Rogerio A. Lobo

Background: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by menstrual irregularities and hyperandrogenic manifestations, has been increasingly associated with psychological distress and impaired self-image. However, results regarding sexual function (SF) in PCOS women are still controversial, and their interpretation is complicated by the use of different SF assessment tools across studies. Aim: To evaluate female sexual dysfunction in PCOS women diagnosed through modified Rotterdam criteria by conducting specific meta-analyses for each validated SF questionnaire and assess the influence of overweight/obesity (OW/O) on these outcomes. Methods: A Systematic Review (PRISMA) of 8 databases was performed until March 2024. Meta-analysis employed STATA software, employing a random-effects model to compare groups via Hedges’ g and standardized mean difference (SMD). Heterogeneity (I2 statistic; Q test) and publication bias (funnel plots; Egger’s test) were assessed. Outcomes: The influence of PCOS and OW/O on SF. Results: A total of 6171 articles were initially screened, and 40/6171 studies were included in this systematic review. Meta-analyses were performed solely for the Female Sexual Function Index (FSFI) score as it was the only SF assessment tool widely used across published studies. Pooled meta-analysis results showed that PCOS women had significantly lower FSFI scores in all fields than controls: total FSFI: -0.4 (95% CI -0.45; -0.36, I2 = 94.3%); desire: -0.22 (95% CI -0.26; -0.17, I2 = 90.8%); arousal: -0.3 (95% CI -0.34; -0.25, I2 = 94.1%); lubrication: -0.31 (95% CI -0.36; -0.26, I2 = 93%); orgasm: -0.27 (95% CI -0.32; -0.22 I2 = 89.2%); satisfaction: -0.23 (95% CI -0.28; -0.18, I2 = 81.5%); pain: -0.3 (95% CI -0.35; -0.25, I2 = 91.1%). OW/O PCOS women scored with higher lubrication scores than OW/O controls (SMD = 0.3 95% CI [0.03;0.58], P = .02, I2 = 0%). Clinical Translation: These findings emphasize the importance of incorporating SF assessments into PCOS follow-up protocols and multidisciplinary care. Strengths and Limitations: Strengths include a large cohort, analysis of an OW/O subgroup, and robust quality assessment using the Newcastle–Ottawa Scale. The main limitation was the lack of published studies using SF-assessment tools other than the FSFI, which precluded meta-analyses for other questionnaires. Conclusion: While PCOS women experience significantly impaired SF than controls, those with OW/O and PCOS may have comparable or even enhanced SF in certain domains, particularly lubrication, suggesting that the interplay between obesity and SF in PCOS women may not always be negative. By integrating routine screening with a multidisciplinary approach, we can more effectively address the sexual health challenges faced by PCOS women, ultimately empowering them to achieve optimal health and overall well-being.

Background: Women have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.Method: Women (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.Result: The median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).Conclusion: Higher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women.This study was a multicenter, randomized, double-...

Objective: To better characterize the metabolic alterations in various phenotypes of polycystic ovary syndrome (PCOS) in a large homogeneous (Sicilian) Mediterranean population with a low prevalence of obesity.Design: Retrospective study.Patients: A total of 1215 consecutively evaluated women with PCOS divided into four Rotterdam phenotypes (A, B, C and D) and in 108 matched ovulatory, nonhyperandrogenic women.Measurements: BMI, fasting glucose, total cholesterol, HDL cholesterol, triglycerides, LDL cholesterol and an oral glucose tolerance test.Results: The overall prevalence of obesity was 31%, metabolic syndrome 6.6%, diabetes 2.1%, altered glucose metabolism 13.1%, and abnormal lipid profile 60%. Phenotype B had the highest prevalence of obesity, metabolic syndrome, altered glucose metabolism and lipid abnormalities compared to other PCOS phenotypes and controls. Phenotype A was more obese and more women had metabolic syndrome compared to phenotypes C and D but phenotype C had a similar prevalence of altered glucose metabolism and lipid abnormalities compared to phenotype A which had a higher BMI. These metabolic abnormalities in A and C were higher compared to phenotype D and controls. Multivariate analysis showed that BMI predicts only abnormalities in fasting glucose and triglycerides, while there was no association with androgens.Conclusions: In Mediterranean women with PCOS from Sicily with a lower prevalence of obesity, the prevalence of diabetes, altered glucose metabolism and metabolic syndrome were much lower than reported in US studies. Phenotype B was the most metabolically affected phenotype, followed by phenotype A. Phenotype C had an intermediate disorder but with a high prevalence of altered glucose metabolism and lipid alterations. Only the normoandrogenic phenotype D had no metabolic abnormalities.

