Endothelial dysfunction in PCOS: role of obesity and adipose hormones

Purpose

Polycystic ovary syndrome (PCOS) is an extremely prevalent disorder in which elevated blood markers of cardiovascular risk and altered endothelial function have been found. This study was designed to determine if abnormal carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) in young women with PCOS may be explained by insulin resistance and elevated adipocytokines.

Methods

A prospective study in 50 young women with PCOS (age: 25.2 ± 1 years; body mass index [BMI]: 28.7 ± 0.8) and 50 matched ovulatory controls (age: 25.1 ± 0.7 years; BMI: 28.5 ± 0.5) was performed. Carotid IMT, brachial FMD, and blood for fasting glucose, insulin, leptin, adiponectin and resistin were measured.

Results

PCOS, IMT was increased (P <.01), FMD was decreased (P <.01), fasting insulin was increased (P <.01), QUICKI (a marker of insulin resistance) was decreased (P <.01), and adiponectin was lower (P <.05), whereas leptin and resistin were not different compared with matched controls. Whereas BMI or waist/hip ratios did not correlate with IMT or FMD, insulin and QUICKI correlated positively and negatively with IMT (P <.01). There was a significant negative correlation between adiponectin and IMT (P <.05). These correlations were unchanged when adjusting for BMI and the correlation between IMT and adiponectin was unaffected by insulin resistance parameters.

Conclusions

These data suggest that young women with PCOS have evidence for altered endothelial function. Adverse endothelial parameters were correlated with insulin resistance and lower adiponectin. Both insulin resistance and adiponectin appear to be important parameters. It is hypothesized that the type of fat distribution may influence these factors. © 2006 Elsevier Inc. All rights reserved.     

The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome

ObjectivesAberrant circulating adipokines are considered to be related to the pathological mechanism of polycystic ovary syndrome (PCOS). This study aims to evaluate the relationship between plasma omentin-1 levels, metabolic and hormonal parameters in the setting of non-obese Chinese women with PCOS.Material and methodsThis was a case-controlled, cross-sectional study of 153 non-obese (BMI < 25 kg/m²) PCOS and 114 age-matched healthy non-obese control individuals. Levels of plasma omentin-1, fasting blood glucose, insulin and sexual hormones and ovary volume were analyzed in all subjects.ResultsPlasma omentin-1 levels of non-obese PCOS individuals were significantly lower than in healthy non-obese controls. Body Mass Index (BMI), homeostasis model of assessment for insulin resistance index (HOMA-IR), levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), LH/FSH ratio and ovary volume (OV) were significantly higher in subjects with PCOS than controls. In the HOMA-IR stratified subgroups, PCOS individuals with insulin resistance had lower omentin-1 than those without insulin resistance after BMI adjustment. Omentin-1 was negatively correlated with BMI, HOMA-IR and fasting insulin. Multiple linear regressions revealed that BMI contributed to omentin-1 levels. Ovary volume was negatively correlated to HOMA-IR but had no correlation with omentin-1.ConclusionsPlasma omentin-1 concentrations were decreased in the non-obese PCOS group. Insulin resistance could further decrease plasma omentin-1 in non-obese individuals with PCOS independent of BMI status.     

Elevated fasting insulin is associated with cardiovascular and metabolic risk in women with polycystic ovary syndrome

AimsPCOS is associated with various immediate and long term health complications. The aim of this study was to investigate the association of serum fasting insulin concentration with cardiovascular and metabolic risk factors in women with polycystic ovary syndrome.MethodsA total of 349 women, 249 women with polycystic ovary syndrome and 100 age-matched healthy controls, were recruited in this case-control study. Fasting insulin and various other biochemical, hormonal and clinical parameters were measured in all participants. The correlation of insulin with cardiometabolic risk factors was evaluated in PCOS women with normal and high serum insulin concentration.ResultsFasting Insulin, BMI, WHR, FAI, LH: FSH, HOMA, QUICKI were significantly higher in PCOS women compared with healthy controls (p < 0.01). Fasting insulin showed a positive correlation with more cardiovascular and metabolic risk factors in PCOS compared to controls. The BMI, BAI, LAP, HOMA IR, QUICKI and FAI were significantly higher (all p < 0.05) in PCOS patients with higher insulin levels than with PCOS women with normal levels.ConclusionFasting insulin is an important determinant in the pathogenesis of obesity and hyperandrogenism in PCOS. It is associated with an increased risk of cardiovascular and metabolic disorders in women with PCOS.     

