The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women

OBJECTIVE To investigate the basal levels of gonadotrophins and sex steroids, with special reference to the effects of obesity and body fat distribution, In premenopausal women, both those with polycystic ovary syndrome (PCOS) and those with normal ovaries and regular menstrual cycles. DESIGN Cross-sectional study. The separate effects of obesity (and body fat distribution and fasting Insulin levels) and PCOS on endocrine variables were evaluated by means of analysis of covariance. PATIENTS Sixty-seven women with anovulatory menstrual cycles and polycystic ovaries according to ultrasonography and 59 women with normal ovaries and regular cycles, both groups covering a wide range of body mass index (BMI, PCOS, 17·6-37·4, mean 25·7 kg/m²; controls, 18·8-40·9, mean 25·1 kg/m²). MEASUREMENTS Serum levels of gonadotrophins, sex steroid hormones, prolactin and GH obtained in the early follicular phase in the controls, fasting insulin levels, anthropometric measures (BMI, skinfolds, waist hip ratio). RESULTS Mean serum concentrations of LH, andro-stenedione, testosterone, the free androgen index (FAI; all P < 0·0001) and DHEAS (P < 0·01) were higher, and serum FSH (P < 0·01) and serum SHBG levels lower (P < 0·0001), in the PCOS group than in the controls. Women with PCOS had a more pronounced upper body fat distribution and higher fasting insulin levels than the controls. Independent of PCOS, BMI was positlvely associated with serum levels of FSH (P < 0·001) and negatively with levels of LH (P < 0·05), LH/FSH ratio (P < 0·0001), SHBG (P < 0·0001) and androstenedione (P < 0·01), whereas for levels of testosterone, FAI and DHEAS the impact of obesity differed significantly between the groups. Thus, in the PCOS group, testosterone levels (P < 0·05) and the FAI (P < 0·001) were positively associated with BMI, whereas they were constant throughout the entire range of BMI in the controls. DHEAS levels were positively associated with BMI in the PCOS group (P < 0·05) and negatively in the controls (P < 0·01). Measures of upper body fat were related to testosterone and FAI levels, independent of BMI. CONCLUSIONS Lower FSH levels were found in women with PCOS than during the early follicular phase of normally ovulating women, suggesting a role in anovulation in PCOS. Obesity itself exerted effects on endocrine variables, with the net result of a reduced LHIFSH ratio and lower serum levels of androstenedione and SHBG in both groups; obesity was associated with increased levels of DHEAS, testosterone and FAI exclusively in the women with PCOS. The results underline the endocrine impact of obesity and body fat distribution and the necessity of applying reference values of BMI matched subjects when establishing the endocrine profile of women with PCOS.     

The impact of intensified exercise training on insulin resistance and fitness in overweight and obese women with and without polycystic ovary syndrome

Objective To evaluate mechanisms of insulin resistance (IR) in overweight and obese women with and without polycystic ovary syndrome (PCOS) and explore relationships between IR, fitness and body mass index (BMI) at baseline and following exercise intervention. Design Prospective controlled intensified exercise intervention study. Patients A total of 20 overweight (BMI > 25 kg/m²) and obese (>30 kg/m²), reproductive‐aged PCOS women and 13 non‐PCOS overweight, healthy controls of comparable BMI and age were studied at baseline. Measures were repeated in 13 PCOS and eight control women following three 1‐h exercise sessions per week over 12 weeks. Measurements Insulin resistance was measured by glucose infusion rate on euglycaemic hyperinsulinaemic clamp, and fitness was assessed by VO_2max. Results At baseline, PCOS women were 46% more insulin resistant than controls (175·6 vs 257·2 mg/m²/min, P < 0·05) with IR independently associated with VO_2max and BMI in the PCOS group only (P < 0·01). Postexercise IR improved across both groups (P < 0·01). In PCOS women, IR improved by 16% (P < 0·05) but was not restored to the same level as controls (P < 0·05). Improvement in IR and in VO_2max was related to the PCOS group (r² = 0·85, P < 0·05), yet change in IR and in fitness was not related. No associations were found in controls. Conclusions While intensified exercise improves IR in PCOS women, a higher IR persisted following exercise in PCOS women, and a clear relationship between improved IR and improved fitness was not found. Therefore, other mechanisms of, and therapies for, IR must be explored in PCOS as IR remains higher than observed in non‐PCOS controls.     

