Increased arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS) without comorbidities: one more characteristic inherent to the syndrome?

Background Polycystic ovary syndrome (PCOS) is associated with adverse metabolic effects. Some cardiovascular disease (CVD) risk markers are increased in women with PCOS. However, early markers of atherosclerosis are also associated with obesity and insulin resistance, which are related to PCOS. These markers may result either directly from PCOS or indirectly as a consequence of the comorbidities associated with the syndrome. Context To assess the presence of early CVD markers in young, nonobese women with PCOS. Patients Forty women with PCOS and 50 healthy women with regular menstrual cycles, matched for age and body mass index (BMI). Measurements The following CVD markers were assessed by ultrasonography: common carotid artery (CCA) stiffness index (β), distensibility and intima–media thickness (IMT), and brachial artery flow‐mediated dilatation (FMD). Inflammatory markers, including interleukin (IL)‐6, tumour necrosis factor (TNF)‐α, homocysteine, C‐reactive protein (CRP), glycaemia, lipid profile and insulin, were also assessed. Results CCA β was higher in PCOS than in control women (3·72 ± 0·96 vs. 3·36 ± 0·96, P = 0·04) and CCA distensibility was lower (0·31 ± 0·08 vs. 0·35 ± 0·09 mmHg^?1, P = 0·02). Waist circumference, total testosterone and the Free Androgen Index (FAI) were higher in PCOS patients than in controls (78·2 ± 10·0 vs. 71·5 ± 7·2 cm, P = 0·001; 88·1 ± 32·4 vs. 57·1 ± 21·2 ng/dl, P < 0·01; 12·7 ± 15·7%vs. 4·7 ± 2·3%, P < 0·01, respectively), while SHBG was reduced (37·9 ± 19·1 vs. 47·8 ± 18·3 nmol/l, P = 0·01). The remaining variables did not differ between the groups. Conclusions Young women with PCOS exhibit changes in vascular elasticity even in the absence of classical risk factors for CVD, such as hypertension and obesity.     

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.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS)

Objective Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS. Design An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index ≥ 30 kg/m². Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months. Measurements The primary end‐point was a change in weight; secondary end‐points were a change in FAI and insulin resistance. Results The mean weight loss of 6·2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0·2 kg, P = 0·96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (–6·0 ± 0·1%vs. –2·8 ± 0·1%, P = 0·04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (–45·0 ± 5·0%vs. –16 ± 2·0%, P = 0·02); FAI (–53·0 ± 5·0%vs. –17·0 ± 12·2%, P = 0·02)]. HOMA‐IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4·4 ± 0·5 vs. 3·4 ± 0·4 vs. 2·7 ± 0·3, respectively, P < 0·01) but not at all in the metformin only group (3·4 ± 0·7 vs. 3·4 ± 0·8 vs. 3·7 ± 0·8, respectively, P = 0·80). Total cholesterol and LDL reduced significantly in both groups, but improvements in triglycerides and HDL were limited to the rimonabant/metformin group. Conclusions In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.     

Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults*

OBJECTIVES The role of growth hormone in maintaining normal body composition and bone strength In adults has attracted much interest recently. We have assessed body composition and bone mass in GH deficient hypopituitary adults on conventional replacement therapy and compared them with matched controls. DESIGN AND SUBJECTS A cross-sectional Study Of 64 growth hormone deficient hypopituitary adults (29 males and 35 females) on conventional replacement therapy and a large number of healthy control subjects matched for age, sex and body mass index (BMI). MEASUREMENTS Skinfold thicknesses at two sites (triceps and subscapular), waist and hip girth circumferences were assessed by standard methods. Body composition was assessed using total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Bone mineral mass was assessed at the lumbar spine and the total body by DEXA. Not every patient and control participated In every measurement. RESULTS Obesity was common in the hypopituitary patients; BMI (mean±SD) was 27·5 ± 4·6 kg/m² and body weight was 111·8 ±185% of the maximal ideal for height (P< 0·001). The sum of subscapular and triceps skinfolds was significantly higher in hypopituitary patients than in controls (men 46+15 vs 37±14mm, P<0·05; women 55±13 vs 47±17mm, P<0·05). Waist to hip circumference ratio was significantly greater In female hypopituitary patients than in matched controls but was not significantly different in men (men 0·94± 0·07 vs 0·91 ± 0·07, NS; women 0·84±0·09 vs 0·77±0·05, P < 0·001). The difference between patients and controls in the sum of skinfolds and the waist to hip ratio were present In non-obese (BMI < 26 kg/m²) subjects (21 patients and 32 controls). TBK corrected for body weight was significantly lower In hypopituitary patients (n= 44) than in controls (n= 31) (men 43·±5.6 vs 50·1 ± 5·9 mmollkg, P < 0·003; women: 34·0 ± 3.2 vs 40·6 ± 5·3 mmol/kg, P < 0.0001). BIA-derived body water content (corrected for body weight) was significantly lower In hypopituitary patients (n= 56) than in controls (n= 57) (0·492 ± 0·064 vs 0·545 ± 0·067 1/kg, P < 0.0004). Percentage body fat derived from ail the three methods was significantly higher in hypopituitary patients than in normal controls In both sexes (from TBK men 34·7 ± 94 vs 28·8 ± 7·0%, P < 0·05; women 37·8 ± 8·7 vs 30·4 ± 9·7%, P < 0·01; from BIA men 29·3 ± 8·5 vs 23·2 ± 8·4%, P < 0·01; women 34·6 ± 8.1 vs 29·3 ± 9·1%P < 0·01; and from DEXA: men 24·8 ± 6·8 vs 20·4 ± 6·1 %, P < 0·05; women 38·9 ± 7·9 vs 32·5 ± 9·8%, P < 0·01). There was a significant difference between non-obese patients and controls in BIA-derived percentage fat in both sexes and in TBK-derived percentage fat In females only. Bone mineral density (BMD) of the lumbar spine in the L2-L4 region was lower in hypopituitary patients than in controls (men 1·116±0·129 vs 1·311 ± 0·131 g/cm², P <0·0001; women 1·001 ±0·122 vs 1·131 ±0·138g/cm², P < 0·001). Spine BMD was also reduced in hypopituitary patients compared to the young adult and age and weight matched reference data. Total body BMD was significantly lower in patients than In controls (men 1·186 ± 0·102 vs 1·250 ± 0·080 g/cm², P < 0·05; women 1·080 ± 0·077 vs 1·149 ± 0·073 g/cm², P < 0·005). CONCLUSIONS Hypopituitary adults on conventional therapy have abnormal body composition with increased fat content, reduced body water content and reduced bone mineral mass     

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.     

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS)

Background Nonenzymatic advanced glycation and oxidation end‐products, advanced glycation end‐products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. Objective To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Design Clinical trial. Patients One hundred and ninety‐three age‐ and BMI‐matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty‐eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Measurements Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. Results The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7·96 ± 1·87 U/ml, P < 0·001) compared with those with isolated hyperandrogenaemia (5·61 ± 0·61 U/ml), anovulation (5·53 ± 1·06 U/ml), US‐PCO morphology (5·26 ± 0·25 U/ml) and controls (5·86 ± 0·89 U/ml). Conclusions In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.     

Disproportional geometry of the proximal femur in patients with Turner syndrome: a cross-sectional study

Objective Patients with Turner syndrome (TS) have altered growth and increased risk of osteoporosis due to oestrogen deficiency and possibly a host of other factors. Thus, TS patients have a 4·9‐fold increased risk of femoral neck fractures. Most patients are treated with oestrogen during puberty and adolescence to facilitate pubertal development and prevent secondary osteoporosis. The geometry of the hip is a predictor for hip fractures independent of bone mineral density (BMD). The purpose of the present study was to investigate the variation of the geometry of the hip in patients with TS in comparison with healthy controls. Patients The study population comprised 58 patients with TS (aged 22–67 years) and 60 age‐matched healthy women (aged 21–65 years). Measurements Hip axis length (HAL), neck width (NW), neck shaft angle (NSA), and femoral head‐radius (HR) on dual‐energy X‐ray absorptiometry (DXA) screen images. These parameters related to age of oestrogen supplementation, menarche, and duration of oestrogen exposure. Results Height was 146·6 ± 6·9 cm and 167·1 ± 6·2 cm (P < 0·1) and weight 57·4 ± 13·9 kg and 62·3 ± 8·3 kg (P < 0·001) in patients and controls, respectively. After adjustment for differences in height, HAL was not significantly different (9·4 ± 0·5 vs. 9·5 ± 0·5 cm; NS) in TS compared with controls while NW was significantly increased (3·5 ± 0·4 cm vs. 3·3 ± 0·2 cm, P < 0·001), NSA was similar (129 ± 4°vs. 130 ± 4°, NS), and HR was significantly decreased (4·1 ± 0·4 vs. 4·5 ± 0·3 cm, P < 0·001). The duration of oestrogen exposure was significantly shorter among TS, but did not correlate significantly with the geometrical parameters in either TS or controls. Conclusion Our data demonstrates that hip geometry is disproportionate in TS compared with normal controls. The altered hip geometry, however, cannot explain the increased risk of hip fracture in TS.     