Metabolic characteristics and adverse pregnancy outcomes for women with hyperglycaemia in pregnancy as a function of insulin resistance

Aim. Recent studies have shown that women with hyperglycaemia in pregnancy and insulin resistance have a greater risk of adverse pregnancy outcomes than women with normoglycaemic pregnancies. This study aimed to determine adverse pregnancy outcomes of women with hyperglycaemia in pregnancy only as a function of insulin resistance.Methods. From a prospective cohort study, we included 1,423 women with hyperglycaemia in pregnancy whose insulin resistance was evaluated using homoeostatic model assessment for insulin resistance (HOMA-IR) when care was first provided for this condition. We compared the adverse pregnancy outcomes for different tertiles of HOMA-IR (intertertile range 1.9 and 3.3).Results. Increasing HOMA-IR tertiles were positively associated with the rate of insulin therapy (tertile 1, 2 and 3: 32.7, 47.0 and 58.7%, P < 0.0001), caesarean section (23.7, 26.0 and 32.2%, respectively, P < 0.01), gestational hypertension (1.3, 2.8 and 5.4% respectively, P < 0.01), preeclampsia (1.5, 2.8 and 4.5% respectively, P < 0.05), large-for-gestational-age infant (13.3, 10.4 and 17.6% respectively, P < 0.05), and neonatal hypoglycaemia (0.8, 1.5 and 3.2% respectively, P < 0.05). Women in the 3rd HOMA-IR tertile were more likely to have insulin therapy (odds ratio 2.09 (95% interval confidence 1.61–2.71)), hypertensive disorders (2.26 (1.42–3.36)), and large-for-gestational-age infant (1.42 (1.01–1.99)) than those in the 1st and 2nd tertiles combined in multivariable logistic regression analyses adjusted for gestational age at HOMA-IR measurement, glycaemic status, age, body mass index, family history of diabetes, parity and ethnicity.Conclusion. Despite suitable care and increased rates of insulin therapy during pregnancy, higher insulin resistance in women with hyperglycaemia in pregnancy was associated with a greater risk of adverse pregnancy outcomes.     

Association of insulin resistance,insulin and leptin levels with coronary in-stent restenosis

