Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome.

STUDY QUESTION: What are the most relevant factors associated with non-alcoholic fatty liver disease (NAFLD) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Insulin resistance (IR) and lipid accumulation product (LAP) are independently associated with NAFLD in PCOS. WHAT IS KNOWN ALREADY: Obesity and IR are frequently present in both women with PCOS and subjects having NAFLD. The coexistence of PCOS and NAFLD might synergistically increase the risk for both type 2 diabetes (T2DM) and cardiovascular disease (CVD). LAP, calculated from waist circumference (WC) and triglycerides (TGs) concentrations [(WC-58) × TGs], has been shown to represent an integrated marker of cardiometabolic risk in women with PCOS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 600 Caucasian women diagnosed with PCOS by the Rotterdam criteria between May 2008 and May 2013. PARTICIPANTS, SETTINGS, METHODS: The study was done at the university hospitals in Belgrade, Serbia and Thessaloniki, Greece. All subjects underwent anthropometric measurements and analyses of fasting blood glucose, insulin, lipids, total testosterone and SHBG, as well as liver tests (transaminases, γ-glutamyltransaminase, total bilirubin and alkaline phosphatase). Calculations for a NAFLD liver fat score (NAFLD-LFS) (with, accordingly, determination of metabolic syndrome and testing for T2DM) as well as homeostasis model assessment of IR (HOMA-IR), LAP as a marker of visceral adiposity, and free androgen index (FAI) were performed. We evaluated the prevance of NAFLD and analyzed associations of the above variables with NAFLD. MAIN RESULTS AND THE ROLE OF CHANCE: NAFLD was more prevalent in patients with PCOS than in controls (50.6 versus 34.0%, respectively). Women with PCOS had higher readings for WC, LAP, insulin and HOMA-IR, total cholesterol and TGs than controls (P < 0.001). In PCOS women, the NAFLD-LFS significantly (P < 0.001) correlated with WC, BMI, glucose, HOMA-IR, TGs, LAP and FAI. In multivariate logistic regression, HOMA-IR and LAP were independently associated with NAFLD (P ≤ 0.001). LIMITATIONS, REASONS FOR CAUTION: A possible weakness of the study may be the absence of structural confirmation of liver status. Hovewer, liver biopsy is invasive, difficult to perform in large populations and carries some risk of complications while magnetic resonance spectroscopy does not provide any information regarding the presence of fibrosis and is not routinely available. Another possible limitation could be the measurement of total testosterone by radioimmunoassay, which can be inaccurate when determining low levels of testosterone. Finally, fewer controls than subjects in the study group could have affected the significance of the results. WIDER IMPLICATIONS OF THE FINDINGS: There is a debate on the most accurate clinical method for diagnosing liver disease as an early predictor of T2DM and CVD in general population and in PCOS women. There current study provided data on this issue from a cohort of Caucasian women with PCOS. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant by the Serbian Ministry of Science and Education (grant nos 41009 and 175032). All authors have no competing interests.

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning.