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Susanne Hahn, Manuel Backhaus, Martina Broecker-Preuss, Susanne Tan, Tiina Dietz, Rainer Kimmig, Markus Schmidt, Klaus Mann and Onno E Janssen

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.

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Matthias Möhlig, Martin O Weickert, Elham Ghadamgadai, Andrea Machlitt, Bettina Pfüller, Ayman M Arafat, Andreas F H Pfeiffer and Christof Schöfl

Objective: Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS.

Design: Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women.

Results: A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = −0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP.

Conclusions: Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.

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Alessandra Gambineri, Flaminia Fanelli, Federica Tomassoni, Alessandra Munarini, Uberto Pagotto, Ruth Andrew, Brian R Walker and Renato Pasquali

Context

Abnormal cortisol metabolism in polycystic ovary syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic–pituitary–adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.

Objective

To assess cortisol clearance and whole-body and tissue-specific activities of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) in PCOS.

Design

Case–control study.

Setting

Medical center.

Patients

A total of 20 overweight–obese unmedicated Caucasian women with PCOS, aged 18–45 years, and 20 Caucasian controls matched for age, BMI, body fat distribution, and HSD11B1 genotypes (rs846910 and rs12086634).

Main outcome measures

Cortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-[2H]4-cortisol infusion, cortisol clearance was calculated and whole-body HSD11B1 activity was assessed as the rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic HSD11B1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose HSD11B1 activity and HSD11B1 mRNA were measured, ex vivo, in biopsies.

Results

Urinary cortisol metabolite excretion, deuterated cortisol clearance, and the rate of appearance of d3-cortisol did not differ between patients with PCOS and controls. However, hepatic HSD11B1 conversion of oral cortisone to cortisol was impaired (P<0.05), whereas subcutaneous abdominal adipose tissue HSD11B1 mRNA levels and activity were increased (P<0.05) in women with PCOS when compared with controls.

Conclusions

Tissue-specific dysregulation of HSD11B1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.

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Valeria Tagliaferri, Daniela Romualdi, Maurizio Guido, Antonio Mancini, Simona De Cicco, Christian Di Florio, Valentina Immediata, Chantal Di Segni and Antonio Lanzone

Objective

To evaluate the link among thyroid function, glucose/insulin metabolism and steroid hormones in women with polycystic ovary syndrome (PCOS), and to verify if the body mass index (BMI) might influence the interplay between PCOS features and subclinical hypothyroidism (SCH).

Study design

Case–control study conducted from January to December 2014.

Methods

One-hundred fifty-four young women with PCOS, according to Rotterdam criteria, and 88 controls were enrolled in an academic research environment. Anthropometric evaluation, hormonal and lipid assays, oral glucose tolerance test (OGTT) and euglycaemic–hyperinsulinaemic clamp were performed. Hirsutism was assessed with the Ferriman–Gallwey (FG) score.

Main results

SCH was found in 14% of PCOS subjects and in 1% of controls (P < 0.01). In PCOS women, TSH levels were directly correlated with fasting glycaemia, but not with other hormonal and metabolic parameters. When PCOS patients were classified on the basis of BMI, TSH levels significantly correlated with insulin secretion, insulin resistance, DHEAS and cortisol levels in obese PCOS women. Inverse correlations were found between TSH and both oestradiol and SHBG in the same group. In nonobese PCOS patients, only waist-to-hip ratio values were correlated with TSH. The prevalence of SCH was not different between nonobese and obese PCOS groups (14 and 15% respectively). However, SCH was associated with higher levels of insulin, DHEAS, cortisol and FG score only in the obese subgroup.

Conclusions

Our data confirm that the prevalence of SCH is increased in PCOS women. The presence of SCH is associated with endocrine and metabolic imbalances of PCOS, and the excessive body weight seems to promote this interplay.

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Susanne Hahn, Uwe Haselhorst, Beate Quadbeck, Susanne Tan, Rainer Kimmig, Klaus Mann and Onno E Janssen

Objective: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level.

Design: We assessed the correlation of metabolic and endocrine parameters with leptin and sOB-R levels in 122 PCOS women (aged 27 ± 5.7 years) and 81 healthy controls (aged 25 ± 4.0 years).

Methods: Leptin and sOB-R levels were measured using ELISA kits. In addition, anthropometric variables, body fat and endocrine parameters were evaluated and a glucose tolerance test performed to assess indices of insulin resistance and glucose metabolism.

