Albrecht Giuliani

Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome

OBJECTIVES Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of the metabolic syndrome (MS). Hence, the aim of our study was to investigate the association of 25(OH)D levels and the components of the MS in PCOS women. METHODS 25(OH)D levels were measured by means of ELISA in 206 women affected by PCOS. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS The prevalence of insufficient 25(OH)D levels (<30 ng/ml) was 72.8% in women with PCOS. PCOS women with the MS had lower 25(OH)D levels than PCOS women without these features (17.3 vs 25.8 ng/ml respectively; P<0.05). In multivariate regression analysis including 25(OH)D, season, body mass index (BMI), and age, 25(OH)D and BMI were independent predictors of homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI; P<0.05 for all). In binary logistic regression analyses, 25(OH)D (OR 0.86, P=0.019) and BMI (OR 1.28, P<0.001) were independent predictors of the MS in PCOS women. We found significantly negative correlations of 25(OH)D levels with BMI, waist circumference, waist-to-hip ratio, systolic and diastolic blood pressure, fasting and stimulated glucose, area under the glucose response curve, fasting insulin, HOMA-IR, HOMA-beta, triglycerides, and quotient total cholesterol/high-density lipoprotein (HDL) and positive correlations of 25(OH)D levels with QUICKI and HDL (P<0.05 for all). CONCLUSION We demonstrate that low 25(OH)D levels are associated with features of the MS in PCOS women. Large intervention trials are warranted to evaluate the effect of vitamin D supplementation on metabolic disturbances in PCOS women.

Association of FTO gene with hyperandrogenemia and metabolic parameters in women with polycystic ovary syndrome

Variants in the fat mass and obesity-associated gene (FTO) are associated with obesity and type 2 diabetes mellitus. Women with polycystic ovary syndrome (PCOS) are frequently affected by obesity and impaired glucose tolerance. The aim of this study was to investigate the impact of FTO variants (rs9939609) on metabolic and endocrine parameters in PCOS women. We genotyped the single nucleotide polymorphism rs9939609 (T/A) in 288 PCOS women and performed metabolic and hormonal measurements, oral glucose tolerance test, hirsutism score, and lipometry. The A/T + A/A genotype showed an increased prevalence in overweight/obese PCOS patients (odds ratio [OR] = 1.91, P = .028) and in PCOS women with impaired glucose tolerance (OR = 3.23, P = .009). The A allele was associated with a significant increase in free testosterone (P = .042), weight (P = .024), body mass index (P = .011), 2-hour glucose (P = .047), 1-hour insulin (P = .032), and AUCins (area under the curve insulin) (P = .038). In a logistic regression analysis, the A allele was associated with free testosterone (P = .025; OR = 1.54; 95% confidence interval, 1.06-2.25; B = 0.86). Total body fat (percentage) (P = .016), total fat mass (P = .013), visceral adipose tissue mass (P = .044), and subcutaneous fat mass (P = .011) were significantly increased in PCOS women carrying the A allele. We demonstrated that variants within the FTO gene influence hyperandrogenemia and anthropometric parameters in women with PCOS, indicating an important role of FTO variants not only in obesity and diabetes but also in hyperandrogenism in women with PCOS.

The Lipid Accumulation Product Is Associated with Impaired Glucose Tolerance in PCOS Women

