Pathogenesis Of PCOS Research Articles

THU650 Prevalence Of Hyperandrogenemia, PCOS And Obesity In Mothers Of Daughters With PCOS

Abstract Disclosure: J. Cai: None. K. Brewer: None. R. Sisk: None. R.S. Legro: None. A.E. Dunaif: None. Prenatal exposure to androgens produces phenocopies of PCOS in animal models. In mice, there is evidence for transgenerational prenatal androgen effects. Human studies considered to support the hypothesis that intrauterine actions of androgens play a major role in PCOS pathogenesis come from (1) health registries where PCOS in mothers and daughters was diagnosed by ICD codes and (2) retrospective assessment of mother’s PCOS status in cohorts of affected women. Maternal PCOS status has not been directly assessed. As part of our genetic analyses of PCOS, we have prospectively recruited 678 mothers and 540 fathers of 678 women fulfilling NIH criteria for PCOS with confirmed hyperandrogenism and ovulatory dysfunction (OD). All subjects had fasting blood samples for reproductive hormones measured in central labs. Mothers completed a validated questionnaire for reproductive history. We tested the hypothesis that maternal PCOS accounted for PCOS in her daughter. We also investigated the contribution of maternal compared to paternal obesity to daughters’ obesity. We limited the analysis to mothers age 50 yrs and younger, with FSH <40 mIU/mL; 108 fathers were available from these families. Continuous data are reported as median and data range. Age (yrs): daughters 23 (13-24), mothers 46 (34-50), fathers 48 (37-69). Daughters had significantly higher BMI (kg/m2) (35.3, 18.5-60.0) than mothers (28.9, 18.7-54.1) and fathers (29.6, 18.4-55.5) (both P <0 .0001), while BMI did not differ in mothers and fathers. Hyperandrogenemia (HA), defined as total testosterone >58 ng/dL, biologically available testosterone >15 ng/dL or DHEAS >2683ng/mL, was present in 14.4% (20/139) of mothers, of these, 2.2% (3/139) fulfilled NIH criteria for PCOS, HA+OD. The prevalence of obesity, BMI ≥ 30.0 kg/m2, (66.2% daughter, 44.8% mother, and 45.7% fathers) was increased in daughters compared to both mothers (p= 0.0004) and fathers (p< 0.0001). Mothers with HA had higher BMI than those without it (P= 0.011). The odds ratio for obesity in daughters was 5.16 (1.97, 13.48) with maternal obesity and 2.29 (0.95, 5.52) with paternal obesity. Only ∼14% of reproductive-age mothers had HA, which we have shown in an underlying reproductive phenotype in PCOS families (Legro. Proc Natl Acad Sci USA, 1998); ∼ 2% of mothers fulfilled NIH criteria for PCOS. Although the PCOS reproductive phenotype ameliorates with age, it is clear that many affected daughters did not have a mother with hormonal features of PCOS. These findings do not support the hypothesis that prenatal androgen exposure is a final common path to PCOS in humans. The prevalence of obesity was higher in daughters than in parents and in HA mothers compared mothers without HA suggesting that obesity was associated with features of PCOS. Maternal obesity conferred greater risk for obesity in daughters than paternal obesity. Presentation: Thursday, June 15, 2023

Insulin Resistance in Obese and Non-obese PCOS Patients using Homeostasis Model Assessment – Insulin Resistant: A Comparison Study

Aim: this study was conducted to assess the insulin resistance in obese PCOS patients in comparison with non-obese PCOS women. Methodology: a comparative observational study was conducted on 165 Libyan PCOS women; 81 obese PCOS and 84 non-obese PCOS attending the out-patient clinic of Albayda Fertility Teaching Center and two private clinics in Albayda city/Libya, in the period between January 2021 and January 2023. All subjects undergone day 2 pelvic ultrasound scan, relevant hormonal assay and an overnight insulin and glucose levels were measured and used for insulin resistance calculation, using Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) formula, 2.6 was used as a HOMA-IR cutoff value. Result: of the total 165 PCOS women, 81 (49%) were obese with BMI ≥30 kg/m2 (study group) and 84 (51%) were non-obese (control group) PCOS. The prevalence of insulin resistance (IR) in all the included PCOS patients was 39% and the difference in prevalence of IR was non-significant between obese and non-obese PCOS (p=0.44). Insulin resistance was significantly higher among the obese PCOS (mean HOMA-IR =3) than non-obese PCOS group (mean HOMA-IR = 2.4) with P-value < 0.001. Insulin resistance had a significant positive correlation with fasting insulin and glucose levels but was not significantly correlated with BMI, age, LH, or with testosterone. Conclusion: both obese and non-obese PCOS women have insulin resistance, strengthening the aetiological role of Insulin resistance in PCOS pathogenesis. However, the insulin resistance was significantly higher among the obese PCOS accordingly life-style modifications might be beneficial in restoring PCOS pathogenesis.

