Granulosa cell survival and proliferation are altered in polycystic ovary syndrome.

The cause of polycystic ovary syndrome (PCOS), the commonest endocrine abnormality affecting women of reproductive age, remains in large part unknown, although studies to date suggest an intrinsic ovarian abnormality. Developing oocytes have an interdependent relationship with the surrounding granulosa cells, and it is possible that dysfunction of these cells contributes to the abnormal folliculogenesis characteristic of PCOS. This study tested the hypothesis that differences in granulosa-cell proliferation and apoptosis adversely affect follicular development. Granulosa cells were prepared from follicular fluid aspirated from 4- to 8-mm follicles of unstimulated ovaries in the course of routine laparoscopy or laparotomy. Fourteen women with anovulatory PCOS and 9 with regular ovulatory cycles were sampled. Immunocytochemical analysis was used to estimate rates of proliferation and apoptosis, and the real-time polymerase chain reaction technique to analyze gene expression profiles of apoptotic regulators. Granulosa cells from PCOS patients exhibited significantly lower apoptotic rates than did cells from regularly ovulating women. Reduced rates of apoptosis were associated with decreased levels of caspase-3, an apoptotic effector, and with increased levels of the antiapoptotic survival factor cellular inhibitor of apoptosis proteins-2 in the PCOS group that were coupled to higher rates of cell proliferation. These immunocytochemical findings were confirmed by the results of gene expression profiling. These findings demonstrate significant differences in rates of granulose cell proliferation and cell death in women with anovulatory PCOS compared to those with normal ovulatory function. These differences involve the decreased expression of apoptotic effectors and increased expression of a cell survival factor. Improved treatment strategies for PCOS are a possibility.

Polycystic ovary syndrome (PCOS) is a status that impact a woman’s hormone levels.A total of (128) samples was divided into four groups (Obese with PCOS, low weight with PCOS ,Obese without PCOS ,and Healthy control) collected from Kamal Al-Samarraiehospital, Ministry-of Health in Baghdad-Iraq during the period of April 2017- August 2017. The aim of the study toevaluation from Serum AdiponectinIrisin and Apelin in Iraqi obese women patients with PCOS. The result shows The BMI of obese with PCOS patients and obese without PCOS was significantly higher (P<0.05) when compared to the values of the control group. No significant with other groups ,also Significant increase of Prolactin (p<0.05) in Obese with PCOS and low weight with PCOS groups in relation to Obese without PCOS and control groups. A non- significant elevation (p>0.05)when comparing between Obese without PCOS, and control groups. The levels of FSH , LH and Testosterone showed significantly change(p<0.05) in Obese with PCOS and low weight with PCOS groups when comparing with Obese without PCOS and control group. followed by no-significant with other groups ,also shows significant change(p<0.05)when comparing between Obese without PCOS and control group ,showed that adiponectin level showed a significant higher level in the control group ,Obese without PCOS group ,low weight with PCOS patients ,and Obese with PCOS patients . Oppositely, the results of the Irisin showed a significant higher level in the Obese with PCOS patients then the low weight with PCOS group followed by the Obese without PCOS and control group. While Apelin level recorded the highest level Obese with PCOS group.

Our study aimed to investigate the association of telomerase activity (TA) and telomere length (TL) in granulosa cells (GCs) with IVF outcomes of polycystic ovary syndrome (PCOS) patients, and the effects of oral contraceptive pill (OCP) pretreatment on these two parameters. One hundred sixty-three infertile women were enrolled and divided into a PCOS group (n=65) and a non-PCOS group (n=98). The PCOS group was further divided into an OCP pretreatment group (n=35) and a non-OCP pretreatment group (n=30), a TA <0.070 group (n=34) and a TA ≥0.070 group (n=31), and a TL <1 group (n=41) and a TL ≥1 group (n=24), respectively. No obvious differences were observed in TA between these groups. The TL was 0.971 in PCOS group and 1.118 in non-PCOS group (P=0.005). The patients with TL ≥1 accounted for 36.9% in PCOS group and 54.1% in non-PCOS group (P=0.032). The average duration of infertility for PCOS patients was 5years in TA <0.070 group and 4years in TA ≥0.070 group (P=0.038), and 5years in TL <1 group and 3years in TL ≥1 group (P=0.006), respectively. No obvious differences were observed in IVF outcomes between these groups. No obvious differences were observed in TA, TL, or IVF outcomes between OCP pretreatment group and non-OCP pretreatment group in PCOS patients. Shorter TL was found in PCOS patients. The TA levels did not change significantly in PCOS patients. PCOS patients with a lower TA level and shorter telomeres had an earlier onset of infertility symptoms. No predictive value was found for TA and TL in terms of embryo quality or IVF outcomes in PCOS patients, and no effect OCP pretreatment was observed on either TA and TL.

