OBJECTIVE: To assess the impact of intermittent fasting, with or without probiotic supplementation, versus a calorie-restricted diet on anthropometric measures, metabolic status and gonadal variables in women with polycystic ovary syndrome (PCOS).
METHODS: This is a randomized, placebo-controlled, parallel-arm clinical trial. The effects of the 14:10 early time-restricted eating (eTRE) strategy alone or combined with probiotics, on obese women with PCOS, were investigated. Participants were divided into three groups: eTRE plus probiotics (n = 30), eTRE plus placebo (n = 30) and a control group following a standard three-meal-per-day diet with daily calorie restriction (DCR) (n = 30). Over 8 weeks, various anthropometric, metabolic, menstrual and gonadal variables were assessed.
RESULTS: A total of 90 individuals were included in the study, with a mean body weight of 81.4 kg, and a mean age of 30 years. Mean (standard deviation) weight loss was not different between the groups at week 8 (TRE + probiotic: -2.2 [1.6] kg vs. TRE + placebo: -2.9 [2.7] kg vs. DCR: -2.5 [1.7] kg). Results revealed that, while all three regimes led to reductions in body weight, body mass index, vascular risk indicators, hirsutism and acne scores, there were no statistically significant differences between the eTRE groups and the control group in terms of weight loss, or improvements in metabolic, menstrual and gonadal variables (P > .05). Additionally, combining probiotics with eTRE did not benefit hormonal and cardiometabolic factors (P > .05).
CONCLUSIONS: The eTRE alone or eTRE plus probiotics did not result in significantly greater weight loss or improvements in metabolic, menstrual and gonadal variables compared with the standard three-meal DCR diet.

BACKGROUND: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification.
METHODS: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran\'s Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted.
RESULTS: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences.
CONCLUSIONS: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

The association between serum copper and polycystic ovary syndrome (PCOS) lacks definitive conclusions, and the intricate interactions with in vitro fertilization (IVF) cycle characteristics in infertility remain insufficiently explored. This retrospective study included 560 patients with tubal infertility (no-PCOS) and 266 patients with PCOS undergoing IVF at the Affiliated Suzhou Hospital of Nanjing Medical University from January 2018 to December 2022. Patients\' basic characteristics, hormonal and metabolic parameters, essential trace elements, and IVF cycle characteristics were measured and analyzed. The results revealed a significantly elevated serum copper level in the PCOS group compared to the control group [17.27 (15.54, 19.67) vs 15.4 (13.87, 17.35), μmol/L; p < .001]. Spearman correlation analyses revealed a significant positive correlation between serum copper concentration and body mass index (BMI), fasting glucose (FG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) in the no-PCOS group. Additionally, a notable negative correlation with high-density lipoprotein (HDL) was observed (r = -.184, p < .001). Within the PCOS group, serum copper concentration correlated significantly with BMI (r = .198, p = .004) and TG (r = .214, p = .002). The linear trend analysis indicated no significant relationship between serum copper concentration and ovarian response as well as preimplantation outcomes in both groups after adjusting for confounding factors. Our study provided evidence of elevated serum copper concentration in PCOS patients, closely associated with lipid metabolism but showing no correlation with IVF outcomes. These findings provide valuable real-world data, enriching our nuanced understanding of the role of copper in female fertility.

