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ObjectivesManagement options for PCOS, as the most prevalent endocrine disorder in women of reproductive age, using natural supplements have a high priority for physicians, especially based on the etiological pathways. Therefore, this study was conducted to describe the effect of resveratrol on the angiogenesis pathway, for management of PCOS through assessing VEGF, HIF1 gene expression, and laboratory parameters.MethodsIn this triple-blind RCT, PCOS was confirmed in ICSI candidates based on the Rotterdam criteria. Sixty-two patients that met the inclusion criteria were randomly assigned to two groups. All patients took resveratrol 800 mg/day or placebo for 40 days orally from the beginning of their previous menstruation cycle until the oocyte retrieval day. The serum levels of different hormones were measured, and the expression of HIF1 & VEGF genes was quantified by real-time PCR.ResultsAs for the laboratory hormone assay in 61 PCOS patients, a significant mean difference was seen in the FSH, LH, TSH, and testosterone between the two groups (P < 0.05). The results showed a reduction in the expression of VEGF & HIF1 genes under the effect of resveratrol in the granulosa cells (P = 0.0001). The number of mature oocytes, cleavage rate, fertilization rate, and fertility rate were not significantly different between the two groups (P > 0.05), but the high-quality oocyte rate and high-quality embryo rate were higher in the resveratrol group (P < 0.05).ConclusionsBased on the results, resveratrol may improve some outcomes of PCOS patients, probably through changing the serum levels of some sex hormones and expression of VEGF & HIF1 genes in the angiogenesis pathway of granulosa cells.

PurposeTo investigate the effectiveness of a biphasic IVM culture strategy at improving IVM outcomes in oocytes from small follicles (< 6 mm) compared with routine Standard IVM in patients with polycystic ovaries.MethodsThis prospective pilot study was performed in 40 women with polycystic ovaries whose oocytes were randomized to two IVM culture methods. Patients received a total stimulation dose of 450 IU rFSH. Cumulus-oocyte complexes (COCs) from follicles < 6 mm and ≥ 6 mm were retrieved and cultured separately in either a prematuration medium with c-type natriuretic peptide followed by IVM (CAPA-IVM), or STD-IVM. Primary outcomes were maturation rate, embryo quality, and the number of vitrified day 3 embryos per patient.ResultsUse of the CAPA-IVM system led to a significant improvement in oocyte maturation (p < 0.05), to a doubling in percentage of good and top-quality day 3 embryos per COC, and to an increased number of vitrified day 3 embryos (p < 0.001), compared to STD IVM. Oocytes from follicles < 6 mm benefited most from CAPA-IVM, showing a significant increase in the amount of good and top-quality embryos compared to STD IVM. CAPA-IVM yielded significantly (p < 0.0001) less GV-arrested oocytes and larger oocyte diameters (p < 0.05) than STD IVM.ConclusionsCAPA-IVM brings significant improvements in maturation and embryological outcomes, most notably to oocytes from small antral follicles (< 6 mm), which can be easily retrieved from patients with a minimal ovarian stimulation. The study demonstrates the robustness and transferability of the CAPA-IVM method across laboratories and populations.

Background Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications. Methods A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1 H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS). Results Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity. Conclusions Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.

Abstract Background Observational studies have shown a link between elevated body mass index (BMI) and the risk of polycystic ovary syndrome (PCOS). While Mendelian randomization (MR) studies in Europeans have suggested a causal role of increased BMI in PCOS, whether the same role is suggested in Asians has yet to be investigated. We used MR studies to infer causal effects using genetic data from East Asian populations. Methods and Findings We performed a 2-sample bidirectional MR analysis using summary statistics from genome-wide association studies (GWAS) of BMI (with up to 173 430 individuals) and PCOS (4386 cases and 8017 controls) in East Asian populations. Seventy-eight single nucleotide polymorphisms (SNPs) correlated with BMI were selected as genetic instrumental variables to estimate the causal effect of BMI on PCOS using the inverse-variance weighted (IVW) method. To test the reliability of the results, further sensitivity analyses included MR–Egger regression, weighted median estimates, and leave-one-out analysis. The IVW analysis indicated a significant association between high BMI and the risk of PCOS (odds ratio per standard deviation higher BMI, 2.208; 95% confidence interval 1.537 to 3.168, P = 1.77 × 10–5). In contrast, the genetic risk of PCOS had no significant effect on BMI. Conclusions The results of our bidirectional MR study showed that an increase in BMI causes PCOS, while PCOS does not cause an increased BMI. This study provides further genetic support for a link between BMI and PCOS. Further research is needed to interpret the potential mechanisms of this association.