BackgroundIn-stent restenosis remains the major limitation of coronary stent implantation. Leptin is a hormone strongly related to insulin resistance (IR). Moreover, insulin resistance and hyperinsulinemia are common in patients with coronary heart disease (CHD), each of the previous metabolic and hormonal factors might be involved in restenosis after stent implantation.ObjectiveThis study was planned to evaluate the relationship between insulin resistance, insulin, leptin levels and coronary in-stent restenosis after coronary stent implantation in non-diabetic patients with CHD and to determine their value in prediction of restenosis.Patients and methodsThe study included 48 non-diabetic CHD patients with previous successful coronary stent implantation. They were divided into two groups according to the presence of in-stent restenosis on follow-up coronary angiography (6–9 months after stent implantation). The first group was CHD patients with in-stent restenosis which included 20 patients, the second group was CHD patients without restenosis which included 28 patients. All patients were subjected to complete clinical examination including determination of body mass index (BMI), waist to hip ratio (WHR) and laboratory investigations including fasting plasma glucose (FPG), fasting plasma insulin (FP insulin), lipid profile (total cholesterol, HDL-C, LDL-C, TG), glycoselated hemoglobin (HbA1c), plasma leptin, estimation of homeostasis model assessment of IR (HOMA-IR). All subjects were submitted to OGTT with estimation of 2-h post-prandial glucose (2-hPP glucose) and sum post-prandial insulin levels (sum PP insulin). Follow-up coronary angiography was done for all patients with the estimation of minimal luminal diameter (MLD), diameter stenosis % and late lumen loss.ResultsThere was highly significant increase in each of FP insulin, sum PP insulin, HOMA-IR, leptin, diameter stenosis % and late lumen loss (P < 0.001) and a highly significant decrease of MLD (P < 0.001) in CHD patients with in-stent restenosis when compared to CHD patients without in-stent restenosis. MLD is negatively correlated to each of FP insulin (r = −0.49, P < 0.001), sum PP insulin (r = −0.60, P < 0.001) HOMA-IR (r = −0.63, P < 0.001) and leptin (r = −0.55, P < 0.001) while late lumen loss was positively correlated to each of FP insulin (r = 0.98, P < 0.001), sum PP insulin (r = 0.70, P < 0.001), HOMA-IR (r = 0.67, P < 0.001) and leptin (r = 0.72, P < 0.001). Multiple regression analysis revealed that each of FP insulin, sum PP insulin, HOMA-IR and leptin can be considered an independent predictor of in-stent restenosis (P < 0.001).ConclusionOur study revealed that insulin resistance, fasting and post-prandial hyperinsulinemia and hyperliptinemia are considered predictors of coronary in-stent restenosis. Evaluation of HOMA-IR, insulin levels after standard OGTT and leptin levels are important tools in an attempt to recognize subjects at risk of early restenosis among non-diabetic, CHD patients undergoing percutaneous coronary revascularization and stent implantation.     

Polycystic ovary syndrome is not associated with genetic variants that mark risk of type 2 diabetes

Polycystic ovary syndrome (PCOS) is a disorder of irregular menses, hyperandrogenism and/or polycystic ovary morphology. A large proportion of women with PCOS also exhibit insulin resistance, β-cell dysfunction, impaired glucose tolerance and/or type 2 diabetes (T2D). We therefore hypothesized that genetic variants that predispose to risk of T2D also result in risk of PCOS. Variants robustly associated with T2D in candidate gene or genome-wide association studies (GWAS; n = 56 SNPs from 33 loci) were genotyped in women of European ancestry with PCOS (n = 525) and controls (n = 472), aged 18–45 years. Metabolic, reproductive and anthropomorphic data were examined as a function of the T2D variants. All genetic association analyses were adjusted for age, BMI and ancestry and were reported after correction for multiple testing. There was a nominal association between variants in KCNJ11 and risk of PCOS. However, a risk score of 33 independent T2D-associated variants from GWAS was not significantly associated with PCOS. T2D variants were associated with PCOS phenotype parameters including those in THADA and WFS1 with testosterone levels, ENPP/PC1 with triglyceride levels, FTO with glucose levels and KCNJ11 with FSH levels. Diabetes risk variants are not important risk variants for PCOS.     

Differential effects of insulin sensitivity on androgens in obese women with polycystic ovary syndrome or normal ovulation

The differential effects of insulin sensitivity and adiposity on androgen concentrations in women with polycystic ovary syndrome (PCOS) are unclear. To address this issue, we divided 43 overweight women into 4 groups based on both their clinical classification (PCOS or normal) and whether they were insulin resistant (IR) or insulin sensitive (IS) by their steady-state plasma glucose concentrations. Total testosterone concentrations were significantly increased as a function of both clinical classification (PCOS vs normal, P < .0001) and steady-state plasma glucose concentration (IR vs IS, P = .002). Mean testosterone concentrations were higher in PCOS-IR compared with PCOS-IS, normal-IR, or normal-IS women (P < .005). In addition, there was a statistically significant interaction (P = .03) between clinical classification (PCOS vs normal) and insulin sensitivity (IR vs IS) for testosterone concentrations. In contrast, androstenedione concentrations were higher in women with PCOS (P = .001), irrespective of whether they were IR or IS (P = .31); and no interaction between clinical classification and insulin sensitivity was discerned (P = .34). These results indicate that both PCOS and insulin resistance independently contributed to increased total testosterone concentrations within a group of overweight/obese women. These findings are consistent with the hypothesis that the ovaries of women with PCOS are hypersensitive to the ability of insulin to increase testosterone production and that the more insulin resistant the patient, the higher the testosterone concentration. In contrast, androstenedione concentrations seem to be independent of differences in insulin resistance. Our findings emphasize the need to increase understanding of the factors that modulate ovarian androgen secretion.     

