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.

CYP21A2 mutations in women with polycystic ovary syndrome (PCOS).

The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.

The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia.

The aim of the present study was to evaluate the impact of obesity and insulin resistance on testosterone formation from androstenedione and its contribution to biochemical hyperandrogenemia in all different phenotypic subgroups of PCOS patients. The case-control study included 1087 PCOS women and 206 regularly menstruating, ovulatory controls. The main clinical measurements included anthropometric and basal hormonal characteristics and evaluation of hyperandrogenic and insulin resistance-related features. The results were the following: In PCOS women with biochemical hyperandrogenemia, obesity significantly lowers serum A levels and increases T to A ratio. These findings were not present in PCOS women with clinical hypeandrogenemia and in normal ovulatory controls.

Peroxisome proliferator-activated receptor-γ and -δ polymorphisms in women with polycystic ovary syndrome.

The aim of the study was to examine the frequency and relationship of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ gene polymorphisms to polycystic ovary syndrome (PCOS) characteristics. We conducted a case-control study protocol, which included 183 PCOS women and 148 healthy volunteers. Genetic, clinical, hormonal, and metabolic characteristics of PCOS patients and controls were estimated and compared. Genotype and allele frequencies did not differ significantly. The Pro(12) Ala polymorphism in exon 2 of the PPAR-γ gene was found in low frequency. Regarding the polymorphism in exon 6, the T-allele carrier PCOS women had significantly lower total testosterone levels. Regarding the +294T/C polymorphism in the exon 4 of the PPAR-δ gene, the C-allele carrier PCOS women had significantly higher fasting glucose levels. In conclusion, the PPAR-γ gene polymorphisms do not appear to affect the risk for PCOS, except for the reduced testosterone levels. The +294T/C polymorphism in the exon 4 of the PPAR-δ gene seems to cause an increase in fasting glucose levels.

Genetics of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a syndrome involving defects in primary cellular control mechanisms that result in the expression of chronic anovulation and hyperandrogenism. This syndrome has been for many years one of the most controversial entities in gynecological endocrinology. Polycystic ovary syndrome has been proven to be a familial condition. Although the role of genetic factors in PCOS is strongly supported, the genes that are involved in the etiology of the syndrome have not been fully investigated until now, as well as the environmental contribution in their expression. The heterogeneity of the syndrome entertains the mystery around this condition which concerns thousands of infertile women worldwide. Some genes have shown altered expression suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling steroidogenesis, steroid hormones action, gonadotrophin action and regulation, insulin action and secretion, energy homeostasis, chronic inflammation and others. The present review of the contemporary literature constitutes an effort to present all the trends in the current research for the etiology of polycystic ovary syndrome.

Adiponectin levels in women with polycystic ovary syndrome: a systematic review and a meta-analysis.

BACKGROUND: Conflicting results regarding adiponectin levels in women with polycystic ovary syndrome (PCOS) have been reported. To evaluate adiponectin levels in PCOS, a systematic review of all studies comparing adiponectin levels in women with PCOS with healthy controls and a meta-analysis of those involving women with similar body mass index (BMI) were performed. The influence of possible effect modifiers, such as insulin resistance (IR) and testosterone, was investigated. The influence of obesity was investigated through a 'nested' meta-analysis after within-study BMI stratification and appropriate pooling. METHODS: Literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL (through June 2008), references from relevant studies and personal contact with the authors. Thirty-one studies, reporting data on 3469 subjects, were reviewed and 16 included in the main meta-analysis. RESULTS: Women with PCOS demonstrated significantly lower adiponectin values [weighted mean difference (95% confidence interval) -1.71 (-2.82 to -0.6), P < 10(-4)], yet with significant between-study heterogeneity. Lower adiponectin levels are associated with the IR observed in women with PCOS, compared with controls. IR, but not total testosterone, was found significant among biological parameters explored in the meta-regression model. Hypoadiponectinaemia was present in both lean and obese women with PCOS when compared with non-PCOS counterparts. Data on high molecular weight (HMW) adiponectin are limited (three studies). CONCLUSIONS: After controlling for BMI-related effects, adiponectin levels seem to be lower in women with PCOS compared with non-PCOS controls. Low levels of adiponectin in PCOS are probably related to IR but not to testosterone. Total adiponectin should not be used as a biomarker of PCOS severity. Further investigation is needed for HMW adiponectin levels in PCOS.