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.     

Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome.

Aims Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre‐eclampsia, and was it safe for mother and neonate? Methods In the current study, pre‐eclampsia and other pregnancy outcomes were prospectively studied in 90 women with PCOS who conceived on metformin 1.5–2.55 g/day, and had ≥ 1 live birth (97 pregnancies, 100 live births) compared with 252 healthy women (not known to have PCOS) with ≥ 1 live birth, consecutively delivered in a community obstetrics practice. Results Women with PCOS were older than controls (33 ± 5 vs. 29 ± 6 years, P < 0.0001), more likely to be > 35 years old at conception (23 vs. 13%, P = 0.028), much heavier (93 ± 23 vs. 72 ± 18 kg, P < 0.0001, BMI 33.8 ± 7.8 kg/m² vs. 25.6 ± 5.9, P < 0.0001), and more likely to be Caucasian (97 vs. 90%, P = 0.05), but there were similar numbers with preconception Type 2 diabetes mellitus [2/90 (2.2%) vs. 1/252 (0.4%), P = 0.17]. Pre‐eclampsia in PCOS (5/97 pregnancies, 5.2%), did not differ (P = 0.5) from controls (9/252, 3.6%), nor did it differ (P = 1.0) in PCOS vs. control primigravidas [2/45 (4.4%) vs. 4/91 (4.4%)]. Development of gestational diabetes in PCOS did not differ from controls [9/95 pregnancies (9.5%) vs. 40/251 (15.9%), P = 0.12]. Of the 100 live births to 90 women with PCOS, there were no major birth defects. Mean ± sd birth weight of the 80 live births ≥ 37 weeks gestation in women with PCOS (3414 ± 486 g) did not differ from controls’ 206 live births ≥ 37 weeks (3481 ± 555 g), P = 0.34, nor did the percentage of ≥ 37 week gestation neonates ≥ 4000 g (12.5 vs. 17.5%, P = 0.3) or ≥ 4500 g (1.3 vs. 2.9%, P = 0.7). Conclusions Metformin is not associated with pre‐eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus.     

Effect of exercise training on A-FABP, lipocalin-2 and RBP4 levels in obese women

Objective Lipocalin family proteins, including adipocyte fatty acid‐binding protein (A‐FABP), lipocalin‐2 and retinol‐binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We have evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers. Study subjects Thirty obese Korean women and 15 age‐matched nonobese control subjects were studied. Design Concentrations of the lipocalin family proteins were compared between obese and nonobese women and were evaluated before and 3 months after an exercise programme consisting of aerobic exercise (45 min/session, 300 kcal/day) and muscle strength training (20 min/session, 100 kcal/day) five times a week. Results Obese women exhibited higher A‐FABP levels compared to nonobese women (21·4 ± 6·4 µg/l vs. 13·6 ± 4·4 µg/l, P < 0·001). However, neither lipocalin‐2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin‐2 was marginally significant (P = 0·054). Circulating A‐FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin‐2 and high‐sensitivity C‐reactive protein (hsCRP) levels. After 3 months of the exercise training programme, serum A‐FABP levels decreased significantly from 21·4 ± 6·4 µg/l to 19·3 ± 6·8 µg/l (P = 0·038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin‐2 and RBP4 levels, although IL‐6 levels increased after the exercise programme. Conclusion Exercise training with weight loss induced a significant reduction in circulating A‐FABP levels in obese Korean women.     

