PPAR-α inhibits DHEA-induced ferroptosis in granulosa cells through upregulation of FADS2.

BACKGROUND: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian dysfunction. Ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Emerging evidence indicates that ferroptosis may have a significant role in the pathogenesis of PCOS, highlighting the importance of studying this mechanism to better understand the disorder and potentially develop novel therapeutic interventions. METHODS: To create an in vivo PCOS model, mice were injected with dehydroepiandrosterone (DHEA) and the success of the model was confirmed through further assessments. Ferroptosis levels were evaluated through detecting ferroptosis-related indicators. Ferroptosis-related genes were found through bioinformatic analysis and identified by experiments. An in vitro PCOS model was also established using DHEA treated KGN cells. The molecular binding relationship was confirmed using a chromatin immunoprecipitation (ChIP) assay. RESULTS: In PCOS model, various ferroptosis-related indicators such as MDA, Fe2+, and lipid ROS showed an increase, while GSH, GPX4, and TFR1 exhibited a decrease. These findings indicate an elevated level of ferroptosis in the PCOS model. The ferroptosis-related gene FADS2 was identified and validated. FADS2 and PPAR-α were shown to be highly expressed in ovarian tissue and primary granulosa cells (GCs) of PCOS mice. Furthermore, the overexpression of both FADS2 and PPAR-α in KGN cells effectively suppressed the DHEA-induced increase in ferroptosis-related indicators (MDA, Fe2+, and lipid ROS) and the decrease in GSH, GPX4, and TFR1 levels. The ferroptosis agonist erastin reversed the suppressive effect, suggesting the involvement of ferroptosis in this process. Additionally, the FADS2 inhibitor SC26196 was found to inhibit the effect of PPAR-α on ferroptosis. Moreover, the binding of PPAR-α to the FADS2 promoter region was predicted and confirmed. This indicates the regulatory relationship between PPAR-α and FADS2 in the context of ferroptosis. CONCLUSIONS: Our study indicates that PPAR-α may have an inhibitory effect on DHEA-induced ferroptosis in GCs by enhancing the expression of FADS2. This discovery provides valuable insights into the pathophysiology and potential therapeutic targets for PCOS.

Unmasking the morphological alteration of erythrocytes among women suffering from PCOS.

Dyslipidemia is frequently observed in polycystic ovarian syndrome (PCOS). Changes in plasma lipid levels potentially alter erythrocyte membrane lipid composition due to lack of inbuilt lipid synthesis machinery. Therefore, development of morphologically altered erythrocytes in PCOS patients with dyslipidemia is expected. However, this has not been established so far. So, we took this opportunity to explore the morphological alterations among dyslipidemic PCO women. We recruited thirty-five dyslipidemic PCOS women (satisfying Rotterdam criteria, without medication) and twenty-five age-matched healthy controls. Scanning electron microscopy revealed a significant increase in the number of stomatocytes, acanthocytes, and echinocytes in the PCO group. PCO group showed a considerable decrease in plasma antioxidant levels. Elevated lipid peroxidation, protein carbonylation, and decreased free thiol group in erythrocyte membrane in PCOS suggest oxidative degradation of the erythrocyte membrane. Elevated intracellular ROS levels, increased methemoglobin formation, and a decrease in NADPH methemoglobin reductase in PCOS also indicate altered physicochemical property of hemoglobin due to oxidative overload. Additionally, these patients exhibit a rise in erythrocyte membrane cholesterol and triglyceride, which promotes the membrane to become less fluidic and less fragile. Thus, these results corroborate a potential role in altering erythrocyte morphology among dyslipidemic PCO women.

