist) on frequency and severity of moderate-to-severe vasomotor symptoms (VMS) and sleep disturbance. In this analysis, persistence of fezolinetant efficacy was investigated over 52 weeks. Methods This double-blind Phase 3 study randomized women aged ≥40–65 years with moderate-to-severe VMS associated with menopause (average of ≥7 hot flashes/day) to once-daily placebo or fezolinetant 30mg or 45mg for 12 weeks. Women completing 12 weeks entered an extension period, with those on placebo re-randomized to fezolinetant 30mg or 45mg (placebo/fezolinetant), and those originally on fezolinetant remaining on their dose for an additional 40-weeks. Fezolinetant efficacy was evaluated vs placebo for 12-weeks through change in VMS frequency, VMS severity, and Patient-reported Outcomes Measurement Information System Sleep Disturbance–Short Form 8b (PROMIS) Total Score. Persistence of efficacy for fezolinetant was evaluated descriptively (without statistical comparisons) over the extension period. Results The analysis comprised 484 women (fezolinetant 30mg n=166, fezolinetant 45mg n=167, placebo/fezolinetant 30mg n=76, placebo/fezolinetant 45mg n=75). Improvement in VMS frequency and severity observed through week 12 (statistically significant differences vs placebo) was maintained throughout the 52-week total study period for those receiving fezolinetant. Fezolinetant demonstrated further reductions in VMS frequency and severity from baseline to beyond week 12. For VMS frequency, there was a least squares (LS) mean (SE) baseline-to-week 12 reduction of –6.83 (0.39) VMS/day for fezolinetant 30mg and –7.50 (0.39) for 45mg, and a mean (SD) baseline-to-week 52 reduction of –8.03 (4.53) for fezolinetant 30mg and –8.48 (3.98) for 45mg. For VMS severity, LS mean (SE) baseline-to-week 12 reduction was –0.64 (0.06) for 30mg and –0.77 (0.06) for 45mg, and mean (SD) baseline-to-week 52 reduction was –0.83 (0.82) for fezolinetant 30mg, and –0.95 (0.78) for 45mg. Women re-randomized from placebo to fezolinetant experienced a reduction in frequency and severity of VMS consistent with that in women receiving fezolinetant throughout the study. Fezolinetant also reduced PROMIS-assessed sleep disturbance, with a LS mean (SE) baseline-to-week 12 reduction of –4.1 (0.5) for fezolinetant 30mg and –5.5 (0.5) for 45mg (statistically significant difference vs placebo for fezolinetant 45mg) and a mean (SD) baseline-to-week 52 reduction of – 6.3 (7.3) for fezolinetant 30mg and –5.7 (7.9) for 45mg. The safety profile observed for the 40-week extension period was consistent with that of the 12-week placebo-controlled period. Conclusion Fezolinetant 30mg and 45mg once daily were efficacious for treatment of moderate-to-severe VMS associated with menopause. Efficacy was persistent and reductions in VMS frequency were maintained during the extension period, at levels consistent with weeks 1 through 12. Fezolinetant 45mg improved sleep at week 12 and improvement was maintained through the active treatment extension period. No safety signals of concern were apparent for either fezolinetant dose. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Background: In addition to short stature and ovarian insufficiency, women with Turner syndrome (TS) are at increased risk for multiple chronic health conditions, especially as they age. Reports describing the presence of comorbidities in older adult women with TS are limited. The objective of this study was to examine the prevalence of endocrine, gynecological, and other chronic medical conditions in a large cohort of adult TS patients. Methods: We performed a retrospective chart review of women with TS attending our adult TS clinic jointly run by gynecology and endocrinology at a university-based ambulatory hospital in Toronto, Canada. All patients had a diagnosis of TS based on karyotype testing and attended at least one clinic visit between February 1, 2015 and July 1, 2018. Data were collected from electronic medical records and included information on patients’ medical conditions, results of screening and blood tests and clinical measurements. Prevalence of diseases was determined for the whole cohort and stratified by age, <40 and ≥40 years. Statistical comparison between older and younger woman was done using the chi-square test. Results: We identified 122 adult women with TS. The mean age was 37.7 years (range: 19-68), and 40.2% were > 40 years of age at clinic visit. The mean age at diagnosis was 11.4 years. The mean height of was 146.8cm (+/-8.06) and the mean BMI was 27.1 (+/-6.24). The majority of patients (84.4%) were on hormone therapy, with the most common type being the oral contraceptive pill (47.6%). Regarding endocrine conditions, 24.5% had hypothyroidism, 16% had dysglycemia (either diabetes or pre-diabetes), and 27.9% had decreased bone mass (either osteoporosis, osteopenia or low bone density). The prevalence of hypothyroidism and dysglycemia were significantly higher among older women (hypothyroidism 36.7% age ≥ 40 vs. 17.8% age < 40, p=0.018; dysglycemia 24.5% age ≥ 40 vs. 5.5% age <40, p= 0.023). Gynecological conditions were identified in 35% of overall patients and were significantly higher among older women (42.8% age ≥ 40 vs. 13.7% age < 40, p=0.0028). With regards to other medical conditions, 41% had hearing impairment, 36.1% had cardiac abnormalities, 18.8% had renal abnormalities and 9% had celiac disease. Women > 40 years had a higher prevalence of hearing impairment (59.1% age > 40 years vs. 28.8% age < 40 years, p=0.0008), while the prevalence of cardiac, renal abnormalities and celiac disease was similar between age groups. Conclusions: The results of this study indicate a high prevalence of medical and gynecological conditions in women with TS, especially those > 40 years of age. This cohort is unique given the older age of our patients as well as the high burden of comorbid disease that we identified. Our study further underscores the importance of multidisciplinary adult TS clinics for monitoring and screening women with TS for comorbidities throughout adulthood.