Polycystic ovary syndrome (PCOS) is a disease caused by excessive ovarian androgen secretion due to hypothalamic-pituitary-ovarian hormone abnormalities. We retrospectively investigated the treatment status of patients diagnosed with PCOS who visited a domestic tertiary hospital in order to analyze the use patterns and safety of drugs. Patients diagnosed with PCOS between July 2014 and September 2022 were examined, excluding patients younger than 13 years and those not receiving medication. Patients aged 21 years or younger were designated as the adolescent group and patients aged 22 years or older were designated as the adult group for comparative statistical analysis. The total number of patients was 212, including 105 adolescents (49.5%) and 107 adults (50.5%). Comorbidities were ovarian cyst in 20 (9.4%) patients, endometriosis in 19 (9%), diabetes in 14 (6.6%), thyroid dysfunction in 12 (5.7%), hypertension in 10 (4.7%), dyslipidemia in 10 (4.7%), and androgenic alopecia in 6 (2.8%). Symptoms were oligomenorrhea in 91 (42.9%) patients, amenorrhea in 72 (34%), hirsutism in 36 (17%), acne in 24 (11.3%), and infertility in 10 (4.7%). During the study period, 114 patients (53.8%) were prescribed medroxyprogesterone acetate (MPA), 66 (31.1%) were given oral contraceptives (specifically, ethinyl estradiol + drospirenone prescribed to 52 (24.5%)), and 17 (8%) were concurrently prescribed MPA and oral contraceptives. Forty-five (21.2%) patients changed prescriptions, with 10 (22.2%) switching due to side effects and 8 (17.8%) due to a therapeutic failure. A total of 5 patients (2.4%) discontinued the drug. Adverse drug reactions occurred in 15 patients (7.1%), with 5 being adolescents (4.8%) and 10 being adults (9.3%). MPA alone and ethinyl estradiol with drospirenone were the most prescribed medications for PCOS. Over the study, 45 patients changed prescriptions, 50 were lost to follow-up, and 5 adults discontinued medications.

OBJECTIVE: Metformin is clinically effective in treating polycystic ovary syndrome (PCOS) with insulin resistance (IR), while its efficacy varies among individuals. This study aims to develop a machine learning model to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR.
METHODS: This is a retrospective analysis of a multicenter, randomized controlled trial involving 114 women diagnosed with PCOS and IR. All women received metformin treatment for 4 months. We incorporated 27 baseline clinical variables of the women into the construction of our machine learning model. We firstly compared four commonly used feature selection methods to screen valuable clinical variables. Then we used the valuable variables as inputs to evaluate the performance of five machine learning models, including k-Nearest Neighbors (KNN), Support Vector Machine (SVM), Logistic Regression (LR), Random Forest (RF), and Extreme Gradient Boosting (Xgboost), in predicting the efficacy of metformin.
RESULTS: Among the five machine learning models, SVM performed the best with an area under the receiver operating characteristic curve (AUC) of 0.781 (95% confidence interval [CI]: 0.772-0.791). The key predictive variables identified were homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and low-density lipoprotein cholesterol (LDL-C).
CONCLUSIONS: The developed machine learning model could be applied to to predict the efficacy of metformin in improving insulin sensitivity among women with PCOS and IR. The result could help doctors evaluate the efficacy of metformin in advance, optimize treatment plans, and thereby enhance overall clinical outcomes.

OBJECTIVE: Can an extended letrozole (LE) regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle?
CONCLUSIONS: There was no statistical difference in ovulation rate between patients with PCOS using the extended LE regimen and those using the conventional LE regimen.
BACKGROUND: LE has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with LE alone, and the extended LE regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored.
UNASSIGNED: This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with LE from January 2021 to October 2022.
METHODS: Participants were randomly assigned to receive an extended (5 mg LE daily for 7 days) or conventional regimen (5 mg LE daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies.
RESULTS: The ovulation rate among patients receiving an extended LE regimen was slightly higher than the rate with a conventional LE regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% CI]: 0.881 [0.768-1.009]) or the per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% CI]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39 ± 0.62 vs 1.37 ± 0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27 ± 1.72 mm vs 9.57 ± 2.28 mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% CI]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% CI]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects.
CONCLUSIONS: The major concerns regarding this study are its single-center and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings.
CONCLUSIONS: A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various LE treatment durations.
BACKGROUND: This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest.
BACKGROUND: Chinese Clinical Trial Registry (ChiCTR2100042082).
UNASSIGNED: 13 January 2021.
UNASSIGNED: 21 January 2021.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common ovarian dysfunction. Recent studies showed the effectiveness of licorice on metabolic profiles with inconsistent findings. So, we investigated the effect of licorice on obesity indices, glycemic indices, and lipid profiles in women with PCOS.
METHODS: This randomized, double-blind, placebo-controlled trial was performed on 66 overweight/obese women with PCOS. The participants were randomly assigned to receive either 1.5 gr/day licorice extract plus a low-calorie diet (n = 33) or placebo plus a low-calorie diet (n = 33) for 8 weeks. Participants\' anthropometric indices and body composition were assessed using standard protocols. Fasting blood sugar (FBS), insulin levels, low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) were measured using enzymatic kits. The homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-B) were calculated using valid formulas.
RESULTS: Between-group comparisons demonstrated significant differences between the groups in terms of obesity indices (body weight, BMI, and body fat), lipid profiles (TG, TC, LDL-C, and HDL-C), FBS and insulin levels, HOMA-IR, and HOMA-B at the end of the study (P < 0.05). Supplementation with licorice plus a low-calorie diet was also more effective in improving all parameters than a low-calorie diet alone after adjusting for confounders (baseline values, age, weight changes, and physical activity changes) (P < 0.05).
CONCLUSIONS: The findings showed that licorice consumption leads to improvements in obesity indices, glucose homeostasis, and lipid profiles compared to placebo. Due to possible limitations of the study, further research is needed to confirm these findings.