SPIOMET4HEALTH—efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial

BackgroundPolycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5–10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs.MethodsIn this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO.DiscussionThe present study will be the first to evaluate—in a randomised, double-blind, placebo-controlled way—the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention.Trial registrationEudraCT 2021–003177-58. Registered on 22 December 2021.https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58.

Perspectives of PCOS Pathophysiology: Exploring the Interplay between PCOS and the Gut Microbiota

PCOS is a gynecological and metabolic concern for numerous women of reproductive age. Its pathophysiology broadly entails hyperandrogenism, insulin resistance, and neuroendocrine dysfunction, and is heavily influenced by genetic and epigenetic factors. However, its precise aetiology remains unclear. The gut microbiome is a major endocrine organ and plays a key role in host metabolism through its metabolites which regulate diverse host physiology like metabolism, immunity, etc. Numerous studies have described associations of altered microbiota in the progress and development of major human diseases. The studies conducted on animals and humans have suggested that the gut microbiota and its metabolites are involved in the pathogenesis of PCOS and its associated attributes such as insulin resistance, obesity and inflammation. Moreover, supplementation of probiotics/prebiotics has been reported to relieve the adverse metabolic and hormonal parameters effectively. Knowledge of this link between gut dysbiosis and PCOS has also spurred research interest in exploring novel management of PCOS. In this review, we have discussed the role of gut microbiota dysbiosis and its metabolite in the progression and treatment of PCOS.

Serum adiponectin in women with polycystic ovary syndrome

Background: An imbalance of different adipocytokines may play a role in the pathogenesis of PCOS. This study aimed to observe the association and diagnostic utility of adiponectinin PCOS and its manifestations. Methods: This cross-sectional study included 40 newly diagnosed females of reproductive age (18-40 years) with PCOS on the basis of international evidence-based guidelines and an equal number of matched healthy control. Along with clinical information, blood was drawn for biochemical and hormonal analysis. Glucose was measured by glucose oxidase, lipid by glycerol phosphate dehydrogenase peroxidase, all hormones by CMIA, and adiponectin by ELISA method. Insulin resistance was measured by homeostasis model assessment (HOMA-IR) and defined with a cut-off of 2.6. Results:Patients with PCOS had lower serum adiponectin than controls without significant differences even irrespective of body mass index status(ns for all). Adiponectin levels had no significant associations or correlations with any manifestations among patients with PCOS (ns for all). ROC curve analysis showed that serum adiponectin could not be used as a marker of PCOS. It was a poor marker of both metabolic syndrome [AUC (95% CI): 0.64 (0.46-0.81] and insulin resistance [AUC (95% CI): 0.61 (0.44-0.79)] in patients with PCOS. Conclusion: Our study failed to find any significant association between adiponectin and PCOS and its characteristics. Serum adiponectin could not be used as a marker of PCOS. It was a poor marker of insulin resistance and metabolic syndrome among patients with PCOS. Bangladesh J Medicine 2023; 34(3): 206-213

Non-coding RNA genes modulate PI3K/AKT signaling pathway in polycystic ovary syndrome.

The PI3K protein kinase B (PI3K/AKT) signaling pathway has crucial roles in insulin signaling and other endocrine disorders. The purpose of this study is to validate the association of PCOS with PI3K/AKT pathway target genes, miRNA486-5p, and miRNA483-5p as well as to evaluate the outcome of metformin on the pathogenesis of PCOS. METHODS: This case-controlled study included 3 subject groups: twenty healthy females (control group), twenty PCOS females before treatment, and twenty PCOS females treated with metformin at a dose (500mg 3 times per day for 3 months). The following gene expressions were assessed by real-time PCR: PI3K, AKT, ERK, GLUT4, miRNA486-5p, and miRNA483-5p in the whole blood. There was a significant decrease in miRNA486-5p and miRNA483-5p in the PCOS group with a significant negative correlation between miRNA486-5p and PI3K and a significant negative correlation between miRNA483-5p and ERK. Metformin treatment resulted in significant elevation of the studied miRNA, significant downregulation of PI3K/AKT target genes, and significant amelioration of the gonadotrophic hormonal imbalance and insulin resistance markers: fasting blood glucose, HBA1C, fasting insulin, and GLUT4 gene expression. miRNA486 and miRNA483 downregulation may contribute to the etiology of PCOS, influence glucose metabolism, and result in IR in PCOS. Metformin's upregulation of those miRNAs affects glucose metabolism by controlling the expression of GLUT4, ameliorates PCOS-related insulin resistance, and improves PCOS-related hormonal imbalance by controlling the PI3K/AKT signaling pathway.