BACKGROUND Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances. Lipid accumulation product (LAP) is an emerging cardiovascular risk factor. We aimed to investigate the association of LAP with impaired glucose tolerance (IGT) in PCOS and control women. METHODS The LAP was calculated as [waist circumference (centimeters) - 58] × [triglycerides (millimoles per liter)] in 392 PCOS and 140 body mass index (BMI)-matched control women within the same age range. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS PCOS women had significantly higher LAP levels than control women in age-adjusted analyses [22.2 (10.9-46.2) and 18.2 (10.7-36.3), respectively, P = 0.001). In PCOS and control women, age, BMI, blood pressure, fasting and stimulated glucose, fasting and stimulated insulin, and free testosterone progressively increased, whereas SHBG decreased across LAP quartiles. In PCOS and control women, receiver operating characteristic curve analysis revealed that the best cutoff value for LAP to define the presence of IGT was 44.1 and 41.8, respectively [sensitivity 79.5%, specificity 80.5%, and area under the curve (AUC) 0.86 and sensitivity 82.3%, specificity 90.5%, and AUC 0.86, respectively]. In PCOS and control women, receiver operating characteristic curve analyses for BMI (0.77 and 0.54, respectively) and waist circumference (0.80 and 0.72, respectively) to define IGT revealed lower AUC. Odds ratios for IGT for PCOS women in the highest LAP, BMI, and waist-to-hip ratio quartile were 41.81 (5.52-316.54), 10.24 (2.94-35.63), and 18.45 (4.19-81.30), respectively, when compared with PCOS women in the lowest LAP, BMI, and WHR quartile, respectively. CONCLUSION LAP is an easily obtainable and cheap marker associated with IGT in PCOS and control women.

Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women

In a recent genome-wide association study investigating Han Chinese PCOS women 3 loci that are strongly associated with PCOS were identified on chromosome 2p16.3 (rs13405728), 2p21 (rs13429458), and 9q33.3 (rs2479106). The aim of the study was to investigate the impact of rs13405728, rs13429458, and rs2479106 variants on PCOS susceptibility in a Caucasian cohort of PCOS and control women. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed in 545 PCOS and 317 control women. The rs13405728, rs13429458, and rs2479106 polymorphisms were genotyped. There was no significant difference in genotype frequencies of rs13405728 and rs13429458 variants between PCOS and controls. There was a trend towards an association of the rs2479106 variant with PCOS susceptibility (p=0.053). PCOS women with the rs2479106 GG genotype had significantly higher WHR than PCOS women carrying the AG and AA genotype (p=0.034 and p=0.020, respectively). Moreover, QChol/HDL and LDL levels were significantly higher in PCOS women carrying the rs2479106 GG genotype when compared to those carrying the AA genotype (p=0.024 and p=0.035, respectively). PCOS women carrying the G allele of rs13405728 had significantly higher AUCgluc, glucose-30 min, and AUCins levels than those carrying the AA genotype (p=0.039, p=0.047, and p=0.044, respectively). In PCOS women, rs13405728 genotypes are associated with glucose and insulin metabolism. Moreover, rs2479106 genotypes were associated with increased WHR levels and an adverse serum lipid profile. Further, we observed a trend towards decreased PCOS susceptibility within carriers of the rs2479106 G-allele. Further studies in large Caucasian PCOS cohorts are warranted to confirm our findings.

Assessment of glucose metabolism in polycystic ovary syndrome: HbA1c or fasting glucose compared with the oral glucose tolerance test as a screening method

STUDY QUESTION Are HbA1c and fasting glucose (FG) useful in predicting the presence of prediabetes and type 2 diabetes (T2DM) in a large cohort of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER HbA1c and FG are not suitable as screening tools for prediabetes in a large cohort of PCOS women but do show a good level of agreement with T2DM. WHAT IS KNOWN ALREADY Women with PCOS have an increased risk of prediabetes and T2DM. As performing an oral glucose tolerance test (OGTT) is time consuming, HbA1c and FG have been suggested as screening tools for prediabetes and T2DM. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of 671 women with PCOS conducted from 2006 to 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was carried out at the endocrinological outpatient department of the Medical University of Graz, Austria. We performed 75 g 2-h OGTTs and measured HbA1c in 671 women with PCOS aged 16-45 years with a median BMI of 24.2 (21.3-30.1) kg/m². PCOS was defined according to the Rotterdam criteria. Prediabetes (FG 100-125 mg/dl and/or 2-h glucose 140-199 mg/dl and/or HbA1c 5.7-6.4%) and T2DM (FG ≥ 126 mg/dl and/or 2-h glucose ≥200 mg/dl and/or HbA1c ≥ 6.5%) were diagnosed according to the American Diabetes Association (ADA) criteria. Levels of agreement between different definitions were analyzed using κ-index. MAIN RESULTS AND THE ROLE OF CHANCE According to the ADA criteria, we found prediabetes and T2DM in 12.8% (n = 76) and 1.5% (n = 9) of PCOS women, respectively. When using elevated HbA1c (5.7-6.4%) for defining prediabetes, 19 (3.2%) of all PCOS women had prediabetes with a κ-index of 0.36. When using elevated FG (100-125 mg/dl) for defining prediabetes, 31 (5.2%) of all the PCOS women were diagnosed with prediabetes with a κ-index of 0.05. Further, elevated HbA1c (≥6.5% defining T2DM) was found in six (0.9%) PCOS women (κ-index 0.80), and elevated FG (≥126 mg/dl diagnosing T2DM) was found in seven PCOS women (1%; κ-index 0.82). LIMITATIONS, REASONS FOR CAUTION Our results are limited to an Austrian cohort of PCOS women diagnosed by Rotterdam criteria with a median BMI in the normal weight range. WIDER IMPLICATIONS OF THE FINDINGS Our results are in line with results from previous smaller PCOS cohorts. Our findings do not support the recommendation that FG or HbA1c can be used for the screening of prediabetes in women with PCOS. For such women, OGTT should be performed for screening of prediabetes. Whether this finding is generalizable to other cohorts remains to be determined in further studies.

