Susanne Hahn

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance

OBJECTIVE Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR. DESIGN The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities. RESULTS In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects. CONCLUSION Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.

The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome.

Background  Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear.

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).

BackgroundThe polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS.MethodsWe conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4).ResultsThe FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously.ConclusionThe stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.

Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome.

Abstract Background: One of the main criteria to establish a diagnosis of polycystic ovary syndrome (PCOS) is hyperandrogenemia. Recent observations suggest that total testosterone may not be a sensitive marker for the detection of androgen excess. The aim of the present study was to compare the value of different androgen determinations for diagnosis of PCOS. Methods: Untreated PCOS patients (n=133; mean age 28 years) and healthy control women (n=54; mean age 28 years) were included in the study. Measurements of total testosterone and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstendione, dehydroepiandrosterone sulfate (DHEAS) and albumin were performed. In addition, the free androgen index (FAI), free and bioavailable testosterone were calculated. Clinical signs of hyperandrogenism were evaluated by physical examination. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the sensitivity and specificity of different androgen determinations to detect PCOS, defined as clinical hyperandrogenism and irregular cycles compatible with the National Institutes of Health criteria of chronic anovulation and clinical or biochemical hyperandrogenism. Results: All biochemical parameters of hyperandrogenism were significantly higher in PCOS patients than in controls (all p<0.0001). The highest AUC-ROC was found for bioavailable testosterone (0.852) followed by FAI (0.847) and free testosterone (0.837). Lower AUC-ROC was found for SHBG, total testosterone and androstendione (0.765, 0.799 and 0.706, respectively). When FAI=4.97 was taken as a cutoff value, sensitivity was 71.4% and specificity was 85.2%. A cutoff of 0.78 nmol/L for bioavailable testosterone had even higher sensitivity of 75.9%, but slightly lower specificity of 83.3%. FAI and bioavailable testosterone correlated significantly (all p<0.05) with total testosterone, androstendione, LH/FSH ratio and DHEAS. In addition, free testosterone, bioavailable testosterone and FAI correlated significantly with hirsutism scores, and ovarian volume and follicle count. Conclusions: ROC analysis provided evidence that calculated testosterone indices (bioavailable testosterone, FAI, free testosterone) are useful parameters for the discrimination of PCOS patients and healthy controls. Clin Chem Lab Med 2007;45:202–7.

Retinol-binding protein 4 levels are elevated in polycystic ovary syndrome women with obesity and impaired glucose metabolism

OBJECTIVE Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4), a new fat-derived adipokine, has been described to be elevated in obesity and type 2 diabetes. The aim of the present study was to investigate whether serum RBP4 levels are correlated with metabolic parameters, indices of insulin resistance, and endocrine variables in German PCOS women. DESIGN We assessed the correlation between metabolic and endocrine parameters with RBP4 levels in 200 PCOS patients and 64 healthy controls. METHODS Serum RBP4 was measured by enzyme-linked immunosorbent assay (Immundiagnostik AG, Bensheim, Germany). In addition, anthropometric variables, clinical signs of hyperandrogenism, and body fat were evaluated, and a glucose tolerance test was performed to assess parameters of insulin resistance and glucose metabolism. RESULTS Taking the entire PCOS cohort, RBP4 levels were positively correlated with body mass index (BMI), body fat, waist circumference, fasting glucose, and area under the curve for glucose (all P<0.05), but not with indices of insulin resistance. On the other hand, PCOS women with impaired glucose metabolism had higher RBP4 levels than PCOS women with normal glucose metabolism (median 30.6, range 23.3-73.9 versus median 26.3, range 6.4-61.4, P<0.05). Furthermore, no differences were found in RBP4 levels between lean PCOS women and BMI-matched healthy controls. CONCLUSION In German PCOS women, serum RBP4 levels are associated with obesity and parameters of glucose metabolism but not with PCOS per se.