Integrated bioinformatics analysis elucidates granulosa cell whole-transcriptome landscape of PCOS in China

BackgroundPolycystic ovary syndrome (PCOS) is a common reproductive, neuroendocrine, and metabolic disorder in women of reproductive age that affects up to 5–10% of women of reproductive age. The aetiology of follicle development arrest and critical issues regarding the abnormal follicular development in PCOS remain unclear. The present study aims to systematically evaluate granulosa cell whole-transcriptome sequencing data to gain more insights into the transcriptomic landscape and molecular mechanism of PCOS in China.MethodsIn the present study, the microarray datasets GSE138518, GSE168404, GSE193123, GSE138572, GSE95728, and GSE145296 were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, differential expression analysis was performed on the PCOS and control groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in PCOS. Finally, hub genes and their associated ncRNAs were validated by qPCR in human-luteinized granulosa (hGL) cells and were correlated with the clinical characteristics of the patients.ResultsA total of 200 differentially expressed mRNAs, 3 differentially expressed miRNAs, 52 differentially expressed lncRNAs, and 66 differentially expressed circRNAs were found in PCOS samples compared with controls. GO and KEGG enrichment analyses indicated that the DEGs were mostly enriched in phospholipid metabolic processes, steroid biosynthesis and inflammation related pathways. In addition, the upregulated miRNA hsa-miR-205-5p was significantly enriched in the ceRNA network, and two hub genes, MVD and PNPLA3, were regulated by hsa-miR-205-5p, which means that hsa-miR-205-5p may play a fundamental role in the pathogenesis of PCOS. We also found that MVD and PNPLA3 were related to metabolic processes and ovarian steroidogenesis, which may be the cause of the follicle development arrest in PCOS patients.ConclusionsIn summary, we systematically constructed a ceRNA network depicting the interactions between the ncRNAs and the hub genes in PCOS and control subjects and correlated the hub genes with the clinical characteristics of the patients, which provides valuable insights into the granulosa cell whole-transcriptome landscape of PCOS in China.

Polycystic Ovarian Syndrome and their Management through Yoga Therapy: A Narrative Review

ABSTRACT Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder among women, with a prevalence ranging from 2.2% to 26%. PCOS is associated with unhealthy lifestyle and physical inactivity affects disproportionately. Yoga is mind-body stress-relieving therapy, and by the different interventions researchers are increasing their focus on the benefits of yoga for PCOS. It is also important for physicians and health -care professionals to understand the therapeutic efficacy of yoga intervention, in terms of its type, duration, and frequency on various PCOS risk factors. After discussing the pathogenesis of PCOS, the present review summarizes the current scientific understanding of the effects of yoga on PCOS and the risk factors associated with such as obesity, stress, and insulin sensitivity. An extensive search in Google scholar, Medline, PubMed, Scopus, and Cochrane Library was searched using the keywords “Polycystic Ovarian Syndrome,” “Obesity,” “Stress,” “Epidemiology,” “Pathophysiology,” “Diagnostic criteria,” and “Effect of yoga.” Based on these preliminary results, yoga therapy reduces the risk factor associated with the PCOS that may be suggested as a safer and affordable therapy for PCOS. More rigorous research and well-designed trials that have a higher standard of methodology and evaluate yoga’s long-term impacts on PCOS are needed. Understanding yoga’s biochemical and molecular mechanisms of action on various metabolic pathways is also needed.

O-222 Functional characterization and clinical implications of patient-specific iPSC-derived endothelial cells to unravel the pathogenesis associated with androgen-mediated endothelial dysfunction in polycystic ovarian syndrome