The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome

Background Polycystic ovary syndrome (PCOS) is considered predominantly as a hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Context PCOS diagnostic criteria [National Institute of Health (NIH), Rotterdam Consensus (ROT), Androgen Excess Society (AES)] are unanimous recognized. We aimed to assess in women with suspected PCOS whether the application of the three diagnostic criteria differently characterizes the metabolic profile and insulin sensitivity. Design Retrospective study in a cohort of women admitted to our Outpatient Clinic for suspected PCOS. Patients Two hundred and four women with suspected PCOS in comparison to a group of normal, age‐matched Sicilian women (N = 34) without signs of metabolic syndrome. Measurements We evaluated hyperandrogenaemia and clinical hyperandrogenism, ovarian morphology, hypothalamo–hypophyseal axis and metabolic syndrome parameters. An oral glucose tolerance test (OGTT; 75 g glucose) measured areas under the curve (AUC) for insulin, C peptide and homeostasis model assessment of insulin‐resistance (HOMA‐IR) were performed. Results The prevalence of PCOS was 51% according to NIH, 83% to ROT and 70·6% to AES, and only 100 patients were qualified simultaneously under these three criteria. The prevalence of the metabolic syndrome in PCOS women was 26·92% (NIH), 21·77% (ROT) and 23·61% (AES), respectively. In comparison to healthy women, PCOS women showed increased fasting insulinaemia (PCOS/ROT: P = 0·028; PCOS/NIH: P = 0·007; PCOS/EAS: P = 0·023), 120 min insulin after OGTT insulinaemia (for the three criteria: P < 0·001), AUC_2h insulin (for the three criteria: P < 0·001) and AUC_2h C peptide (for the three criteria: P < 0·001). Conclusions Our study highlights the fact that regardless of the diagnostic criteria used, evaluation of the metabolic parameters and insulin sensitivity is important for a correct diagnosis of PCOS and a therapeutic approach.     

Correlation between heart rate control during exercise and exercise capacity in patients with chronic atrial fibrillation

Background:

Rate control is an acceptable alternative to rhythm control in patients with chronic atrial fibrillation (AF).

Hypothesis:

The aim of this study of AF patients was to understand the correlation between their exercise capacity and both heart rate (HR) and HR variation index during exercise.

Methods:

The exercise capacity of 85 male patients with chronic AF was measured using a cardiopulmonary exercise test (CPX). Within this population, we compared the exercise tolerance of patients with a normal chronotropic response (maximal HR 85%–115% that of the maximal age‐predicted HR during CPX) to those whose HR response exceeded this range. Two similar comparisons were made by dividing the subject population according to (1) whether or not their HR variation index (HRVI) during CPX exceeded 10 bpm/min, and (2) whether their HR during the 6‐minute walk test exceeded 110 bpm.

Results:

Patients with an HRVI not over 10 bpm/min showed higher maximal oxygen uptake compared to patients with a higher HRVI (26.7 ± 6.1 vs 22.8 ± 4.8 mL O₂/kg/min, P = 0.002) and a longer distance walked during CPX (705.6 ± 200.3 vs 520.9 ± 155.5 m, P<0.001). No other significant influence on exercise capacity was seen. Multivariate regression analysis revealed that both the body mass index and the HRVI during CPX were independent predictors of the maximal oxygen uptake.

Conclusions:

Better HRVI control on CPX was correlated with better exercise capacity in patients with chronic AF. © 2011 Wiley Periodicals, Inc. Jefferson Jaber, MD was supported by a fellowship grant from CNPq, Brazil. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

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.     

Value of the intravenous and oral glucose tolerance tests for detecting subtle impairments in insulin sensitivity and beta-cell function in former gestational diabetes

Objective Women with former gestational diabetes mellitus (fGDM) often show defects in both insulin sensitivity and beta‐cell function but it is not clear which defect plays the major role or which appears first. This might be because fGDM women are often studied as a unique group and not divided according to their glucose tolerance. Different findings might also be the result of using different tests. Our aim was to study insulin sensitivity and beta‐cell function with two independent glucose tolerance tests in fGDM women divided according to their glucose tolerance. Design and patients A total of 108 fGDM women divided into normal glucose tolerance (IGT; N = 82), impaired glucose metabolism (IGM; N = 20) and overt type 2 diabetes (T2DM; N = 6) groups, and 38 healthy control women (CNT) underwent intravenous (IVGTT) and oral glucose tolerance tests (OGTT). Measurements Insulin sensitivity and beta‐cell function were assessed by both the IVGTT and the OGTT. Results Both tests revealed impaired insulin sensitivity in the normotolerant group compared to controls (IVGTT: 4·2 ± 0·3 vs. 5·4 ± 0·4 10^?4 min^?1 (µU/ml)^?1; OGTT: 440 ± 7 vs. 472 ± 9 ml min^?1 m^?2). Conversely, no difference was found in beta‐cell function from the IVGTT. However, some parameters of beta‐cell function by OGTT modelling analysis were found to be impaired: glucose sensitivity (106 ± 5 vs. 124 ± 7 pmol min^?1 m^?2 mm ^?1, P = 0·0407) and insulin secretion at 5 mm glucose (168 ± 9 vs. 206 ± 10 pmol min^?1 m^?2, P = 0·003). Conclusions Both insulin sensitivity and beta‐cell function are impaired in normotolerant fGDM but the subtle defect in beta‐cell function is disclosed only by OGTT modelling analysis.     