Apoptotic Markers Indicate Nonalcoholic Steatohepatitis in Polycystic Ovary Syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement. METHODS In 192 PCOS patients [age, 29.0 +/- 6.7 yr; body mass index (BMI), 31.5 +/- 8.2 kg/m(2)] and 73 age-matched controls (age, 28.6 +/- 8.0 yr; BMI, 24.1 +/- 4.6 kg/m(2)), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only. RESULTS M30 levels were significantly elevated in PCOS patients after correction for BMI (304.7 +/- 223.1 vs. 86.3 +/- 165.6 U/liter; P < 0.001). M30 correlated significantly with BMI, AUCI, glucose secretion, low-density lipoprotein, low high-density lipoprotein, and free androgen index. AUCI turned out to be the only independent M30-determining factor in the multiple regression analysis with an effect size of 7.9%. Fifty-one of 186 (27.4%) PCOS patients showed M30 levels of at least 395 U/liter, indicating NASH. CONCLUSION These data demonstrate elevation of apoptotic cell death, its correlation with IR, and a high prevalence of NASH in PCOS patients. Given this high prevalence, PCOS may be a risk factor for progressive hepatic sequelae. Incidence data are of strong interest.

Maladaptive Coping With Illness in Women With Polycystic Ovary Syndrome

OBJECTIVE To investigate associations between active and passive coping, psychiatric symptoms of depression and anxiety, and quality of life in women with polycystic ovary syndrome (PCOS). To assess the relative contribution of these coping strategies to reduced quality of life in an attempt to clarify the possible relevance of coping for impaired psychosocial well-being in PCOS. DESIGN Internet-based survey. PARTICIPANTS 448 German women with PCOS. METHODS Coping (Freiburg Questionnaire of Coping-with-Illness), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), and quality of life (Short Form 12 Health Survey [SF-12]) were assessed in an Internet-based survey. Correlation and regression analyses were conducted. RESULTS In women with PCOS, passive coping was significantly associated with greater anxiety (r= .65; p < .001), depression (r= .61; p < .001), and reduced psychological quality of life (r=-.64, p < .001). In stepwise multiple regression analyses, passive coping, together with depression, anxiety and body mass index (BMI), explained 50.1% of the SF-12 psychological sum score, while active coping did not enter any regression model. CONCLUSION Data suggested that faced with the diagnosis of PCOS, passive coping may constitute a maladaptive strategy associated with anxiety and depression symptoms and compromised quality of life. Hence, efforts to incorporate psychosocial aspects into counselling and care for women with PCOS should take coping strategies into consideration. Nurses and other health care providers may help to improve coping strategies through education and psychosocial support in women with PCOS.

Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants.

The Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in premenopausal women and is associated with features of the insulin resistance syndrome, altered glucose homeostasis, and central obesity. Inflammation appears to be a link between obesity and insulin resistance, because adipose tissue is one major source of proinflammatory cytokines. Since peroxisome proliferator-activated receptor (PPAR)gamma affects adipocyte differentiation as well as insulin sensitivity, we investigated whether the levels of proinflammatory factors in PCOS patients are related to sequence variations of the PPAR gamma gene. Proinflammatory cytokine levels, i.e. IL-1 beta, IL-6, IL-7, IL-8, IL-17 and TNFalpha, were evaluated in PCOS patients (n=21) in comparison to obese controls (n=120). Next to this the complete coding sequence of the PPAR gamma gene was investigated by resequencing all probands. We show that the levels of IL-8 and IL-17 were unchanged, IL-1 beta, IL-6 and TNFalpha were elevated and the level of IL-7 was decreased in PCOS patients compared to obese controls. Sequence analyses of the PPAR gamma gene indicated that neither the common polymorphisms P12A or H478 H, nor novel polymorphisms (E79Q, V32G, -39 T>C, c.480 +33 t > g,) or unique sequence variations (S22S, A23A, T41A, S226C, K272 T, I484I, c.819 +24 a>c) detected in this investigation revealed evidence for a direct association of PPAR gamma with altered IL-7, IL-1beta, IL-6 and TNFalpha levels in PCOS patients. So, alterations in inflammatory serum markers appear to be a feature of PCOS per se, and are independent of PPAR gamma variants.

