Pathogenesis Of PCOS Research Articles

Relation of mitochondrial DNA copy number and variants with the clinical characteristics of polycystic ovary syndrome

Mounting evidences suggests mitochondrial dysfunction as a novel contributor in the pathogenesis of PCOS. Herein, we analyzed mtDNA copy number, a biomarker of mitochondrial function in women with PCOS and non-PCOS participants and study its correlation with their clinical characteristics. In this study, we further analyzed association of 383 mtDNA variants, as reported previously by us, with characteristic traits of PCOS and perform structural analysis of mutated protein. Our results indicate relative mitochondrial DNA (mtDNA) copy number to be significantly reduced in women with PCOS compared to non-PCOS group and significantly inversely related to waist to hip ratio (WHR), triglycerides and positively related to high density lipoprotein-cholesterol (HDL-C). After adjustment of the age in the PCOS group, significantly negative correlation of mtDNA copy number with WHR was observed. Unsupervised hierarchical clustering analysis revealed rare, low heteroplasmic mtDNA variants such as 12556G, 1488T, 9200G, 9670G, 3308G, 14480G, 15914T and 5426G to be strongly associated with PCOS related traits. Among these variants, variant 12256G in ND5 gene affected both the flexibility and overall stability of the protein structure. This study is first to reveal significant correlation of mtDNA copy number with WHR in women with PCOS indicating link between mitochondrial dysfunction with central obesity in PCOS. we also first time showed association of rare mtDNA variants with characteristics traits of PCOS highlighting the clinical significance of rare mtDNA variants, which may cumulatively act as early predictors of risk of PCOS and its related comorbidities which may help in the management of PCOS.

N-acetylcysteine supplementation improves endocrine-metabolism profiles and ovulation induction efficacy in polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS.MethodsFemale C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups.ResultsSimilar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005).ConclusionNAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS.

DIA proteomic and PRM validation through human granulose cells profiles screen suitable biomarkers for polycystic ovary syndrome patients

The aim of this study is to identify differentially expressed proteins (DEPs) in granulose cells (GCs) from women with or withoutpolycystic ovary syndrome (PCOS) via data independent acquisition (DIA) proteomic analysis.A total of 63 women were recruited for this study, 34 PCOS patients as experimental group (P), and 29 women without PCOS as Normal group (NP). DIA-based proteomic analysis was performed to identify DEPs in GCs between the P and NP samples. Certain typical DEPs were further validated by Parallel reaction monitoring (PRM), and correlation analysis was performed between these DEPs and the clinical characteristics.Cell vitality was measured by CCK-8 assay. DIA analysis revealed 174 significantly DEPs, of which 7 were upregulated and 167 downregulated. Bioinformatics analysis was performed to analysis the significantly DEPs. The PRM experiment confirmed TOP2A and SPHKAP were upregulated significantly in P by comparing to NP, while GM2A, MRPS16, APOA2 and FGF2 were downregulated significantly. Most notably, Correlation analysis revealed that TOP2A, SPHKAP, MRPS16 and FGF2were positively correlated with TG, AMH and Age, but negatively correlated with Menarche age, DBIL, FT3, Basal serum FSH and LH.Meanwhile, CCK-8 assay has shown that downregulation of FGF2 could weaken cell viability. Finally, a panel of DEPs were identified in the GCs of patients with PCOS, of which certain significant DEPs might play essential roles in the pathogenesis of PCOS, could be regarded as candidate biomarkers for PCOS.

Dysbiotic alteration in the fecal microbiota of patients with polycystic ovary syndrome.

Gut microbiota plays a critical role in the development of PCOS. There is a complex and close interaction between PCOS and gut microbiota. The relationship between the pathogenesis and pathophysiological processes of PCOS and the structure and function of the gut microbiota needs further investigation.

Exploring the Association of Biochemical Characterization and Genetic Determinants of TNF-α, CXCR2, and CCR5 Delta 32 Mutation with Predisposition to Polycystic Ovary Syndrome.

