Severe Vasomotor Symptoms Research Articles

Obesity, smoking, and risk of vasomotor menopausal symptoms: a pooled analysis of eight cohort studies

Frequent and severe vasomotor symptoms during menopause are linked with adverse health outcomes. Understanding modifiable lifestyle factors for the risk of vasomotor menopausal symptoms is important to guide preventive strategies. We investigated the associations between body mass index and smoking, their joint effects with the risk of vasomotor symptoms, and whether the associations differed by menopausal stage. The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events pooled data on 21,460 midlife women from 8 studies (median age, 50 years; interquartile range, 49-51 years) for the cross-sectional analysis. Four studies provided data for the prospective analysis (n=11,986). Multinomial logistic regression models with 4 categories of frequency/severity for the outcome of vasomotor symptoms were used to estimate relative risk ratios and 95% confidence intervals that were adjusted for within-study correlation and covariates. At baseline, nearly 60% of the women experienced vasomotor symptoms. One-half of them were overweight (30%) or obese (21%), and 17% were current smokers. Cross-sectional analyses showed that a higher body mass index and smoking more cigarettes with longer duration and earlier initiation were all associated with more frequent or severe vasomotor symptoms. Never smokers who were obese had a 1.5-fold (relative risk ratio, 1.52; 95% confidence interval, 1.35-1.73) higher risk of often/severe vasomotor symptoms, compared with never smokers who were of normal-weight. Smoking strengthened the association because the risk of often/severe vasomotor symptoms was much greater among smokers who were obese (relative risk ratio, 3.02; 95% confidence interval, 2.41-3.78). However, smokers who quit at <40 years of age were at similar levels of risk as never smokers. Prospective analyses showed a similar pattern, but the association attenuated markedly after adjustment for baseline vasomotor symptoms. Furthermore, we found that the association between body mass index and vasomotor symptoms differed by menopausal status. Higher body mass index was associated with increased risk of vasomotor symptoms in pre- and perimenopause but with reduced risk in postmenopause. High body mass index (≥25 kg/m2) and cigarette smoking substantially increased women's risk for experiencing frequent or severe vasomotor symptoms in a dose-response manner, and smoking intensified the effect of obesity. However, the effect of body mass index on the risk of vasomotor symptoms was opposite among postmenopausal women. Maintaining a normal weight before the menopausal transition and quitting smoking at <40 years of age may mitigate the excess risk of vasomotor symptoms in midlife.

A critical appraisal of vasomotor symptom assessment tools used in clinical trials evaluating hormone therapy compared to placebo.

Vasomotor symptoms (VMS) have been consistently reported as the leading predictor of health-related quality of life (HRQOL) among menopausal women, and the strongest indication for treatment. The North American Menopause Society endorses the use of oral estrogen for the treatment of VMS based on a Cochrane meta-analysis. The Cochrane review concludes that oral hormone therapy reduces the frequency and severity of VMS. The objective of this review is to critically appraise the outcome measures used in these clinical trials to evaluate whether there is adequate evidence that oral hormone therapy improves HRQOL. Each trial in the 2004 Cochrane review of oral hormone therapy for the management of VMS was evaluated with respect to study design, outcome measures, and method of analysis. Twenty-four randomized, double-blind, placebo-controlled clinical trials were appraised. Six trials were excluded from the Cochrane meta-analysis due to inadequate reporting of outcome measures. Of the remaining trials, 15 trials assessed only symptom frequency and/or severity. One trial used a subscale of the General Health Questionnaire. Two trials used the Greene Climacteric Scale, a validated outcome measure in menopausal women, to directly assess the impact of hormone therapy on HRQOL. Both studies showed an improvement in HRQOL in the hormone-treated group, although the sample size was small (n = 118) and the effect was modest. Although oral hormone therapy improves VMS scores, there is a paucity of evidence on whether it improves HRQOL in menopausal women. Future studies using validated, patient-reported outcome measures that directly assess HRQOL are needed.