A functional GNAQ promoter haplotype is associated with altered Gq expression and with insulin resistance and obesity in women with polycystic ovary syndrome

Objectives The G-protein Gq, encoded by GNAQ, is involved in glucose metabolism. The GNAQ promoter harbours three polymorphisms. The TT(−695/−694)GC polymorphism was already shown to affect Gq transcription. Accordingly, we (i) characterized the GNAQ promoter polymorphisms G(−173)A and G(−168)A, (ii) investigated potential influences upon the TT(−695/−694)GC polymorphism and (iii) studied the associations with metabolic abnormalities in polycystic ovary syndrome (PCOS). Methods Characterization of the polymorphisms was performed with electrophoretic mobility shift assays and reporter assays. Inhibition of lipolysis and Gq expression were measured in adipocytes isolated from female mammary tissue. We genotyped 266 healthy Caucasians, 265 women with PCOS, and 293 healthy, age-matched female controls to associate GNAQ promoter polymorphisms and haplotypes with anthropometric and metabolic variables. Results The A(−168) allele was associated with significantly decreased transcriptional activity and altered transcription factor binding, whereas the G(−173)A polymorphism appeared functionally silent. Linkage and haplotype frequencies analysis resulted in four common haplotypes. In adipose tissue, a 44% higher Gq mRNA concentration was observed in homozygous GC(−695/−694)-G(−168) haplotypes compared with homozygous TT(−695/−694)-G(−168) haplotypes (P=0.046). This was associated with increased insulin inhibition of lipolysis in isolated adipocytes. In PCOS patients, the homozygous GC-G haplotype was associated with decreased insulin resistance and body mass index (BMI) compared with the homozygous TT-G haplotype (homeostatic model assessment of insulin resistance: 3.4±0.4 vs. 5.6±0.7 mmol/l×mmol/l2, P=0.001; fasting insulin: 86.6±11.9 vs. 128.8±16.5 pmol/l, P=0.003; BMI: 29.3±1.2 vs. 33.9±1.3 kg/m2, P=0.002). No association with BMI was found in healthy women. Conclusion G(−168)A is functionally relevant and in linkage with TT(−695/−694)GC. GNAQ promoter diplotypes are associated with insulin resistance and obesity in PCOS.

Genetic variations in SREBP-1 and LXRα are not directly associated to PCOS but contribute to the physiological specifics of the syndrome

The polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder consisting of reproductive disturbances associated with all aspects of the metabolic syndrome and genetic components in the pathology of this complex disease is very likely. Accordingly, variations in single genes might affect specific features of PCOS and thereby help to define different subgroups. SREBP-1 or LXRα have been shown to be genetically linked to lipid metabolism or insulin sensitivity. As these are two major aspects of the PCOS phenotype, we evaluated both genes in a cohort of 153 PCOS patients. Analyses of both genes revealed in SREBF-1, i.e. SREBP-1a and SREBP-1c, not any variation and in the LXRα gene no novel sequence variations. Common variants of LXRα (rs2279238:G; all:0.8658; PCOS:0.8627; controls: 0.8686 or A: all:0.13412; PCOS:0.1373; controls:0.1314; (OR (95% CI) 0.9508 (0.4226–2.1385); rs11039155: G: all:0.8767; PCOS:0.8663; controls:0.8857 and A all:0.1233; PCOS:0.1337; controls:0.1143; (OR (95% CI) 0.8383 (0.3618–1.9371)) were also not directly associated to PCOS. Combined analyses of both polymorphism revealed that there was no difference of distribution between the groups. In contrast, analyses of the impact of these polymorphisms on metabolic parameters of the syndrome indicated significant differences related to genotypes. The data indicated that rs11039155 increases metabolic risk, whereas rs2279238 has a protective effect on the overall metabolic risk. The investigation of the PCOS group presented indicates that the combined analyses of variations in putative candidate genes allowed a genotype-phenotype correlation for metabolic features.