In this case control study, we used amplification-refractory mutation system (ARMS)-PCR to detect and determine the presence of the polymorphic variants TNF-α, CCR5-delta32, and CXCR2 in the study subjects. These gene polymorphs may serve as critical candidate gene variants in PCOS pathogenesis and therapeutics. The case-control study's findings revealed that the majority of the biochemical and endocrine serum biomarkers examined in the investigation-including lipids (LDL, HDL, and cholesterol), T2DM markers (fasting glucose, free insulin, and HOMA-IR), and hormones (FSH, LH, testosterone, and progesterone)-exhibited statistically significant changes in PCOS patients. The distributions of TNF-α (rs1800629), CCR5-delta32, and CXCR2 (rs2230054) genotypes analyzed within PCOS patients and healthy controls in the considered population were significant (p < 0.05). The heterozygosity of CXCR2-CA, TNF-α GA, and CCR5(WT+Δ32*) genotypes was significantly associated with PCOS susceptibility, with high OR and p < 0.05 in the codominant model. Similarly, the A allele of the TNF-α and CXCR2 genes, along with the CCR5Δ32*(mutant) allele, was significantly associated with PCOS susceptibility, with high OR and p < 0.05. Likewise, the CXCR2 (CA+AA) vs CC genotype was associated with increased susceptibility to PCOS, with OR 2.25, p < 0.032. Our study concludes that TNF-α rs1800629G>A, CXCR2-rs2230054C>T, and CCR5-Delta32 rs333 are potential loci for developing PCOS in the Tabuk population. These findings might eventually be useful in identifying and classifying those who are at risk for PCOS. To validate these results, it is advised that further longitudinal studies be conducted in diverse ethnic populations and with larger sample sizes.

IL-18BP Therapy Ameliorates Reproductive and Metabolic Phenotypes in a PCOS Mouse Model by Relieving Inflammation, Fibrosis and Endoplasmic Reticulum Stress.

There is a chronic inflammation in PCOS patients, which is correlated with the pathogenesis of PCOS. IL-18 and IL-18BP are related with some inflammatory diseases, while less explored in PCOS. Whether IL-18BP could be a potential drug of PCOS remains unknown.IL-18 and testosterone levels were evaluated in serum of 10 non-PCOS control patients and 20 PCOS patients. Female C57/BL6 mice were gavaged with letrozole to induce PCOS mouse model and IL-18 level was evaluated in the serum of PCOS mouse model, and IL-18 is intraperitoneally injected in female mice, IL-18BP is intraperitoneally injected in the PCOS mice models. Then the body weights, estrous cycles, reproductive hormones and morphology of ovaries were analyzed. The level of ovarian chronic inflammation, fibrosis and endoplasmic reticulum (ER) stress are evaluated.IL-18 levels are increased in the serum of PCOS patients and PCOS mice models respectively. The serum DHEAS, iWAT weight and adipocyte size were increased in IL-18 group compared to the control group (P < 0.05). In the PCOS mouse model treated with IL-18BP, the body weight and serum LH/FSH ratio was decreased compared to the PCOS group (P < 0.05). The expression levels of inflammatory factors and fibrosis-related genes, the expression level of endoplasmic reticulum stress-related genes, and the ROS positive area of ovarian tissue was decreased (P < 0.05).IL-18 is involved in inducing PCOS phenotypes, while IL-18BP relieves PCOS phenotypes by alleviating ovarian chronic inflammation, fibrosis and ER stress in PCOS mice.