OBJECTIVE: Vitamin D deficiency and variations in the vitamin D binding protein (VDBP) gene may play a role in the development of Polycystic ovary syndrome (PCOS). This study aims to investigate the association of the rs4588 polymorphism with PCOS in Iranian women, as well as its association with infertility and recurrent pregnancy loss (RPL) in these patients.
RESULTS: The analysis revealed statistically significant differences in the distributions of genotypes and alleles of the rs4588 polymorphism among the three groups (p < 0.0001). The AC genotype and A allele showed an association with an elevated risk of PCOS and infertility. In this study, no association was found between genotypes and alleles of the rs4588 polymorphism and the risk of RPL in women with PCOS. Subjects with the AA or AC genotype exhibited significantly higher levels of LDL compared to those with the CC genotype.

Polycystic ovary syndrome (PCOS) is a leading cause of infertility, with an estimated worldwide prevalence between 5% and 15%. We conducted a case-control study with 121 PCOS patients and 155 controls to assess the association between coffee intake and the presence of having a diagnosis of PCOS in women in Murcia, Spain. The PCOS diagnosis was determined following Rotterdam criteria (the presence of two of the following three conditions: hyperandrogenism, oligo-anovulation, and/or polycystic ovarian morphology). Coffee consumption was assessed using a validated food frequency questionnaire. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. Coffee consumption was categorized into never, less than one cup per day, one cup per day, and two or more cups per day. We found a significant inverse linear trend: the higher the coffee consumption, the lower the probability of having PCOS in multivariable analysis (p-trend = 0.034). Women who presented with PCOS were less likely to drink one cup of coffee compared to those who had never drunk coffee (OR = 0.313, 95% CI: 0.141-0.69). The consumption of at least one cup of coffee per day may be associated with a decrease in PCOS symptoms.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder with significant metabolic implications, including an increased risk of cardiovascular diseases and diabetes. Kallistatin, a serine proteinase inhibitor with anti-inflammatory and antioxidative properties, has been identified as a potential biomarker for PCOS due to its role in modulating inflammation and oxidative stress.
METHODS: This prospective cohort study was conducted at a university hospital\'s gynecology clinic. It included 220 women diagnosed with PCOS and 220 healthy controls matched for age and body mass index. Kallistatin levels were quantitatively assessed using enzyme-linked immunosorbent assay (ELISA) techniques. Associations between kallistatin levels and clinical manifestations of PCOS, including hyperandrogenism and metabolic profiles, were examined.
RESULTS: Kallistatin levels were significantly lower in patients with PCOS (2.65 ± 1.84 ng/mL) compared to controls (6.12 ± 4.17 ng/mL; p < 0.001). A strong negative correlation existed between kallistatin levels and androgen concentrations (r = -0.782, p = 0.035). No significant associations were found between kallistatin levels and insulin resistance or lipid profiles.
CONCLUSIONS: The findings indicate that reduced kallistatin levels are closely associated with PCOS and could serve as a promising biomarker for its diagnosis. The specific correlation with hyperandrogenism suggests that kallistatin could be particularly effective for identifying PCOS subtypes characterized by elevated androgen levels. This study supports the potential of kallistatin in improving diagnostic protocols for PCOS, facilitating earlier and more accurate detection, which is crucial for effective management and treatment.