Retinol-binding protein in nonobese women with polycystic ovary syndrome

Objective Although polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance, cardiovascular disease and various metabolic diseases, the mechanisms linking PCOS to metabolic changes are not fully understood. Retinol‐binding protein (RBP) was recently reported as an adipocytokine that may link insulin resistance and lipid metabolism. The aim of this study was to investigate the potential role of RBP in women with PCOS. Research design and methods Fifty women with PCOS and 40 healthy women, all of whom were age‐ and weight‐matched, were studied. Blood was obtained to determine RBP levels as well as metabolic and hormonal parameters, and the homeostasis model assessment of insulin resistance (HOMA‐IR) was calculated for each subject. Results The RBP levels were higher (P < 0·01) in women with PCOS after adjusting for age, body mass index (BMI), mean blood pressure, triglyceride (TG), high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, fasting glucose, fasting insulin, estimated glomerular filtration rate (GFR), LH/FSH, total testosterone and SHBG levels. PCOS status was the strongest predictor of elevated RBP levels. In both the PCOS and control groups, RBP levels were significantly correlated with HOMA‐IR (P = 0·03 in the PCOS group; P = 0·01 in controls). In addition, RBP levels were significantly correlated with total cholesterol, LDL‐cholesterol and TG levels in PCOS (P < 0·01, P < 0·01 and P = 0·01, respectively). Conclusions Higher RBP levels in the PCOS group, when compared to the non‐PCOS group, were observed, and this difference may play a role in the pathophysiology found in women with PCOS. Further studies are needed to clarify the role of RBP in these women.     

The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study

Objective This study was designed to evaluate the prevalence of the metabolic syndrome (MetS) and insulin resistance (IR) in a large population‐based study in Iran. Research design and methods Anthropometric measurements, biochemical parameters and IR were compared between 136 polycystic ovary syndrome (PCOS) subjects and 423 healthy controls recruited from among 1126 reproductive aged women (18–45 year). PCOS and MetS were diagnosed using the Rotterdam criteria and Joint Interim Statement, respectively. IR was defined using the homeostatic model assessment‐IR). Results Among the PCOS subjects, the mean ± SD age, body mass index (BMI) and waist circumference were 31 ± 7·7 years, 26·4 ± 5·8 kg/m² and 84 ± 13·3 cm, respectively; corresponding values among healthy controls were 36 ± 7·5 years, 26·4 ± 5·0 kg/m² and 85 ± 11·9 cm, respectively. Age and BMI adjusted prevalences of MetS in PCOS subjects and controls were 18·5% (CI 95%, 15·3–21·7%) and 18·3% (CI 95%, 15·1–21·5%), respectively [P = not significant (NS)]. Age and BMI adjusted prevalences of IR in PCOS and healthy controls were 27·2% (CI 95%, 23·5–30·9%) and 24·2% (CI 95%, 20·6–27·8%), respectively (P < 0·01). Conclusions Metabolic syndrome was no more frequent in a representative sample of PCOS Iranian population than in healthy controls. However, the prevalence of IR in PCOS appears to be higher than in controls. It seems that the association between PCOS and MetS needs more consideration.     

Abnormal heart rate recovery after maximal cardiopulmonary exercise stress testing in young overweight women with polycystic ovary syndrome

Objective Heart rate recovery (HRR) is a measure derived from exercise test, defined as the fall in heart rate during the first minute after maximal exercise. Abnormal HRR is a measure of autonomic dysfunction associated with an increased mortality. This study was performed to evaluate the HRR in polycystic ovary syndrome (PCOS). Design Prospective controlled clinical study. Patients Seventy‐five PCOS women compared to 75 healthy women matched for age (21·7 ± 2·1 years vs. 21·9 ± 1·8 years, respectively) and body mass index (BMI) (29·0 ± 2·6 kg/m² vs. 29·1 ± 2·9 kg/m², respectively). Measurements Subjects were studied for their hormonal and metabolic profile, and underwent cardiopulmonary exercise test (CPX). Results PCOS women showed a significantly reduced HRR (12·9 ± 1·8 vs. 20·4 ± 3·1 beats/min, P < 0·001) compared to healthy controls, an impairment in maximal oxygen consumption (18·0 ± 2·3 ml/kg/min vs. 29·3 ± 3·9 ml/kg/min) and in oxygen consumption at anaerobic threshold (13·6 ± 2·6 ml/kg/min vs. 24·2 ± 3·0 ml/kg/min). In PCOS women, abnormal HRR was inversely correlated to BMI (r = ?0·582, P < 0·001) and to the area under the curve for insulin (r = ?0·596, P < 0·001). Conclusions Our data demonstrate an abnormal HRR after maximal CPX in young overweight PCOS patients, and that HRR should be investigated as a further potential marker of increased cardiovascular risk in PCOS.     