Early termination of menstrual function: modern views on pathogenesis and consequences

One of the problems of modern endocrine gynecology is the increase in the number of women living in the peri-menopausal and post-menopausal period, therefore the study of the climacteric syndrome pathogenesis is of considerable interest to scientists. Separate issues are the problem of early termination of menstrual function, which can be based on both spontaneous and surgically induced ovarian stops. The article presents modern and evidentiary data concerning the pathogenetic factors of early ovarian exhaustion, such as genetic, infectious, social factors, bad habits. Particular attention is paid to the possible iatrogenic factors of premature cessation of menstrual function, such as the use of oral combined contraceptives and chemotherapy for oncological diseases. Actually, the views of oral contraceptives have done fundamental changes over the last decade, from the protective effect of gonadotropic hormone synthesis inhibition on the maintenance of the ovarian reserve to the current perception it as a damaging factor.Theories of the development of changes in extragenital organs and systems with timely and premature menopause are identified, namely, the time theory and the theory of the critical window. The actual data concerning the characteristics of the menopausal period in patients with early termination of menstrual function, in particular, the more rapid development of atherosclerosis, lipid regulation disorders, osteoporosis and its complications, are given. The mechanisms of increased cardiovascular morbidity and mortality risk of in the case of early cessation of menstrual function are discussed – a sharp imbalance of lipid metabolism with an level up of the atherogenic lipoproteins fractions, estrogen-dependent suppression of fibrinolysis, endothelial disfunction.The greater tendency of women with early menopause to develop depression is emphasized. The actual tension of waiting for or excluding the diagnosis of early menopause, which completes the period of young self-perception of a woman, exacerbates hormonal disorders. Most of all the duration of cyclic estrogen exposure determines the risk of depression developing, but there is also a dependence on ethnicity, the severity of vasomotor symptoms, smoking, and excess body weight. From these perspectives, early cessation of menstrual function is an independent risk factor for postmenopausal depression.

Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women

Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women

Attitudes to the prescription of menopause hormone therapy for vasomotor symptoms and osteoporosis for patients of different ages: A survey of gynecologists in Belgium

IntroductionThe interpretation of the literature on menopause hormone therapy (MHT) has evolved enormously over the last decade. In recent years, guidelines have reinstated the place of MHT. AimThis survey analyzes the prescription (initiation and maintenance) of MHT in relation to patient age and therapy indications. Material and methodTwo vignettes were sent to gynecologists working in Belgium in a random survey. One vignette concerned the initiation of therapy for a woman who was either 52 or 62 years old, suffering either from severe vasomotor symptoms (VSM) or from osteoporosis. The second vignette concerned the maintenance of MHT or switching to another medication in a woman aged 62 years who suffered either from VSM (when stopping MHT) or from osteoporosis. The physicians were asked how they would treat these two patients. ResultsWe analyzed 443 vignettes from 222 physicians. Initiation of MHT84% of the respondents would initiate MHT for a 52-year-old woman with VMS, whereas only 32% would do so for a 52-year-old woman who had osteoporosis (chi square = 33; p < 0.001). 51% would initiate MHT for a 62-year-old woman with VMS, whereas only 14% would do so for a 62-year-old woman with osteoporosis (chi square = 17; p < 0.001). Maintenance of therapy87% would maintain MHT for a 62-year-old woman with severe VMS and 52% would do so for a 62-year-old woman with osteoporosis (Chi Square 31; p < 0.001). ConclusionVMS are recognized as an indication for MHT, but osteoporosis much less so, even for women around the age of 50.

Self-regulation model applied to menopause: a mixed-methods study

Objectives: Considering that bio-psycho-sociocultural variables influence menopause, this research aimed to assess the suitability of the self-regulation model in explaining the menopausal experience, and to explore differences among participants with different characteristics (e.g. health, sexual related) regarding menopause representations.Methods: Overall, 27 Portuguese women aged 40–65 years were assessed for sociodemographics, health, and sexual activity, as well as menopausal status and symptoms. Semi-structured in-depth interviews were conducted. A directed content analysis was performed, and the qualitative data presented. Afterward, the frequencies of the categories were analyzed through quantitative methods (Mann–Whitney U tests).Results: Aging was the most frequently mentioned feature regarding menopause Identity, whereas vasomotor symptoms were the most mentioned regarding Negative Consequences and menses cessation regarding Positive Consequences. Features related to Cause (hormonal changes) and Control (need for acceptance) of menopause were also identified. No differences were found in the frequency of menopause representations between women with different characteristics (e.g. with higher vs. lower vasomotor symptom severity).Conclusion: The suitability of the self-regulation model to explain these women’s menopause experience was confirmed and the representations did not vary among participants with different characteristics. This research might help professionals and researchers in developing comprehensive interventions, based on this theoretical model.