Abstract Study question Whether and how the endothelial cell (EC) dysfunction is involved in the pathogenesis of PCOS revealed by iPSC-based disease modeling? Summary answer PCOS-specific iPSC-derived ECs were successfully established and the results showed that EC proliferation and function were impaired in PCOS through the androgen receptor(AR)-mediated signaling pathway. What is known already ECs have been shown to play critical biological roles in the regulation of vascular tone and inflammatory process and any injury to ECs or disturbance in their homeostasis is called EC dysfunction, which has been recognized as an early marker of atherosclerosis and cardiovascular diseases. Several studies have also revealed indirect evidence of EC dysfunction among women with PCOS, including elevated circulatory markers of endothelial damage and impaired vascular structure. But whether and how EC dysfunction is involved in the pathogenesis of PCOS is still unclear. Study design, size, duration This is an experimental study at tertiary university hospital. iPSCs were established from skin fibroblasts and peripheral blood mononuclear cells from two patients with PCOS and two control participants. Participants/materials, setting, methods iPSCs were differentiated into ECs through monoculture with chemically defined conditions. Single cell RNA sequencing (scRNA-seq) was performed on the iPSCs-derived ECs to compare the differences between PCOS and control. iPSCs-derived ECs were treated with different dosages (1, 10 and 100 nM) of dihydrotestosterone (DHT). Cell cycle phases were analyzed by flow cytometry with BrdU incorporation assay. The expression of AR, cyclin-dependent kinase 1 (CDK1) and vascular endothelial growth factor (VEGF) were analyzed using rtPCR. Main results and the role of chance Up to 90% of iPSC-derived ECs successfully expressed EC markers, including CD31, CD144 and von Willebrand Factor in both PCOS and control groups, showing a high differentiation efficiency in the present study. The pathway enrichment analysis of transcriptomic data of iPSC-derived ECs showed functional differences involving cell cycle process, VEGF signaling and apoptotic process between PCOS and control. Analysis using sc-RNA seq revealed decreased cellular proliferation in the PCOS iPSC-derived ECs compared to control group, which was due to cell cycle arrest revealed by flow cytometry. The modulating effects of androgen on the proliferation and gene expression of iPSC-derived ECs were further investigated. DHT at doses ranging from 1 to 100 nM stimulated iPSC-derived ECs proliferation in the control group through upregulation of AR, CDK1 and VEGF gene expression. In contrast, DHT did not promote the cellular proliferation of PCOS iPSC-derived ECs at physiological concentrations of 1 and 10 nM and the expression of AR, CDK1, and VEGF remained unchanged. These data suggest that DHT-induced cellular proliferation and the expression of associated genes were more sensitive and dose-dependent in the control iPSC-derived ECs and blunted in the PCOS iPSC-derived ECs. Limitations, reasons for caution One of the major limitations of our study was the limited number of cases during the establishment of iPSCs, which was unable to reflect the heterogeneity and complexity of PCOS. Wider implications of the findings Impaired cellular proliferation and differentially expressed genes involved in cell proliferation, immune responses, cardiovascular functions, and apoptosis were observed among PCOS iPSC-derived ECs. Additionally, androgen-induced ECs proliferation was blunted in PCOS through a diminished AR/VEGF/cyclin D1 signaling pathway, which might hinder VEGF-dependent vascular repair and probably increase cardiovascular risks. Trial registration number not applicable

P-670 Altered immunological conditions in women with PCOS and its correlation with the development and progression in infertile women with severe polycystic ovaries

Abstract Study question What is the impact of the dysfunctional lymphoid cells on the development and progression in infertile women with severe polycystic ovaries syndrome (SPCOS). Summary answer The dysfunctional lymphoid cells in immune system was deeply correlated with follicular remodeling, which prompting the progression of SPCOS. What is known already PCOS has been confirmed as a low-level chronic inflammation impacting on ovulation and luteinization regulated by a cytokine-mediated inflammatory response orchestrated by lymphocytes, granulocytes, and macrophages. However, the exact relationship between immunologic dysfunction and the pathogenesis of PCOS is still not clarified. Study design, size, duration A prospective cohort study including a total of 129 women aged 18 to 35 years were enrolled. PCOS patients with polycystic ovaries (ultrasound measurement of the number of ≥ 80 follicles ≥3 mm in diameter) were referred to SPCOS in this study. Peripheral Blood (PB) were collected to detect the immunological changes by using flow cytometry: CD8+ T cell (CD3+,CD8+); CD4+ T cell (CD3+,CD4+); NK cell (CD45+,CD3-,CD56+); NKT cell (CD45+,CD3+,CD56+); Treg cell (CD4+CD25hi); B cell (CD3-CD19+). Participants/materials, setting, methods PB from SPCOS cohort (n = 64) and healthy controls (n = 115) were collected to detect the immunological conditions. Furthermore, the discarded tissues from SPCOS patients (n = 5) who needed to avoid OHSS by surgical ovarian wedge resection and women undergoing fertility preservation procedures (n = 3) were digested to single cell suspension, which were used to outline the ovarian homeostasis changes by using scRNA-seq. Main results and the role of chance Peripheral blood NK cells from SPCOS patients were significantly decreased than those from healthy group (10.7% vs. 14.9 ± 6.2%, p = 0.04). Conversely, NKT cells in the PB of the SPCOS women were 11.2% vs. 6.9 ± 3.5% (P = 0.02), while B lymphocytes were 15.6% vs. 12.6 ± 4.2% (P = 0.04), compared to healthy controls. Furthermore, the immune cells and distinct cellular clusters of SPCO were disturbed in severe polycystic ovaries. The CD8+ T cell populations in ovarian of SPCOS group were strongly decreased (32.49% vs.22.35%, p < 0.001) and T cell activation signaling was downregulated by lowly expressed PTPRC, APBB1IP, LCP11 and MX12. Besides, the cytotoxicity-associated genes IFNG and TNF were highly expressed, especially in CD4+ T cells. The chemokines released by activated CD4+ T cells may increase the production and recruitment of CD8+ T cell and induce the compositional and functional alteration of ovarian, thereby prompting the progression of PCOS. Limitations, reasons for caution The study group is limited and transcriptome analysis covers much, but not enough. Although suggestive associations between immunological conditions and the severity of PCOS have concluded, additional animal models studies should be conducted to confirm our findings further. Wider implications of the findings The expression profiles of lymphoid cells provide deep insight into the molecular mechanisms of PCOS. Signaling receptors and gene data set will aid in future studies on the interorgan communication. It also facilitated discovery of novel biomarker for PCOS diagnosis and new immunological treatment. Trial registration number Not applicable