Total and high-molecular weight adiponectin in women with the polycystic ovary syndrome

Adiponectin, an adipokine with antidiabetic properties, forms multimers; and the high-molecular weight (HMW) form most closely correlates with insulin sensitivity (S_i). Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared with healthy controls and that HMW adiponectin correlates with testosterone and S_i. A cross-sectional study involving 13 women with PCOS and 13 age- and body mass index-matched healthy controls was performed. Waist-to-hip ratios (WHRs), glucose, insulin, sex hormone-binding globulin, total testosterone, and total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from sex hormone-binding globulin and total testosterone, and S_i was determined using a frequently sampled intravenous glucose tolerance test. The study's primary outcomes were differences in total and HMW adiponectin between women with PCOS and healthy control women. Total adiponectin (P < .01), HMW adiponectin (P < .01), and the ratio of HMW to total adiponectin (P = .03) were lower in women with PCOS compared with healthy women. Total and HMW adiponectin levels correlated inversely with WHR (P < .01) and free testosterone (P < .01) and positively with S_i (P < .001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of S_i. Women with PCOS have lower total and HMW adiponectin levels compared with healthy women. High-molecular weight adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.     

Insulin-like peptide 5 is associated with insulin resistance in women with polycystic ovary syndrome

AimsInsulin-like peptide 5 (INSL5) plays an important part in metabolic processes in vitro and in vivo. We hypothesized that INSL5 levels are associated with the presence of polycystic ovary syndrome (PCOS) and insulin resistance (IR).MethodsCirculating INSL5 levels were measured by an enzyme-linked immunosorbent assay in the PCOS group (n = 101) and control (n = 78) groups. The relationship between INSL5 and IR was evaluated by using regression models.ResultsThe levels of circulating INSL5 were elevated in the individuals with PCOS (P < 0.001) and significantly associated with homeostasis model assessment of insulin resistance (HOMA-IR, r = 0.434, P < 0.001; HOMA-IS, r = 0.432, P < 0.001; QUICKI, r = −0.504, P < 0.001). The subjects in the highest tertile of INSL5 levels were more likely to have PCOS (odds ratio: 12.591, 95 % confidence interval 2.616–60.605) as compared with the lowest tertile after adjustment for potential confounders. Furthermore, the multiple linear regression analyses after adjustment for confounders showed an independent association between INSL5 levels and HOMA-IR (β = 0.024, P < 0.001).ConclusionsCirculating INSL5 concentration is linked to PCOS, possibly through increased insulin resistance.     

Evaluation of insulin sensitivity status in polycystic ovarian syndrome

ObjectiveTo identify the risk arising from polycystic ovarian syndrome (PCOS) which would help the clinician to make early interventions.MethodsFasting and postprandial serum glucose and serum insulin levels were estimated in 26 cases of PCOS and 26 healthy women were selected as controls. Calculation of quantitative insulin sensitivity check index (QUICKI) in all the subjects was utilized to analyze its sensitivity and reliability. Also body mass index and waist circumference in all these subjects were measured as obesity plays a key role in the pathogenesis of PCOS.ResultsHyperglycemia was observed in 11% of the cases and hyperinsulinemia was a consistent feature in 46% of the patients. The postprandial insulin levels in cases were statistically significant (P=0.006). Sensitivity to insulin as indicated by QUICKI in the postprandial state was less in cases than in controls (P=0.13). The BMI was markedly raised in 15% and moderately raised in about 38% of the cases (P=0.024). Waist circumference was significantly raised in about 61% of the cases (>80 cm) (P<0.001).ConclusionsOur study indicates that QUICKI, BMI and waist circumference are simple, quick and may act as early markers in identifying the risks of developing metabolic syndrome. Obesity, being a consistent finding in most cases suggested its key role in the pathogenesis of PCOS.     