Serum lipoprotein lipid profile in women with the polycystic ovary syndrome: relation to anthropometric, endocrine and metabolic variables

OBJECTIVE Although often associated with insulin resistance and glucose intolerance, various lipoprotein abnormalities have been found in polycystic ovary syndrome (PCOS) but not Invariably so when the degree of obesity is taken into account. We have therefore Investigated the serum lipid profile in a group of women with polycystic ovary syndrome with and without obesity. DESIGN Cross-sectional study of serum lipoprotein lipids and plasma free fatty acids in relation to anthropometric, metabolic and hormonal variables in women with PCOS and weight-matched controls. PATIENTS Twenty-four obese (Pob, mean BMI ± SD 30·6±3·3kg/m²) and 25 non-obese (Pnob, 22·2 ±2·3kg/m²) women with PCOS. Twenty obese (Cob, 30·2 ± 3·5 kg/m²) and 20 non-obese (Cnob, 21·4 ± 1·5 kg/m²) controls. MEASUREMENTS Fasting concentrations of plasma free fatty acids, serum cholesterol and triglycerides in high density lipoproteins (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) In relation to insulin sensitivity index (M/I; assessed with the euglycaemic insulin clamp), glucose tolerance (k-value; intravenous glucose tolerance test), basal serum hormone concentrations, and body fat distribution (skinfolds and waist hip ratio). RESULTS Plasma concentrations of free fatty acids were markedly higher in Pob than in the other groups (all P < 0 001). The lipoprotein lipids did not differ between Pob and Cob, or between the non-obese groups, whereas both obese groups had higher serum concentrations of triglycerides, totally and in VLDL, and lower HDL-cholesterol than their non-obese counterparts. Pob also had higher serum levels of total and LDL-cholesterol than Pnob. Pob had a more pronounced subcutaneous truncal-abdominal adiposity, higher fasting insulin levels and lower M/I than the other groups, and a lower k-value than Cob. Cob had higher levels of fasting insulin than Cnob. Free fatty acid levels correlated with the k-value (inversely) in both women with PCOS and controls, and with M/I (inversely), age and testosterone levels in PCOS. Step-wise regression analysis for the total population, comparing endocrine, anthropometric and metabolic explanatory variables, showed that the serum levels of HDL-cholesterol and triglycerides were mainly correlated with body fat distribution (both) and fasting insulin levels (triglycerides), and levels of total and LDL-cholesterol with BMI and age. CONCLUSIONS Plasma free fatty acid correlations were markedly increased In obese women with PCOS, closely associated with the lower insulin sensitivity and lower glucose tolerance in these women. In spite of these profound metabolic aberrations, the lipoprotein lipid profile was not significantly more abnormal in obese women with PCOS than in their weight-matched controls.     

Polycystic ovary syndrome is associated with atherogenic changes in lipoprotein particle number and size independent of body weight