Differential expression of miR-21, miR-222, and Let-7b in serum and follicular fluid of polycystic ovary syndrome: Correlation with biochemical parameters

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Recently, it was discovered that microRNAs (miRNAs), which circulate freely in the circulation or biofluids, have diagnostic or prognostic potential. The current study looked at the levels of expression of three miRNAs in the serum and follicular fluid (FF) of PCOS patients and healthy women. MethodWe have shortlisted the most studied miRNAs—miR-21, miR-222, and Let-7b—from the previous literature, followed by individual quantification using real-time polymerase chain reaction (PCR). ResultsThe present study results showed differences in the expression of miR-21, miR-222, and Let-7b in PCOS patients compared to controls. The area under the receiver operating characteristic (ROC) area under the curve (AUC) for miR-21, miR-222, and Let-7b was 0.70, 0.65, and 0.75 in serum and 0.55, 0.66, and 0.59 in FFs, respectively. The combined ROC of the three miRNAs showed an AUC 0.86 for serum and 0.62 for FF samples. miR-21 showed a positive correlation with body mass index (BMI), and luteinizing hormone (LH) level; miR-222 showed a positive correlation with LH, fasting blood sugar (FBS), and 2-h plasma glucose (PG); while anti-mullerian hormone (AMH), age, erythrocyte sedimentation rate (ESR) and 2-h PG were found to be negatively correlated with Let-b expression. Regression analyses showed a negative association of miR-21 with menarche, progesterone, menses, and antral follicle count (AFC), while serum miR-222 was associated with BMI and age. Let 7-b had a negative association with serum, oocytes, and the LH/FSH ratio. Bioinformatics indicates their predicted targets are potentially involved in microRNA in cancer, diabetes, the P53 signaling pathway, prolactin signaling, the Hippo signaling pathway, Ras signaling, and pathways in cancer. ConclusionThe study found that serum Let-7b, miR-222, and miR-21 were differentially expressed in PCOS patients, suggesting potential involvement in the pathogenesis or progression of PCOS.

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 PCOS utilizing the protein-protein interaction networks that were constructed based on the putative disease-causing genes for PCOS. Design No animals were used in this research because this study is an In-Silico studies which mainly uses softwares and online analysis tools. Participants/Materials, Settings Genes datasets related with PCOS were obtained from Genecard. Methods The protein-protein interaction networks (PPIN) of PCOS were created using the String Database after genes related with PCOS were obtained from Genecard. 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 Genecard database provided the source for the identification of a total of 1072 potential genes related with 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 stereoidogenesis, breast cancer pathway, regulation of lipid and glucose metabolism by AMPK pathway, and ovarian stereoidogenesis. The integrated analysis that was performed in the current study demonstrated that these hub clusters and their connected genes are closely associated to the pathogenesis of PCOS. Limitations Several of the significant genes that were identified in this study, such as ACVR1, SMAD5, BMP6, SMAD3, SMAD4 and AMH. 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 to 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.

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

BackgroundPolycystic 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. MethodsTo 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. ResultsIn 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. ConclusionsOur 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.

Impact of dehydroepiandrosterone sulfate and free androgen index on pregnancy and neonatal outcomes in PCOS patients

BackgroundPolycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with infertility and pregnancy complications. The pathogenesis of PCOS and its impact on reproductive function may be influenced by the source of androgens, including testosterone, free androgen, dehydroepiandrosterone sulfate (DHEAS). However, the differential effects of these androgen on pregnancy and neonatal outcomes and the cut-off value of East Asian population with PCOS remain unclear.MethodsA retrospective cohort study was conducted at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2015 to November 2022, involving 636 cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Subgroup analyses were performed using cut-off values of 6.4 for free androgen index (FAI), 9.5 µmol/L for DHEAS. Pregnancy and neonatal outcomes were compared between groups. Restricted cubic spline (RCS) was used to identify significant cut-off values affecting pregnancy.ResultsHigher FAI levels (> 6.4) were associated with decrease in clinical pregnancy rate (PR) (50.61% vs. 41.66%, p = 0.024), live birth rate (LBR) (42.42% vs. 32.35%, p = 0.011). When DHEAS levels exceeded 9.5 µmol/L, there was a significant decrease in clinical PR (51.27% vs. 42.73%, P = 0.039), LBR (42.73% vs. 32.73%, P = 0.012). Negative correlations were also observed between DHEAS levels and cumulative pregnancy rate (70.57% vs 56.62% p = 0.002) and cumulative live birth rate (CLBR) (59.35% vs 43.37%, p = 0.0007). Both FAI and DHEAS elevated is associated with the lowest clinical pregnancy rate (37.84%). Conversely, when solely FAI is elevated, the pregnancy rate increases to 52.38%, while an elevation in DHEAS alone is associated with a pregnancy rate of, both of which are lower than when neither FAI nor DHEAS are elevated (60.68%). The live birth rates exhibit a similar trend (30.00% vs 40.00% vs 41.83% vs 44.48%). RCS revealed a significant decrease in CPR and CLBR when DHEA levels exceeded 7.69 umol/L, while the cut-off value of FAI was 6.36 for CPR and CLBR.ConclusionIn conclusion, PCOS patients with biochemical hyperandrogenism show unsatisfactory clinical PR and CLBR when undergoing assisted reproductive technology (ART). This may be attributed to the influence of both adrenal-derived DHEAS and ovarian-derived FAI on the unfavorable pregnancy outcomes.

