Lipidomics reveals altered biosynthetic pathways of glycerophospholipids and cell signaling as biomarkers of the polycystic ovary syndrome.
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ABSTRACT:
SUBMITTER: Jove M
PROVIDER: S-EPMC5796992 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Women with polycystic ovary syndrome (PCOS) are more likely to develop endometrial cancer (EC). The molecular mechanisms which increase the risk of EC in PCOS are unclear. Derangements in lipid metabolism are associated with EC, but there have been no studies, investigating if this might increase the risk of EC in PCOS. This was a cross-sectional study of 102 women in three groups of 34 (PCOS, EC and controls) at Nottingham University Hospital, UK. All participants had clinical assessments, followed by obtaining plasma and endometrial tissue samples. Lipidomic analyses were performed using liquid chromatography (LC) coupled with high resolution mass spectrometry (HRMS) and the obtained lipid datasets were screened using standard software and databases. Using multivariate data analysis, there were no common markers found for EC and PCOS. However, on univariate analyses, both PCOS and EC endometrial tissue samples showed a significant decrease in monoacylglycerol 24:0 and capric acid compared to controls. Further studies are required to validate these findings and investigate the potential role of monoacylglycerol 24:0 and capric acid in the link between PCOS with EC.
| S-EPMC7370092 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS).Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses.This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m2). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite ?-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between groups were observed in concentrations of free fatty acids or vitamin D metabolites. Evaluation of the relationship of metabolites with clinical characteristics showed 1) negative associations of essential and BCAA with insulin sensitivity and sex hormone-binding globulin and 2) positive associations with homeostasis model of insulin resistance and free testosterone; metabolites were not associated with BMI or percent body fat.PCOS was associated with significant metabolic alterations not attributed exclusively to androgen-related pathways, obesity, or MetS. Concentrations of essential amino acids and BCAA are increased in PCOS, which might result from or contribute to their insulin resistance.
| S-EPMC5520539 | biostudies-literature
Project description: Not available
| S-EPMC7753500 | biostudies-literature
Project description:BackgroundWomen with polycystic ovary syndrome (PCOS) manifest a host of ovarian defects like impaired folliculogenesis, anovulation, and poor oocyte quality, which grossly affect their reproductive health. Addressing the putative epigenetic anomalies that tightly regulate these events is of foremost importance in this disorder. We therefore aimed to carry out DNA methylome profiling of cumulus granulosa cells and assess the methylation and transcript expression profiles of a few differentially methylated genes contributing to ovarian defects in PCOS. A total of 20 controls and 20 women with PCOS were selected from a larger cohort of women undergoing IVF, after carefully screening their sera and follicular fluids for hormonal and biochemical parameters. DNA extracted from cumulus granulosa cells of three women each, from control and PCOS groups was subjected to high-throughput, next generation bisulfite sequencing, using the Illumina HiSeq 2500® platform. Remaining samples were used for the validation of methylation status of some identified genes by pyrosequencing, and the transcript expression profiles of these genes were assessed by quantitative real-time PCR.ResultsIn all, 6486 CpG sites representing 3840 genes associated with Wnt signaling, G protein receptor, endothelin/integrin signaling, angiogenesis, chemokine/cytokine-mediated inflammation, etc., showed differential methylation in PCOS. Hypomethylation was noted in 2977 CpGs representing 2063 genes while 2509 CpGs within 1777 genes showed hypermethylation. Methylation differences were also noted in noncoding RNAs regulating several ovarian functions that are dysregulated in PCOS. Few differentially methylated genes such as aldo-keto reductase family 1 member C3, calcium-sensing receptor, resistin, mastermind-like domain 1, growth hormone-releasing hormone receptor and tumor necrosis factor, which predominantly contribute to hyperandrogenism, premature luteolysis, and oocyte development defects, were explored as novel epigenetic candidates in mediating ovarian dysfunction. Methylation profiles of these genes matched with our NGS findings, and their transcript expression patterns correlated with the gene hypo- or hypermethylation status.ConclusionOur findings suggest that the epigenetic dysregulation of genes involved in important processes associated with follicular development may contribute to ovarian defects observed in women with PCOS.