A combined, bioidentical, oral, 17β-estradiol and progesterone capsule for the treatment of moderate to severe vasomotor symptoms due to menopause

ABSTRACTIntroduction: Many women seek treatment to alleviate menopausal vasomotor symptoms (VMS). Numerous women use combination compounded hormone therapy (CHT) to achieve the benefits of estrogen/progesterone for endometrial protection. TX-001HR is a combination of bioidentical 17β-estradiol (E2) and progesterone (P4) in a single capsule designed for continuous daily use to treat moderate to severe VMS.Areas covered: This drug profile describes the efficacy and safety of 4 doses of this E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, 0.25/50) for treating moderate to severe VMS in menopausal woman with a uterus.Expert opinion: In REPLENISH (NCT01942668), the two highest doses of TX-001HR significantly reduced VMS frequency and severity at 4 and 12 weeks versus placebo (co-primary endpoints); all doses met the primary endpoint of endometrial safety. Rates of amenorrhea were high and improved over time; the Menopause Quality of Life and Medical Outcomes Study-Sleep instruments improved with E2/P4. TX-001HR was well tolerated and had no clinically significant impact on vital signs, metabolic or coagulation parameters, or breast safety. The combination bioidentical E2/P4 capsule (1 mg/100 mg dose was FDA-approved as Bijuva in October 2018) may provide a safe, effective, rigorously studied alternative for women with a uterus who prefer CHT for relief of VMS.

Vasomotor symptoms in aging Chinese women: findings from a prospective cohort study

Purpose: This study aimed to prospectively determine the prevalence, duration, and severity of vasomotor symptoms (VMS) during menopause in a Chinese longitudinal cohort.Methods: This longitudinal cohort study recruited 187 participants from an urban Chinese community. The presence, frequency, degree, and duration of VMS were measured and analyzed.Results: A total of 83.4% of participating women experienced hot flashes and 82.9% reported night sweats, with nearly half reporting moderate to severe VMS (more than 3 times per day, or rated 4 or greater on a 1–8 severity scale). The median duration for both hot flashes and night sweats was 4.5 years. In a generalized linear mixed model, presence of VMS was significantly related to menopause stages, serum follicle stimulating hormone concentrations, general distress levels, and baseline body mass index.Discussion and conclusions: The prevalence of VMS in this longitudinal cohort was higher than that of previous Chinese cross-sectional studies and consistent with prior studies in western women. Meanwhile, the duration of symptomatic years in our study was shorter than that of western women. These results indicate that the difference in VMS between western and Chinese women appears to be in terms of the duration of symptoms, not prevalence.

Severity of hot flushes is inversely associated with dietary intake of vitamin B6 and oily fish

Objectives: This study investigated the links between the severity of vasomotor symptoms (VMS) and the dietary consumption of a variety of nutrients.Method: A cross-sectional analysis of the first-visit records of 262 women aged 40–65 years was conducted. The severity of their hot flushes (HF) and night sweats (NS) and their dietary consumption of nutrients were evaluated using the Menopausal Health-Related Quality of Life Questionnaire and the brief-type self-administered Diet History Questionnaire, respectively. The relationships between severity of HF/NS and dietary intake were analyzed separately for 43 major nutrients. We then evaluated different food items as sources of the nutrients.Results: After adjustment for age, body mass index, menopausal status, and background factors significantly related to VMS, only vitamin B6 (VB6) was significantly related to severity of HF (adjusted odds ratio per 10 μg/MJ in VB6 intake, 0.92; 95% confidence interval, 0.86–0.97). Moreover, a significant inverse relationship was found between the consumption of oily fish as a source of VB6 and the severity of HF.Conclusions: VB6 and oily fish intake is inversely associated with the severity of HF in middle-aged women. Therefore, increased intake of VB6 could help attenuate HF.