Biomarkers to inform the management of polycystic ovary syndrome: A review of systematic reviews.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) is the commonest endocrine condition affecting reproductive age women. Many biomarkers may aid assessment and management, however evidence is limited on their utility in clinical practice. We conducted a review of systematic reviews to identify the most useful biomarkers in the clinical management of PCOS. METHODS: We searched MEDLINE, EMBASE, CENTRAL and HTA until August 2023 for reviews evaluating biomarkers in PCOS women compared to healthy controls. Methodological quality was assessed using the AMSTAR2 tool. We reported pooled evidence for each biomarker with 95% confidence intervals from the most recent, up-to-date, and best quality review. RESULTS: From 3360 citations, we included 75 systematic reviews (88 biomarkers, 191,792 women). Most reviews (50/75, 67%) were moderate quality, but reported high heterogeneity (66/75, 88%). We identified 63 abnormal biomarkers in women with PCOS versus healthy controls. Of these, 22 core biomarkers could help evaluate the multisystemic impact of PCOS and inform patient management and surveillance: dehydroepiandrosterone, prolactin, sex hormone-binding globulin, total and free testosterone, anti-Mullerian hormone, systolic and diastolic blood pressure, c-reactive protein, fibrinogen, oral glucose tolerance test, homoeostatic model assessment-insulin resistance index, fasting insulin, total cholesterol, triglycerides, lipoprotein(a), HDL, LDL, non-HDL-cholesterol, ferritin, iron, and 25-hydroxy-vitamin D. CONCLUSION: We identified 22 core biomarkers assessing the multisystemic impact of PCOS and inform its clinical management. Future research is required to establish validated healthcare pathways.

Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Diacerein mitigates endocrine and cardio-metabolic disruptions in experimental PCOS mice model by modulating AdipoR1/ PON 1.

BACKGROUND: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. METHODS: A total of 18 adult female mice (Parkes strain), aged 4-5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. RESULTS: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. CONCLUSION: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.

Patuletin Ameliorates Inflammation and Letrozole-Induced Polycystic Ovarian Syndrome in Rats.

Concerns about inflammation-related issues affecting female reproductive health are growing. Chronic low-grade inflammation in women with polycystic ovarian syndrome (PCOS) affects follicular growth, ovulation, and androgen production. The present investigation aimed to elucidate the efficacy of flavonoid patuletin in ameliorating the letrozole-induced PCOS and associated inflammation in rats. Female Wistar rats (32 days old) were divided into five groups (n = 12): Group I, control; Group II, vehicle control; Group III, letrozole oral (1 mg/kg) for 28 days; Group IV and Group V treatment groups, patuletin i.p. (25 mg/kg) and clomiphene citrate + metformin i.p. (50 mg/kg + 300 mg/kg), respectively. Leterozole-induced PCOS and ovarian inflammation were ameliorated by patuletin, as reflected in the improved histopathology, prevention of cyst formation, significant upregulation of growth factors such as growth differentiation factor 9 (GDF-9) and bone morphogenetic protein-15 (BMP-15) expression, and a decrease in the pro-inflammatory cytokines TNF-α, IL-6, and COX-2. Additionally, the plasma levels of reproductive hormones were restored. Upregulation of FSH-R, PR, and CYP19a1, along with downregulation of ERα, LHR, CYP17a1, CYP11a1 and HSDß17a1, showed the regulation of gonadotropin receptors and steroid biosynthesis genes in ovarian tissues. Patuletin demonstrated a promising protective approach against the biological model of PCOS by increasing the inflammation in ovarian tissues with consequent regulation of growth factors, enzymes, and hormones, and might be used as adjuvant therapy in the treatment of problems related to female reproductive health.

The efficacy of Linum usitatissimum seeds to inhibit estrogen receptor as a natural therapy for PCOS: An in silico and in vitro analysis.

Polycystic ovarian syndrome (PCOS) is an endocrinological disorder aroused due to hormonal disturbances. It is characterized by anovulation due to an excess of androgen and estrogen hormones, thus leading to the formation of multiple cysts, imposing life-threatening conditions. This manuscript aimed to introduce a natural estrogen receptor (ESR) inhibitors that can provide protection against PCOS. The computational analysis of Linum usitatissimum seeds  compounds against ESR alpha receptor was performed, and the binding affinities of the ligand compounds and receptor proteins were scrutinized. Nine lignin compounds were docked, and the results were compared with that of reference estrogen receptor inhibitors, clomiphene, and tamoxifen. The binding affinity scores for pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol were -10.67, -10.66, -10.91, and -10.60 kcal mol-1 , respectively. These were comparable to the binding affinity score of reference compounds -11.406 kcal mol-1 for clomiphene and -10.666 kcal mol-1 for tamoxifen. Prime MM-GBSA studies showcased that Linum usitatissimum seeds compounds exhibit significant efficacy and efficiency towards receptor protein. Moreover, MD-simulation studies were performed and the results depict that the lignin compounds form stable complexes at 300 K throughout the simulation time. For further clarity, in-vitro experiments were carried out. The results exhibit the decline in cell proliferation in a concentration-dependent manner by extract 1 (ethyl acetate) EX1 and extract 2 (petroleum ether) EX2. Hence, providing evidence regarding the anti-estrogenic activity of the sample extracts. Collectively, these results showed that flax seed can reduce the levels of estrogen, which can induce ovulation and prevent cyst formation, and ultimately can provide protection against PCOS.