Investigating the interplay between AMH gene polymorphism rs10407022 and clinical indicators in polycystic ovary syndrome

PurposePCOS is a multifaceted endocrine disorder with a complex etiology that includes genetic and environmental influences. The Anti-Mullerian Hormone is essential in menstrual disorders and fertility, as it is involved in growth differentiation and folliculogenesis. The AMH gene polymorphism, specifically p.Ile49Ser, has been proposed to play a role in the pathogenesis of PCOS, but its significance in Indian populations has yet to be determined. MethodsA case-control study was carried out on 129 women from Gujarat, India, aged 13 to 40 years (59 with PCOS and 70 controls). Clinical, biochemical, and hormonal parameters were examined, and tetra-ARMS PCR was used for genotyping the AMH gene polymorphism (p.Ile49Ser). The relationships between polymorphism, hormonal imbalances, and PCOS were studied using different statistical methods. ResultsThe mean BMI in the PCOS group was significantly higher (27.32 ± 5.71) in comparison to the control group (23.81 ± 5.47, p = 0.001), with 67.80% of PCOS cases being obese. Notably, serum LH and T levels were significantly higher in PCOS women, whereas DHEAS levels were significantly lower (p < 0.05). However, the distribution of AMH gene rs10407022 genotypes and alleles did not differ significantly between groups, and no associations with PCOS risk were found. ConclusionObesity and hormonal imbalances have a significant impact on PCOS in Gujarati women, according to this study. Even though the AMH gene polymorphism (p.Ile49Ser) did not show a significant association with PCOS, the findings encourage further genetic research in diverse Indian populations to uncover the complex genetic background of PCOS.

GRIM19 deficiency aggravates metabolic disorder and ovarian dysfunction in PCOS

ContextPolycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Retinoid-interferon-induced mortality 19 (GRIM19) is a functional component of mitochondrial complex I that plays a role in cellular energy metabolism. However, the role of GRIM19 in the pathogenesis of PCOS is still unclear. ObjectiveTo investigate the role of GRIM19 in the pathogenesis of PCOS. DesignWe first measured the expression of GRIM19 in human granulosa cells (hGCs) from patients with and without PCOS (n = 16 per group), and then established a PCOS mouse model with WT and Grim19+/− mice for in vivo experiments. Glucose uptake-related genes RAC1 and GLUT4 and energy metabolism levels in KGN cells were examined in vitro by knocking down GRIM19 in the cell lines. Additionally, ovulation-related genes such as p-ERK1/2, HAS2, and PTX3 were also studied to determine their expression levels. ResultsGRIM19 expression was reduced in hGCs of PCOS patients, which was negatively correlated with BMI and serum testosterone level. Grim19+/− mice with PCOS exhibited a markedly anovulatory phenotype and disturbed glycolipid metabolism. In vitro experiments, GRIM19 deficiency inhibited the RAC1/GLUT4 pathway, reducing insulin-stimulated glucose uptake in KGN cells. Moreover, GRIM19 deficiency induced mitochondrial dysfunction, defective glucose metabolism, and apoptosis. In addition, GRIM19 deficiency suppressed the expression of ovulation-related genes in KGN cells, which was regulated by dihydrotestosterone mediated androgen receptor. ConclusionsGRIM19 deficiency may mediate ovulation and glucose metabolism disorders in PCOS patients. Our results suggest that GRIM19 may be a new target for diagnosis and treatment.

