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Levels of circulating insulin cell-free DNA in women with polycystic ovary syndrome - a longitudinal cohort study.

ABSTRACT: BACKGROUND:Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of ?-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since ?-cell death is common to the development of T1D as well as in T2D, we aimed to investigate if insulin-coding DNA is more abundant in circulation of PCOS women (vs Controls) and if their levels change after 6?yr. follow-up as a potential measure to predict future T2D. METHODS:A cohort of 40 women diagnosed with PCOS according to Rotterdam 2003 criteria and eight healthy controls were examined at baseline and 6?years follow-up. Clinical measurements for evaluation of glucose homeostasis as well as blood/serum samples were obtained at each visit. Methylated and unmethylated INS cfDNA were quantified using droplet digital PCR. Differences between groups were assessed using Kruskall-Wallis test and Wilcoxon Signed rank test. RESULTS:At baseline, there was no detectable difference in copy number (copies/?L) of methylated (p =?0.74) or unmethylated INS cfDNA (p =?0.34) between PCOS and Control groups. At follow up, neither methylated (p =?0.50) nor unmethylated INScfDNA levels (p =?0.48) differed significantly between these groups. Likewise, when pooling the groups, there was no difference between baseline and follow up, in terms of copies of methylated or unmethylated INS cfDNA (p =?0.38 and p =?0.52, respectively). There were no significant correlations between counts of unmethylated or methylated cfDNA and the clinical measurements of ?-cell function and pre-diabetes. CONCLUSION:The circulating level of unmethylated and methylated INScfDNA is similar between PCOS and Controls and cannot be used to predict islet ?-cell loss and progression to Type 2 diabetes in a 6-year follow-up. TRIAL REGISTRATION:The Danish Data Protection Agency (REG-31-2016. Approval: 01-12-2015) and by the Danish Scientific Ethical committee of Region Zealand (Journal no. SJ-525. Approval: 13-06-2016), Clinicaltrials.gov, ( NCT03142633 , registered 1. March, 2017, Retrospectively registered).

SUBMITTER: Udesen PB

PROVIDER: S-EPMC6451227 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Levels of circulating insulin cell-free DNA in women with polycystic ovary syndrome - a longitudinal cohort study.

Udesen Pernille Bækgaard PB Sørensen Anja Elaine AE Joglekar Mugdha V MV Hardikar Anandwardhan A AA Wissing Marie Louise Muff MLM Englund Anne-Lis Mikkelsen AM Dalgaard Louise Torp LT

Reproductive biology and endocrinology : RB&E 20190405 1

<h4>Background</h4>Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of β-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since β ...[more]

PMID: 30953560

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Project description:IntroductionPolychlorinated biphenyls (PCBs), organic lipophilic pollutants that accumulate through diet and increase with age, have been associated with polycystic ovary syndrome (PCOS) and shown to affect microRNA (miRNA) expression. This work aimed to determine if PCBs were associated with circulating miRNAs and whether there were any correlations with serum PCB/miRNA levels and hormonal changes.Methods29 non-obese PCOS and 29 healthy control women, with similar age and body mass index (BMI), had their serum miRNAs measured together with 7 indicator PCBs (PCB28, PCB52, PCB101, PCB118, PCB138, PCB153, PCB180) using high resolution gas chromatography coupled with high resolution mass spectrometry.ResultsIn the combined study cohort, four miRNAs (hsa-miR-139-5p, hsa-miR-424-5p, hsa-miR-195-5p, hsa-miR-335-5p) correlated with PCBs, but none correlated with metabolic parameters. hsa-miR-335-5p correlated with FSH. When stratified, 25 miRNAs correlated with PCBs in controls compared to only one (hsa-miR-193a-5p) in PCOS; none of these miRNAs correlated with the metabolic parameters of BMI, insulin resistance, or inflammation (C-reactive protein, CRP). However, of these 25 miRNAs in controls, hsa-miR-26a-5p, hsa-miR-193a-5p, hsa-miR-2110 and hsa-miR-195-5p positively correlated with luteinizing hormone (LH), hsa-miR-99b-5p and hsa-miR-146b-5p correlated with estradiol, hsa-miR-193a-5p correlated with progesterone, hsa-miR-195-5p correlated with follicle stimulating hormone (FSH), and hsa-miR-139-5p and hsa-miR-146b-5p negatively correlated with anti-müllerian hormone (AMH) (all p<0.05). hsa-miR-193a-5p in PCOS cases correlated with estradiol.ConclusionIn this cohort of women, with no difference in age and BMI, and with similar PCB levels, the miRNAs correlating to PCBs associated with menstrual cycle factors in healthy menstruating controls versus the anovulatory PCOS subjects. The PCB-associated miRNAs did not correlate with non-reproductive hormonal and metabolic parameters. This suggests that PCB effects on miRNAs may result in changes to the hypothalamo-ovarian axis that may thus affect fertility.