Low fetal oxygen saturation at birth and acidosis.

Objective To measure umbilical cord blood oxygen saturation, to calculate preductal oxygen saturation at birth, and to assess its predictive value for acidosis. Methods Umbilical cord blood samples of 1537 live-born singleton neonates were analyzed. Oxygen saturation was measured by spectrophotometry; pH and base excess were measured by a pH and blood gas analyzer. Preductal oxygen saturation was calculated with an empirical equation. Acidosis was defined as 2 standard deviations (SDs) below the mean of umbilical artery (UA) pH or base excess (7.09 and −10.50 mmol/L, respectively). The predictive value for acidosis of UA and umbilical vein (UV) oxygen saturation and calculated preductal oxygen saturation was determined with receiver operating characteristic curves. Results The mean values (±SD) of UV, UA, and calculated preductal oxygen saturation were 52 ± 18%, 26 ± 17%, and 31 ± 16%, respectively. Forty-seven neonates had UA pH less than 7.09 and 60 had UA base excess less than −10.50 mmol/L. The UV, UA, and calculated preductal oxygen saturation showed considerably weaker relations to UA base excess (multiple r2 = .056, .003, and .017, respectively; P < .001) than to UA pH (multiple r2 = .112, .126, and .148, respectively; P < .001). Receiver operating characteristic areas under the curve were higher when predicting low pH compared with low base excess (for UV, UA, and calculated preductal oxygen saturation: 0.716 versus 0.699, 0.747 versus 0.586, and 0.765 versus 0.628, respectively). The difference was significant for UA oxygen saturation (P < .05). All tests showed high sensitivity and negative predictive values, but low specificity and positive predictive values. Conclusion Low fetal oxygen saturation measured at birth seemed to be associated with low fetal pH and base excess values, but its predictive value for acidosis in an unselected population was limited, particularly if acidosis was metabolic.

Fatty liver index in polycystic ovary syndrome.

INTRODUCTION Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances and might be affected by hepatic steatosis. The fatty liver index (FLI) was developed as a simple and accurate predictor of hepatic steatosis. We aimed to analyze the association of FLI with endocrine and metabolic parameters in a cohort of PCOS and control women. METHODS FLI was calculated using body mass index (BMI), waist circumference, triglycerides, and gamma-glutamyl transferase in 611 PCOS and 139 BMI-matched control women within the same age range. Elevated FLI was defined as >60. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS PCOS women had significantly higher FLI levels than control women in age-adjusted analyses (11.4 (4.3-48.8) and 8.8 (3.9-35.0), respectively, P=0.001), whereas fibrosis indices were similar (aspartate amino transferase-to-platelet ratio index) or lower (FIB-4) respectively. In binary logistic regression analysis adjusted for age, odds ratio (OR) for elevated FLI was 2.52 (1.31-4.85), P=0.006, for PCOS women when compared with controls. PCOS women with high FLI levels had an adverse anthropometric, metabolic, and endocrine risk profile. The prevalence of elevated FLI was 88.7% in PCOS women with metabolic syndrome (MS) and 11.3% in PCOS women without MS (P<0.001). In control women, elevated FLI was present in 66.7% of women with MS and 30.8% of women without MS. CONCLUSION High FLI levels are a common finding in obese PCOS women and are closely linked to MS. FLI calculation might be a useful tool for identifying PCOS patients at high risk for metabolic and hepatic disturbances.