Assessment of left ventricular diastolic function and the Tei index by tissue Doppler imaging in patients with primary hyperparathyroidism

Background The aim of this study was to assess left ventricular (LV) systolic and diastolic function and myocardial performance (the Tei index) by tissue Doppler imaging (TDI) in patients with primary hyperparathyroidism (PHPT). Methods We prospectively evaluated 21 patients with PHPT [nine women, 12 men; aged 50 ± 11 years, serum calcium 2·9 ± 0·17 mmol/l, intact PTH (iPTH) 51·5 ± 52·1 pmol/l] and 27 healthy control subjects (13 women, 14 men; aged 49 ± 10 years, serum calcium 2·35 ± 0·12 mol/l, iPTH 2·9 ± 0·9 pmol/l). LV systolic and diastolic function was assessed by conventional echocardiography and by TDI. Early diastolic (Em), late diastolic (Am) and peak systolic (Sm) mitral annular velocities, the ratio Em/Am and the Tei index were calculated from TDI measurements. Mitral inflow velocities, colour M‐mode flow propagation velocity (Vp), relative wall thickness (RWT) and LV mass index (LVMI) were assessed by two‐dimensional echocardiography. Results Em and Em/Am were lower in patients with PHPT than in healthy controls (11·2 ± 1·5 cm/s vs. 13·5 ± 2·5 cm/s, P = 0·005; 0·94 ± 0·27 vs. 1·36 ± 0·44, P = 0·02, respectively). In patients with PHPT, the Tei index was significantly higher than that in controls (0·45 ± 13·6 vs. 0·33 ± 8·1, P = 0·02). Peak (E) velocity and the ratio of E to peak late (A) velocity (E/A) were lower in those with PHPT than in those without (59 ± 15 cm/s vs. 72 ± 19 cm/s, P = 0·02; 0·8 ± 0·15 vs. 1·1 ± 0·33, P = 0·001, respectively). Patients with PHPT had significantly higher RWT (0·50 ± 0·02 cm vs. 0·41 ± 0·02 cm, P = 0·0001), isovolumetric relaxation time (IVRT) (115 ± 13 ms vs. 103 ± 11 ms P = 0·04) and A velocity (79 ± 16 cm/s vs. 68 ± 13 cm/s P = 0·05) than controls. Vp was lower in PHPT patients than in healthy subjects (42 ± 9·98 cm/s vs. 54 ± 19·01 cm/s P = 0·04). There were no significant differences between the two groups regarding LV end‐diastolic and end‐systolic dimensions, LVMI, deceleration time of the mitral E wave, Am and Sm. Conclusion TDI analysis of mitral annular velocities, Em/Am and the Tei index is useful for assessing LV diastolic dysfunction in patients with PHPT. The parameters obtained from the lateral mitral annulus by TDI can be used for the identification of LV diastolic dysfunction in PHPT patients.     

The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study

Objectives The incretin hormone glucagon‐like peptide‐1 (GLP‐1) retards gastric emptying and decreases caloric intake. It is unclear whether increased GLP‐1 concentrations achieved by inhibition of the inactivating enzyme dipeptidyl peptidase‐4 (DPP‐4) alter gastric volumes and satiation in people with type 2 diabetes. Methods In a double‐blind, placebo‐controlled crossover design, 14 subjects with type 2 diabetes received vildagliptin (50 mg bid) or placebo for 10 days in random order separated by a 2‐week washout. On day 7, fasting and postmeal gastric volumes were measured by a ^99mTc single‐photon emission computed tomography (SPECT) method. On day 8, a liquid Ensure® meal was consumed at 30 ml/min, and maximum tolerated volume (MTV) and symptoms 30 min later were measured using a visual analogue scale (VAS) to assess effects on satiation. On day 10, subjects ingested water until maximum satiation was achieved. The volume ingested was recorded and symptoms similarly measured using a VAS. Results Vildagliptin raised plasma GLP‐1 concentrations. However, fasting (248 ± 21 vs. 247 ± 19 ml, P = 0·98) and fed (746 ± 28 vs. 772 ± 26 ml, P = 0·54) gastric volumes did not differ when subjects received vildagliptin or placebo. Treatment with vildagliptin did not alter the MTV of Ensure® (1657 ± 308 vs. 1389 ± 197 ml, P = 0·15) or water compared to placebo (1371 ± 141 vs. 1172 ± 156 ml, P = 0·23). Vildagliptin was associated with decreased peptide YY (PYY) concentrations 60 min after initiation of the meal (166 ± 27 vs. 229 ± 34 pmol/l, P = 0·01). Conclusions Vildagliptin does not alter satiation or gastric volume in people with type 2 diabetes despite elevated GLP‐1 concentrations. Compensatory changes in enteroendocrine secretion could account for the lack of gastrointestinal symptoms.     