Association of lipid profile and obesity in patients with polycystic ovary syndrome.

Objective. Abnormal lipid profile and obesity increase the risk of polycystic ovary syndrome (PCOS). PCOS patients may have a greater risk of infertility, metabolic syndrome (MetS) and cardiovascular disease (CVD) due to abnormal lipid profile and obesity. The aim of the study was to find the association between abnormal lipid profile and obesity in patients with PCOS. Methods. In this case-control study, a total of 102 female subjects (51 diagnosed PCOS and 51 age-matched healthy controls) were enrolled, aged between 20-40 years. Biochemical parameters such as total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), very low-density lipoprotein-cholesterol (VLDL-C), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were estimated. Anthropometric parameters such as body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) were recorded. A p<0.05 was considered statistically significant. Results. Mean of BMI, WC, WHR, LH, FSH, TC, TG, LDL-C, and VLDL-C was found significantly elevated in patients with PCOS as compared to controls (p<0.01). However, the mean of HDL-C was found significantly reduced in patients with PCOS as compared to controls (p<0.01). BMI has shown a significant positive correlation with WC (r=0.562, p<0.01) and WHR (r=0.580, p<0.01) among PCOS patients. LH has shown a significant positive correlation with FSH (r=0.572, p<0.01) among PCOS patients. TC has shown a significant positive correlation with TG (r=0.687, p<0.01), LDL-C (r=0.917, p<0.01), and VLDL-C (r=0.726, p<0.01) among PCOS patients. Conclusion. The results showed that abnormal lipid profile and obesity have a significant association with PCOS patients. Regular monitoring and treatment of PCOS patients are required to reduce the risk of infertility, MetS, and CVD.

The effects of different exercises on weight loss and hormonal changes in women with polycystic ovarian syndrome: a network meta-analysis study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine illnesses. There is evidence that exercise training positively affects on improvement of the pathogenic factors in women with PCOS. On the other hand, some studies reported similar effects of aerobic and resistance exercises or no effect of exercises on the improvement of the pathogenic factors. The aim of the current study was to perform a network meta-analysis of RCTs to evaluate the efficacy of exercises on body mass index (BMI), hormone concentrations, and regular menstruation in women with PCOS. METHODS: The search was performed from databases of PubMed, Scopus, and Web of Science with the keywords of exercise, resistance exercise, aerobic exercise, endurance exercise, yoga, polycystic ovary syndrome, randomized controlled trial based on the CONSORT, BMI, sex hormone and regular menstruation from inception until April 15, 2022. Bayesian random-effects network meta-analyses were performed to calculate mean difference and 95% credible intervals. RESULTS: Out of 1140 studies, 19 were eligible for inclusion. The results showed that moderate-intensity aerobic exercise effectively reduces BMI compared to no intervention and Yoga. No other forms of exercise led to weight loss. Additionally, exercise had no impact on sex hormones and regular menstruation. It was concluded that moderate-intensity aerobic exercise is the most effective for reducing BMI in women with PCOS. CONCLUSIONS: Due to the limitations regarding the small sample size and lack of subgroup and sensitivity analysis, the results of this study demonstrated that moderate-intensity, aerobic exercise is the most effective exercise for reducing BMI, while the other exercises were ineffective. Moderate-intensity aerobic exercise is suggested to decrease the BMI in women with PCOS. SYSTEMATIC REVIEW REGISTRATION: This systematic review and network meta-analysis study was registered in PROSPERO (CRD42022324839).

