Menopause and MHT in 2024: addressing the key controversies - an International Menopause Society White Paper.

The vision of the International Menopause Society (IMS) is that all women across the world will have easy and equitable access to evidence-based knowledge and health care, empowering them to make fully informed midlife health choices. The aim of this White Paper is to provide a well-balanced educational narrative of the menopause and menopause hormone therapy (MHT) from IMS experts, leading into World Menopause Day 2024. This is achieved by exploring the anthropology and history of menopause, the principles and controversies of prescribing MHT, and by placing this into regulatory and menopause society contexts. The White Paper also lays the groundwork for the forthcoming updated IMS recommendations on menopause and will act as a blueprint for the future ethical management of menopause from practical and aspirational perspectives. An important section of the paper is 'The 5Ws of prescribing MHT': WHO is MHT for; WHAT types and doses of MHT; WHEN should MHT be started and stopped; WHY is MHT important; WHERE can MHT be accessed? A key points summary of this information is provided for healthcare professionals and the public. The summary provides 'easy to access' advice regarding several recent controversial MHT prescribing issues in the healthcare and media spotlights.

Insights on estetrol, the native estrogen: from contraception to hormone replacement therapy.

Estetrol (E4) is a natural estrogen that has recently emerged as new option for contraception and hormone replacement therapy (HRT). Unlike other estrogens, E4 primarily stimulates nuclear estrogen receptor alpha (ERα) and does not activate membrane ERα. For this reason, this novel estrogen has tissue-specific effects across various organs such as liver, vascular endothelium, mammary glands, brain, vagina, and uterus. The selective activation of the nuclear ERα results in distinct pharmacological properties that contribute to its unique therapeutic profile. Moreover, E4 shows minimal interaction with the hepatic cytochrome P450 enzyme system, leading to a favorable pharmacokinetic profile and a reduced potential for drug-drug interactions. Currently, E4 is commercially available in combination with drospirenone as a combined oral contraceptive and its application in HRT is undergoing late-stage clinical development. Many studies have demonstrated that E4 has a lower impact on hemostatic and metabolic parameters compared to other estrogens, potentially reducing the risk of adverse effects commonly associated with hormonal therapies such as thromboembolic events or dyslipidemia. Beyond its role in contraception and HRT, E4 shows promising therapeutic potential in other medical fields, including neuroprotection in neonatal hypoxic-ischemic encephalopathy, enhancement of hematopoietic stem cell transplantation outcomes and prostate cancer management. This review synthesizes the latest evidence on E4 primarily focusing on its pharmacological characteristics and clinical applications. The findings suggest that E4 versatility and peculiar mechanism of action may represent an important therapeutic option for a broad spectrum of medical conditions.

Gene-environment interaction in functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

Validation and cultural translation for the Brazilian Portuguese version of the Estro-Androgenic- Symptom Questionnaire in Women.

Objective: This study aimed to translate and validate the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese language, as we hypothesized that this tool would be consistent for addressing the specific context of hormonal symptoms in menopause. Methods: In a cross-sectional study, a total of 119 women with Genitourinary Syndrome of Menopause (GSM) and 119 climacteric women without GSM were included. The EASQ-W was translated, and its psychometric properties were rigorously examined. Participants completed questionnaires covering sociodemographic details, the EASQ-W, and the Menopause Rating Scale (MRS). A subgroup of 173 women was re-invited after 4 weeks for test-retest analysis of the EASQ-W. Additionally, the responsiveness of the questionnaire was evaluated in 30 women who underwent oral hormonal treatment. Results: The internal consistency of the EASQ-W was found to be satisfactory in both GSM and control groups (Cronbach's alpha ≥ 0.70). Notably, a floor effect was observed in both groups; however, a ceiling effect was only evident in the sexual domain of the GSM group. Construct validity was established by comparing the EASQ-W with the MRS, yielding statistically significant correlations (0.33831-0.64580, p < 0.001). The test-retest reliability over a 4-week period was demonstrated to be satisfactory in both the GSM and control groups (ICC 0.787-0.977). Furthermore, the EASQ-W exhibited appropriate responsiveness to oral hormonal treatment (p < 0.001). Conclusion: This study successfully translated and validated the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese, with satisfactory internal consistency, test-retest reliability, and construct validity.

Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials.

Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed. Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms. Design, Setting, and Participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023). Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks. Main Outcomes and Measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12. Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable. Conclusions and Relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS. Trial Registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

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.