The Role of ADAM17 in PCOS Pathogenesis: A review Paper

This review primarily focuses on the Role of metalloproteinase (ADAM 17). Gynaecological disease contributes to approximately 4.5% of the worldwide disease burden. Gynecological problems in women of reproductive age are linked to both In terms of diagnosis and treatment. Because there are no defined biomarkers, identifying gynaecological disorders, particularly malignancies, has been difficult in most cases, and histopathological exams remained the gold benchmark. M.M.P.s, ADAMs, and ADAMTSs, as well as their endogenous inhibitors (TIMPs), influence the protease-dependent bioavailability of local niche components. ADAM 17 has been implicated in various pathological processes, including inflammatory response, cardiovascular disease, and, recently, ovarian dysfunction. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age and is characterised by chronic anovulation, insulin resistance, and increased prevalence of cardiovascular risk factors. So far, the PCOS has not assessed the circulating levels of MMPs and their tissue inhibitors (TIMPs). This review will concentrate on the Role of (ADAM17) in regulating gynaecological disorder (PCOS) and their consequent modulation for therapeutic intervention.

Identification and validation of senescence-related genes in polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is an exceedingly intractable issue affecting female endocrine and reproductive health. However, the etiology and intricate pathological mechanisms of PCOS remain unclear. Nowadays, aging was found to share multiple common pathological mechanisms with PCOS, which causes probing into the pathogenesis of PCOS from senescence. However, no bioinformatics analyses have specifically focused on connection between PCOS and ovarian aging.MethodsDifferentially expressed aging-related genes in PCOS were identified and then analyzed using function enrichment method. Hub genes were determined based on multiple algorithms, and expression validation of hub genes was performed in both datasets and experiments (human granulosa-like tumor cell line, KGN; human Granulosa Cell, hGCs). Finally, a transcription factor-miRNA-gene network of hub genes was constructed.ResultsHere, we identified 73 aging-related differential expression genes (ARDEGs) by intersecting DEGs in PCOS and senescence-related gene set. Furthermore, we performed biological functions and potential pathways of ARDEGs and potential hub genes were also screened by multiple algorithms. From the perspective of immune dysfunction, we analyzed the correlation between PCOS and immune cells. Finally, TF-miRNA-gene networks were constructed. Finally, TF-miRNA-gene networks were constructed.ConclusionsOur work aimed to elucidate the relation between PCOS and cellular senescence based on bioinformatics strategy, deepening the understanding of mechanisms and to seek for novel therapy strategies for improving reproductive lifespan and female health. Exploring the potential molecular mechanism of cell aging in PCOS is expected to bring a new breakthrough for PCOS diagnosis and therapy strategies. And this, might deepen our understanding about intricate mechanisms of ovarian aging.