Objective: In the REPLENISH trial, women receiving TX-001HR—an oral, softgel capsule, combining 17β-estradiol (E2) and progesterone (E2 mg/P4 mg 1/100, 0.5/100), had significantly improved vasomotor symptoms, while having their endometrium protected from hyperplasia. The objective here was to describe P4 levels sufficient to counteract the potential endometrial effects of 1 or 0.5 mg oral E2 with TX-001HR. Methods: In REPLENISH (phase 3; NCT01942668), serum P4, E2, and estrone (E1) levels were characterized in postmenopausal women treated with TX-001HR (E2 mg/P4 mg: 1/100, 0.5/100, [0.5/50, 0.25/50 and placebo not reported here]) at baseline, week 12, and month 12 for P4, and at baseline, weeks 4 and 12, and months 6, 9, and 12 for E2 and E1. In a phase 1 study, pharmacokinetic parameters were assessed after 7 daily doses of oral E2 mg/P4 mg (1/100 and 0.5/100). Results: In REPLENISH (n = 1,835), mean P4 levels were 0.39 to 0.55 ng/mL with 100-mg P4 doses; E2 levels were 42.3 to 45.6 pg/mL and 23.0 to 27.4 pg/mL for the 1-mg and 0.5-mg E2 doses, respectively; E1 levels were 214 to 242 pg/mL and 114 to 129 pg/mL for the 1-mg and 0.5-mg E2 doses. In the phase 1 study (n = 40; day 7), mean C _avg for P4 was 0.66 ng/mL with 100-mg P4 doses; E2 was 38.1 pg/mL and 29.2 pg/mL for 1 mg and 0.5 mg E2, respectively; and E1 was 211 and 106 pg/mL for 1 mg and 0.5 mg E2. All three analytes reached steady state within 7 days; accumulation ratios were 1.36 to 1.94. Conclusions: P4 levels observed with TX-001HR were similar in the phase 1 and 3 studies, and were associated with no endometrial hyperplasia with either E2 daily dose over 1 year in the REPLENISH phase 3 study, which showed significant improvements in menopausal vasomotor symptoms.

Objective: This study aimed to evaluate the effects of TX-001HR (17β-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes. Methods: Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized. Results: A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1–4%, 6–11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population. Conclusions: In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.

To evaluate factors associated with interpregnancy interval (IPI) among women treated with in vitro fertilization (IVF).

OBJECTIVE: To evaluate efficacy, endometrial safety, and overall safety of a single-capsule 17β-estradiol–progesterone (TX-001HR) for treating menopausal moderate-to-severe vasomotor symptoms. METHODS: REPLENISH was a phase 3, 12-month, randomized, double-blind, placebo-controlled, multicenter trial. Women (aged 40–65 years) with vasomotor symptoms and a uterus were randomized to daily estradiol (mg)–progesterone (mg) (1/100, 0.5/100, 0.5/50, or 0.25/50), and women in the vasomotor symptoms substudy (women with moderate-to-severe hot flushes [seven or greater per day or 50 or greater per week]) to those estradiol–progesterone doses or placebo. The primary safety endpoint was endometrial hyperplasia incidence at 12 months in all women (the total population), and the primary efficacy endpoints were frequency and severity changes (from daily diaries) in moderate-to-severe vasomotor symptoms with estradiol–progesterone compared with placebo at weeks 4 and 12 in the vasomotor symptoms substudy. A sample size of 250 women in each active treatment arm with two or less endometrial hyperplasia cases would result in 1% or less annual incidence (upper bound 2.5% or less, one-sided 95% CI). RESULTS: One thousand eight hundred forty-five women were enrolled and randomized from August 2013 to October 2015; 1,835 received medication (safety population); 1,255 were eligible for the endometrial safety population; 726 comprised the vasomotor symptoms substudy; their mean age and body mass index were 55 years and 27, respectively; one third were African American. No endometrial hyperplasia was found. Frequency and severity of vasomotor symptoms significantly decreased from baseline with 1 mg estradiol and 100 mg progesterone and 0.5 mg estradiol and 100 mg progesterone compared with placebo at week 4 (frequency: by 40.6 and 35.1 points [1 mg and 100 mg and 0.5 mg and 100 mg, respectively] vs 26.4 points [placebo]; severity: by 0.48 and 0.51 vs 0.34 points) and week 12 (by 55.1 and 53.7 vs 40.2; severity: by 1.12 and 0.90 vs 0.56); 0.5 mg estradiol and 50 mg progesterone improved (P<.05) frequency and severity at week 12, and 0.25 mg estradiol and 50 mg progesterone frequency but not severity at weeks 4 and 12. CONCLUSION: No endometrial hyperplasia was observed while single-capsule estradiol–progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol–progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01942668.