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

Many women seek treatment to improve menopausal vasomotor symptoms (VMS). The selection of women most likely to benefit from menopause hormone therapy (MHT) is crucial in clinical practice. There is general agreement that women younger than 60 years or who initiate MHT within the first 10 years of menopause, with no contraindications, have greater benefits considering symptomatic relief and additional advantages. This group may have the advantage of protection from osteoporosis and from other chronic diseases that affect postmenopausal women, namely cardiovascular disease (CVD). Cumulating evidence supports MHT for symptomatic women. However, inadequate use according to the needs of symptomatic women led to a burden of suffering worldwide. In recent years, the emergent use of non-regulated body-identical hormones (non-rBHT) can expose patients to potential harms. These hormone preparations are not regulated through the same tests of safety, efficacy or dosing consistency as regulated-BHT (r-BHT). The POESIT (Portugal + Spain + Italy) recommendations highlight the use of 17ß-estradiol (E2) and micronized progesterone (P4) as the real r-BHT. In addition, the group emphasizes as an example the data from the REPLENISH study with 1 mg E2/100 mg P4. The combination of the two hormones in one convenient pill showed a clear reduction or elimination of hot flashes and an improvement in sleep quality and, consequently, quality of life. At the same time, this combination has shown high rates of amenorrhea and no significant impact on lipid, glucose or coagulation parameters. Both the REPLENISH study and a real-life retrospective study pointed to the possibility of a lower risk of venous thromboembolism (VTE) with this formulation than with other combinations.

Management of obesity in menopause.

The increasing prevalence of obesity imposes significant health challenges, particularly in women undergoing menopause. Effective obesity management is essential to mitigate associated comorbidities and improve quality of life. The pillars of obesity treatment encompass lifestyle modifications, pharmacotherapy and surgical interventions. Pharmacotherapy may be considered for women who do not achieve adequate weight loss through lifestyle changes alone and have obesity or overweight with risk factors. Bariatric surgery is reserved for individuals with severe obesity or those with obesity-related complications. During menopause, hormonal changes contribute to weight gain and fat redistribution, complicating obesity management. Tailored treatment strategies are necessary to address the unique challenges faced by this population. The role of physicians and gynecologists is pivotal in the multidisciplinary approach to obesity management during menopause. Gynecologists are often the primary health-care providers for menopausal women and are in a unique position to offer guidance on weight management. They can provide personalized counseling, coordinate with nutritionists, endocrinologists and bariatric specialists, and monitor the effects of obesity and its treatment on reproductive health. By integrating obesity management into routine gynecological care, gynecologists can significantly impact the overall health and well-being of menopausal women.

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

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

The influence of sex on heart failure mortality.

AIMS: Little research has investigated how sex may affect the prognosis of patients with chronic heart failure (HF). The present study was aimed at exploring sex-specific differences in prognosis in a cohort of patients with chronic HF, categorized according to severity of left ventricular dysfunction (HFrEF, HFmrEF and HFpEF), right ventricular (RV) dysfunction and ischemic (IHD) or nonischemic (no-IHD) etiology. METHODS: This retrospective analysis included 1640 HF patients of whom 24% were females, 759 patients had IHD, 1110 patients had HFrEF, 147 patients had HFmrEF and 383 patients had HFpEF. The median follow-up period was 63 months (25th-75th 27-93). RESULTS: In the no-IHD group, no statistically significant sex differences emerged regarding survival, regardless of age and severity of cardiac dysfunction. In contrast, in the IHD group, females had a significantly lower event rate than males in the age group between 65 and 79 years [hazard ratio (HR) 0.39; 95% confidence interval (CI): 0.86-0.18; P  < 0.01]; in addition, a lower event rate was observed in females compared with males among patients with HFrEF (HR 0.47; 95% CI: 0.88-0.25; P  < 0.01), among patients without RV dysfunction (HR 0.58; 95% CI: 1.02-0.33; P  = 0.048) and among patients without diabetes (HR 0.44; 95% CI: 0.84-0.23; P  < 0.01). CONCLUSION: In nonischemic patients there was no difference between males and females in terms of survival whereas in patients with ischemic etiology survival was better in females among elderly patients, in HFrEF patients, in the absence of RV dysfunction and in the absence of diabetes.

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.

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.

Expression of miRNA from spent pre-implantation embryos culture media.