O-246 The molecular mechanism of miR-96-5p in the pathogenesis and treatment of polycystic ovary syndrome

Abstract Study question Polycystic ovary syndrome, characterized by the androgen excess and arrest of antral follicles, is lacking novel specific diagnostic biomarkers and therapeutic targets. Summary answer Study of the molecular mechanisms of microRNAs in the etiology and its potential applications in PCOS provides the insight. What is known already Some of molecular mechanisms of microRNAs have been demonstrated involved in the etiology of PCOS Study design, size, duration Clinically, we collected the samples of serum, follicular fluid (FF) and primary human granulosa cells (hGCs) of PCOS patients (n = 70) vs. non-PCOS women (n = 60). Experimentally, we carried out studies with 3-types of induced PCOS-like mice. Participants/materials, setting, methods By analysing the expression levels of miR-96-5p in serum, follicular fluid (FF) and primary human granulosa cells (hGCs) of PCOS patients (n = 70) vs. non-PCOS women (n = 60). as well as in ovaries from 3-types of induced PCOS-like mice. Main results and the role of chance Clinically, we demonstrated that the elevated circulating miR-96-5p levels were significantly correlated with the PCOS disordered endocrine clinical features, and the area under the curve of receiver operating characteristic was 0.8344, with 75.71% specificity and 80% sensitivity. Mechanically, we identified miR-96-5p as an androgen-regulated miRNA that directly targets the forkhead transcription factor FOXO1. Inhibition of miR-96-5p decreased estrogen synthesis, while decreasing the cell proliferation index of KGN via regulating the expression of FOXO1 and its downstream genes. Inversely, inhibition of FOXO1 abrogated the effect of miR-96-5p on estrogen synthesis and proliferation index. Of note, ovarian intra-bursal injection of miR-96-5p agomir rescued the phenotypes of dehydroepiandrosterone-induced PCOS like mice. Limitations, reasons for caution This study needs a large-scale clinical investigation to confirm the specificity and sensitivity of miR-96-5p as a clinical biomaker. Wider implications of the findings In conclusion, our results clarified a vital role of miR-96-5p in the pathogenesis of PCOS and might serve as a novel diagnostic biomarker and therapeutic target for PCOS. Trial registration number no

P-114 Abdominal obesity in Polycystic ovary syndrome patients can increase endometrial stromal cells decidualization

Abstract Study question Whether abdominal obesity can change the decidualization induction potential in PCOS patients? Summary answer We hypothesized that considering the inflammatory origin of abdominal obesity, it may affect decidualization potential of endometrial stromal cells (ESCs). What is known already Polycystic ovary syndrome (PCOS) as a chronic inflammatory disease is the most common hormonal disorder in women of reproductive age, which is often associated with subfertility or infertility due to ovulation disorders and subsequently low pregnancy rate, live birth rate and a high miscarriage rate. Inflammatory Abdominal obesity (AO) is the most common phenotype in PCOS patients, which has a high association with PCOS pathogenesis. Embryo-endometrium cross-talk has a key role in successful embryo implantation, which contains inflammatory phase (decidualization induction). Followed by inflammatory phase for pregnancy support. Study design, size, duration Our study population were consisting of 53 infertile women including PCOS diagnosed according to Rotterdam criteria (n = 25) and normal oogenesis women (male factor infertility) (n = 28) with in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) and frozen embryo transfer (FET) indication. All patients were aged 25-35 referred to Royan Institute between 1st May until 1st December in 2021 for infertility treatments. Participants/materials, setting, methods The embryos were subdivided into four groups: PCOS with AO, PCOS without AO, nonPCOS with AO, and nonPCOS without AO patients. The embryos from each group were single cultured up to the blastocyst stage. Their embryo condition media (ECM) were pooled and added to the culture media of healthy ESCs monolayer to investigate their effects on decidualization potential via gene and protein expression analysis and ESCs migration assay. Main results and the role of chance Results showed that ECM generally can improved decidualization capacity in ESCs. Morphological analysis, migration assay, protein and gene expressional analysis showed PCOS with AO had the highest decidualization potential and revealed by higher expression of decidualization markers (P ≤ 0.05). NonPCOS individuals without AO had the lowest level of both gene and protein decidualization markers (P ≤ 0.05). Limitations, reasons for caution Due to small sample population and the ECM volume limitation, the present study remained focused on the some main decidualization markers rather than extended study. Wider implications of the findings Inflammation may increase endometrial receptivity, allowing more suboptimal embryos to implant; this could explain the high rate of abortion in these cases. Controlling the inflammation in PCOS patients with AO may correct the decidualization profile of these patients. Trial registration number Not applicable