Study question What mechanisms are involved in the ovarian alterations of Polycystic Ovary Syndrome (PCOS) and Morphology? Summary answer PCOS patients associated a distinctive impairment of oxidative phosphorylation and dysregulated complement system in their follicular compartments not found in Polycystic Ovarian Morphology (PCOM) women. What is known already PCOS is a major cause of female infertility characterized by aberrant follicular development and hormonal imbalances leading to reproductive symptoms such as anovulation, poor oocyte quality, and hyperandrogenism. Likewise, PCOM is present in 16-25% of women with regular menses, but the clinical relevance of this ovarian phenotype and its correlation with PCOS remains unclear. Therefore, to establish the specific molecular mechanisms underlying the ovarian alterations in PCOS using High-throughput techniques will allow us to provide a better clinical management and a differential diagnosis with PCOM women. Study design, size, duration Cross-sectional molecular study including samples from 26 patients undergoing an IVF cycle between 2019-2022 at Hospital La Fe (Valencia, Spain). Eight women were considered PCOS, eleven PCOM and seven were control fertile patients. Granulosa cells (GCs) and follicular fluid (FF) samples were obtained during oocyte retrieval to perform RNA-seq and proteomic analysis, respectively. Participants/materials, setting, methods Women with two or more Rotterdam-criteria were considered as PCOS, while PCOM was defined by polycystic ovarian morphology on ultrasound with regular ovulatory cycles. RNA from GCs was obtained and sequenced using NextSeq500-Illumina to identify differentially expressed genes (DEGs) using DESeq2 (R-software). The proteome of FF samples was established by LC-MS/MS and differentially expressed proteins (DEPs) analyzed with limma package. Functional enrichment analysis of DEGs and DEPs (FDR&amp;lt; 0.05) was performed based on KEGG database. Main results and the role of chance RNA-seq data revealed clear distinctions between GCs from PCOS and control women, with 526 DEGs. By contrast, the transcriptomes of PCOS and PCOM were more similar, with only 34 DEGs. Notably, oxidative phosphorylation emerged as the most enriched pathway in both comparisons, showing a differential expression in PCOS. Indeed, 6 out of 12 shared DEGs (MT-TP, MT-ND4L, MT-ND2, MT-ATP8, MT-ND4, and MT-ATP6), were mitochondrial genes found upregulated in PCOS vs. PCOM and control samples. These findings suggest that granulosa cells from PCOS present a dysregulation in oxidative phosphorylation, potentially linked to alterations in those genes associated with the mitochondrial electron transport chain. The proteomic analysis showed 37 DEPs in the FF of PCOS compared with controls, being these DEPs mainly involved in the complement and coagulation cascades, PI3K-AKT pathway, oocyte meiosis and ferroptosis. Furthermore, the PCOS vs. PCOM analysis revealed 42 DEPs, significantly enriched also in complement and coagulation cascades, ferroptosis and glutathione metabolism. Interestingly, fifteen proteins were differentially expressed in both comparisons, with four of them related to the complement system (PROS1, C1S, C1QB and MASP2), suggesting that an alteration in this system at follicular fluid level might be one of the hallmarks of PCOS. Limitations, reasons for caution Further experimental studies are required to validate the specific changes identified in our study. Moreover, to establish how these alterations in the follicular compartments affect the oocytes of PCOS patients should also be explored. Wider implications of the findings Our study focused on specific mechanisms involved in PCOS ovarian alterations, providing new insights into potential biomarkers for an accurate diagnosis and management of this pathology. Dysregulations in oxidative phosphorylation and complement system might play a crucial role in PCOS multifactorial nature, contributing to impaired folliculogenesis and decreased oocyte quality. Trial registration number Not Applicable