Objective Adverse changes in lipoprotein particle number and size are common with insulin resistance and are associated with increased cardiovascular risk. Comprehensive information regarding lipoprotein particle number and size, and how these parameters relate to body weight, insulin resistance and hyperandrogenemia is lacking in polycystic ovary syndrome (PCOS). We tested the hypothesis that PCOS is associated with atherogenic changes in lipoprotein profile independent of body weight and examined the role of insulin resistance and androgens in these atherogenic changes. Design Case–control study performed at Clinical Research Center at an Academic Medical Center in the United States. Patients and measurements Fasting blood was obtained from 25 PCOS and 25 control women of similar age and body mass index (BMI). Lipoprotein particle number and size was determined by nuclear magnetic resonance and compared between the groups. Results The mean BMI for both groups was <30 kg/m² (P = 0·33). Women with PCOS had an increase in very low‐density lipoprotein (VLDL) particle number (P = 0·005), low‐density lipoprotein (LDL) particle number (P = 0·02) and a decrease in high‐density lipoprotein (HDL) size (P = 0·04). LDL size was borderline decreased (P = 0·09). These differences persisted after adjustment for ethnicity, alcohol and tobacco intake and exercise. In stepwise regression models, bioavailable testosterone was the only predictor of LDL cholesterol, triglyceride, VLDL and LDL particle number. Sex hormone binding globulin (SHBG) was the only predictor of LDL and HDL size. Conclusions Independent of body weight, PCOS was associated with changes in lipoprotein profile that increases risk for cardiovascular disease. These changes were present in a mostly nonobese group of women and were more closely related to androgens than fasting insulin.     

Fasting concentrations of nesfatin‐1 are negatively correlated with body mass index in non‐obese males

Background We recently identified a novel anorexigenic protein, nesfatin‐1, which is processed from nesfatin/nucleobindin‐2 (NUCB2). However, the clinical importance of this protein has not been determined. Objective To investigate its clinical significance in humans, we have established a new specific enzyme‐linked immunosorbent assay (ELISA) for human nesfatin‐1 in peripheral blood and measured its circulating concentration in healthy subjects. Design The new sandwich‐type ELISA method was validated and then used to measure nesfatin‐1 levels in plasma samples, under overnight fasting conditions, followed by oral glucose tolerance and meal tests. Patients and measurements A total of 43 nonobese males (age: 24·5 ± 0·6 , body mass index (BMI); 21·1 ± 0·3 kg/m²) were recruited to the study for evaluating fasting concentrations of nesfatin‐1. In those, fifteen subjects underwent a 75‐ g oral glucose tolerance test (OGTT) and another 15 underwent a meal test. In addition, fasting concentrations of nesfatin‐1 were measured in nine males with high BMI (age: 32·4 ± 3·7 , BMI; 37·3 ± 3·8 kg/m²). Results Peripheral concentrations of nesfatin‐1 showed a significant negative correlation with BMI, percentage body fat, body fat weight and blood glucose (P < 0·05). Nesfatin‐1 concentrations were not significantly changed during OGTT and meal tests. Fasting nesfatin‐1 levels were significantly lower in subjects with high BMI compared to nonobese subjects (P < 0·05). Conclusions A new specific and sensitive ELISA for nesfatin‐1 was established. Further accumulation of clinical observations is necessary to clarify the role of circulating nesfatin‐1 in various metabolic disorders.     

Metabolic and cardiopulmonary effects of detraining after a structured exercise training programme in young PCOS women

Objective The aim of the present study was to determine if the favourable cardiopulmonary and metabolic benefits induced by exercise training (ET) programme are maintained after its cessation. Patients Thirty‐two young overweight polycystic ovary syndrome (PCOS) women matched for age and body mass index (BMI) with other 32 PCOS patients was enrolled. The first group [PCOS‐T (trained)] underwent 24‐week ET programme, whereas the second [PCOS‐DT (detrained)] underwent 12‐week ET programme followed by 12‐week detraining period. Methods At baseline, after 12‐ and 24‐week follow‐up, all PCOS women were studied for their hormonal (ovarian and adrenal androgens), metabolic (glucose and insulin) and lipid profile, and underwent cardiopulmonary exercise test. Results After the initial 12‐week ET programme, both PCOS‐T and PCOS‐DT groups, without differences between groups, showed a similar significant (P < 0·05) improvement in BMI, fasting insulin, areas under curve insulin (AUC_INS), glucose and insulin AUC (AUC_GLU/INS), high‐density lipoprotein‐cholesterol (HDL‐C), low‐density lipoprotein‐cholesterol (LDL‐C) and maximal oxygen consumption at cardiopulmonary exercise test (VO_2max). At 24‐week follow‐up, PCOS‐T group showed a significant (P < 0·05) improvement in BMI, fasting insulin, AUC_INS, AUC_GLU/INS, LDL‐C, HDL‐C and VO_2max, in comparison to baseline and 12‐week follow‐up. At same follow‐up visit, the all parameters resulted significantly (P < 0·05) worsened in PCOS‐DT group in comparison to 12‐week follow‐up and PCOS‐T group. In PCOS‐DT group, no parameter assessed at 24‐week follow‐up was significantly different in comparison with baseline. Conclusion In young PCOS women, 12‐week detraining resulted in a complete loss of the favourable adaptations obtained after ET.     

Adult‐type hypolactasia and calcium intake in polycystic ovary syndrome

Objective Adult‐type hypolactasia (ATH) is related to lower calcium and milk intake, which might be associated with obesity and metabolic disturbances. Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances including central obesity. We aimed to examine the association of ATH and calcium intake with anthropometric, metabolic and endocrine parameters in a cohort of PCOS and control women. Design Metabolic, endocrine and anthropometric measurements and oral glucose tolerance tests were performed in 504 PCOS and 366 control women. Genotyping of ATH, defined by the ‐13910 variant of the MCM6 gene, was performed. Calcium intake was assessed by questionnaires. Results Adult‐type hypolactasia was more prevalent in PCOS women (29·8%) than in controls (23·5%) (P = 0·040). PCOS women with ATH had higher waist‐to‐hip ratio (WHR) (0·80 [0·75–0·88] vs 0·78 [0·73–0·85], P = 0·046), glucose 2 h (5·28 [4·57–6·33] mmol/l vs 5·67 [4·68–6·78] mmol/l, P = 0·037), HbA1c (5·2 [5·0–5·4]%vs 5·1 [5·0–5·3]%, P = 0·009), parathyroid hormone (3·72(2·91–4·86] pmol/l vs 3·61 [2·94–4·63] pmol/l, P = 0·030) and Ferriman‐Gallwey‐Scores (FG Scores) (7 [3–12] vs 4 [1–9], P = 0·002) and lower 25(OH)D levels (54·4 [35·2–80·6] nmol/l vs 68·4 [49·7–89·4] nmol/l, P < 0·001) than PCOS women without ATH. The association of 25(OH)D and FG‐Scores with ATH remained significant in age‐, BMI‐ and WHR‐adjusted analyses. PCOS women within the highest quartile of calcium intake had significantly lower testosterone (P = 0·023) and androstenedione (P = 0·032) and significantly higher high‐density lipoprotein (HDL) levels (P = 0·035) than PCOS women with lower calcium intake. Conclusion Our results indicate an association of ATH with PCOS susceptibility. Moreover, ATH might influence WHR, HbA1c and FG‐Scores as well as 25(OH)D levels. Higher calcium intake was associated with lower androgens and higher HDL levels.     

Factors associated with plasma ghrelin level in Japanese general population

Objective Ghrelin is a novel gastric peptide identified in 1999 as a ‘hunger hormone’. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. Methods Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005–2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12‐h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. Results In our population, the mean BMI was 23·8 kg/m², indicating a nonobese population. Results of univariate analysis showed that age (P < 0·001), BMI (P < 0·001), waist (P < 0·001), triglycerides (P < 0·01), FPG (P < 0·01), insulin (P < 0·001) and uric acid (P < 0·05) were inversely associated with ghrelin. High‐density lipoprotein (HDL) cholesterol (P < 0·001) and eGFR (P < 0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P < 0·001). Results of the multiple stepwise regression analysis revealed that age (P < 0·001; inversely), female gender (P < 0·001), insulin (P < 0·001; inversely), HDL cholesterol (P = 0·005), BMI (P = 0·01; inversely) and uric acid (P = 0·045; inversely) were significantly and independently associated with ghrelin. Conclusions The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.     

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.     

Exercise training improves autonomic function and inflammatory pattern in women with polycystic ovary syndrome (PCOS)