Stress and polycystic ovarian syndrome-a case control study among Indian women

BackgroundPolycystic ovarian syndrome (PCOS) is a common hormonal disorder that women belonging to premenopausal age group encounter. Due to its increasing incidence and burden of disease, re-searching the etiopathogenesis of this syndrome is essential and the need of the hour. Recently, the role of stress in the pathogenesis of the syndrome has come into the picture. Hence this study was done to find any significant difference in stress hormone levels between PCOS and healthy controls. MethodsA case-control study was conducted in SRIHER from 2019 to 2021 of which 250 participants were enrolled. Among the 250 subjects, 100 were diagnosed cases of polycystic ovarian syndrome and 150 were healthy women controls. Serum levels of DHEA and Cortisol were measured using ELISA technique and the data obtained was statistically analyzed to check for significance. ResultsThe serum levels of Cortisol and DHEA were found to be significantly elevated in PCOS compared to healthy women with a statistical significance of p = 0.001 and p = 0.01 respectively. The mean and standard deviation (SD) of Cortisol and DHEA among PCOS women were found to be 395.84 ± 195.62 and 6.04 ± 4.9 respectively. On the other hand, the mean and SD of Cortisol and DHEA among healthy controls were found to 256.26 ± 190.92 and 5.05 ± 3.20 correspondingly. ConclusionFrom this study, the stress hormone levels were found to be significantly distinct between the two groups. Stress could play a silent role in the pathogenesis of PCOS and its complications. Interventions to reduce stress among these women can considerably help to reduce the severity of existing symptoms as well as onset of dicey complications.

LncRNA NEAT1 and MALAT1 are involved in polycystic ovary syndrome pathogenesis by functioning as competing endogenous RNAs to control the expression of PCOS-related target genes.

Accumulating evidence has shown an abnormal expression of several non-coding RNAs in ovarian tissues which might be closely linked with the pathogenesis of PCOS. The aim of this study was to identify competing endogenous (ce) RNA network: long non-coding RNA (lncRNA), microRNA (miRNA) and their target genes: androgen receptor (AR), follistatin (FST) and insulin receptor substrate-2 (IRS-2), which are relevant to PCOS, to underline the molecular pathogenesis of PCOS and assist in early diagnosis and treatment. Bioinformatic analysis was performed to retrieve a ceRNA network: [lncRNA (NEAT1 and MALAT1) - miRNA (miR-30a-5p and miR-30d-5p) - mRNA (AR, FST and IRS-2)] linked to PCOS. Expression of the selected RNAs was examined by qPCR in peripheral blood leukocytes obtained from 73 PCOS patients (41 obese and 32 non-obese) and 31 healthy controls. PCOS patients showed significantly higher expression levels of NEAT1, miR-30a-5p, AR, FST and IRS-2, with significantly lower expression levels of MALAT1 and miR-30d-5p relative to controls especially in obese versus non-obese patients. Receiver operating characteristic (ROC) curve analysis indicated that most of the selected RNAs could serve as potential early diagnostic markers for PCOS with the highest efficiency obtained upon combining NEAT1 and miR-30d-5p or MALAT1 and miR-30a-5p with either of PCOS target genes. Moreover, all addressed RNAs had been proved as potential predictors of PCOS. The obtained data of ceRNA network raised the possibility that NEAT1 overexpression may increase the expression levels of AR, FST and IRS-2 by sponging miR-30d-5p, while low expression of MALAT1 may allow higher expression of the above genes via increasing miR-30a-5p, suggesting their involvement in PCOS pathogenesis and promising role for future diagnosis and targeted therapy.

Relationship Between Genetic Polymorphisms in Cell Cycle Regulatory Gene TP53 and Polycystic Ovarian Syndrome: A Case-Control Study and In Silico Analyses.

Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic condition with several potential causes. Insulin resistance is a hallmark of PCOS that often coexists with hirsutism, hyperandrogenism, being overweight, and hormonal imbalances. The functioning of multiple replication and transcription factors is regulated by tumor suppressor genes (TSGs), which play a crucial role in maintaining genomic integrity and controlling the cell cycle of granulosa cells. In the present study, we examined how three single nucleotide polymorphisms (SNPs) in TP53, a cell cycle regulatory gene, affect the risk of developing PCOS in asample of an Iranian population. Genomic DNA was extracted from 200 PCOS patients and 200 healthy women to analyze TP53 rs17880604, rs1625895, and rs1042522 SNPs using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings revealed that the majority of PCOS cases were overweight [25 < body mass index (BMI) < 30]. A positive association was observed between the TP53 rs1042522 SNP and the risk of PCOS under codominant heterozygous and overdominant genetic patterns (odds ratio > 1). Meanwhile, a negative association was observed between TP53 SNPs (rs1625895, rs17880604) and susceptibility to PCOS under codominant heterozygous and dominant models of inheritance (odds ratio < 1). Moreover, different genotype and haplotype combinations of rs17880604/rs1625895/rs1042522 conferred a decreased risk ofPCOS in our population. We found no statistical difference in the frequency of TP53 genotypes between PCOS cases and/or controls in terms of BMI, waist circumference, prolactinlevel, and markers of lipid and carbohydrate profile (P > 0.05). Molecular dynamic prediction showed that the missense substitution in the 17p13.1 position (rs1042522) could change the properties and secondary structure of the p53 protein. As inherited risk factors, TP53 variations may play a pivotalrole in the pathogenesis ofPCOS among Iranian women. Replicated population-based studies on other ethnicities are required to findthegenetic contributionof variants of TP53, or SNPs located in otherTSGs, to the etiology of this endocrine disease.