Results: In PCOS patients, no correlation was found between leptin or sOB-R and parameters of hyper-androgenism. However, as expected, body mass index (BMI), body fat, waist circumference and indices of insulin resistance were significantly correlated with leptin in PCOS subjects and controls. In a subgroup analysis of lean, overweight and obese PCOS patients, significant differences were found in leptin (29.7 ± 20.7 vs 45.4 ± 25.0 vs 67.7 ± 28.8 ng/ml, P < 0.0001) and sOB-R (8.0 ± 3.4 vs 6.4 ± 2.5 vs 5.7 ± 2.3 ng/ml, P < 0.05). Compared with BMI-matched controls, lean PCOS patients had lower sOB-R levels (8.0 ± 3.4 vs 12.7 ± 4.7 ng/ml, P < 0.0001) and higher free leptin indices (4.5 ± 3.9 vs 2.8 ± 2.2, P = 0.0285).

Conclusion: Taking into account that low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance.

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E Vassilatou, D A Vassiliadi, K Salambasis, H Lazaridou, N Koutsomitopoulos, N Kelekis, D Kassanos, D Hadjidakis and G Dimitriadis

Objective

Limited data exist concerning the presence of polycystic ovary syndrome (PCOS) in premenopausal women with nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prevalence of PCOS in overweight and obese premenopausal women with NAFLD.

Design

Prospective, observational, and cross-sectional study.

Methods

We studied 110 apparently healthy, overweight, and obese (BMI: 25.1–49.1 kg/m2) premenopausal women (age: 18–45 years) reporting no or minimal alcohol consumption for NAFLD with abdominal ultrasonography after excluding causes of secondary liver disease and for PCOS (Rotterdam criteria) with clinical examination, biochemical evaluation, and pelvic ultrasonography. Insulin resistance (IR) was assessed by homeostasis model assessment of IR (HOMA-IR), and free androgen index was calculated.

Results

NAFLD was detected in 71/110 women (64.5%). Women with NAFLD compared to women without NAFLD were more commonly diagnosed with PCOS (43.7% vs 23.1%, respectively, P=0.04), metabolic syndrome (30.2% vs 5.3%, respectively, P=0.003), and abnormal lipid profile (81.1% vs 51.3%, P=0.002). All women with abnormal glucose metabolism had NAFLD (P=0.01). Although PCOS was associated with NAFLD (OR 2.6, 95% CI: 1.1–6.2, P=0.04), in a multivariate analysis higher HOMA-IR values (OR 2.2, 95% CI: 1.1–4.4, P=0.02) and triglyceride levels (OR 1.01, 95% CI: 1.00–1.02, P=0.04) independently predicted NAFLD, after adjusting for age, BMI, and waist-to-hip ratio.

Conclusions

These findings indicate an increased prevalence of PCOS in overweight and obese premenopausal women with NAFLD, although it is not supported that the syndrome is primarily involved in NAFLD. Evaluation for PCOS may be considered in these women.

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Barbara Mlinar, Marija Pfeifer, Eda Vrtačnik-Bokal, Mojca Jensterle and Janja Marc

Objective

In polycystic ovary syndrome (PCOS), insulin resistance (IR) appears with high prevalence and represents the major cause of cardiometabolic complications. Lipin 1β regulates lipid metabolism and augments insulin sensitivity. The impact of lipin 1β expression in visceral and subcutaneous adipose tissue of PCOS patients on IR was studied for the first time.

Methods

Eighty-five PCOS patients and 44 controls were enrolled for subcutaneous tissue biopsy, of whom 25 patients and 30 controls also underwent visceral adipose tissue biopsy. Gene expression of lipin 1β was measured, together with that of peroxisome proliferator-activated receptor γ, lipoprotein lipase, hormone-sensitive lipase, adiponectin and glucose transporter 4 in subcutaneous and visceral adipose tissue. Markers of obesity, IR and PCOS were also measured.

Results

In PCOS patients, lipin 1β expression in both adipose depots was lower than in controls: 0.76 (0.67–0.84) vs 1.16 (0.90–1.43) for visceral and 0.91 (0.73–1.10) vs 1.30 (1.03–1.57) for s.c. depot (both P<10−4). The difference remained significant after adjustment for body mass index (BMI) and also when comparing only lean patients with lean controls. In PCOS patients, visceral adipose lipin 1β expression correlated negatively with homeostasis model assessment–IR (r=−0.474, P=0.017), BMI (r=−0.511, P=0.009) and waist circumference (r=−0.473, P=0.017), waist circumference remaining significant (P=0.027) in multiple regression. Subcutaneous lipin 1β expression in PCOS correlated negatively with BMI, waist circumference and plasma triglycerides, and positively with high density lipoprotein-cholesterol. Subcutaneous, but not visceral lipin 1β expression, correlated positively with the studied genes.