A specific elevation in tissue plasminogen activator antigen in women with polycystic ovarian syndrome

There is increasing evidence that elevated plasma levels of hemostatic factors [fibrinogen, factor VII, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator (t-PA) antigen] are independently linked to risk for coronary heart disease (CHD). Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for CHD and type 2 diabetes, but there are few data on hemostatic markers in women with PCOS. Seventeen women with PCOS (defined on the basis of elevated testosterone and oligomenorrhea) and 15 healthy women matched as a group for body mass index (BMI) were recruited. Insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique. Factor VIIc was determined by a clotting assay; fibrinogen was determined by nephelometry; and t-PA, D-dimer, and von Willebrand factor antigens were measured by ELISA techniques. Of these hemostatic markers, only t-PA concentration was significantly (P = 0.013) elevated in women with PCOS relative to controls. t-PA correlated with BMI in both PCOS and controls (r = 0.428, P < 0.1; and r = 0.686, P < 0.01) and inversely with the insulin sensitivity index (r = -0.590, P < 0.05; and r = -0.620, P < 0.05, respectively). After further adjustment for BMI and insulin sensitivity, there remained a significant difference in t-PA between cases and controls (P = 0.017). Together, age and insulin sensitivity explained 39% of the variance in t-PA in women with PCOS (P < 0.05). Total testosterone did not correlate significantly with t-PA in either group. We conclude that women with PCOS have significantly increased t-PA concentrations relative to women with normal menstrual rhythm and normal androgens. We suggest that elevated t-PA and dysfibrinolysis may be a factor in the increased cardiovascular morbidity seen in PCOS.     

Evidence of proatherogenic inflammation in polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have chronic low-level inflammation that can increase the risk of atherogenesis. We measured circulating proatherogenic inflammatory mediators in women with PCOS (8 lean: body mass index, 18-25 kg/m²; 8 obese: body mass index, 30-40 kg/m²) and weight-matched controls (8 lean, 8 obese). Blood samples were obtained fasting and 2 hours after glucose ingestion to measure interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), matrix metalloproteinase-2, plasminogen activator inhibitor-1 (PAI-1), and activated nuclear factor κB in mononuclear cells. Truncal fat was determined by dual-energy x-ray absorptiometry. Fasting MCP-1 levels were elevated in lean women with PCOS compared with lean controls (159.9 ± 14.1 vs 121.2 ± 5.4 pg/mL, P < .02). Hyperglycemia failed to suppress matrix metalloproteinase-2 in lean women with PCOS compared with lean controls (1.7 ± 1.2 vs −4.8 ± 1.6 pg/mL, P < .002). Among women with PCOS, obese individuals exhibited higher fasting sICAM-1 (16.1 ± 0.8 vs 10.5 ± 1.0 ng/mL, P < .03) and PAI-1 (6.1 ± 0.7 vs 3.4 ± 0.8 ng/mL, P < .03) levels. Trend analysis revealed higher (P < .005) IL-6, sICAM-1, CRP, PAI-1, systolic and diastolic blood pressures, triglycerides, fasting insulin, and homeostasis model assessment of insulin resistance index in women with PCOS compared with weight-matched controls, and the highest levels in the obese regardless of PCOS status. Fasting MCP-1 levels correlated with activated nuclear factor κB during hyperglycemia (P < .05) and androstenedione (P < .004). Truncal fat correlated with fasting IL-6 (P < .004), sICAM-1 (P < .006), CRP (P < .0009), and PAI-1 (P < .02). We conclude that both PCOS and obesity contribute to a proatherogenic state; but in women with PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.     