Background Polycystic ovary syndrome (PCOS) is a common female reproductive‐age endocrine disease predominantly characterized by chronic anovulation, hyperandrogenism, insulin‐resistance and low‐grade inflammatory status. Exercise training (ET) favourably modulates cardiopulmonary function and insulin‐sensitivity markers in PCOS women. The present study investigated the effects of ET on autonomic function and inflammatory pattern in PCOS women. Study design Prospective baseline uncontrolled clinical study. Methods One‐hundred and eighty five PCOS women referred to our department were screened for the inclusion into the study protocol from March 2004 to July 2007. One‐hundred and twenty four PCOS women met the criteria for the inclusion into the study protocol and were subdivided into two groups each composed of 62 patients: PCOS‐T (trained) group underwent 3‐month ET program, whereas PCOS‐UnT (untrained) group did not. At baseline and at 3‐month follow‐up, hormonal and metabolic profile, cardiopulmonary parameters, autonomic function (as expressed by heart rate recovery, HRR) and inflammatory pattern [as expressed by C‐reactive protein (CRP) and white blood cells (WBCs) count] were evaluated. Results PCOS‐T showed a significant (P < 0·05) improvement in maximal oxygen consumption (VO_2max) and in post‐exercise HRR, and a significant (P < 0·001) decrease in CRP and WBCs; whereas no statistically significant changes of the same parameters were observed in PCOS‐UnT. Multiple linear regression analysis showed that 3‐month HRR is linearly related to the inclusion in training group (β = 0·316, P < 0·001), VO_2max (β = 0·151, P = 0·032) and the ratio between glucose and insulin area under curve (AUC) (β = 0·207, P = 0·003), and inversely related to body mass index (β = –0·146, P = 0·046), insulin AUC (β = –0·152, P = 0·032), CRP (β = –0·165, P < 0·021), and WBCs count (β = –0·175, P = 0·039). Conclusions Exercise training improves autonomic function and inflammatory pattern in PCOS women.     

Visfatin, low-grade inflammation and body mass index (BMI)

Objective Visfatin is an adipokine with revealing roles in inflammatory mechanisms but its implication in inflammation related to excessive adiposity/obesity is not studied yet. Our aim was to investigate the relations of visfatin with inflammation markers and body mass index (BMI) in the peripheral blood mononuclear cells (PBMCs), a type of cells closely related to inflammatory mechanisms. Design Cross‐sectional study, quantification of visfatin, TNF‐α, IL‐6 mRNA in PBMCs. Patients Eighty‐three supposed healthy individuals from the STANISLAS cohort, belonging in three BMI categories: BMI < 25 kg/m² (lean), 25 kg/m² ≤ BMI < 30 kg/m² (overweight) or BMI ≥ 30 kg/m² (obese). Measurements We measured visfatin gene expression (by real‐time quantitative PCR), in relation to gene expression of the pro‐inflammatory cytokines TNF‐α, IL‐6 in PBMCs and to anthropometric parameters (weight, BMI, waist : hip ratio), blood pressure, lipid profile, glucose and inflammatory markers (C‐reactive protein, lymphocyte count). Results Visfatin expression in PBMCs was significantly associated with BMI in a negative way (r = –0·21, P = 0·05). Global anova analysis test for lean and over‐weight/obese individuals showed a negative significant association between visfatin expression in PBMCs and BMI both for men and women (P = 0·05 and P = 0·01, respectively) and these associations remained significant after separating subjects in three groups (lean, overweight, obese) for men and women (P = 0·02 and P = 0·05, respectively). Correlation analysis between levels of expression of visfatin and TNF‐α showed a significant positive linear association (r² = 0·27, P < 0·0001). Conclusion These findings reveal a probable new role of visfatin in inflammation reflected in PBMCs, in the context of obesity.     

A comparison between rimonabant and metformin in reducing biochemical hyperandrogenaemia and insulin resistance in patients with polycystic ovary syndrome (PCOS): a randomized open-label parallel study

Context Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome. Objective To compare the effects of insulin sensitization with metformin to weight reduction by rimonabant on biochemical hyperandrogenaemia and insulin resistance in patients with PCOS. Design A randomized, open‐label parallel study. Setting Endocrinology outpatient clinic in a referral centre. Subjects Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index (BMI) ≥ 30 kg/m² were recruited. Intervention Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Main outcome measures The primary end‐point of the study was a change in total testosterone. Results After 12 weeks of rimonabant there was a significant reduction (mean ± SEM) in weight (104·6 ± 4·6 vs. 98·4 ± 4·7 kg, P < 0·01), waist circumference (116·0 ± 3·3 vs. 109·2 ± 3·7 cm, P < 0·01), hip circumference (128·5 ± 4·0 vs. 124·1 ± 4·2 cm, P < 0·03), waist–hip ratio (0·90 ± 0·02 vs. 0·88 ± 0·01, P < 0·01) free androgen index (FAI) (26·6 ± 6·1 vs. 16·6 ± 4·1, P < 0·01), testosterone [4·6 ± 0·4 vs. 3·1 ± 0·3 nmol/l (132·7 ± 11·5 vs. 89·4 ± 8·65 ng/dl), P < 0·01] and insulin resistance as measured by the homeostasis model assessment (HOMA) method (4·4 ± 0·5 vs. 3·4 ± 0·4, P = 0·05). There was no change in any of these parameters in the metformin‐treated group. Conclusion This study suggests that the weight loss through rimonabant therapy may be of use in patients with PCOS and appears superior to insulin sensitization by metformin in reducing the FAI and insulin resistance in obese PCOS patients treated over a 12‐week period.     