An Update on the Genetics of Polycystic Ovary Syndrome

PCOS is a common endocrinopathy among women of reproductive age, with a worldwide prevalence of 8 to 13%, depending on the criteria used for diagnosis. It is characterized by a constellation of features, including oligo/anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS is one of the common causes of female infertility. It is also associated with metabolic derangements, including obesity, insulin resistance, and compensatory hyperinsulinemia, which increase the likelihood of developing type 2 diabetes mellitus. Despite extensive research, the etiology of PCOS remains largely unknown. It seems likely that the hypothalamic-pituitary-ovarian axis dysfunction, partial folliculogenesis arrest, insulin resistance, and ovarian and adrenal androgen secretion may play a role in the pathogenesis of PCOS. Familial clustering of the cases of PCOS points to a genetic component linked with it. The initial genetic studies suggest an autosomal dominant pattern of inheritance of the disorder in some families; however, most studies support multifactorial origin. Since PCOS is a complex trait, the typical form of inheritance of PCOS follows a non-Mendelian pattern and involves complex genetic mechanisms. Studies involving linkage and association have suggested a connection between genetic variations and the risk of developing PCOS in certain families or populations. Through genome-wide association studies and next-generation sequencing techniques, several candidate genes have been identified that play a role in the etiopathogenesis of the disorder. Pathogenic variants of various genes such as INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc. in some PCOS cases are linked as underlying etiologic associations. This review aims to provide insight into the current genetic knowledge about PCOS. Discovering the genetic factors and pathways involved in the disorder will help us better comprehend the underlying mechanisms of the disorder.

The physiological functions and therapeutic potential of exosomes during the development and treatment of polycystic ovary syndrome.

Polycystic ovary syndrome is a very common disease of gynecological endocrine, accompanied by irregular menstruation, hyperandrogenism, metabolic abnormalities, reproductive disorders and other clinical symptoms, which seriously endangers women's physical and mental health, but its etiology and pathogenesis are not completely clear. Recently, the contribution of exosomes to the diagnosis and treatment of various diseases in the biomedical field has attracted much attention, including PCOS. Exosomes are extracellular vesicles secreted by cells, containing various biologically active molecules such as cell-specific proteins, lipids, and nucleic acids. They are important signaling regulators in vivo and widely participate in various physiopathological processes. They are new targets for disease diagnosis and treatment. Considering the important role of non-coding RNAs during the development and treatment of PCOS, this article takes exosomal miRNAs as the breakthrough point for elucidating the physiological functions and therapeutic potential of exosomes during the development and treatment of PCOS through analyzing the effects of exosomal miRNAs on ovarian follicle development, hormone secretion, oxidative stress, inflammatory response and insulin resistance, thus providing new research directions and theoretical basis for PCOS pathogenesis, clinical diagnosis and prognosis improvement.

Dehydroepiandrosterone-induced polycystic ovary syndrome mouse model requires continous treatments to maintain reproductive phenotypes

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Animal models have been developed and used as tools to unravel the pathogenesis of PCOS, among which most postnatal models employ continuing experimental manipulations. However, the persistence and stability of these animals after modeling is unknown. Dehydroepiandrosterone (DHEA)-induced PCOS mouse model is commonly used in PCOS studies. Thus the aim of the present study was to investigate the reproductive features of DHEA-induced PCOS mice fed a normal chow or an high-fat diet (HFD) with treatment withdrawal or consecutive treatments after PCOS mouse models were established.MethodsPrepubertal C57BL/6 J mice (age 25 days) were injected (s.c.) daily with DHEA on a normal chow or a 60% HFD for 20 consecutive days to induce PCOS mouse models. Mice injected with the vehicle sesame oil were used as controls. After 20 days, mice were divided into 2 groups, namely “Continue dosing group” and “Stop dosing group”. The animals were consecutively treated with DHEA or DHEA + HFD, or housed without any treatment for 2 or 4 weeks. Estrous cycles were evaluated during this period. At the end of the experiment, serum testosterone (T) levels were measured and the morphology of ovaries was evaluated.ResultsThe mice in Continue dosing groups maintained reproductive phenotypes of PCOS mouse models. In contrast, 2 or 4 weeks after PCOS models were established, the mice with treatment withdrawal in Stop dosing groups exhibited normal serum testosterone levels, regular estrous cycle, and relatively normal ovarian morphology. In addition, even with consecutive treatments, there was no marked difference in body weight between DHEA mice on the normal chow or an HFD in Continue dosing groups and the control animals 3 weeks after modeling.ConclusionsAfter PCOS mice were induced with DHEA or DHEA + HFD, the mice still need consecutive treatments to maintain reproductive phenotypes to be regarded as PCOS mice that meet the diagnostic criteria of PCOS defined by the 2003 Rotterdam criteria.