Polycystic ovarian syndrome (PCOS) is related to pro‐apoptotic and pro‐inflammatory conditions generated by Endoplasmic reticulum (ER) stress. This study aimed to determine the effect of Astaxanthin (ASX), as carotenoid with potent antioxidant and anti‐inflammatory properties, on serum inflammatory markers, apoptotic factors and ER stress‐apoptotic genes in peripheral blood mononuclear cells (PBMCs) of women with PCOS. This randomized, double‐blind clinical trial included 56 PCOS patients aged 18–40. For 8 weeks, subjects were randomly assigned to one of two groups: either 12 mg ASX (n = 28) or placebo (n = 28). Real‐time PCR was used to quantify gene expression associated with ER stress‐apoptosis in PCOS women's PBMCs. The levels of TNF‐α, IL18, IL6 and CRP were determined by obtaining blood samples from all patients before and after the intervention using Enzyme‐linked immunosorbent assay (ELISA). Also, the levels of active caspase‐3 and caspase‐8 were detected in the PBMC by ELISA kit. Furthermore, we evaluated the efficacy of ASX on disease symptoms. Following the 8‐week intervention, ASX supplementation was able to reduce the expression of GRP78 (p = 0.051), CHOP (p = 0.008), XBP1 (p = 0.002), ATF4 (0.038), ATF6 (0.157) and DR5 (0.016) when compared to the placebo. However, this decrease was not statistically significant for ATF6 (p = 0.067) and marginally significant for GRP78 (p = 0.051). The levels of TNF‐α (p = 0.009), IL‐18 (p = 0.003), IL‐6 (p = 0.013) and active caspase‐3 (p = 0.012) were also statistically significant lower in the therapy group. However, there was no significant difference in CRP (p = 0.177) and caspase‐8 (p = 0.491) levels between the treatment and control groups. In our study, ASX had no significant positive effect on BMI, hirsutism, hair loss and regularity of the menstrual cycle. It appears that ASX may benefit PCOS by changing the ER stress‐apoptotic pathway and reducing serum inflammatory markers; however, additional research is required to determine this compound's potential relevance.

Polycystic ovary syndrome (PCOS) is an endocrine disease associated with infertility and metabolic disorders in reproductive-aged women. In this study, we evaluated the expression of eight genes related to endometrial function and their DNA methylation levels in the endometrium of PCOS patients and women without the disease (control group). In addition, eight of the PCOS patients underwent intervention with metformin (1500 mg/day) and a carbohydrate-controlled diet (type and quantity) for three months. Clinical and metabolic parameters were determined, and RT-qPCR and MeDIP-qPCR were used to evaluate gene expression and DNA methylation levels, respectively. Decreased expression levels of HOXA10, GAB1, and SLC2A4 genes and increased DNA methylation levels of the HOXA10 promoter were found in the endometrium of PCOS patients compared to controls. After metformin and nutritional intervention, some metabolic and clinical variables improved in PCOS patients. This intervention was associated with increased expression of HOXA10, ESR1, GAB1, and SLC2A4 genes and reduced DNA methylation levels of the HOXA10 promoter in the endometrium of PCOS women. Our preliminary findings suggest that metformin and a carbohydrate-controlled diet improve endometrial function in PCOS patients, partly by modulating DNA methylation of the HOXA10 gene promoter and the expression of genes implicated in endometrial receptivity and insulin signaling.

Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18–40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care. Baseline subcutaneous adipose tissue gene expression was related to weight change after the lifestyle intervention. A total of 55 obese/overweight women provided subcutaneous adipose samples at study entry. Weight loss was significant after behavioral modification (−2.2%, p = 0.0014), while there was no significant weight loss in the control group (−1.1%, p = 0.12). In microarray analysis of adipose samples, expression of 40 genes differed significantly between subgroups of those with the greatest weight loss or weight gain. 10 genes were involved in metabolic pathways including glutathione metabolism, gluconeogenesis, and pyruvate metabolism. Results were confirmed by real-time polymerase chain reaction (RT-PCR) in all 55 subjects. Expressions of GSTM5, ANLN, and H3C2 correlated with weight change (R = −0.41, p = 0.002; R = −0.31, p = 0.023 and R = −0.32, p = 0.016, respectively). GSTM5, involved in glutathione metabolism, was the strongest predictor of weight loss, and together with baseline waist-hip ratio (WHR) explained 31% of the variation in body weight change. This study shows that baseline subcutaneous adipose tissue genes play a role for body weight outcome in response to lifestyle intervention in overweight/obese women with PCOS.

PurposePolycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is typically accompanied by a defective oxidative defense system. Here, we investigated the effect of astaxanthin (AST) as a powerful antioxidant on the oxidative stress (OS) response and assisted reproductive technology (ART) outcomes in PCOS patients.MethodsIn this double-blind, randomized, placebo-controlled trial, PCOS patients were randomly assigned into two groups. The intervention group received 8 mg AST, and the control group received the placebo daily for 40 days. The primary outcomes were the serum and follicular fluid (FF) levels of the OS biomarkers and the expression levels of the specific genes and proteins in the oxidative stress response pathway. The secondary outcomes were considered ART outcomes.ResultsAccording to our findings, a 40-day course of AST supplementation led to significantly higher levels of serum CAT and TAC in the AST group compared to the placebo group. However, there were no significant intergroup differences in the serum MDA and SOD levels, as well as the FF levels of OS markers. The expression of Nrf2, HO-1, and NQ-1 was significantly increased in the granulosa cells (GCs) of the AST group. Moreover, the MII oocyte and high-quality embryo rate were significantly increased in the AST group compared to the placebo group. We found no significant intergroup difference in the chemical and clinical pregnancy rates.ConclusionAST treatment has been shown to increase both serum TAC levels and activation of the Nrf2 axis in PCOS patients’ GCs.Trial RegistrationClincialTrials.gov Identifier: NCT03991286.