Dissociation of endothelial function and arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS)

Objective Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk but it is not clear if this is independent of obesity and insulin resistance. This study therefore investigates endothelial function and arterial stiffness in nonobese, noninsulin resistant women with PCOS. Design This is cross‐sectional case–control study. Patients A total of 19 young women with PCOS, with body mass index (BMI) <30 kg/m², and 19 healthy controls matched for age and BMI were included in the study. Measurements Endothelial function was assessed with flow mediated dilatation (FMD) of the brachial artery, while arterial stiffness was assessed with pulse wave velocity (PWV) and augmentation index (AI). Results There were no significant differences between PCOS and control subjects when assessing the following clinical and biochemical variables: blood pressure, homeostasis model assessment insulin‐resistance index, lipids and oestradiol. Women with PCOS had higher free androgen index scores (5·14 ± 3·47 vs. 3·25 ± 1·42, P = 0·036). The PCOS subjects had significantly lower FMD of the brachial artery compared with the controls (6·5 ± 2·9%vs. 10·5 ± 4·0%, P < 0·01). There were no significant differences in markers of arterial stiffness (PWV 5·8 ± 1·1 vs. 6·0 ± 1·0, P = 0·58, AI 16·5 ± 10·2 vs. 20·3 ± 10·2, P = 0·25). Conclusions Women with polycystic ovary syndrome who are young, nonobese, and have no biochemical evidence of insulin resistance, have abnormal vascular function, but normal arterial stiffness, when compared with age and weight matched control subjects. Whether this leads to a greater risk of cardiovascular disease requires further investigation.     

Extremes of an aromatase index predict increased 25-year risk of cardiovascular mortality in older women

Background Peripheral conversion of androgens to oestrogens via aromatase is the primary source of oestrogen in postmenopausal women and may play a role in cardiovascular health. Design Prospective. Participants, Measurements The association of an index of aromatase activity (AROM), the serum oestrone‐to‐androstenedione ratio, with 25‐year cardiovascular disease (CVD) mortality was examined in 819 postmenopausal non‐oestrogen using women (mean age at baseline = 72). Results Overall, 247 deaths were attributed to CVD. The median AROM value was 60 (95% range 17–129). AROM was positively correlated with age (r = 0·28) and body mass index (BMI) (r = 0·22) (P < 0·001). The age‐adjusted risk for CVD mortality was significantly elevated for women in the lowest (HR = 2·01, 95% CI 1·31–3·12) and highest (HR = 1·51, 95%CI 1·02–2·22) quintiles of AROM, compared with the middle quintile. This U‐shaped association persisted after additional adjustment for BMI, waist‐to‐hip ratio, exercise, smoking, alcohol use and traditional CVD risk factor covariates. There was a significant interaction of AROM and BMI (P = 0·001), such that high AROM was associated with a 63% reduction in risk of CVD death for women with low BMI (<22 kg/m²), but with 2·1‐ to 2·5‐fold increased risk in women with mid‐range (22–<25 kg/m²) and high (≥25 kg/m²) BMI. Oestradiol did not influence AROM associations and was not independently related to CVD death. Conclusions These results suggest that aromatase is a novel endocrine factor predictive of CVD mortality among postmenopausal women. If confirmed, additional studies are needed to determine whether extremes of aromatase reflect genetic influences or underlying disease processes.     