Polycystic ovarian syndrome elevates the distress of sexual pain in Iranian women with infertility.

BACKGROUND: Sexual dysfunction may lead to sexual distress in women with infertility, while polycystic ovarian syndrome (PCOS) may escalate this distress. This study aimed to investigate the role of PCOS in the relationship between sexual dysfunction and sexual distress in Iranian women with infertility. METHODS: The Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), and Depression and Anxiety modules of the DASS-21 were cross-sectionally investigated in 190 women with infertility (103 women with PCOS and 87 women without PCOS). RESULTS: There were negative correlations between sexual function domains and sexual distress (P < .001) in the total sample. Moderation analysis revealed that higher levels of impaired desire, arousal, and pain elevated sexual distress in the PCOS group. After adjusting for depression and anxiety, only the association between sexual pain and sexual distress was moderated by PCOS condition (P = .008). CONCLUSIONS: The findings suggest that impaired sexual function is associated with increased levels of sexual distress in infertile female patients. Importantly, comorbid PCOS renders patients susceptible to sexual distress where sexual pain is increased. Further research may shed light on the physiological, psychological, and relational aspects of sexual pain and associated distress in infertile female patients with comorbid PCOS.

Is the MIND diet useful for polycystic ovary syndrome? A case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent cause of ovulatory infertility and endocrine abnormalities in reproductive-age women. Although the MIND diet has been introduced to improve brain function, evidence shows that the MIND diet is rich in beneficial food groups that can have a preventive effect on other metabolic disorders. The present study was conducted to investigate the association between adherence to the MIND diet and PCOS. METHODS: This age and BMI frequency-matched case-control study was conducted on 216 women between January 2018 and March 2019 in Yazd, Iran. PCOS was diagnosed based on Rotterdam criteria. Participants were selected by convenience sampling method. The validated 178-item food frequency questionnaire was used to assess the usual dietary intake. Logistic regression was used to estimate the association between the MIND diet and PCOS. RESULTS: The findings of the present study showed a significant inverse association between adherence to the MIND diet and PCOS in the crude model (OR for T3 vs. T1: 0.12 (95% CI: 0.05-0.25), P-value < 0.001) and multivariable-adjusted model including energy intake, age, BMI, waist circumference, marital status, pregnancy history, drug use history, education and physical activity (OR for T3 vs. T1 = 0.08 (95% CI: 0.03-0.19), P-value < 0.001). Adherence to the MIND diet had a protective effect of 92%. CONCLUSION: Although the results of the present study showed that higher adherence to the MIND diet is associated with a lower risk of PCOS, more studies are needed to confirm these findings in the future.

Comparison of premenstrual symptoms, psychological well-being, and nutritional status between Palestinian women with and without polycystic ovarian syndrome: a case-control study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a widely seen reproductive and endocrinological disorder. PCOS can exert substantial effects on many aspects of an individual's life, including reproductive health and psychological well-being. The objective of this study was to assess the nutritional status, premenstrual syndrome, and mental health of women affected by PCOS in comparison to women without PCOS. METHODOLOGY: A case-control observational study in Palestine included 100 PCOS patients and 200 healthy women. The collected data included socio-demographic information, medical history, premenstrual syndrome, mental health, nutritional status, and lifestyle. Anthropometric measurement and the Mediterranean Diet Adherence Screener (MEDAS) were used to evaluate the nutritional status. The General Health Questionnaire (12-GHQ) was used to evaluate the state of mental health. Premenstrual syndrome (PMS) severity was evaluated using a validated Arabic premenstrual syndrome questionnaire. RESULTS: The study's findings indicated that there was a statistically significant increase in the three dimensions of PMS among participants with PCOS, p < 0.05. Similarly, PCOS patients demonstrated elevated ratings across all aspects of mental health, p < 0.05. In terms of the other variables, it has been observed that PCOS patients have a notably greater prevalence of perceived sleep disturbances and decreased adherence to the Mediterranean diet. Regression analysis revealed that PCOS is associated with mental health problems indicated by a higher GHQ score (OR: 1.09; 95% CI: 1.03; 1.16, p < 0.05), lower adherence to the MD diet (OR: 0.86; 95% CI: 0.76; 0.98, p < 0.05), and pre-menstrual syndrome, especially the physical symptoms (OR: 1.06; 95% CI: 1.003; 1.12, p < 0.05) after adjusting for age, smoking, waist-hip ratio, and body mass index (BMI). CONCLUSION: The study has linked polycystic ovary syndrome to negative mental health outcomes and an increased severity of premenstrual syndrome (PMS). Additional investigation is required in order to establish a causal association between polycystic ovary syndrome (PCOS) and lifestyle behaviors within the Palestinian population. Intervention and instructional studies are necessary to investigate the efficacy of management strategies in alleviating the effects of polycystic ovary syndrome (PCOS) on both physical and mental well-being.