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women of reproductive age, and its etiology remains poorly understood. Altered activities of long noncoding RNAs (lncRNAs) have been associated with human diseases and development. However, the roles of lncRNAs are unknown in reproductive medicine. We investigated the potential role of lncRNAs in the pathogenesis of PCOS, using human granulosa cells (GCs) and the KGN cell line. We used microarrays to compare lncRNA expression profiles in GCs from seven patients with PCOS and seven matched women. GC samples were collected during 2014 to 2016 from infertile women in Guangzhou, China. Quantitative real-time polymerase chain reaction was used to measure levels of the lncRNA HCG26 in GCs from 53 patients with PCOS and 50 controls. HCG26 was knocked down with locked nucleic acid GapmeRs in KGN cells to examine its role in cell proliferation, aromatase and follicle-stimulating hormone receptor gene expression, and estradiol production. A total of 862 lncRNA transcripts and 998 messenger RNA transcripts were differentially expressed (greater than or equal to twofold change; P < 0.05) in PCOS GCs compared with those of controls. HCG26 levels were upregulated in patients with PCOS and were associated with antral follicle count. HCG26 knockdown in KGN cells inhibited cell proliferation and cell-cycle progression and increased aromatase gene expression and estradiol production. Our study reports the lncRNA profiles in GCs from patients who have PCOS and those from healthy women and suggests that dysregulated lncRNAs may play vital roles in GC proliferation and steroidogenesis, providing insights into the pathogenesis of PCOS.

Periodontal disease in polycystic ovary syndrome

Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age with well established metabolic abnormalities. There are numerous diagnostic criteria generating several reproductive diagnostic phenotypes [National Institute of Health (NIH) hyperandrogenic anovulatory PCOS and non-NIH PCOS including hyperandrogenic ovulatory or non-hyperandrogenic anovulatory PCOS]. There is ongoing debate regarding the optimal diagnostic criteria for PCOS and on the metabolic implications of newer non-NIH PCOS phenotypes. METHODS We reviewed the literature on the presence of risk factors for type 2 diabetes (DM2) and cardiovascular disease (CVD) across the reproductive diagnostic phenotypes of PCOS with the aims of comparing the metabolic features of the NIH and non-NIH groups and identifying potential high metabolic risk phenotypes of PCOS. RESULTS NIH PCOS patients present with greater obesity, abdominal obesity, insulin resistance (IR) and risk factors for DM2 and CVD compared with non-NIH ovulatory and non-hyperandrogenic PCOS patients. Where differences in metabolic features exist between the phenotypes, they are generally related to the degree of total and abdominal obesity. There is emerging evidence suggesting ovulatory and non-hyperandrogenic PCOS have greater metabolic abnormalities than controls primarily linked to abdominal adiposity. There is currently no evidence that non-hyperandrogenic PCOS is associated with a less adverse metabolic profile than ovulatory PCOS. CONCLUSIONS Current metabolic evidence appears to justify the inclusion of both non-NIH PCOS groups (ovulatory and non-hyperandrogenic) as PCOS subgroups. NIH PCOS is associated with a more adverse metabolic profile including greater total and abdominal obesity, IR and risk factors for CVD and DM2 than non-NIH phenotypes.

PCOS is a common endocrine disorder in women of reproductive age, with granulosa cells playing a key role in its development. This study aims to identify shared differentially expressed genes (DEG) in granulosa cells and blood from PCOS patients, offering potential biomarkers and therapeutic targets. Transcriptomic data were obtained from the Gene Expression Omnibus (GEO) database: GSE95728 (granulosa cells; 7 PCOS, 7 controls) and two blood-based datasets, GSE85932 and GSE54248 (12 PCOS, 12 controls). In silico tools were employed to identify DEG, hub genes, and protein-protein interactions and to explore predicted drug targets. DEG analysis revealed that Vanin-2 (VNN2) and Interleukin-1 receptor type 2 (IL1R2) were consistently dysregulated in PCOS patients. Dysferlin (DYSF), Carbonic Anhydrase 4 (CA4), and Solute Carrier Family 2 Member 14 (SLC2A14) were differentially expressed between the blood datasets, while Aquaporin 9 (AQP9), C-X-C Motif Chemokine Receptor 1 (CXCR1), and Annexin A3 (ANXA3) were dysregulated in GSE95728 (granulosa cells) and GSE54248 (blood). Functional enrichment highlighted immune and metabolic pathways. Protein-protein interaction analysis identified AQP9 as a hub gene. Drug prediction analysis suggested that IL1R2 could be targeted by anakinra, while VNN2 was predicted to interact with pantothenic acid. The dysregulation of VNN2 and IL1R2 across tissue types suggests their involvement in immune-inflammatory processes in PCOS. The expression of AQP9 and other metabolism-related genes indicates possible immune-metabolic crosstalk, aligning with known PCOS pathophysiology. VNN2 and IL1R2 show potential as biomarkers or therapeutic targets in PCOS. Further validation is needed to confirm their clinical significance and roles.