Depletion of gut microbiota influents glucose metabolism and hyperandrogenism traits of mice with PCOS induced by letrozole

BackgroundPolycystic ovary syndrome (PCOS) is a multifaceted disorder that impacts metabolism, reproduction, as well as endocrine function, characterized by excessive levels of androgen and insulin resistance. The gut microbiota has been implicated in the pathogenesis of PCOS. However, the precise mechanisms through which the gut microbiota influences PCOS still require further elucidation.MethodsThe PCOS mouse model was established through the administration of letrozole to both conventional and antibiotics-treated mice. The evaluation of glucose metabolism, sex hormone levels, and ovarian morphology was conducted. Furthermore, the fecal samples from each group of mice were subjected to 16S rRNA gene sequencing, and functional prediction of gut microbiota was proceeded using PICRUSt2 to explore potential mechanisms.ResultsBy using letrozole-induced PCOS mice model, we manifested that antibiotic intervention significantly reduced the serum total testosterone level and ameliorated glucose intolerance. Antibiotic treatment reduced the number of amplicon sequence variants (ASVs), as well as the Shannon and Simpson index. Meanwhile, letrozole induced a significant increase in the Shannon and Simpson index instead of ASVs. Through random forest model analysis, the results revealed significant alterations in three distinct groups of microbiota, namely Clostridia_vadinBB60_group, Enterorhabdus, and Muribaculaceae after letrozole treatment. Further correlation analysis revealed a positive association between alterations in these microbiota and both serum total testosterone levels and the area under the curve (AUC) of blood glucose in IPGTT. The administration of antibiotics led to a decrease in the absolute abundance of 5 ASVs belonging to unclassified Clostridia_vadinBB60_group, unclassified Enterorhabdus, and unclassified Muribaculaceae, which exhibited a positive correlation with the levels of total testosterone in mice serum, as well as the area under the curve of blood glucose in IPGTT. Moreover, 25 functional pathways of gut microbiome were significantly discrepant between the letrozole-treated mice with and without antibiotics.ConclusionThese results suggest that disturbance of the gut microbiota may take participate in the progression of PCOS and manipulating the composition of the gut microbiota may be a therapeutic approach for managing PCOS.

TO EVALUATE THE RELEVANCE OF MEDOSARATA IN CURRENT SCENARIO W.S.R. TO PCOS

Ayurveda is a living science with a big concern to follow the Siddhant of “Swasthsya Swasthya Rakshan.” The Ayurvedic concept of preventive aspect of health is very useful now a days as the people in the modern era are unable to pay attention to their health due to their hectic lifestyles &amp; may suffer from a number of lifestyle disor-ders. Ayurveda proposed many measures to protect health. For the diagnosis &amp; prevention of diseases there should be knowledge of Tridhoshas, Saptadhatus, Malas as well as an understanding of Sarata is also crucial. Dhatu Sarata is an assessment of body by examine the excellent and fine quality status of Dhatu. It is a component of Dashavidha Pariksha. Both physical and emotional health are impacted by Dhatu's Sara-Asara state, we can observe a dhatu's impacts on many bodily parts while it is in the Asar state. So, differ-ent kinds of lifestyle &amp; metabolic diseases are caused by impaired Dhatus. PCOS is common lifestyle and meta-bolic disorders in female &amp; is characterized by a combination of hyperandrogenism, irregular menses, chronic anovulation, hyperinsulinemia, obesity, polycystic ovaries, infertility. As per our classical texts, a few diseases may be correlated with PCOS like Pushpaghnijataharini1 (kashyap samhita), Aartavakshay2, Granthi, Bandhya3 yonivyapad, Sthaulya etc. The proposed pathogenesis of PCOS is as follows, due to Visham Aahar vihar Agni getting vitiated causing Agnimandya which leads to the formation of Aamras resulting Dhatvagni mandya. This Samaras dhatu vitiated the Aartava(Updhatu of Ras) &amp; Kapha Dosha. METHODOLOGY: This papers content is based on Ayurveda classics with the accessible commentaries, textbook of contemporary medical sciences, and a number of articles to better comprehend the idea Medosarata, Mandagni, Mans-Medodusthi &amp; the patho-genesis, symptoms etc of PCOS. RESULT: Thus, sedentary lifestyle is a precipitating factor for Dhatvagni Man-dya and Medodhatu Dushti in the pathogenesis of PCOS. Therefore, the purpose of present article is exploring awareness about lifestyle as well as the medical perspective of PCOS.