Comparison of physical activity levels and dietary habits between women with polycystic ovarian syndrome and healthy controls of reproductive age: a case-control study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a reproductive hormonal anomaly prevalent among women of reproductive age, with an alarmingly high prevalence of 52% among Pakistani women. This study aims to compare the daily physical activity and dietary habits of women with PCOS with age-matched healthy controls living in Lahore, Pakistan. METHODS: A case-control study design was used to collect data from a private hospital situated in Lahore, Pakistan. Data was collected from 115 participants of reproductive age (18-45 years) using a researcher-administered questionnaire. Demographic variables, reproductive characteristics, anthropometric measurements, and seven days of physical activity levels using the international physical activity questionnaire (IPAQ-Short version) and seven days of dietary intake using the food frequency questionnaire (7 days-FFQ) were used to measure the dietary habits of the participants. Mosby's Nutritac v4.0 software was used to estimate the macronutrients, vitamins, and minerals present in dietary intake. The glycaemic index and glycaemic load were calculated to compare the quality and quantity of carbohydrate consumption between the two groups. RESULTS: The 49 PCOS cases, newly identified using the Rotterdam criteria, mean age 24.63 years (SD ± 4.76), and 66 healthy controls, mean age 23.24 years (SD ± 5.45), were compared. A significant difference (p ≤ 0.05) was found for reproductive characteristics, daily physical activity, and polyunsaturated fat and vitamin intake between the two groups. A binary logistic regression analysis showed that food with a low glycaemic index (GI ≤ 40) reduced the odds of PCOS occurrence by OR = 1.94. Similarly, food nutrients with a low glycaemic load (GL ≤ 10) can reduce PCOS occurrence by OR = 1.60. CONCLUSION: The daily physical activity levels and dietary habits of women of reproductive age can influence their reproductive characteristics and polycystic ovarian morphology. A diet with a low glycaemic load and index can produce beneficial reproductive health effects among women of reproductive age.

Cross-talk between oxidative stress and lipid metabolism regulators reveals molecular clusters and immunological characterization in polycystic ovarian syndrome.

BACKGROUND: Changes in the oxidative stress and lipid metabolism (OSLM) pathways play important roles in polycystic ovarian syndrome (PCOS) pathogenesis and development. Consequently, a systematic analysis of genes related to OSLM was conducted to identify molecular clusters and explore new biomarkers that are helpful for the diagnostic of PCOS. METHODS: Gene expression and clinical data from 22 PCOS women and 14 normal women were obtained from the GEO database (GSE34526, GSE95728, and GSE106724). Consensus clustering identified OSLM-related molecular clusters, and WGCNA revealed co-expression patterns. The immune microenvironment was quantitatively assessed utilizing the CIBERSORT algorithm. Multiple machine learning models and connectivity map analyses were subsequently applied to explore potential biomarkers for PCOS, and nomograms were employed to develop a predictive multigene model of PCOS. Finally, the OSLM status of PCOS and the hub genes expression profiles were preliminarily verified using TUNEL, qRT‒PCR, western blot, and IHC assays in a PCOS mouse model. RESULTS: 19 differential expression genes (DEGs) related to OSLM were identified. Based on 19 DEGs that were strongly influenced by OSLM, PCOS patients were stratified into two distinct clusters, designated Cluster 1 and Cluster 2. Distinct differences in the immune cell proportions existed in normal and two PCOS clusters. The random forest showed the best results, with the least cross-entropy and the utmost AUC (cross-entropy: 0.111 AUC: 0.960). Among the 19 OSLM-related genes, CXCR1, ACP5, CEACAM3, S1PR4, and TCF7 were identified by a Bayesian network and had a good fit with PCOS disease risk by the nomogram (AUC: 0.990 CI: 0.968-1.000). TUNEL assays revealed more severe DNA damage within the ovarian granule cells of PCOS mice than in those of normal mice (P < 0.001). The RNA and protein expression levels of the five hub genes were significantly elevated in PCOS mice, which was consistent with the results of the bioinformatics analyses. CONCLUSION: A novel predictive model was constructed for PCOS patients and five hub genes were identified as potential biomarkers to offer novel insights into clinical diagnostic strategies for PCOS.