Alteration of ghrelin-neuropeptide Y network in obese patients with polycystic ovary syndrome: role of hyperinsulinism

Objective Insulin, ghrelin, neuropeptide Y (NPY) and leptin interact in the regulation of energy homeostasis. Most of these signals are altered in polycystic ovary syndrome (PCOS), which is characterized by a high prevalence of obesity. The present study was conducted to evaluate ghrelin–NPY and ghrelin–leptin interplays in relation to insulin secretion in obese PCOS subjects. Design Pilot prospective study. Patients Seven obese PCOS women and seven age–weight matched controls. Measurements Hormonal measurements, oral glucose tolerance test (OGTT) and a ghrelin test (1 µg/kg i.v. bolus). PCOS patients repeated the clinical work‐up after 4 months of metformin treatment (1500 mg/day orally). Results At baseline, PCOS women showed a significantly higher insulinaemic response to the OGTT compared to controls (P < 0·05). In basal conditions, PCOS women exhibited lower NPY levels than controls (P < 0·01). Ghrelin injection markedly increased NPY in controls (P < 0·01), whereas PCOS women showed a deeply blunted NPY response to the stimulus (area under the curve – AUC–NPY: P < 0·01 vs. controls.). Metformin treatment induced a significant decrease in insulin levels (P < 0·01) and the concomitant recovery of NPY secretory capacity in response to ghrelin (AUC–NPY: P < 0·05 vs. baseline) in PCOS women. Leptin levels, which were similar in the two groups, were not modified by ghrelin injection; metformin did not affect this pattern. Conclusion Hyperinsulinaemia seems to play a pivotal role in the alteration of NPY response to ghrelin in obese PCOS women. This derangement could be implicated in the physiopatology of obesity in these patients.     

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.     

Hypothalamic–Pituitary–Adrenal (HPA) axis functioning in relation to body fat distribution

Objective To relate hypothalamic–pituitary–adrenal (HPA) axis functioning and HPA feedback functioning to body fat distribution in normal weight to obese subjects. Patients 91 men and 103 women [age 18–45 years, BMI 19–35 kg/m², waist‐to‐hip ratio (WHR) 0·6–1·1] Measurements Anthropometry, body composition using hydrodensitometry and deuterium dilution method, cortisol variability by measuring 5‐h cortisol concentrations, HPA axis feedback functioning using a dexamethasone suppression test, and HPA axis functioning under a challenged condition consisting of a standardized high‐intensity test with ingestion of 4 mg dexamethasone. Results In men, an inverse relationship was observed between 5‐h cortisol exposure (nmol/ml) and fat mass index (FMI) (kg/m²) (r = ?0·55, P < 0·001). In women, relationships were observed between 5‐h cortisol exposure (nmol/ml.min) and WHR (r = ?0·49, P < 0·001), maximal workload (r = 0·32, P < 0·001) as well as oral contraceptive use (r = 0·38, P < 0·001). Similarly, in men, an inverse relationship was observed between negative feedback expressed as baseline concentrations minus post dexamethasone cortisol concentrations (nmol/ml) and FMI (r = ?0·53, P < 0·001). In women, relationships were observed between negative feedback expressed as baseline concentrations minus post dexamethasone cortisol concentrations (nmol/ml) and WHR (r = ?0·43, P < 0·001), maximal workload (r = 0·30, P < 0·001) as well as oral contraceptive use (r = 0·43, P < 0·001) in women. Moreover, an inverse relationship was observed between HPA axis functioning in a challenged condition expressed as percentage increase of cortisol concentrations after standardized high‐intensity test with ingestion of 4 mg dexamethasone (%) and waist circumference (r = ?0·21, P < 0·10) in men and WHR (r = ?0·21, P < 0·05) in women. In men, strong positive relationships were observed between FMI and waist circumference (r = 0·85, P < 0·001), as well as waist‐to‐hip ratio (r = 0·70, P < 0·001). Conclusion Disturbance of HPA axis functioning under basal and challenged conditions is related to visceral fat accumulation.