This study examines the expression of three microRNAs (hsa-miR-661, hsa-miR-21-5p, hsa-miR-372-5p) in spent pre-implantation embryos culture media to identify possible new non-invasive biomarkers of embryo competence, predictive of development to the blastocyst stage. A preliminary analysis on 16 patients undergoing IVF cycles was performed by collecting and stored spent culture media on the fifth/sixth day of embryo culture. Expression of miRNAs was evaluated according to the embryos' fate: 1) NE/DG: non-evolved or degenerate embryos; 2) BLOK: embryos developed to the blastocyst stage. Preliminary results revealed a higher miRNAs expression in NE/DG spent media. To elucidate the roles of these miRNAs, we employed a robust bioinformatics pipeline involving: 1) in-silico miRNA Target Prediction using RNAHybrid, which identified the most-likely gene targets; 2) Construction of a Protein-Protein Interaction network via GeneMania, linking genes with significant biological correlations; 3) application of modularity-based clustering with the gLay app in Cytoscape, resulting in three size-adapted subnets for focused analysis; 4) Enrichment Analysis to discern the biological pathways influenced by the miRNAs. Our bioinformatics analysis revealed that hsa-miR-661 was closely associated with pathways regulating cell shape and morphogenesis of the epithelial sheet. These data suggest the potential use of certain miRNAs to identify embryos with a higher likelihood of developing to the blastocyst stage. Further analysis will be necessary to explore the reproducibility of these findings and to understand if miRNAs here investigated can be used as biomarkers for embryo selection before implantation into the uterus or if they may be reliable predictors of IVF outcome.

Insights into the vulvar component of the genitourinary syndrome of menopause (GSM).

Genitourinary syndrome of menopause is a comprehensive term that groups genital, urinary and sexual signs and symptoms mainly due sex hormone deficiency and aging, with a crucial impact on quality of life of midlife women. While this broad definition captures the common underlying physiopathology and the frequent overlap of symptomatology, improving knowledge about different components of genitourinary syndrome of menopause may be relevant for individualized treatment, with possible implications for efficacy, compliance and satisfaction. This narrative review focuses on the vulvar component of genitourinary syndrome of menopause, highlighting anatomical and functional peculiarities of the vulva that are responsible for some of the self-reported symptoms, as well as specific signs at physical examination. Increasing evidence points towards a pivotal role of vulvar vestibular health in the occurrence of sexual pain, one of the most common and distressing symptoms of genitourinary syndrome of menopause, which should be evaluated with validated scales taking a biopsychosocial perspective. This is an essential step in the recognition of different phenotypes of genitourinary syndrome of menopause and in the assessment of the most effective diagnostic and therapeutic algorithm. Menopausal vulvar health deserves more research into tailored non-hormonal and hormonal treatment options.

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.

Body Image and Other Mood Vulnerabilities in Adolescents with Polycystic Ovary Syndrome and Metabolic Alterations.

INTRODUCTION: Psychological vulnerability is a relevant component of polycystic ovarian syndrome (PCOS), but it is still under-explored, especially during adolescence. The aim of this study was to describe a selection of psychometric characteristics in a clinical sample of Italian adolescents with PCOS. Moreover, we reported the associations of body image, eating attitudes, and mood with metabolic features. METHODS: Our sample included 128 adolescent girls (age range: 14-19 years) with PCOS. Validated psychometric questionnaires were administered: State Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Body Attitude Test (BAT), Bulimia Investigation Test (BITE), Eating Attitudes Test (EAT), and Perceived Stress Scale (PSS). RESULTS: Anxiety was the most prevalent mood disorder (63.1% trait anxiety and 57% state anxiety). Our cohort also showed a high prevalence of depression (39.1%), body image dissatisfaction (49.2%), disordered eating (11.7%), and bulimic risk (41.4%). PCOS adolescents with obesity and insulin resistance (IR) had statistically significant higher body image distress compared to those with normal weight and without IR (p < 0.001). The Sobel test for mediation showed that body image dissatisfaction mediates the relationship between state anxiety and bulimic risk (Z = 3.42, p < 0.001) and between depression and bulimic risk (Z = 4.59, p < 0.001). CONCLUSIONS: A considerable number of patients with PCOS experience psychological disorders during adolescence. IR and obesity play a role in the distress associated with body image, further contributing to psychological vulnerability, especially in the bulimic domain. A comprehensive biopsychosocial approach in adolescents with PCOS represents the basis for effectively managing and preventing complications arising from both psychological and biological disorders in adulthood.

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.

Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

OBJECTIVE: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects. METHODS: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome. RESULTS: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice. CONCLUSIONS: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.