| S-EPMC6458760 | biostudies-literature
Project description:BackgroundIn this study, we aimed to identify novel biomarkers for polycystic ovary syndrome (PCOS) and analyze their potential roles in immune infiltration during PCOS pathogenesis.MethodsFive datasets, namely GSE137684, GSE80432, GSE114419, GSE138518, and GSE155489, were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were selected from the train datasets. The least absolute shrinkage and selection operator logistic regression model and support vector machine-recursive feature elimination algorithm were combined to screen potential biomarkers. The test datasets validated the expression levels of these biomarkers, and the area under the curve (AUC) was calculated to analyze their diagnostic value. Quantitative real-time PCR was conducted to verify biomarkers' expression in clinical samples. CIBERSORT was used to assess differential immune infiltration, and the correlations of biomarkers with infiltrating immune cells were evaluated.ResultsHerein, 1265 DEGs were identified between PCOS and control groups. The gene sets related to immune response and adaptive immune response were differentially activated in PCOS. The two diagnostic biomarkers of PCOS identified by us were HD domain containing 3 (HDDC3) and syndecan 2 (SDC2; AUC, 0.918 and 0.816, respectively). The validation of hub biomarkers in clinical samples using RT-qPCR was consistent with bioinformatics results. Immune infiltration analysis indicated that decreased activated mast cells (P = 0.033) and increased eosinophils (P = 0.040) may be a part of the pathogenesis of PCOS. HDDC3 was positively correlated with T regulatory cells (P = 0.0064), activated mast cells (P = 0.014), and monocytes (P = 0.024) but negatively correlated with activated memory CD4 T cells (P = 0.016) in PCOS. In addition, SDC2 was positively correlated with activated mast cells (P = 0.0021), plasma cells (P = 0.0051), and M2 macrophages (P = 0.038) but negatively correlated with eosinophils (P = 0.01) and neutrophils (P = 0.031) in PCOS.ConclusionHDDC3 and SDC2 can serve as candidate biomarkers of PCOS and provide new insights into the molecular mechanisms of immune regulation in PCOS.
| S-EPMC9258136 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is known as the most common metabolic/endocrine disorder among women of reproductive age. Its complicated causality assessment and diagnostic emphasized the role of non-coding regulatory RNAs as molecular biomarkers in studying, diagnosing and even as therapeutics of PCOS. This review discusses a comparative summary of research into microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) that are molecularly or statistically related to PCOS. We categorize the literature in terms of centering on either miRNAs or lncRNAs and discuss the combinatory studies and promising ideas as well. Additionally, we compare the pros and cons of the prominent research methodologies used for each of the abovementioned research themes and discuss how errors can be stopped from propagation by selecting correct methodologies for future research. Finally, it can be concluded that research into miRNAs and lncRNAs has the potential for identifying functional networks of regulation with multiple mRNAs (and hence, functional proteins). This new understanding may eventually afford clinicians to control the molecular course of the pathogenesis better. With further research, RNA (with statistical significance and present in the blood) may be used as biomarkers for the disease, and more possibilities for RNA therapy agents can be identified.
| S-EPMC8817139 | biostudies-literature
Project description:Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium.
| S-EPMC7016287 | biostudies-literature
Project description:BackgroundThe polycystic ovary syndrome (PCOS) is the most common endocrine associated with insulin resistance, even in the absence of overweight. The global lipid profile of the follicular fluid in PCOS with normal weight as yet has not been investigated. The objection of this pilot study was to explore the changes of lipids in the follicular fluid of PCOS with normal weight.MethodsFollicular fluid samples were collected from patients who underwent IVF, including normal-weight women without PCOS (control group, n = 10) and normal-weight women with PCOS (PCOS group, n = 8). A lipidomic analysis was performed by high performance liquid chromatography/ mass spectrometry (HPLC-MS). Multidimensional statistical analysis was performed to disclose the global differences between the two groups. Further, differential lipid analysis between the two groups was performed by Fold Change Analysis (FC Analysis) and T-test to screen potential markers.ResultsAll 812 species of 32 subclasses of lipids were identified by lipidomics analysis. 108 kinds of lipids were considered as the potential candidate differential metabolites with the score of variable importance in the project (VIP) more than 1 by the orthogonal partial least squares discriminant analysis. 32 lipids were significantly different between the PCOS group and the control group simultaneously with FC > 1.5 or FC < 0.67, p-value < 0.05 and VIP value > 1. These differential species of lipid belong to lipid subclasses including triglycerides (TG), phosphatidylethanolamines (PE) and phosphatidylinositols (PI).ConclusionThe identified differential lipids in the follicular fluid may be considered as candidate biomarkers as well as therapeutic targets of PCOS with normal-weight.
| S-EPMC8515674 | biostudies-literature
Project description:Aberration in miRNA expression or DNA methylation is a causal factor for numerous pathological conditions including polycystic ovarian syndrome PCOS, a common endocrine disorders and leading cause of infertility. The epigenetic interactions between miRNA and DNA methylation remain unexplored in PCOS. Few studies have reported that the key genes and pathways involved in polycystic ovary syndrome(PCOS). Our study helps to understand the molecular pathogenesis of PCOS in human ovarian granulosa cells and identifiy genes and pathways that may be potential therapeutic targets for PCOS treatment..
2019-10-08 | GSE138518 | GEO
Project description:BackgroundPolycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels.Design and methodsWe conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls.ResultsOverall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls.ConclusionsOur findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.
| S-EPMC5578435 | biostudies-literature