Effect of hypocaloric diet plus sibutramine treatment on hormonal and metabolic features in overweight and obese women with polycystic ovary syndrome: a randomized, 24-week study.

OBJECTIVE: To examine the effect of hypocaloric diet plus sibutramine on body composition, hormonal and metabolic parameters in overweight and obese patients with polycystic ovary syndrome (PCOS). DESIGN: Open-label, randomized study at an outpatient clinic. PATIENTS: A total of 59 overweight and obese (18-39 years old) women with PCOS. MEASUREMENTS: All patients were placed in a hypocaloric diet plus sibutramine (10 mg per day) for the first month and then on a hypocaloric diet plus sibutramine (10 mg per day, group S) or hypocaloric diet only (group D) for the subsequent 6 months. Body composition, hormonal and metabolic features and insulin sensitivity (oral glucose tolerance test, OGTT) were evaluated at baseline and at 3 and 6 months of treatment. RESULTS: Body weight reduced in both groups but the reduction was greater with sibutramine (-15.4+/-1.1 vs -11.1+/-1.9% in groups S and D, respectively, P<0.05). At 6 months, a greater percent of patients lost more than 10% of initial body weight in group S than D (81 vs 52.9%). In both groups, all women with abnormal OGTT at baseline presented normal glucose tolerance after 6 months. Free androgen index (FAI), glucose area under the curve and fasting triglyceride (TG) concentration were reduced after 6 months in group S only (P<0.05). No changes in cardiovascular risk factors, prolactin and hepatic enzymes levels were observed in both groups. CONCLUSION: A hypocaloric diet and a diet plus sibutramine both result in significant weight loss in overweight and obese women with PCOS. Patients who received sibutramine showed a greater weight loss and improvement in hyperandrogenemia and insulin sensitivity after 6 months of treatment. The amelioration of insulin resistance in this group could not be totally explained by weight loss. Total testosterone, FAI and TG levels reduction could be a possible mechanism. Finally, sibutramine increased compliance to diet and it was well tolerated from these patients.

Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system.

The pairing of the kisspeptins (KP) with the KISS1 (GPR54) receptor has received growing attention since the description of the receptor as a molecular switch for puberty. The role of KP and its receptor, GPR54, in puberty is the most exciting finding made in the field of reproductive biology since the discovery of Gonadotropin Releasing Hormone (GnRH) in 1970s. A significant body of evidence across several species now suggests that KISS1 (GPR54) activation is a critical point in the commencement of puberty, although further investigation is required to characterize the interaction between KP and GnRH cascade. Given such pivotal roles of kisspeptins and GPR54 as gatekeepers of reproductive function, and the proven ability of sex steroids to physiologically regulate this system, it is plausible that environmental compounds with ability to interfere oestrogen and/or androgen signaling (agonists or antagonists) may target the hypothalamic kiss-1/GPR54 system, thereby inducing functional alterations of the hypothalamic-pituitary-gonadal axis. Synthetic agonists targeting KISS1 (GPR54) may represent novel therapeutic agents for the treatment of hypogonadotrophic hypogonadism in some affected individuals. The diverse multifunctional nature of the KP is beginning to unravel. The unexpected role of these peptides in puberty has raised a number of important questions that remain to be answered.

Is the Y chromosome all that is required for sex determination?

The gender identity of a person is the final result of genetic, hormonal and morphologic sex. Over a long period sex determination, and, specifically, male sex determination, has been correlated to the presence of the Y chromosome, which in turn has been the karyotype signal of the testes. However, research has provided data to convince that this theory is only part of the truth. In addition to the Y chromosome, a multitude of other genes influence sex determination and are able to cause male to female sex-reversal and vice versa. It is of great interest that these genes are located in more than one autosomal chromosomes or even in the X chromosome. It has become obvious that sex determination, according to the genetic sex, is a complicated matter that not only requires the presence of Y chromosome. This fact triggered extensive research of the Y chromosome and led to great insight into its structure, origin, evolution and eventual fate in humans.