Uterine bleeding rates with hormone therapies in menopausal women with vasomotor symptoms

Introduction: Bleeding and spotting are major reasons why women discontinue use of hormone therapy (HT) taken to treat menopausal vasomotor symptoms (VMS). The REPLENISH trial (NCT01942668) evaluated TX-001HR (TherapeuticsMD, Boca Raton, FL), a single oral capsule containing bioidentical 17β-estradiol (E2) and progesterone (P4), for treating moderate to severe menopausal VMS in women with a uterus; the 1 mg E2/100 mg P4 dose was recently approved as Bijuva™ by the US Food and Drug Administration (FDA; October 2018). This report compares the incidence of uterine bleeding with TX-001HR to other FDA-approved menopausal HT and unapproved compounded bioidentical HT (CHT).

Self-regulation model applied to menopause: a mixed-methods study

Objectives: Considering that bio-psycho-sociocultural variables influence menopause, this research aimed to assess the suitability of the self-regulation model in explaining the menopausal experience, and to explore differences among participants with different characteristics (e.g. health, sexual related) regarding menopause representations.Methods: Overall, 27 Portuguese women aged 40-65 years were assessed for sociodemographics, health, and sexual activity, as well as menopausal status and symptoms. Semi-structured in-depth interviews were conducted. A directed content analysis was performed, and the qualitative data presented. Afterward, the frequencies of the categories were analyzed through quantitative methods (Mann-Whitney U tests).Results: Aging was the most frequently mentioned feature regarding menopause Identity, whereas vasomotor symptoms were the most mentioned regarding Negative Consequences and menses cessation regarding Positive Consequences. Features related to Cause (hormonal changes) and Control (need for acceptance) of menopause were also identified. No differences were found in the frequency of menopause representations between women with different characteristics (e.g. with higher vs. lower vasomotor symptom severity).Conclusion: The suitability of the self-regulation model to explain these women's menopause experience was confirmed and the representations did not vary among participants with different characteristics. This research might help professionals and researchers in developing comprehensive interventions, based on this theoretical model.

Predictors of Frequency and Severity of Vasomotor Symptoms: Results from the REPLENISH Trial [19M

INTRODUCTION: The objective of this analysis was to determine whether baseline characteristics can predict the frequency and severity of hot flushes (HF) in postmenopausal women. METHODS: REPLENISH was a phase 3, randomized, double-blind, placebo-controlled trial that evaluated the safety and efficacy of TX-001HR (17β-estradiol/progesterone oral capsule) in 767 postmenopausal women, who had ≥50 moderate to severe HF/week at baseline. Post hoc associations of baseline characteristics (age, race, BMI, smoking, time since last menstrual period [LMP], age at LMP, tubal ligation, parity, estradiol levels, and menopause-specific quality of life [MENQOL] total and vasomotor domain scores) with frequency and severity of hot flushes were evaluated. RESULTS: Baseline predictors for having ≥50 moderate to severe HF/week were BMI (P=.0299), MENQOL total score (P<.0001), and MENQOL Vasomotor domain score (P<.0001). For every unit increase in BMI, the odds of having ≥50 moderate to severe HF decreased by 12.6% while a one-point increase in MENQOL total and vasomotor scores increased the odds by 20.9% and 110.9%, respectively. Baseline predictors for HF severity were current smoking (P=.0042), and MENQOL overall (P<.0001) and vasomotor (P<.0001) scores. Multiple regression analyses showed that the MENQOL vasomotor score was the best predictor of severity (R2=0.1876; P<.0001), followed by MENQOL total score + smoking (R2=0.0325; P<.0001). Other baseline characteristics evaluated were not predictors of HF frequency and/or severity. CONCLUSION: In REPLENISH, baseline BMI, smoking, and MENQOL total and vasomotor scores were predictors for moderate to severe HF frequency and/or severity. These characteristics could potentially be used to predict women's HF frequency and severity at menopause.