Clinical Diagnostic Values of C1q/TNF-Related Protein-3 for Polycystic Ovary Syndrome Women with Insulin Resistance.

Polycystic ovary syndrome (PCOS) is the most common disease caused by complex endocrine and metabolic abnormalities in women. Insulin resistance is considered an important pathophysiological factor in the pathogenesis of PCOS. Here we investigated the clinical values of C1q/TNF-related protein-3 (CTRP3) as predictive factor for insulin resistance. Our study included 200 patients with PCOS, among which 108 had insulin resistance. Serum CTRP3 levels were measured using enzyme-linked immunosorbent assay. Predictive values of CTRP3 for insulin resistance was analyzed using receiver operating characteristic (ROC) analysis. Correlations of CTRP3 to insulin levels, obesity measurements and blood lipid levels were determined using Spearman's correlation analysis. Our data suggested that PCOS patients with insulin resistance had a higher obesity, lower high-density lipoprotein cholesterol, higher total cholesterol, higher insulin levels and lower CTRP3 levels. CTRP3 had a high sensitivity (72.22%) and specificity (72.83%). CTRP3 significantly correlated to insulin levels, body mass index, waist-to-hip ratio, high-density lipoprotein, and total cholesterol levels. The predictive value of CTRP3 in PCOS patients with insulin resistance was supported by our data. Our findings suggest that CTRP3 is involved in the pathogenesis and insulin resistance of PCOS, which indicates its value as an indicator for the PCOS diagnosis.

Genetic contribution between APE1 variants in polycystic ovarian syndrome

IntroductionPolycystic Ovarian Syndrome (PCOS) has been identified as a gynecological, hormonal, and metabolic condition in women of reproductive age. Genetic studies can contribute to understand the pathogenesis of PCOS; which can be beneficial in early diagnosis and long-term management of the disease. Apurinic/apyrimidinic endonuclease 1 (APE1) has been related in the literature to polycystic ovarian syndrome. AimThe purpose of this study was to investigate the effects of −656 T > G and 1349 T > G single nucleotide polymorphisms (SNPs) in the APE1 gene in Saudi women with PCOS. MethodsThis study includes 100 PCOS women and 100 healthy controls were genotyped for −656 T > G and 1349 T > G SNPs using PCR-RFLP method. Serum sample was used for FBG and lipid profile tests. The obtained biochemical and genotypes data were entered into Excel and utilized for statistical analysis. ResultsClinical data presented in Table 1 was used to calculate the t-tests between PCOS and control subjects and results indicate age, weight, BMI, TG, LDLC and PCOS family history was associated (p < 0.0001). Genotype and allele frequencies showed the negative association in −656 T > G SNP (GG vs TT: OR-1.15 (0.61–2.17); p = 0.65 and GG + TG vs TT: OR-1.17 (0.67–2.04); p = 0.57) and positive association in 1349 T > G SNP (GG vs TT: OR-3.52 (1.48–8.36); p = 0.003 and GG + TG vs TT: OR-2.84 (1.27–6.31); p = 0.008) in APE1 gene. Anova analysis was not associated with any one of the involved parameters (p > 0.05). ConclusionThis study found that the 1349 T > G SNP was related with PCOS in Saudi women. However, the −656SNP had no favorable effect on the APE1 gene.

Global trends in polycystic ovary syndrome research: A 10-year bibliometric analysis.