Analyzing the infertility burden of polycystic ovarian syndrome in China: A comprehensive age-period-cohort analysis with future burden prediction (1990-2030).

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a common but complex endocrine disorder widely linked to infertility and miscarriage. This study assessed the correlation between PCOS and infertility. METHODS: Using the latest data from the Global Burden of Disease 2019 database, we conducted an in-depth assessment of the disease burden attributed to PCOS in China. This analysis was performed using the joinpoint regression, age-period-cohort, and autoregressive integrated moving average (ARIMA) models. RESULTS: Between 1990-2019, an upward trend was observed in the age-standardized prevalence of PCOS-related female infertility in China. Joinpoint regression analysis revealed an increasing trend in the age-standardized prevalence of PCOS-related female infertility burden indicators as well as the average annual percentage change and annual percentage change across all age groups in China. In terms of the cohort effect, the period rate ratios associated with the age-standardized prevalence of PCOS-related infertility increased steadily over time. The ARIMA model predicted a relatively swift upward trend in the age-standardized prevalence of PCOS-related infertility in China from 2020-2030. CONCLUSION: The age-standardized prevalence of PCOS-related female infertility in China has increased between 1990-2019. The ARIMA model predicted that the age-standardized prevalence of this disease may continue to increase over the next decade. This study can increase the public's attention, improve women's health awareness, and have a certain significance for reducing female infertility related to PCOS.

IGF2BP2 and IGFBP3 Genotypes, Haplotypes, and Genetic Models Studies in Polycystic Ovary Syndrome.

BACKGROUND: Insulin resistance has been correlated with the genetic diversity within the insulin-like binding proteins genes. Moreover, insulin resistance is one of the key characteristics of the widespread reproductive endocrine condition known as polycystic ovarian syndrome (PCOS). Hence, this study is aimed to determine the association between IGFBP3 and IGF2BP2 gene variants and PCOS risk. METHODS: A total of 300 subjects (150 PCOS cases diagnosed based on Rotterdam ESHRE/ASRM consensus criteria and 150 healthy subjects) were recruited in this case-control cross-sectional study. Tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR) was used for genotyping rs11705701, whereas genotyping of rs1470579 and rs2854744 was done employing PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The CC and AA+AC genotypes of rs1470579 conferred an increased risk of PCOS in our population. Regarding the rs2854744, an increased risk of PCOS was observed under the codominant homozygous (TT vs. GG) model by 2.54 fold. The C allele of rs1470579 and T allele of rs2854744 enhanced PCOS risk by 1.97 and 1.46 folds, respectively. Haplotype analysis showed that the Ars1470579Ars11705701 haplotype conferred a decreased risk of PCOS (odds ratio = 0.53, 95% confidence interval = 0.34-0.83, p = 0.006). The AC/GG/GT, AA/GA/GT, AC/GA/GG, and AC/GA/GT genotype combinations of rs1470579/rs11705701/rs2854744 were associated with a decreased risk of the disease. CONCLUSIONS: IGF2BP2 rs1470579 and IGFBP3 rs2854744 enhanced PCOS susceptibility in a Southeastern Iranian population. Further investigation involving larger cohorts representing diverse ethnic backgrounds is needed to confirm the current findings.

Prediction of the Signaling Pathway in Polycystic Ovary Syndrome Using an Integrated Bioinformatics Approach.