Incretin hormone secretion in women with polycystic ovary syndrome: roles of obesity, insulin sensitivity, and treatment with metformin

In normal subjects, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for 70% of the insulin response during a meal; but in diabetic subjects and other insulin-resistant conditions, the incretin effect is impaired. Polycystic ovary syndrome (PCOS) is associated with insulin resistance, and the pathophysiologic mechanisms behind PCOS resemble those of type 2 diabetes mellitus; therefore, women with PCOS may have alterations in the incretin hormone response. Metformin is widely used in the treatment of both type 2 diabetes mellitus and PCOS. Metformin may exert some of its effect on glucose metabolism by increasing GLP-1 biosynthesis and secretion and thereby increasing the incretin effect. The objective of the study was to measure incretin hormone secretion in women with PCOS and to evaluate the effect of metformin treatment. Cross-sectional comparison of 40 women with PCOS (19 lean and 21 obese) and 26 healthy control women (9 lean and 17 obese) and longitudinal evaluation of the effects of 8 months of metformin 1000 mg twice daily in women with PCOS were performed. Plasma concentrations of GIP and GLP-1 were determined frequently during a 75-g glucose tolerance test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp. The incretin hormone response did not differ between subjects with and without PCOS. Subgroup analysis showed lower GIP (area under the curve [AUC]) levels in obese women with PCOS compared with obese control women (P < .05) and compared with lean women with PCOS (P < .05). Metformin increased GIP (AUC) and GLP-1 (AUC) in lean women with PCOS (P < .05), and a similar trend was seen in the obese women (P = .07). The GIP secretion is attenuated in obese women with PCOS, whereas treatment with metformin increases the levels of both GIP and GLP-1 in women with PCOS.     

Insulin resistance and hyperandrogenemia independently predict nonalcoholic fatty liver disease in women with polycystic ovary syndrome

AimsTo find the prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in Asian Indian polycystic ovary syndrome (PCOS) women.Materials and methodsThis is a prospective, cross-sectional study conducted at a tertiary care hospital from South India. Sixty women fulfilling the Rotterdam (2003) criteria for PCOS were recruited for the study. All participants were evaluated with ultrasound abdomen for fatty liver and additional biochemical investigations including fasting plasma glucose, postprandial plasma glucose, serum insulin, lipid profile and liver function tests.ResultsThe mean age of the study population was 24.06 ± 5.9 (range: 15–39) years. Oligomenorrhea, hirsutism and acne were present in 58 (96.7%), 37 (61.7%) and 33 (55%) women. Mean BMI of the study population was 29.5 ± 5.28 (range: 19.95 to 45.44) kg/m². Fifty (83.3%) women were obese (BMI: ≥ 25 kg/m²). Twenty-three (38.3%) women with PCOS had NAFLD. Three women each had isolated elevation of alanine transaminase (ALT) and aspartate transaminases (AST) whereas three women had elevation of both. All women with elevated transaminases had NAFLD. By univariate analysis, factors associated with NAFLD were serum total cholesterol, serum insulin, HOMA-IR, hyperandrogenism, ALT and AST. On multiple regression analysis using linear regression, HOMA-IR and hyperandrogenemia were the only significant predictors of NAFLD.ConclusionOur study reports NAFLD in more than one third of Asian Indian women with PCOS. In addition to insulin resistance (HOMA-IR), hyperandrogenemia is an independent predictor of NAFLD in women with PCOS.     

