Circulating miRNAs in Women with Polycystic Ovary Syndrome: A Longitudinal Cohort Study.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) often change their metabolic profile over time to decrease levels of androgens while often gaining a propensity for the development of the metabolic syndrome. Recent discoveries indicate that microRNAs (miRNAs) play a role in the development of PCOS and constitute potential biomarkers for PCOS. We aimed to identify miRNAs associated with the development of an impaired metabolic profile in women with PCOS, in a follow-up study, compared with women without PCOS. METHODS AND MATERIALS: Clinical measurements of PCOS status and metabolic disease were obtained twice 6 years apart in a cohort of 46 women with PCOS and nine controls. All participants were evaluated for degree of metabolic disease (hypertension, dyslipidemia, central obesity, and impaired glucose tolerance). MiRNA levels were measured using Taqman® Array cards of 96 pre-selected miRNAs associated with PCOS and/or metabolic disease. RESULTS: Women with PCOS decreased their levels of androgens during follow-up. Twenty-six of the miRNAs were significantly changed in circulation in women with PCOS during the follow-up, and twenty-four of them had decreased, while levels did not change in the control group. Four miRNAs were significantly different at baseline between healthy controls and women with PCOS; miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p, which were decreased in PCOS. After follow-up, miR-28-3p, miR-139-5p, and miR-376a-3p increased in PCOS women to the levels observed in healthy controls. Of these, miR-139-5p correlated with total testosterone levels (rho = 0.50, padj = 0.013), while miR-376-3p correlated significantly with the waist-hip ratio at follow-up (rho = 0.43, padj = 0.01). Predicted targets of miR-103-3p, miR-139-5p, miR-28-3p, and miR-376a-3p were enriched in pathways associated with Insulin/IGF signaling, interleukin signaling, the GNRH receptor pathways, and other signaling pathways. MiRNAs altered during follow-up in PCOS patients were enriched in pathways related to immune regulation, gonadotropin-releasing hormone signaling, tyrosine kinase signaling, and WNT signaling. CONCLUSIONS: These studies indicate that miRNAs associated with PCOS and androgen metabolism overall decrease during a 6-year follow-up, reflecting the phenotypic change in PCOS individuals towards a less hyperandrogenic profile.

Bone mass density in lean and overweight women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome is a condition characterized by hormonal and metabolic disturbances that may affect bone health. The purpose of this study was to investigate the effect of polycystic ovary syndrome on bone mineral density and to examine which clinical characteristics of the syndrome could influence bone mineral density. MATERIALS AND METHODS: We examined 183 premenopausal women: 158 women with polycystic ovary syndrome and 25 healthy age- and body mass index matched controls. Bone mineral density and body composition were investigated by whole-body dual energy X-ray absorption. Total and free testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, estradiol, fasting insulin and glucose, parathyroid hormone, calcium and 25-OH-cholecalciferol were measured. The effect of polycystic ovary syndrome on bone mineral density was analyzed by statistical two-way analysis of variance tests and multiple linear regressions for investigating the connection between bone mineral density and selected clinical parameters. RESULTS: Women with polycystic ovary syndrome had significantly lower bone density in the lumbar vertebrae L1-L4 compared to healthy controls, independently of body mass index. We found that total lean body mass was the most important associating factor for bone mineral density and these were strongly correlated throughout all regression analyzes. We found no connection between lumbar bone density and androgen status, hyperinsulinemia, estradiol or calcium homeostasis. CONCLUSIONS: Premenopausal women with polycystic ovary syndrome have lower bone mineral density in the lumbar vertebrae L1-L4 compared to healthy controls. Total lean body mass and polycystic ovary syndrome are significantly associated to this finding.

[Thromboembolic event following in vitro fertilisation].