Oral 17β-estradiol/progesterone (TX-001HR) and quality of life in postmenopausal women with vasomotor symptoms

Objective:The aim of the study was to describe the effects of TX-001HR (17β-estradiol [E2] and natural progesterone [P4] in a single oral capsule) on menopause-specific quality of life in women with moderate to severe vasomotor symptoms (VMS).Methods:The REPLENISH study (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial which evaluated four E2/P4 doses in postmenopausal women with VMS and a uterus. Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were included in a VMS substudy. Participants self-administered the Menopause-Specific Quality of Life (MENQOL) questionnaire. Baseline changes in MENQOL overall and domains were determined as well as correlations between changes in MENQOL scores and VMS frequency or severity.Results:In the VMS substudy, women treated with E2/P4 had significantly greater improvements from baseline in their MENQOL overall score at week 12, and months 6 and 12, compared with placebo (all, P < 0.05, except the lowest E2/P4 dose at months 6 and 12). Improvements from baseline for the MENQOL vasomotor domain score were significantly greater with TX-001HR doses versus placebo at all time points (all, P < 0.01). Changes in MENQOL vasomotor scores moderately correlated with changes in VMS frequency (r = 0.56, P < 0.0001) and severity (r = 0.55, P < 0.0001).Conclusion:In the REPLENISH trial, women with moderate to severe VMS treated with most E2/P4 doses reported significant improvements in quality of life from baseline to 12 weeks compared with placebo, which were maintained up to 12 months. TX-001HR, if approved, may provide the first oral hormone therapy formulation in a single capsule containing E2 and P4 for the treatment of VMS in postmenopausal women with a uterus.

SAT-238 Predictors Of Vaginal/Uterine Bleeding With Oral TX-001HR (Estradiol and Progesterone) Capsules Taken For Menopausal Vasomotor Symptoms

Vaginal bleeding associated with hormone therapy (HT) is the most common reason for treatment discontinuation. Cumulative amenorrhea rates (no bleeding or spotting for 13 cycles) ranging from 23% to 49% with current HT options1-3 are relatively lower than the 56% to 73% observed in the REPLENISH trial.4 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated TX-001HR (bioidentical 17β-estradiol and progesterone [E2/P4] combined in a single, oral softgel capsule; 1 mg E2/100 mg P4 FDA approved as BIJUVATM; TherapeuticsMD, Boca Raton, FL) vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). Overall, the proportion of women with no bleeding was high (74%-90%) with up to 1 year of TX-001HR. The objective of this analysis was to determine predictors of vaginal bleeding. Univariate analyses were used to assess the impact of age, race, BMI, smoking, time since last menstrual period (LMP), age at LMP, tubal ligation, parity, baseline E2 concentration, and baseline frequency and severity of VMS (mild=1 to severe=3) on the incidence of vaginal bleeding at any time during the study (cumulative incidence at cycle 13) and for bleeding that occurred in the first 3 months of the study (cumulative incidence at cycle 3). Predictors of vaginal bleeding with HT (at cycle 13) were age, time since LMP, E2 concentration, and severity of VMS. The likelihood of bleeding was reduced by 42% for every 5-year increase in age (P<0.0001) and by 39% for every 5-year increase in the time since LMP (P<0.0001). Incidence of bleeding significantly decreased by 54% with baseline E2 levels <10 pg/mL (P=0.0001), 59% with E2 levels <5 pg/mL (P<0.0001), and 47% for E2 levels 5 to <10 pg/mL (P=0.0040), when compared with E2 levels ≥10 pg/mL. There was 33% less bleeding reported for women with less severe VMS (<2.5 points). No statistically significant differences in reports of bleeding were noted for race, BMI, smoking, age at LMP, tubal ligation, parity, or baseline frequency of moderate to severe VMS. Similar predictors were noted for bleeding at cycle 3, except for baseline VMS severity, which was no longer a significant predictor. Cumulative amenorrhea was relatively high in TX-001HR users. Vaginal bleeding in women treated with TX-001HR increased in women who were younger, experienced their LMP more recently, and had higher baseline E2 concentrations. Even though the rate/amount of bleeding was relatively low overall,4 these data may help clinicians inform women who may be more likely to experience vaginal bleeding while taking combined E2/P4 for menopausal symptoms. 1. Prempro tablets PI. Wyeth Pharmaceuticals. 2. Activella tablets PI. Novo Nordisk FemCare AG. 3. Angeliq Tablets PI. Berlex. 4. Lobo RA, et al. Obstet Gynecol. 2018;132:161-170.