Background Vitamin D deficiency in women diagnosed with polycystic ovary syndrome (PCOS) remarkably decreases the chance of pregnancy, which might be related to its impact on metabolic abnormalities in these patients. It is hypothesized that vitamin D supplementation influences metabolic profile of these patients and indirectly might affect fertility and the outcomes. Therefore, this study was conducted to determine the effects of vitamin D supplementation on the levels of anti-Müllerian hormone (AMH), metabolic profiles, and gene expression of insulin and lipid metabolism in infertile women with PCOS who were candidate for in vitro fertilization (IVF). Methods This study was a randomized, double-blinded, placebo-controlled trial conducted among 40 infertile women, aged 18–40 years, diagnosed with PCOS and was candidate for IVF. Participants were randomly assigned into two intervention groups for receiving either 50,000 IU vitamin D or placebo ( n  = 20 each group) every other week for 8 weeks. Gene expression for insulin and lipid metabolism was conducted using peripheral blood mononuclear cells (PBMCs) of women with PCOS, via RT-PCR method. Results Vitamin D supplementation led to a significant reduction in serum AMH (− 0.7 ± 1.2 vs. − 0.1 ± 0.5 ng/mL, P  = 0.02), insulin levels (− 1.4 ± 1.6 vs. -0.3 ± 0.9 μIU/mL, P  = 0.007), homeostatic model of assessment for insulin resistance (− 0.3 ± 0.3 vs. -0.1 ± 0.2, P  = 0.008), and a significant increase in quantitative insulin sensitivity check index (+ 0.009 ± 0.01 vs. + 0.001 ± 0.004, P  = 0.04), compared with the placebo. Moreover, following vitamin D supplementation there was a significant decrease in serum total- (− 5.1 ± 12.6 vs. + 2.9 ± 10.9 mg/dL, P  = 0.03) and LDL-cholesterol levels (− 4.5 ± 10.3 vs. + 2.5 ± 10.6 mg/dL, P = 0.04) compared with the placebo. Conclusion Overall, the findings of this trial supported that 50,000 IU vitamin D supplementation every other week for 8 weeks had beneficial effects on insulin metabolism, and lipid profile of infertile women with PCOS who are candidate for IVF. These benefits might not be evident upon having sufficient vitamin D levels. Trial registration This study was retrospectively registered in the Iranian website ( www.irct.ir ) for clinical trials registration ( http://www.irct.ir : IRCT20170513033941N27).

Objective To evaluate whether liraglutide or roflumilast significantly affects body weight when compared to metformin in obese women with PCOS. Design/main outcome measure A 12-week prospective randomized open-label study was conducted with 45 obese women with PCOS diagnosed by the ASRM-ESHRE Rotterdam criteria. They were randomized to metformin (MET) 1000 mg BID or liraglutide (LIRA) 1.2 mg QD s.c. or roflumilast (ROF) 500 mcg QD. The primary outcome was change in measures of obesity. Results Forty-one patients (aged 30.7 ± 7.9 years, BMI 38.6 ± 6.0 kg/m 2 , mean ± SD) completed the study. Subjects treated with LIRA lost on average 3.1 ± 3.5 kg ( p  = 0.006), on ROF 2.1 ± 2.0 kg ( p  = 0.002) vs. 0.2 ± 1.83 kg in MET group. BMI decreased for 1.1 ± 1.26 kg/m 2 in LIRA ( p  = 0.006), for 0.8 ± 0.99 kg/m 2 in ROF ( p  = 0.001) vs. 0.1 ± 0.67 kg/m 2 in MET. LIRA was superior to MET in reducing weight ( p  = 0.022), BMI ( p  = 0.020), waist circumference ( p  = 0.007). LIRA also resulted in decrease in VAT area ( p  = 0.015) and more favorable dynamics in glucose homeostasis during OGTT. ROF resulted in reduction of waist circumference ( p  = 0.023). In addition, ROF led to testosterone reduction ( p  = 0.05) and increase in menstrual frequencies ( p  = 0.009) when compared to baseline. Conclusion Short-term monotherapy with liraglutide or roflumilast was associated with significant weight loss in obese PCOS. Liraglutide was superior to metformin, whereas roflumilast resulted in greater, yet not statistically significant, mean weight loss when compared to metformin. Reduction of body weight with liraglutide resulted in improvement of body composition. Trial registration ClinicalTrials.gov NCT02187250 .