OBJECTIVES: The purpose of this study was to define the underlying biological mechanisms of polycystic ovarian syndrome (PCOS) utilizing the protein-protein interaction networks (PPINs) that were constructed based on the putative disease-causing genes for PCOS. DESIGN: No animals were used in this research because this is an in silico study that mainly uses software and online analysis tools. Participants/Materials, Settings: Gene datasets related to PCOS were obtained from Genecards. METHODS: The PPINs of PCOS were created using the String Database after genes related to PCOS were obtained from Genecards. After that, we performed an analysis of the hub-gene clusters extracted from the PPIN using the ShinyGO algorithm. In the final step of this research project, functional enrichment analysis was used to investigate the primary biological activities and signaling pathways that were associated with the hub clusters. RESULTS: The Genecards database provided the source for the identification of a total of 1,072 potential genes related to PCOS. The PPIN that was generated by using the genes that we collected above contained a total of 82 genes and three different types of cluster interaction interactions. In addition, after conducting research on the PPIN with the shinyGO plug-in, 19 of the most important gene clusters were discovered. The primary biological functions that were enriched in the key clusters that were developed were ovarian steroidogenesis, the breast cancer pathway, regulation of lipid and glucose metabolism by the AMPK pathway, and ovarian steroidogenesis. The integrated analysis that was performed in the current study demonstrated that these hub clusters and their connected genes are closely associated with the pathogenesis of PCOS. LIMITATIONS: Several of the significant genes that were identified in this study, such as ACVR1, SMAD5, BMP6, SMAD3, SMAD4, and anti-mullerian hormone. It is necessary to do additional research using large samples, several centers, and multiple ethnicities in order to verify these findings. CONCLUSIONS: The integrated analysis that was performed in the current study demonstrated that these hub clusters and their connected genes are closely associated with the pathogenesis of PCOS. This information may possibly bring unique insights for the treatment of PCOS as well as the investigation of its underlying pathogenic mechanism.

Circ_0043314 Modulates Proliferation and Apoptosis of Ovarian Granulosa Cells in Polycystic Ovarian Syndrome via the MicroRNA-146b-3p/Apelin 13 Axis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. At present, the pathogenesis has not been clarified, and the clinical application of drugs and lifestyle intervention may not prevent disease progression. This study aimed to investigate how circ_0043314 regulates ovarian granulosa cell biological functions to provide a theoretical basis for the treatment of patients with PCOS. MicroRNA (miR)-146b-3p/Apelin 13 axis was used to investigate the mechanism by which circ_0043314 regulated ovarian granulosa cell proliferation and apoptosis in PCOS via miR-146b-3p/Apelin 13 axis. Participants/Materials, Methods: Ovarian tissues (cortical tissues) from 35 PCOS patients and 35 normal controls, as well as HEK293T and human ovarian granulosa cell line (KGN, COV434), were included in this study. We examined the expression levels of circ_0043314, miR-146b-3p, and Apelin 13 in PCOS tissues. Ovarian granulosa cells were transfected with corresponding plasmids to clarify the influence of circ_0043314, miR-146b-3p, or Apelin 13 on proliferation and apoptosis of ovarian granulosa cells through MTT and flow cytometry assays. Moreover, the relationships among circ_0043314, miR-146b-3p, and Apelin 13 were analyzed through dual-luciferase and RNA immunoprecipitation assays. RESULTS: Circ_0043314 and Apelin 13 were highly expressed and miR-146b-3p was lowly expressed in ovarian tissues of PCOS compared with non-PCOS controls. Downregulation of circ_0043314 or upregulation of miR-146b-3p hindered ovarian granulosa cell proliferation and advanced its apoptosis. Downregulation of miR-146b-3p reversed the impacts of downregulation of circ_0043314, and overexpression of Apelin 13 counteracted the influences of upregulation of miR-146b-3p in ovarian granulosa cells. Mechanically, circ_0043314 could bind to miR-146b-3p, and miR-146b-3p directly targeted and modulated Apelin 13 expression. LIMITATIONS: This study was limited by the lack of animal experiments. CONCLUSION: Our data demonstrated that circ_0043314 enhances ovarian granulosa cell proliferation and suppresses its apoptosis via miR-146b-3p/Apelin 13 axis.