Project description:Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation to be of uncertain cause: obesity, insulin resistance, or PCOS itself. The aim of the study was to investigate the WBC (white blood cell) count and CRP (C-reactive protein) concentration in women with PCOS and to determine the factors that affect their concentration. The study included 200 women aged 18-40 with PCOS and 105 healthy women as the control group, recruited in the Department of Gynaecological Endocrinology of Medical University in Warsaw from 2016 to 2018. Each patient underwent clinical, biochemical, and ultrasonographic assessments. WBC and CRP were significantly higher in the PCOS group (Z = -2,353, p = 0,019 and Z = -2,453, p = 0,014). WBC positively correlated with serum insulin at 0, 60, and 120?min during the oral glucose tolerance test (INS0: r = 0,221, p = 0,001; INS1: r = 0,194, p = 0,003; INS2: r = 0,022, p = 0,001), testosterone (r = 0,130, p = 0,046), androstenedione (r = 0,212, p = 0,001), and DHEAS (r = 0,178, p = 0,006) and negatively correlated with progesterone (r = -0,204, p = 0,002), estradiol (r = -0,140, p = 0,032), and SHBG (r = -0,308, p < 0,001). CRP positively correlated with insulin concentration in 0, 60, and 120?min during the oral glucose tolerance test (INS0: r = 0,343, p < 0,001; INS1: r = 0,276, p = 0,001; INS2: r = 0,320, p < 001) and negatively correlated with progesterone (r = -0,194, p = 0,030) and SHBG (-0,244, p = 0,005). We also estimated positive correlation between BMI and serum CRP and WBC concentration. Multiple linear regression analysis showed that CRP values are positively associated with BMI (beta = 0,374, p < 0,001) and insulin level (INS1) (beta = 0,282, p = 0,004); and WBC results are negatively associated with SHGB (beta = -0,284, p < 0,001) but positively associated with testosterone (beta = 0,163, p = 0,024) and BMI (beta = 0,157, p = 0,047). PCOS is associated with increased WBC and CRP concentrations. The main predicting factors of increased CRP are BMI and insulin resistance, but there is also a relationship between WBC count in PCOS and androgen concentration itself so that inflammation may be mediated not only through adiposity but also through increased androgen concentration.

Project description:BACKGROUND:Polycystic ovary syndrome (PCOS) affects 8% to 13% of reproductive-aged women and is associated with reproductive and metabolic dysfunction. Obesity worsens the presentation of PCOS and weight management (weight loss, maintenance or prevention of excess weight gain) is proposed as an initial treatment strategy, best achieved through lifestyle changes incorporating diet, exercise and behavioural interventions. OBJECTIVES:To assess the effectiveness of lifestyle treatment in improving reproductive, anthropometric (weight and body composition), metabolic and quality of life factors in PCOS. SEARCH METHODS:We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, CINAHL and AMED (date of last search March 2018). We also searched controlled trials registries, conference abstracts, relevant journals, reference lists of relevant papers and reviews, and grey literature databases, with no language restrictions applied. SELECTION CRITERIA:Randomised controlled trials (RCTs) comparing lifestyle treatment (diet, exercise, behavioural or combined treatments) to minimal or no treatment in women with PCOS. DATA COLLECTION AND ANALYSIS:Two authors independently selected trials, assessed evidence quality and risk of bias, and extracted data. Our primary outcomes were live birth, miscarriage and pregnancy. We used inverse variance and fixed-effect models in the meta-analyses. We reported dichotomous outcomes as an odds ratio and continuous outcomes as a mean difference (MD) or standardised mean difference (SMD). MAIN RESULTS:We included 15 studies with 498 participants. Ten studies compared physical activity to minimal dietary and behavioural intervention or no intervention. Five studies compared combined dietary, exercise and behavioural intervention to minimal intervention. One study compared behavioural intervention to minimal intervention. Risk of bias varied: eight studies had adequate sequence generation, seven had adequate clinician or outcome assessor blinding, seven had adequate allocation concealment, six had complete outcome data and six were free of selective reporting. No studies assessed the fertility primary outcomes of live birth or miscarriage. No studies reported the secondary reproductive outcome of menstrual regularity, as defined in this review.Lifestyle intervention may improve a secondary (endocrine) reproductive outcome, the free androgen index (FAI) (MD -1.11, 95% confidence interval (CI) -1.96 to -0.26, 6 RCTs, N = 204, I2 = 71%, low-quality evidence). Lifestyle intervention may reduce weight (kg) (MD -1.68 kg, 95% CI -2.66 to -0.70, 9 RCTs, N = 353, I2 = 47%, low-quality evidence). Lifestyle intervention may reduce body mass index (BMI) (kg/m2) (-0.34 kg/m2, 95% CI -0.68 to -0.01, 12 RCTs, N = 434, I2= 0%, low-quality evidence). We are uncertain of the effect of lifestyle intervention on glucose tolerance (glucose outcomes in oral glucose tolerance test) (mmol/L/minute) (SMD -0.02, 95% CI -0.38 to 0.33, 3 RCTs, N = 121, I2 = 0%, low-quality evidence). AUTHORS' CONCLUSIONS:Lifestyle intervention may improve the free androgen index (FAI), weight and BMI in women with PCOS. We are uncertain of the effect of lifestyle intervention on glucose tolerance. There were no studies that looked at the effect of lifestyle intervention on live birth, miscarriage or menstrual regularity. Most studies in this review were of low quality mainly due to high or unclear risk of bias across most domains and high heterogeneity for the FAI outcome.

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Levels of circulating insulin cell-free DNA in women with polycystic ovary syndrome - a longitudinal cohort study.

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Levels of circulating insulin cell-free DNA in women with polycystic ovary syndrome - a longitudinal cohort study.

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