SAT-LB003 Nonsmokers Benefit from Lower Doses of an Estradiol/Progesterone Combination: Results of the REPLENISH Trial

Smoking has previously been reported to result in decreases in estradiol exogenous metabolism1,2,3 and may influence the efficacy of hormone therapy (HT) in postmenopausal women2,3. Importantly, differences in smoking rates among clinical trial populations may also contribute to differences in effects of HT observed across the trials.2 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated 4 doses of TX-001HR (17β-estradiol and progesterone [E2/P4]; 1/100, 0.5/100, 0.5/50, 0.25/50) combined in a single, oral softgel capsule vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). The 1 mg E2/100 mg P4 dose is FDA approved as BIJUVATM (TherapeuticsMD, Boca Raton, FL). In this trial, statistically significant improvements in the frequency and severity of moderate to severe VMS were observed for the two highest doses of TX-001HR (1/100 and 0.5/100) and is reported in detail elsewhere.4 The objective of this analysis was to assess the impact of smoking on estradiol metabolism by analyzing estradiol and estrone concentrations measured throughout the study and to assess the potential impact on efficacy. The overall percentage of current smokers was higher in the Replenish trial (26%) than in many other trials of HT, making analysis of the impact of smoking on estrogen levels and efficacy possible. Estradiol and estrone concentrations at baseline were similar between current smokers and nonsmokers (former/never smokers) for all treatment groups (active and placebo). However, at Weeks 4 and 12, Months 6, 9, and 12, estradiol (25%-32%) and estrone (30%-36%) concentrations were statistically significantly lower in smokers than in nonsmokers for all active estradiol/progesterone treatment groups (1/100, 0.5/100, 0.5/50, 0.25/50). There were no significant differences at any time point in the placebo group. Efficacy in reducing the frequency and severity of VMS was greater in nonsmokers. When evaluating nonsmokers, the 0.25/50 dose also demonstrated statistically significant improvements at Weeks 4 and 12, with a weekly reduction of greater than 14 hot flushes compared to placebo beginning at Week 4 and sustained through week 12. Results from this large Phase 3 clinical trial demonstrated a significant impact of current smoking on estradiol and estrone concentrations and indicate that non-smokers may benefit from lower doses of estradiol and progesterone than smokers. 1. Jensen J, et al. NEJM. 1985;313(16):973-975. 2.Tansavatdi B, et al. Minerva Ginecol. 2004;56:105-114. 3. Ruan X and Mueck AO. Climacteric. 2015;18:38-46. 4. Lobo RA, et al. Obstet Gynecol. 2018;132:161-170. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-237 Combined Bioidentical Estradiol and Progesterone Capsules Improved Quality of Sleep in Postmenopausal Women with Vasomotor Symptoms