BackgroundThe human ovary is the target of autoimmune attack in cases of autoimmune disorders, which can cause ovarian dysfunction. Due to the higher prevalence of Hashimoto’s Thyroiditis (HT) in Polycystic Ovary Syndrome (PCOS) patients, we aimed to evaluate ovarian reserve and the effect of autoimmune exposure time on ovarian reserve in PCOS patients with HT by Anti-Müllerian hormone (AMH) levels.MethodsForty-six PCOS patients and 46 PCOS with HT diagnosed patients who are between 18 and 35 years old were recruited for this study. Detailed medical histories were obtained from all participants. Polycystic ovary image was evaluated and antral follicles were counted by transvaginal ultrasound. Modified Ferriman Gallwey score, body mass index, waist/hip ratio of the patients were examined. Hormonal, biochemical profiles and AMH levels of the patients were evaluated during the early follicular phase. The data of both groups were statistically analyzed with SPSS 18.0.Results20 (43.5%) patients in the PCOS group were fertile, 8 (17.4%) patients in the PCOS + HT group were fertile, fertility rate was significantly lower in PCOS + HT group. The mean AMH value was 8.8 ± 8.8 in the PCOS + HT group and 12.4 ± 8.1 in the PCOS group and it was significantly lower in the PCOS + HT group (p = 0.043). AMH values were significantly negatively correlated with anti-thyroid peroxidase antibody (anti-TPO) level and the duration of HT. There was a significant positive correlation between the anti-TPO level and the duration of HT.ConclusıonWe pointed out that the coexistence of PCOS and HT, two prevalent diseases of reproductive age, further diminished ovarian reserve. More exposure of the ovaries to autoantibodies can cause ovarian destruction, similar to the thyroid gland like HT. Because of all these close relations with PCOS and thyroid dysfunctions, we recommend evaluating both thyroid autoantibodies and hormone levels in PCOS patients at the first visit. Patients with PCOS + HT should be monitored more closely to determine the fertility treatment options and control premature ovarian failure (POF) table.

Regulation of catechol O-methyltransferase expression in granulosa cells: a potential role for follicular arrest in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is an endocrine disorder that occurs in women of reproductive age. Anovulation caused by abnormal follicular development is still the main characteristic of PCOS patients with infertile. Granulosa cell (GC) is an important part of the follicular microenvironment, the dysfunction of which can affect follicular development. Increasing evidence indicates that exosomal miRNAs derived from the follicular fluid (FF) of patients play critical roles during PCOS. However, which follicular fluid-derived exosomal miRNAs play a pivotal role in controlling granulosa cell function and consequently follicular development remain largely unknown, as does the underlying mechanism. Herein, we showed that miR-143-3p is highly expressed in the follicular fluid exosomes of patients with PCOS and can be delivered into granulosa cells. Furthermore, functional experiments showed that translocated miR-143-3p promoted granulosa cell apoptosis, which is important in follicle development. Mechanistically, BMPR1A was identified as a direct target of miR-143-3p. Overexpression of BMPR1A reversed the effects of exosomal miR-143-3p on GC apoptosis and proliferation by activating the Smad1/5/8 signaling pathway. These results demonstrate that miR-143-3p-containing exosomes derived from PCOS follicular fluid promoted granulosa cell apoptosis by targeting BMPR1A and blocking the Smad1/5/8 signaling pathway. Our findings provide a novel mechanism underlying the roles of exosomal-miRNAs in the follicular fluid of PCOS patients and facilitate the development of therapeutic strategies for PCOS.