Conclusions

Lipin 1β appears to be involved in the pathogenesis of IR in PCOS.

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Matthias Möhlig, Joachim Spranger, Michael Ristow, Andreas F H Pfeiffer, Thilo Schill, Hans W Schlösser, Lothar Moltz, Georg Brabant and Christof Schöfl

Objective: Polycystic ovary syndrome (PCOS) is a risk factor for type 2 diabetes mellitus and screening for abnormal glucose metabolism has been recommended by an oral glucose tolerance test (OGTT). This procedure is time-consuming and inconvenient, limiting its general use. Therefore, an easy method is wanted to separate PCOS women with normal from those with potentially abnormal glucose metabolism.

Design: Simple parameters obtained from 101 consecutive PCOS patients were assessed by receiver operating curve analysis for their ability to predict abnormal glucose metabolism.

Results: Comparing discriminating parameters at defined sensitivities revealed that, assessed by homeostasis model assessment (HOMA), insulin resistance (HOMA%S) had the highest specificitiy. At a cut-off point of 73.1%, HOMA%S had a sensitivity of 95.5% and a specificity of 51.9%. Applying this cut-off separated 59 women who had a high probability of abnormal glucose metabolism from 42 women who were at low risk (less than 2.5%). Fasting insulin was the second-best parameter and had a similar specificity. A screening strategy which applies HOMA%S or fasting insulin could almost halve the number of OGTTs by directing them to those PCOS women most likely to be suffering from abnormal glucose metabolism. The negative predictive value of this strategy was 97%. The strategy was tested and confirmed in a second and independent cohort of 264 PCOS women.

Conclusions: HOMA%S, or to a lesser extent fasting insulin, appears to allow for stratified metabolic screening of PCOS women with OGTT.

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Djuro Macut, Svetozar Damjanović, Dimitrios Panidis, Nikolaos Spanos, Biljana Glišić, Milan Petakov, David Rousso, Anargyros Kourtis, Jelica Bjekić and Nataša Milić

Objective: Women with polycystic ovary syndrome (PCOS) are assumed to be at increased risk for cardiovascular diseases. This study examined the variations in oxidised low-density lipoprotein (OxLDL) concentration in relation to insulin levels in young women with PCOS.

Design: Cross-sectional clinical study in tertiary cares research hospitals. A total of 179 women with PCOS (79 overweight) and 56 age- and body mass index-matched controls were examined.

Methods: Blood samples were collected in follicular phase of the cycle for the basal glucose, total-, high-density lipoprotein-cholesterol (HDL-C) and LDL-cholesterol, OxLDL, triglycerides, apolipoprotein–A1 (Apo-A1) and B (Apo-B), lipoprotein (a), insulin, testosterone and sex hormone-binding globulin (SHBG). Homeostatic model index (HOMA) and free androgen index (FAI) were determined.

Results: Overweight and normal weight women with PCOS had higher concentrations of OxLDL than their control counterparts (P=0.007 and 0.003 respectively). Both the basal insulin (P=0.003) and HOMA values (P<0.001) were significantly higher in overweight than normal weight patients. Testosterone and FAI were higher in patients than in the respective controls (P<0.001). The only independent predictor of increased OxLDL concentration in normal weight patients was Apo-B-to-Apo-A1 ratio (P<0.001, odds ratio (OR) 6.1; 95% confidence interval (CI) 2.3–16.4), while in obese PCOS, it was total cholesterol-to-high-density lipoprotein cholesterol ratio (P<0.001, OR 2.8; 95% CI 1.6–4.9).

Conclusion: Young normal weight and overweight PCOS women have similarly increased OxLDL levels. Our results may indicate the presence of primary alteration in lipid metabolism in patients with PCOS. To answer the question whether the alteration in LDL particle size can by itself pose a higher cardiovascular risk, a careful follow-up of these women is needed.

Open access

Lina Schiffer, Punith Kempegowda, Wiebke Arlt and Michael W O’Reilly

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.