Difficulty sleeping is a common complaint of postmenopausal women. In the REPLENISH trial, the oral 17β-estradiol/progesterone (E2/P4) softgel capsule (TX-001HR; 1 mg E2/100 mg P4 FDA approved as BIJUVATM; TherapeuticsMD, Boca Raton, FL), was shown to reduce moderate to severe hot flush frequency and severity and improve quality of life outcomes in menopausal women with a uterus, while protecting the endometrium. In this analysis, the effect of the E2/P4 capsules on “difficulty sleeping” in postmenopausal women experiencing hot flushes, was assessed by the menopause-specific quality of life (MENQOL) questionnaire and also analyzed by age. The phase 3 REPLENISH trial (NCT01942668), evaluated 4 daily doses of E2/P4 capsules in postmenopausal women (40-65 years, intact uterus) with vasomotor symptoms (VMS). Women with moderate to severe hot flushes (≥7/day or ≥50/week) were randomized to E2/P4 (mg/mg) 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo (VMS substudy); women with fewer/less severe VMS were randomized to active E2/P4 doses only for endometrial safety. MENQOL was administered at baseline, week 12, and months 6 and 12. The “difficulty sleeping” item was rated using a 7-item Likert scale ranging from “Not at all bothered” (analysis score of 2) to “Extremely bothered” (analysis score of 8) if difficulty sleeping was experienced, if not experienced, the score for the analysis was set to 1. Changes from baseline to week 12, and months 6 and 12 in all women (MITT population) were analyzed by ANCOVA between each E2/P4 groups vs placebo and stratified by age (pre-specified FDA subgroup; <55 and 55+). Treatment groups in the MITT population (n=1833) were E2/P4 1/100 (n=416), 0.5/100 (n=422), 0.5/50 (n=421), 0.25/50 (n=423) or placebo (n=151). The MITT population had a mean age of 55 years; in the <55-year group (n=927) mean age was 51.2 years and in the ≥55-year group (n=906) mean age was 58.1 years. Mean baseline scores for the “difficulty sleeping” item ranged from 5.1 to 5.8 points. In the MITT population, difficulty sleeping significantly improved from baseline with the three highest E2/P4 doses (1/100, 0.5/100, 0.5/50) compared with placebo at all timepoints (all, P<0.05), except for 0.5/50 at month 6. In women <55 years, the sleep difficulty item significantly improved from baseline at all timepoints with two E2/P4 doses (1/100 and 0.5/50) vs placebo. In women 55+ years, significant improvements from baseline were observed at week 12 with three E2/P4 doses (1/100, 0.5/100, 0.5/50) vs placebo. In REPLENISH, women treated with E2/P4 capsules containing 1 or 0.5 mg E2 demonstrated significant and sustained improvements in the MENQOL difficulty sleeping assessment, especially those <55 years. These data warrant further evaluation.

SAT-239 Bioidentical Estradiol and Progesterone Improved Hot Flushes, Night Sweats and Sweating

In the phase 3 REPLENISH trial of postmenopausal women with a uterus, TX-001HR (TherapeuticsMD, Boca Raton, FL), an oral 17β-estradiol-progesterone (E2/P4) softgel capsule, reduced moderate to severe hot flush frequency and severity and improved quality of life outcomes, while protecting the endometrium. The objective of this analysis was to further determine the effects of the E2/P4 capsules versus placebo on vasomotor symptoms (VMS) as assessed by the menopause-specific quality of life (MENQOL) questionnaire. In the REPLENISH trial (NCT01942668), women with moderate to severe hot flushes (≥7/day or ≥50/week) were randomized 1:1:1:1:1 to daily E2/P4 (mg/mg) of 1/100 (FDA approved as BIJUVATM), 0.5/100, 0.5/50, 0.25/50, or placebo (VMS substudy). Other women (with fewer VMS) were randomized 1:1:1:1 to active E2/P4 doses only. Three of the 29 items in the MENQOL questionnaire assess vasomotor symptoms: hot flushes, night sweats, and sweating. The symptoms, if experienced, were rated using a 7-item Likert scale ranging from “Not at all bothered” (score of 2) to “Extremely bothered” (score of 8); if not experienced, the score was 1. Changes from baseline to week 12, and months 6 and 12 in these 3 items were assessed in the overall efficacy population (MITT) and VMS (MITT-VMS) substudy population. Women were randomized to daily doses of E2/P4 (mg/mg) 1/100 (n=415), 0.5/100 (n=424), 0.5/50 (n=421), 0.25/50 (n=424) or placebo (n=151). Participants (mean age of 55 years and mean BMI of 27 kg/m2) were primarily white (65%) or black (32%). Mean baseline scores ranged from 6.7 to 7.4 for hot flushes, 6.1 to 7.1 for night sweats, and 6.0 to 6.9 for sweating. In the MITT population, women treated with all E2/P4 doses had significantly more favorable improvements from baseline in their hot flushes (range of significant mean changes with E2/P4 vs placebo, -2.9 to -4.3 vs -1.9 to -2.7), night sweats (-3.1 to -4.0 vs -2.4 to -3.0) and sweating (-2.8 to -3.6 vs -2.3 to -3.2) scores at week 12, and months 6 and 12 (all, P≤0.002). Similarly, significant improvements from baseline with E2/P4 vs placebo (all, P≤0.030) were observed in the MITT-VMS substudy population for hot flushes (-3.0 to -4.4 vs -1.9 to -2.7), night sweats (-3.3 to -4.4 vs -2.4 to -3.0), and sweating (-3.1 to -4.2 vs -2.3 to -3.2), except for those treated with the lowest E2/P4 dose (0.25 mg E2/50 mg P4) at months 6 and 12 for sweating. In the REPLENISH trial, compared with placebo, postmenopausal women treated with E2/P4 had significant improvements in their hot flushes, night sweats and sweating as assessed by MENQOL. Benefits continued for up to 12 months of treatment. These results with this first oral hormone therapy formulation combining bioidentical estradiol and progesterone in a single capsule are consistent with the primary REPLENISH results demonstrating efficacy for the treatment of moderate to severe vasomotor symptoms in menopausal women with a uterus.