Inflammatory and endothelial markers in women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) carry a pattern of cardiovascular risk factors. Endothelial dysfunction and chronic inflammation are early findings in the atherosclerotic process. The purpose of the study was to investigate the coexistence of active inflammation markers and endothelial dysfunction in young women with PCOS, and their relationship with metabolic and hormonal abnormalities of the syndrome. MATERIALS AND METHODS: Twenty-five young women with PCOS and 25 controls of similar age and body mass index (BMI) were studied. Endothelial function was assessed by flow-mediated dilatation (FMD) on the brachial artery and smooth muscle cells injury was excluded by nitrate-induced dilatation (NID). Plasma levels of endothelin-1 (ET-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and high sensitivity C-reactive protein (hsCRP) were measured. Hormonal and metabolic profiles were determined in both groups. RESULTS: Flow-mediated dilatation (FMD) was statistically lower in PCOS (P < 0.001), whereas nitrate-induced dilatation (NID) was similar within the two groups. Polycystic ovary syndrome (PCOS) had statistically higher levels of ET-1 (P = 0.03), sICAM-1 (P = 0.01), sVCAM-1 (P = 0.02) and hsCRP (P = 0.01). Furthermore FMD was statistically higher in PCOS population with hsCRP 1 mg L(-1) when compared with PCOS population with hsCRP > 1 mg L(-1) (P = 0.02). Flow-mediated dilatation (FMD) was negatively related to hsCRP (r = -0.512, P = 0.015); ET-1 was positively related to free androgen index (r = 0.27, P = 0.05) and negatively to sex hormone-binding globulin (r = -0.465, P = 0.022); sVCAM-1 was positively related to total testosterone (r = 0.431, P = 0.036); hsCRP was positively related to BMI (r = 0.647, P = 0.001), and negatively related to FMD (r = -0.512, P = 0.015), quantitative insulin sensitivity check index (QUICKI) (r = -0.499, P = 0.018), and MATSUDA index (r = -0.445, P = 0.038). CONCLUSIONS: The present study demonstrates that endothelial dysfunction coexists and is influenced by the presence of increased serum levels of inflammation and endothelial activation markers in young women with PCOS. These parameters appear to be interrelated with hyperandrogenaemia in this insulin-resistant population.

Late pregnancy complications in polycystic ovarian syndrome.

Gestational diabetes mellitus and new-onset hypertension, which includes gestational hypertension and pre-eclampsia, are common complications of pregnancy. Many features of the insulin resistance syndrome have been associated with these conditions. These include glucose intolerance, hyperinsulinemia, hypertension, obesity, and lipid abnormalities. Other accompanying abnormalities may include elevated serum levels of leptin, TNFalpha, plasminogen activator inhibitor-1 and testosterone. The establishment of these features before the onset of gestational diabetes mellitus and hypertension in pregnancy suggests that insulin resistance or associated abnormalities may play a role in these disorders. These observations suggest that therapeutic interventions to reduce insulin resistance may lower the risk of both gestational diabetes mellitus and hypertension in pregnancy.

Anovulation and ovulation induction.

Conventional treatment of normogonadotropic anovulatory infertility is ovulation induction using the antiestrogen clomiphene citrate, followed by follicle-stimulating hormone. Multiple follicle development, associated with ovarian hyperstimulation, and multiple pregnancy remain the major complications. Cumulative singleton and multiple pregnancy rate data after different induction treatments are needed. Newer ovulation induction interventions, such as insulin-sensitizing drugs, aromatase inhibitors and laparoscopic ovarian electrocoagulation, should be compared with conventional treatments. Ovulation induction efficiency might improve if patient subgroups with altered chances for success or complications with new or conventional techniques could be identified, using multivariate prediction models based on initial screening characteristics. This would make ovulation induction more cost-effective, safe and convenient, enabling doctors to advise patients on the most effective and patient-tailored treatment strategy.

The influence of tibolone upon serum leptin levels in post-menopausal women.

OBJECTIVE: To estimate serum leptin levels in post-menopausal women, to relate these to the duration of the post-menopausal period, and to body mass index (BMI), and to assess the influence of tibolone on them. METHODS: Fifteen women (age 49-64 years) were included. Three groups were studied; I, those with normal BMI taking tibolone; II, those with a raised BMI taking tibolone, and III, a group with raised BMI not taking tibolone. Blood samples were drawn before and 1, 2, 6, 9 and 12 months after the initiation of tibolone or, in group III, after the start of the study. RESULTS: Serum leptin concentrations were high in all women with abnormal BMI. Long-term tibolone administration did not have any significant effect on serum leptin concentrations. There was no correlation between serum leptin levels and the age and the duration of post-menopausal period. There was a high positive correlation between serum leptin levels and BMI values. CONCLUSIONS: BMI values affect serum leptin concentrations but long-term tibolone administration does not seem to have any effect on serum leptin levels.