Polycystic ovary syndrome (PCOS) is one of the most common reproductive metabolic disorders in women, significantly affecting the biological functionalities of ovaries. This disease has garnered enormous interest from researchers. However, there is a lack of a comprehensive research concerning assessing the current status and future trends in PCOS field. This study uses bibliometric tools to comprehensively analyze the PCOS-related research progress based on the literature in the past decade. The reported PCOS literature in the past decade is downloaded from the Web of Science database. The bibliometric software is applied to analyze the co-authorship, co-citation, and co-occurrence status. A total of 9936 publications imported into bibliometric tools for analysis show a sharp increase in the annual citations. The USA is dominant in terms of contribution in the field of PCOS, while China is making a significant contribution to the advancement of this field. Monash University is the most prolific institution with the highest H-index value. The contribution of University of Adelaide must be acknowledged. Legro RS and Teede HJ are the most active and influential authors in recent times, while Azziz R is the most contributed pioneer in this field. The Journal of Clinical Endocrinology & Metabolism is the most active journal with the highest number of publications and citations. The pathogenesis of PCOS had been a long-term forefront of research. In recent years, the health management in PCOS prevention and long-term complications was attracting more and more attention. The keywords like "gut microbiota", "microRNAs", "apoptosis", "Myo-inositol", "TNF-alpha", "androgen receptor", and "Vitamin D-deficient" are considered the latest research topics. The study comprehensively analyzes the current status and global trends in the PCOS field, providing a significant reference for researchers to explore this field effectively.

Polycystic ovary syndrome: Identification of novel and hub biomarkers in the autophagy-associated mRNA-miRNA-lncRNA network.

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder prevalent among women of reproductive age. Recent studies show that autophagy participated in the pathogenesis of PCOS, including anovulation, hyperandrogenism, and metabolic disturbances. This study was designed to screen autophagy-related genes (ATGs) that may play a pivotal role in PCOS, providing potential biomarkers and identifying new molecular subgroups for therapeutic intervention. Gene expression profiles of the PCOS and control samples were obtained from the publicly available Gene Expression Omnibus database. The gene lists of ATGs from databases were integrated. Then, the weighted gene co-expression network analysis was conducted to obtain functional modules and construct a multifactorial co-expression network. Gene Ontology and KEGG pathway enrichment analyses were performed for further exploration of ATG's function in the key modules. Differentially expressed ATGs were identified and validated in external datasets with the Limma R package. To provide guidance on PCOS phenotyping, the dysfunction module consists of a co-expression network mapped to PCOS patients. A PCOS-Autophagy-related co-expression network was established using Cytoscape, followed by identifying molecular subgroups using the Limma R package. ps. RNA-sequencing analysis was used to confirm the differential expression of hub ATGs, and the diagnostic value of hub ATGs was assessed by receiver operating characteristic curve analysis. Three modules (Brown, Turquoise, and Green) in GSE8157, three modules (Blue, Red, and Green) in GSE43264, and four modules (Blue, Green, Black, and Yellow) in GSE106724 were identified to be PCOS-related by WGCNA analysis. 29 ATGs were found to be the hub genes that strongly correlated with PCOS. These hub ATGs were mainly enriched in autophagy-related functions and pathways such as autophagy, endocytosis, apoptosis, and mTOR signaling pathways. The mRNA-miRNA-lncRNA multifactorial network was successfully constructed. And three new molecular subgroups were identified via the K-means algorithm. We provide a novel insight into the mechanisms behind autophagy in PCOS. BRCA1, LDLR, MAP1B, hsa-miR-92b-3p, hsa-miR-20b-5p, and NEAT1 might play a considerably important role in PCOS dysfunction. As a result, new potential biomarkers can be evaluated for use in PCOS diagnosis and treatment in the future.

The alterations of circulating mucosal-associated invariant T cells in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting reproductive age females and an important cause of infertility. Although the etiology is complex and its pathogenesis remains unclear, the pathological process of PCOS is tightly related with the immune dysfunction and gut microbial dysbiosis. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells which can regulate inflammation through the production of cytokines and play a role in regulating the gut microbiota. We aim to evaluate the correlation between characteristics of PCOS and MAIT cells as well as their impact on cytokine secretion. Peripheral blood samples were taken from PCOS patients (n=33) and healthy controls (n=30) during 2-5 days of the menstrual period. The frequencies of MAIT cells and T cells were measured by flow cytometry. Cytokines interleukin 17 (IL-17), interleukin 22(IL-22), interferon γ (IFN-γ) and granzyme B were determined by Enzyme-linked immunosorbent assay (ELISA). The frequency of MAIT cells was significantly reduced in the blood of PCOS patients compared with the controls, and negatively correlated with Body Mass Index (BMI), Homeostatic model assessment- insulin resistance (HOMA-IR) index, and Anti Miillerian Hormone (AMH). Thus, the frequencies of MAIT cells decreased in PCOS patients with abnormal weight (BMI≥24kg/m2), higher HOMA-IR (≥1.5), and excessive AMH (≥8ng/ml). The Cytokine IL-17 was significantly higher in PCOS patients and negatively correlated with the frequency of MAIT cells. Even though the IL-22 was lower in PCOS Patients, no correlation with MAIT cells was detected. In subgroup, CD4+MAIT cells correlated with BMI, AMH, and testosterone (T) levels. The frequency change of MAIT cells may play a significant role in the pathogenesis of PCOS. Exploring these interactions with MAIT cells may provide a new target for PCOS treatment and prevention.