OR20-02 Trans-Ethnic Analysis Of PCOS Subtype Genomewide Association Signals Reveals 3 Shared Subtype-Specific Loci

Abstract Disclosure: K. Brewer: None. R. Sisk: None. H. Lee: None. L.M. Moolhuijsen: None. K. van der Ham: None. Y. Louwers: None. J.A. Visser: None. M. Dapas: None. S. Franks: None. J.S. Laven: None. C. Li: None. A.E. Dunaif: None. The phenotypic variation observed in PCOS is suggestive of underlying genetic heterogeneity, but a recent meta-analysis of European ancestry (EA) PCOS cases found that the genetic architecture of PCOS defined by NIH and Rotterdam diagnostic criteria was similar, suggesting that these criteria do not identify biologically distinct disease phenotypes. Using Hierarchical Clustering (HC) in EA NIH PCOS cases, we have identified discrete, stable PCOS subtypes, which we called reproductive and metabolic (Dapas. PLoS Med, 2020); cases that did not cluster were designated as “background”. These subtypes appeared to capture biologically meaningful differences because they were associated with distinct genomewide significant loci. We were unable to replicate 4 of 6 loci since the lead SNPs were neither genotyped nor imputed on the array used for replication, the Metabochip custom array for cardiometabolic traits with additional PCOS-relevant SNPs. Here, we report an updated EA genomewide association study (GWAS) meta-analysis with additional EA NIH PCOS cases, and a trans-ethnic meta-analysis including a Korean ancestry (KA) NIH PCOS cohort (Lee. Hum Reprod, 2015). HC was applied to cases in both cohorts to identify PCOS subtypes. The EA discovery cohort, 620 cases and 2951 controls, was genotyped with the Illumina OmniExpress array. The replication EA cohort, 371 cases and 926 controls, was genotyped with the Metabochip. The KA cohort, 417 cases and 926 controls, was genotyped with the HumanOmni1-Quad v1 array. The imputation of previously reported genotype data was updated using the larger, more deeply sequenced TOPMed (R2) imputation panel. Nine loci were genomewide significant in the EA meta-analysis: 5 novel loci (reproductive subtype); 2 loci (metabolic subtype), including c9orf3; 2 loci (background subtype), including FSHB/ARL14P. Five of 6 other lead SNPs in the original analysis remained nominally significant. Three loci were significant in the trans-ethnic meta-analysis: a novel locus on chr 3, EPHA6, a receptor tyrosine kinase that binds promiscuously GPI-anchored ephrin-A family ligands (rs140766105, p=1.08 x 10-8, reproductive subtype); a previously identified GWAS locus on chr 9, c9orf3 (AOPEP), an aminopeptidase that catalyzes the hydrolysis of amino acid residues from the N-terminus of peptides (rs10761370, p=4.12 x 10-9, metabolic subtype); a previously identified GWAS locus on chr 11, FSHB/ARL14P, FSHB encodes the β-subunit of FSH and is associated with general fertility status, (rs10835649, 1.23 x 10-11, background subtype). We have replicated the 9 distinct subtype loci in the EA meta-analysis providing orthogonal (independent) validation suggesting these subtypes have distinct genetic architecture. For the first time, a trans-ethnic meta-analysis demonstrates that 3 subtype-specific loci play a role in PCOS pathogenesis across diverse populations. Presentation Date: Saturday, June 17, 2023