Controlled ovarian hyperstimulation in assisted reproduction: effect on the immune system

OBJECTIVE To determine how controlled ovarian hyperstimulation (COH) in assisted reproduction affects the immune system. DESIGN A prospective, nonrandomized, case-control study. SETTING Academic research setting. PATIENT(S) Women with regular menstrual cycles undergoing COH in an assisted reproduction program. INTERVENTION(S) Blood samples were collected in the early and late follicular phase, at the time of ovulation, and in the luteal phase during a natural cycle, and at four times during the next cycle, which included COH and IVF. MAIN OUTCOME MEASURE(S) Lymphocyte subpopulations and the differential blood count. RESULT(S) In the natural cycles, a significant increase in the total numbers of lymphocytes, B cells, natural killer cells, and CD3+HLADR+ cells was observed in the late follicular phase, whereas the T helper/T suppressor cell ratio declined. In the hyperstimulated cycles, increases were seen in the total numbers of leukocytes and neutrophils on the day of hCG administration; the number of lymphocytes, monocytes, and neutrophils was increased on the day of oocyte retrieval, and the total number of leukocytes and neutrophils increased during the luteal phase. CONCLUSION(S) Controlled ovarian hyperstimulation with hMG and simultaneous administration of a GnRH antagonist did not affect the immune system.

Evaluation of Risk Profiles by Subcutaneous Adipose Tissue Topography in Obese Juveniles

Objective: To compare subcutaneous adipose tissue topography (SAT‐top) in obese juveniles with age‐matched normal‐weight controls.

Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype.

Objective To evaluate the association between androstenedione, testosterone, and free testosterone and metabolic disturbances in polycystic ovary syndrome. Methods We analyzed the association between androstenedione, testosterone, and free testosterone and metabolic parameters in a cross-sectional study including 706 polycystic ovary syndrome and 140 BMI-matched healthy women. Polycystic ovary syndrome women were categorized into 4 groups: normal androstenedione and normal free testosterone (NA/NFT), elevated androstenedione and normal free testosterone (HA/NFT), normal androstenedione and elevated free testosterone (NA/HFT), elevated androstenedione and free testosterone (HA/HFT). Results Polycystic ovary syndrome women with elevated free testosterone levels (HA/HFT and NA/HFT) have an adverse metabolic profile including 2 h glucose, HbA1c, fasting and 2 h insulin, area under the insulin response curve, insulin resistance, insulin sensitivity index (Matsuda), triglycerides, total and high density lipoprotein cholesterol levels compared to NA/NFT (p<0.05 for all age- and BMI-adjusted analyses). In binary logistic regression analysis adjusted for age and BMI, odds ratio for insulin resistance was 2.78 (1.34–5.75, p = 0.006) for polycystic ovary syndrome women with HA/HFT compared to NA/NFT. We found no significantly increased risk of metabolic disorders in polycystic ovary syndrome women with HA/NFT. In multiple linear regression analyses (age- and BMI-adjusted), we found a significant negative association between androstenedione/free testosterone-ratio and area under the insulin response curve, insulin resistance, and total cholesterol/high density lipoprotein cholesterol-ratio and a positive association with Matsuda-index, and high density lipoprotein cholesterol (p<0.05 for all). Conclusions Polycystic ovary syndrome women with elevated free testosterone levels but not with isolated androstenedione elevation have an adverse metabolic phenotype. Further, a higher androstenedione/free testosterone-ratio was independently associated with a beneficial metabolic profile.