Both polycystic ovary syndrome (PCOS) and psoriasis are associated with insulin resistance and metabolic syndrome. Nonetheless, the incidence of psoriasis in patients with PCOS is unclear. We used the Longitudinal Health Insurance Research Database (LHID) in Taiwan from 2000 to 2012 to perform a retrospective population-based cohort study to elucidate the occurrence of psoriasis in PCOS patients. Patients with PCOS without psoriasis in the index year (the year of PCOS diagnosis) were recruited as the PCOS group. Those without PCOS nor psoriasis (control group) were selected using propensity score matching at a ratio of 4:1. Hazard ratios (HRs) were obtained using the Cox proportional hazards regression model. In total, 4707 and 18,828 patients were included in the PCOS and control groups, respectively. The incidence rates of psoriasis in the control and PCOS groups were 0.34 and 0.70 per 1000 person-years, respectively. The risk of psoriasis was higher in the PCOS group by an HR of 2.07 (95% confidence interval [CI] = 1.25–3.43) compared with the control group. In conclusion, the incidence of psoriasis in the PCOS group was higher than that in the control group. Further studies should be conducted to investigate the mechanism underlying the association, and to benefit the long-term management of patients with PCOS.

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder, characterized by ovarian structural abnormalities that lead to ovulatory dysfunction. The Hippo signaling pathway is crucial in regulating ovarian enlargement and cortical thickening, which are hallmarks of PCOS, although the regulatory mechanisms remain unclear. We assessed the expression of miR-135b and its target gene LATS2 (large tumor suppressor 2) in granulosa cells from both PCOS and normal ovaries using quantitative PCR. Dual-luciferase assays confirmed their direct interaction. The expression and localization of YAP (yes-associated protein), a key effector of the Hippo pathway, were examined through immunofluorescence in granulosa cells (GCs) from both groups. Additionally, the impact of miR-135b overexpression or inhibition on Hippo pathway genes was investigated in the KGN granulosa cell line, with changes in cell proliferation and apoptosis analyzed by cell proliferation assay and flow cytometry. MiR-135b was significantly upregulated (9.15-fold) in PCOS granulosa cells and targeted LATS2, a critical Hippo pathway regulator. Dual-luciferase assays confirmed the miR-135b binding site in the 3'-UTR of LATS2. Mechanistically, high miR-135b expression reduced LATS2 levels, impairing YAP phosphorylation, promoting nuclear translocation of unphosphorylated YAP, and driving excessive granulosa cell proliferation. Our findings suggest that miR-135b overexpression in PCOS ovaries contributes to abnormal granulosa cell proliferation by inhibiting the Hippo pathway. This study enhances our understanding of ovarian abnormalities in PCOS and identifies miR-135b as a potential biomarker and therapeutic target for the disorder.

Objective To investigate the changes in plasma very long chain fatty acids (VLCFAs) in polycystic ovary syndrome (PCOS) patients, and further to explore its relationship with obesity and insulin resistance. Methods Two hundred and five PCOS patients were screened out according to the diagnostic criteria of Rotterdam conference (2003), aged 18-40 years. A group of 117 healthy infertile women of corresponding period was taken as control. These women were chosen randomly from reproductive center due to the problems of uterine tube or males. The plasma hormone levels were examined. Ten kinds of plasma VLCFAs were detected by gas chromatography-mass spectrometry (GC-MS). Data between two groups analysis was performed by t test. Multiple stepwise regression analysis was used to analysize multiple factors of measurement data. Results Compared with normal individuals, plasma VLCFAs levels was disorder in PCOS patients. There is a lower C20: 4n-6/C20: 3n-6 in VLCFAs of PCOS patients, and a higher C20: 1n-9, C20: 2n-7, C20: 3n-6, C22: 4n-6, C20: 5n-3, C22: 5n-3 and C22: 6n-3, compared with the control group(t=0.539-6.155, all P<0.05). In the PCOS group, compared with non-obese patients, obese patients had a higher C20: 0, and lower C20: 3n-6 and C20: 2n-7 (t=-0.927, 2.452, 0.767, both P<0.05). Compared with non insulin resistance group, patients with insulin resistance had a higher C20: 0 and lower C20: 2n-7 and C22: 5n-3 levels (t=-2.064, 2.195, 2.183, both P<0.05). Multiple stepwise regression analysis showed that C20: 2n-7 and C20: 0 were independent risk factors of obesity and insulin resistance, respectively. Conclusions Disturbance metabolism of VLCFA existed in the PCOS patients. The decrease of C20: 2n-7 was probably an influence factor of obesity in PCOS patients and the increase of C20: 0 was probably an influence factor of insulin resistance in PCOS patients. Key words: Polycystic ovary syndrome; Obesity; Insulin resistance; Very long chain fatty acids