The Effects of Myo-Inositol and D-Chiro-Inositol in a Ratio 40:1 on Hormonal and Metabolic Profile in Women with Polycystic Ovary Syndrome Classified as Phenotype A by the Rotterdam Criteria and EMS-Type 1 by the EGOI Criteria.

SETTING: Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS). OBJECTIVES: This study evaluates the frequency of metabolic abnormalities in PCOS patients and the effects of myo-inositol (MI) and D-chiro-inositol (DCI), in a 40:1 ratio on hormonal and metabolic parameters. PARTICIPANTS: Thirty-four women with PCOS phenotype A (endocrine-metabolic syndrome [EMS-type 1]) between the ages of 20-40. DESIGN: Open prospective study with phenotype A (EMS-type I, n = 34) supplemented with 2,255 mg/day of inositol (MI and DCI in a 40:1 ratio) for 3 months. METHODS: The following were measured before and after treatment: serum levels of follicular stimulating hormone, luteinizing hormone (LH), estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), anti-Müllerian hormone, glucose, insulin, HOMA-IR, and body mass index (BMI). RESULTS: 55.9% of the enrolled patients were overweight or obese, 50% affected by IR, 17.6% with a history of gestational diabetes mellitus, and 61.8% had familial diabetes mellitus. At the conclusion of the study, BMI (p = 0.0029), HOMA-IR (p < 0.001) significantly decreased, along with decreased numbers of patients with elevated insulin levels. The supplementation resulted in decreased total testosterone (p < 0.001), free testosterone (p < 0.001), FAI (p < 0.001), and LH (p < 0.001); increased SHBG (p < 0.001) and estradiol (p < 0.001). LIMITATIONS: The present analysis was limited to a 12-week follow-up, which precluded a long-term evaluation of the effects of MI and DCI combination. Also, this period was insufficient to achieve and analyze clinical changes such as restoration of the menstrual cycle, restoration of reproductive function, and clinical manifestations of hyperandrogenism. CONCLUSIONS: Supplementation improved metabolic and hormonal profile in PCOS phenotype A (EMS-type I) patients. This builds upon previous work that demonstrated that combined inositol treatment may be effective in PCOS. The study presented herein, used a reduced concentration than in prior literature; however, a significant change in hormonal and metabolic parameters was still observed.

Effect of irisin on ovarian phosphatidylinositol-3-kinase/protein kinase B signaling pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways of rats with polycystic ovary syndrome.

OBJECTIVE: To investigate the independent effects of irisin on insulin resistance (IR) in ovary of polycystic ovary syndrome (PCOS) and explore possible pathways. METHODS: We established PCOS medel using Poretsky L's method, then PCOS rats were randomly divided into model group (M) and irisin group (I), and normal rats (N) were used as the control. Then rats in the group I were injected with recombinant irisin. Then the levels of circulating fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of IR (HOMA-IR) and PI3K/AKT and MAPK/ERK pathways in each group were observed, as well as the effects of irisin on the levels of circulating HOMA-IR and PI3K/AKT and MAPK/ERK pathways in ovary of PCOS rats were evaluated. RESULTS: Compared with normal group, levels of FBG, FINS, and HOMA-IR of model group were significantly increased (p < 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.015, p = 0.010, p = 0.005, and p = 0.009, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.001, and p = 0.005, respectively) were decreased, while the levels of average optical density of p-ERK, ERK (p = 0.011, and p = 0.013, respectively) and level of mRNA concentration of ERK (p < 0.001) were increased in ovary. After irisin intervention, compared with model group, levels of FBG, FINS, and HOMA-IR of rats in irisin group were significantly decreased (p = 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.030, p = 0.024, p = 0.012, and p = 0.025, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.002, and p = 0.003, respectively) were significantly increased, while the levels of average optical density of p-ERK, ERK (p = 0.004, and p = 0.026, respectively) and level of mRNA concentration of ERK (p = 0.001) were significantly decreased. CONCLUSION: Our study demonstrated that irisin could not only improve circulating insulin resistance, but may also improve ovarian IR through an increase in the activity of PI3K/AKT signaling and a decrease of MAPK/ERK signaling.