Plasma soluble tumour necrosis factor‐α receptor 2 is elevated in obesity: specific contribution of visceral adiposity

Objective We examined the obesity phenotype most strongly associated with increased plasma concentrations of sTNFR2, and compared which of the two markers, TNF‐α or sTNFR2, better predicts indices of plasma glucose‐insulin homeostasis. Design, patients and measurements Plasma sTNFR2 levels were measured in a sample of 287 healthy nondiabetic men [age: 43·9 ± 8·0 years (mean ± SD)], covering a wide range of adiposity values (BMI: 29·0 ± 4·4 kg/m²; waist girth: 100·0 ± 11·7 cm). Results Plasma sTNFR2 levels correlated positively and significantly with BMI (r = 0·36; P < 0·0001), fat mass (r = 0·42; P < 0·0001), waist girth (r = 0·38; P < 0·0001) as well as with visceral (r = 0·37; P < 0·0001) and subcutaneous adipose tissue (AT) (r = 0·40; P < 0·0001) areas measured by computed tomography. Two subgroups (n = 27 in each group) of overweight men (BMI ≥25 kg/m²) were individually matched for similar BMI values, but with markedly different levels of visceral AT (< or ≥130 cm²) and then compared with a control group of 46 lean subjects (with both BMI <25 kg/m² and visceral AT <130 cm²). This analysis revealed that men characterized by high levels of visceral AT had significantly higher concentrations of sTNFR2 compared with obese men with low visceral AT (1861 ± 457 pg/ml vs. 1722 ± 400; P < 0·05) and with lean controls (1570 ± 291 pg/ml; P < 0·001). Whereas subjects classified across tertiles of TNF‐α levels showed no difference in glucose tolerance and insulin levels, subjects in the upper tertile of plasma sTNFR2 levels were characterized with the highest plasma insulin concentrations during the OGTT and had the highest area under the curve of insulin concentrations. Conclusions These results indicate that sTNFR2 levels are more closely related to abdominal AT accumulation than to total adiposity. Furthermore, plasma concentrations of sTNFR2 are independently related to plasma glucose‐insulin homeostasis beyond the known contribution of visceral adiposity.     

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers

Objective There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects. Design Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross‐sectional, community‐based sample of 1853 euthyroid subjects in Busselton, Western Australia. Results There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0·12 kg/m² (95% CI 0·06, 0·18; P < 0·001). The mean BMI ± SD of subjects in the highest quintile of free T4 concentration was 24·4 ± 3·5 kg/m², compared with 26·1 ± 3·8 kg/m² for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0·001) and former smokers (P = 0·011), but not in current smokers (P = 0·77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0·08 kg/m² (95% CI –0·16, 0·32; P = 0·53). Conclusions In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.     

Anxiety is associated with hormonal and metabolic profile in women with polycystic ovarian syndrome

Background Increased prevalence of psychological morbidities, including anxiety, depression and eating disorders, has been reported in women with polycystic ovary syndrome (PCOS) in comparison with normal ovulating, nonhyperandrogenemic women. Aim of the study To investigate the relationship between the degree of anxiety, depression and eating disorders via self‐reported symptoms and the severity of hormonal and metabolic aberrations in women with PCOS. For this purpose, the PCOS cohort was subdivided into three subgroups according to the degree of anxiety. Methods One hundred and thirty women with PCOS of similar age and BMI were studied. In each subject, hormonal and metabolic status as well as psychological profile was assessed with the use of specific questionnaires. Specifically, anxiety (trait and state) was assessed with the use of STAI‐T and STAI‐S, while depression and eating disorders were evaluated with the use of the Beck Depression Inventory and the Eating Attitudes test, respectively. Results The subgroups did not differ in age and BMI. Subjects with the highest STAI‐S compared with those with the lowest STAI‐S displayed significantly higher the homeostasis assessment model‐insulin resistance (HOMA‐IR) and free androgen index values (P < 0·05), respectively. Regarding trait anxiety, assessed by STAI‐T, HOMA‐IR values were significantly elevated (P < 0·05) in the subgroup with the higher STAI‐T score compared with the HOMA‐IR in the group with the lower STAI‐T score. Conclusions In women with PCOS, the degree of anxiety, state and trait (STAI‐S, STAI‐T) appears to vary in a pattern similar to that of hyperandrogenemia and insulin resistance, independently of age and BMI. The pathophysiological mechanisms underlying the association of psychological morbidities with androgen excess and insulin resistance in PCOS remain to be elucidated.