Thromboembolic events constitute a serious complication to assisted reproductive technology, and this is a case report of thrombosis after in vitro fertilisation. A 30-year-old woman had a positive pregnancy test, but she experienced shortness of breath 12 days after oocyte retrieval. D-dimer concentration was elevated, and lung scintigraphy demonstrated an infarction. Low-molecular-weight heparin (LMWH) treatment was initiated, but one week later the patient noticed pain in her left upper extremity. Despite LMWH treatment, ultrasonic examination showed thrombosis in the left subclavian and internal jugular vein.

Atrial natriuretic peptide, copeptin and adrenomedullin levels in polycystic ovary syndrome: a case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) defined by the Rotterdam criteria does not take into account the unhealthy metabolic profile of the syndrome with increased insulin resistance (IR) and overweight favoring development of type 2 diabetes, hypertension and cardiovascular disease (CVD). We assess three vasoactive peptides associated with CVD in women with PCOS. METHOD: Plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin and mid-regional pro-adrenomedullin (MR-proADM) were measured in 98 PCOS patients and 46 age- and BMI-matched healthy women. RESULTS: We found no difference in levels of MR-proANP, copeptin and MR-proADM between the PCOS and control group. Multiple regression analyses on a combined group of PCOS and control subjects demonstrated an inverse correlation between MR-proANP and IR (measured by fasting C-peptide) and a positive correlations between copeptin and IR as well as MR-proADM and BMI. We found no association between peptide levels and different Rotterdam phenotypes. CONCLUSION: Plasma concentrations of MR-proANP, copeptin and MR-proADM were not increased in PCOS compared to age- and BMI-matched controls. Thus, these peptides cannot be used to detect increased risk of CVD in a young PCOS cohort.

Endogenous thrombin potential in polycystic ovary syndrome: the association to body mass index, insulin resistance, and inflammation.

OBJECTIVES: The objective of this study is to investigate plasma endogenous thrombin generation in four different phenotypes of polycystic ovary syndrome (PCOS) defined by Body Mass Index (BMI) and insulin resistance (IR). PCOS is diagnosed according to the Rotterdam criteria. DESIGN: Multicenter cross-sectional study. SETTING: Two major University Hospitals in the Capital region of Denmark. PATIENTS: Hundred forty-eight European women with PCOS were consecutively recruited during April 2010-February 2012. Clinical examination, blood sampling, and DEXA scan were performed. MAIN OUTCOME MEASURES: Endogenous thrombin potential (ETP). RESULTS: PCOS women with phenotype BMI > 25 + IR have increased potential of thrombin generation. ETP is associated with total body fat mass, IR, and CRP. CONCLUSIONS: Obese and insulin resistant women with PCOS have elevated level of ETP corresponding to increased risk of CVD. ETP is related to well-known CVD risk factors in PCOS but not in general to the Rotterdam criteria.

Polycystic ovary syndrome: cardiovascular risk factors according to specific phenotypes.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance. The objective of this cross-sectional study was to investigate the impact of insulin resistance and body mass index (BMI) on inflammatory and hemostatic variables associated with long-term risk of cardiovascular disease in women with PCOS. MATERIAL AND METHODS: 149 premenopausal women with PCOS were recruited consecutively from April 2010 to February 2012 at three Danish University Hospitals. The study was conducted at the Department of Gynecology and Obstetrics, Herlev University Hospital, Denmark. PCOS was diagnosed in accordance with the Rotterdam criteria and the women were classified into four phenotypes according to BMI and insulin resistance measured by the homeostasis model assessment of insulin resistance index. Body composition was determined by dual-energy X-ray absorptiometry. Main outcome measures were the biomarkers C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor antigen. RESULTS: Normal weight insulin-resistant PCOS women were characterized by abdominal obesity and elevated levels of plasma PAI-1. Overweight/obese insulin-resistant PCOS women had increased levels of both PAI-1 and CRP. Of the three Rotterdam criteria, only hyperandrogenemia was significantly associated with the hemostatic risk marker of long-term cardiovascular disease risk. CONCLUSIONS: Surrogate risk markers for cardiovascular disease are elevated in women with PCOS, especially insulin-resistant and overweight/obese women.