Effects of atorvastatin on the insulin resistance in women of polycystic ovary syndrome: A systematic review and meta-analysis

Background:Atorvastatin treatment has been suggested as a therapeutic method for women with polycystic ovary syndrome (PCOS) in many clinical studies. Nonetheless, the effects of atorvastatin on insulin resistance in PCOS patients still remain controversial.Objective:The aim of this report was to evaluate the effects of atorvastatin therapy on the insulin resistance in the treatment of PCOS compared to that of placebo, in order to confer a reference for clinical practice.Methods:Randomized controlled trials (RCTs) of atorvastatin for PCOS published up to August, 2020 were searched. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was measured by the I² test. Sensitivity analysis was also carried out. The outcomes of interest were as follows: fasting glucose concentration, fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) or body mass index (BMI) value.Results:Nine RCTs with 406 participants were included. The difference of fasting glucose concentration in PCOS patients between atorvastatin group and placebo group was not statistically significant (8 trials; SMD −0.06, 95% CI −0.31 to 0.20, P = .66). PCOS patients in atorvastatin group had lower fasting insulin level than those in placebo group (7 trials; SMD −1.84, 95% CI −3.06 to −0.62, P < .003). The homeostasis model assessment of insulin resistance (HOMA-IR) value showed significant decrease in the atorvastatin therapy compared to placebo (6 trials; SMD −4.12, 95% CI −6.00 to −2.23, P < .0001). In contrast to placebo, atorvastatin therapy did not decrease the BMI value significantly in PCOS patients (7 trials; SMD 0.12, 95% CI −0.07 to 0.31, P = .22).Conclusions:Atorvastatin therapy can reduce insulin resistance in the treatment of patients with PCOS. In addition, further large-sample, multi-center RCTs are needed to identify these findings.     

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17–36 years, body mass index (BMI) 29.9 ± 0.9 kg/m², mean ± SD) and 18 control women (25–47 years, BMI 25 ± 1.7 kg/m²). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 ± 1.3 vs 12.1 ± 2.3 μg/l, mean ± SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.     

Assessment of PON1 activity and circulating TF levels in relation to BMI,testosterone, HOMA-IR,HDL-C,LDL-C,CHO, SOD activity and TAC in women with PCOS: An observational study

BackgroundPolycystic Ovary Syndrome (PCOS) is the most common female endocrinopathy among premenopausal women associated with hyperandrogenism, obesity, dyslipidemia, insulin resistance and inflammation. Oxidative stress is an important component of cardio-metabolic risk seen in PCOS.Material and methodsA total of 95 women with PCOS and 95 healthy controls were included in this observational study. Serum PON1 activity and stress markers were measured by spectrophotometric methods. Circulating TF level was measured by ELISA.ResultsWe found decreased PON1 activity and increased TF levels in women with PCOS compared to healthy controls. Fasting insulin, HOMA-IR, testosterone, LDL-C, MDA, PC and SOD activity were significantly increased whereas FGIR, QUICKI, HDLC, CAT and TAC were significantly decreased in PCOS women than controls. We observed a positive association of PON1 activity with FGIR, QUICKI, HDL-C and TAC, and its negative association was observed with LH, testosterone, fasting insulin and HOMA-IR in PCOS women. We further observed a positive association of TF with waist, waist to hip ratio, BMI, glucose 1hr, cholesterol, LDL-C, SGPT, uric acid and SOD activity in PCOS women.ConclusionsDecreased PON1 activity and raised circulating TF levels are respective indicators of pro-inflammatory and procoagulant status in PCOS women. The imbalanced oxidant/antioxidant status further supports the evidences that PCOS is an oxidant state. Further, the association of PON1 activity and TF levels with the clinical, laboratory findings and stress marker levels suggest that these factors taken together are involved in aggravating the pro-inflammatory status in PCOS women.     

Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS Results are expressed as mean ± SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 ± 0.7 vs LP 35.2 ± 1.2, P < 0.01; OC 34.7 ± l.8 vs OP 37.8 ± 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 ± 9 vs LP 179 ± 9, NS; OC 168 ± 12 vs OP 133 ± 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL₂-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38–0.62), LP 0.31 (0.26–0.44), P < 0.05; OC 0.34 (0.21–0.47), OP 0.21 (0.12–0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL₂-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.     

Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark

Objective Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS). Design Retrospective trans‐sectional study. Patients One thousand and two premenopausal women with the diagnoses hirsutism or PCOS were divided according to ethnicity: Caucasian (CA, n = 784), Middle East (ME, n = 190), Asian (n = 14) and others (n = 14). Measurements Clinical evaluation (hirsutism, BMI, waist, blood pressure), hormone analyses (testosterone, sex hormone–binding globulin, prolactin, lipids, insulin, glucose) and transvaginal ultrasound were performed. Oral glucose tolerance tests (OGTT) (n = 499) and ACTH tests (n = 434) were performed in a subgroup of patients. Results (CA vs ME women) CA women were older [32(25–37) vs 25(18–32) years, median (quartiles)] and had increased BMI compared to ME women. After correcting for age and BMI, CA women were less hirsute, but had increased testosterone levels compared to ME women. The Rotterdam criteria were fulfilled in 56% of both populations, but PCO was diagnosed in 47% CA vs 29% ME women, P < 0·01. CA women had increased blood pressure and smoked at a higher frequency (40 vs 23%), whereas area under the curve for insulin during OGTT was decreased, all P < 0·001. Prolactin levels were significantly lower in CA women compared to ME women [7(5–10) vs 9(6–12) μg/l] and were inversely associated with smoking status. Conclusion CA women had a more adverse cardiovascular profile than ME women, whereas insulin sensitivity was higher. The prevalence of the individual Rotterdam criteria differed significantly in the two study populations.     

Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome

Since an increase in tumor necrosis factor alpha (TNFalpha) expression has been associated with insulin resistance, this study was undertaken to determine the status of circulating TNFalpha and the relationship of TNFalpha with insulin levels, body weight, or both in women with polycystic ovary syndrome (PCOS). Fasting serum samples were analyzed in 34 subjects with PCOS, of whom 22 were obese (body mass index [BMI]>27 kg/m2), and in 40 normal control women, of whom 20 were obese. Women with PCOS exhibited a significantly (P<.02) higher mean serum TNFalpha concentration compared with the controls. The serum TNFalpha level and BMI were directly correlated in women with PCOS (r=.48, P<.005) and highly correlated in controls (r=.78, P<.001). When subjects were classified by body weight, the mean serum TNFalpha concentration was significantly (P<.001) elevated in normal-weight women with PCOS compared with normal-weight controls. On the other hand, mean serum TNFalpha concentrations in obese women with PCOS and obese controls were similar and significantly (P<.02) higher than in normal-weight women with PCOS. A direct correlation between serum fasting insulin and TNFalpha was evident in controls (r=.35, P<.03), but not in women with PCOS. However, in the subgroup of obese women with PCOS, fasting insulin directly correlated (r=.49, P<.03) with TNFalpha and the median fasting serum insulin concentration was significantly (P<.05) higher compared with the level in normal-weight women with PCOS and all controls. Fasting insulin and TNFalpha were no longer correlated in controls as a group and in obese women with PCOS when controlling for body weight. Serum TNFalpha did not correlate with luteinizing hormone (LH), testosterone (T), or dehydroepiandrosterone sulfate (DHEAS) in women with PCOS. However, serum insulin was significantly correlated (r=.49, P<.0004) with T and the BMI exhibited a trend for correlation with serum T (r=.33, P=.05) in women with PCOS. Finally, the mean serum LH concentration was significantly (P<.02) higher in normal-weight women with PCOS versus obese women with PCOS, and serum LH levels exhibited a trend for an inverse correlation with the BMI (r=.31, P=.09) in women with PCOS. We conclude that (1) serum TNFalpha is increased in normal-weight women with PCOS and is even higher in obese individuals regardless of whether they have PCOS; (2) factors other than obesity are the cause of elevated serum TNFalpha in normal-weight women with PCOS; and (3) whereas increased circulating TNFalpha may mediate insulin resistance in obesity, which may in turn promote hyperandrogenism in obese women with PCOS, it remains to be demonstrated whether this is also the case in normal-weight women with PCOS.