Consumption of a soy drink has no effect on cognitive function but may alleviate vasomotor symptoms in post-menopausal women; a randomised trial

PurposeCognitive decline is commonly reported during the menopausal transition, with memory and attention being particularly affected. The aim of this study was to investigate the effects of a commercially available soy drink on cognitive function and menopausal symptoms in post-menopausal women.Methods101 post-menopausal women, aged 44–63 years, were randomly assigned to consume a volume of soy drink providing a low (10 mg/day; control group), medium (35 mg/day), or high (60 mg/day) dose of isoflavones for 12 weeks. Cognitive function (spatial working memory, spatial span, pattern recognition memory, 5-choice reaction time, and match to sample visual search) was assessed using CANTAB pre- and post-the 12 week intervention. Menopausal symptoms were assessed using Greene’s Climacteric Scale.ResultsNo significant differences were observed between the groups for any of the cognitive function outcomes measured. Soy drink consumption had no effect on menopausal symptoms overall; however, when women were stratified according to the severity of vasomotor symptoms (VMS) at baseline, women with more severe symptoms at baseline in the medium group had a significant reduction (P = 0.001) in VMS post-intervention (mean change from baseline score: − 2.15 ± 1.73) in comparison to those with less severe VMS (mean change from baseline score: 0.06 ± 1.21).ConclusionsSoy drink consumption had no effect on cognitive function in post-menopausal women. Consumption of ~ 350 ml/day (35 mg IFs) for 12 weeks significantly reduced VMS in those with more severe symptoms at baseline. This finding is clinically relevant as soy drinks may provide an alternative, natural, treatment for alleviating VMS, highly prevalent among western women.

Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials

Objectives: Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women.Methods: Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded.Results: In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4–2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06–0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs.Conclusions: Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.

Association of menopausal symptoms with sociodemographic factors and personality traits.

Aim of the studyTo investigate the association of personality traits with the severity of vasomotor symptoms (VMS) in a predominantly Greek population.Material and methodsA questionnaire-based study of women from the Menopause Clinic of a University Hospital in Athens, Greece. Sociodemographic parameters were documented through a structured interview. All women completed the Menopause Rating Scale (MRS) for the assessment of severity of menopausal symptoms, the Hot Flush Beliefs Scale (HFBS) for the assessment of how women were coping with their symptoms and the Big Five Inventory questionnaires for the assessment of personality traits. Associations between baseline parameters and menopausal symptoms were assessed with univariate and multivariate regression analyses.ResultsOne hundred women were included. Employed women had lower MRS sub-scores (psychological p< 0.001, somatic p< 0.047, urogenital p< 0.008). Married women scored higher in the psychological and somatic domains. Women of university educational level coped significantly better with hot flushes (β coefficient [SE]: 0.72 [0.25], p< 0.01) and night sweats (0.57 [0.19], p< 0.01) than women of primary education, although the significance of these findings was not replicated when taking into account confounders. Regarding personality traits, women with low openness (–0.33 [0.11], p< 0.01) and empathy (–0.83 [0.37], p = 0.03) and high agreeableness (1.13 [0.21], p< 0.001) had more severe menopausal symptoms. In contrast, women with high agreeableness could better cope with their menopausal symptoms (–0.75 [0.36], p = 0.04). These associations were independent of sociodemographic factors.ConclusionsPersonality traits, especially agreeableness, openness and empathy are associated with menopausal symptoms and functionality in postmenopausal women. These associations might serve as indicators of women at risk of experiencing more severe VMS.