Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS)

Objective The beneficial effects of metformin in patients with type 2 diabetes mellitus (T2DM) and polycystic ovarian syndrome (PCOS) are thought to be in part due to weight reduction. However, the mechanisms by which metformin causes weight loss are unclear. We sought to determine whether circulating levels of the anorectic gut hormone peptide tyrosine tyrosine (PYY) show any correlation with metformin‐induced weight loss. Design and patients We examined the acute effects of orally administrated metformin on fasting PYY levels in eight healthy normal‐weight female subjects. Subsequently, we evaluated the effects of 6 months metformin treatment on fasting PYY levels and anthropometric measurements in 20 women with PCOS. Results In normal‐weight females 10 days’ metformin treatment increased fasting PYY levels (P < 0·01). Similarly, in PCOS subjects metformin treatment increased fasting PYY concentrations (P < 0·05). In both groups a marked variation in PYY increase in response to metformin was observed. Long‐term metformin treatment was associated with improvements in weight (P < 0·05), BMI (P < 0·05), fasting glucose (P < 0·05) and menstrual frequency (P < 0·01). Interestingly, change in PYY levels were correlated with change in waist circumference (r = 0·55, P < 0·05). Conclusions Acute and chronic oral metformin administration increase fasting PYY levels and may contribute to metformin's weight loss effect. Further studies are now required to clarify whether changes in circulating PYY levels in response to metformin treatment can be used to predict which patients will subsequently lose weight long‐term and gain cycle restoration.     

Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study

Objectives Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids. Design Cross‐sectional Subjects and measurements We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12–18 years old. Fasting blood was drawn for active ghrelin, leptin, E₂ and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI). Results AA girls had lower BMI than EA and controls (P = 0·003). Log ghrelin was higher in AA than in EA and controls (P < 0·0001), and remained higher after controlling for BMI Z‐scores. Leptin was lower in AA than in the other groups (P < 0·0001), however, the differences did not persist after controlling for BMI Z‐scores. Testosterone was lower in AA than in EA and controls (P = 0·002) and log E₂ trended lower in AA (P = 0·07). We observed inverse associations of log active ghrelin with testosterone (P = 0·01), and positive associations of leptin with testosterone and log E₂ (P = 0·02 and 0·009). Conclusion Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.     

Obestatin and ghrelin levels in obese children and adolescents before and after reduction of overweight

Objectives Obestatin and ghrelin, which are derived from the same gene, are observed to have opposite effects on weight status. The aims of this study were to compare obestatin concentrations in obese and normal‐weight children and to analyse the effect of weight loss on obestatin and ghrelin levels. Methods We examined anthropometrical markers and fasting serum obestatin, ghrelin, leptin, glucose and insulin concentrations in 44 obese children (mean age 11·2 years) before and after participating in a 1‐year outpatient obesity intervention programme based on a high‐carbohydrate, fat‐reduced diet and increased physical activity. Additionally, total ghrelin, obestatin and leptin levels were determined in 22 normal‐weight healthy children of similar age, gender and pubertal stage. Results Obestatin and leptin concentrations were significantly (P < 0·001) higher and ghrelin concentrations were significantly (P < 0·001) lower in obese children compared to nonobese children. In contrast to the 13 children without weight loss, substantial weight loss in 31 children led to a significant (P = 0·007) increase in obestatin and to a significant (P < 0·05) decrease in leptin and insulin concentrations, while ghrelin concentrations did not change significantly. Children with substantial weight loss demonstrated significantly (P = 0·009) lower obestatin and a tendency (P = 0·064) to higher ghrelin concentrations at baseline. Changes in insulin were not related to changes in ghrelin or obestatin. Conclusion The increase in obestatin and the decrease in ghrelin in obese children point towards an adaptation process of weight status. Weight reduction due to a long‐term lifestyle intervention resulted in an increase in obestatin levels.     

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.     

Altered distribution of adiponectin isoforms in children with Prader-Willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones

Objective Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones. Design, patients and measurements We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11·35 years, body mass index (BMI) Z‐score 2·15] and 14 BMI‐matched controls (median age 11·97 years, BMI Z‐score 2·34). Results Despite comparable BMI Z‐scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA‐IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z‐score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0·05), HOMA‐IR (P < 0·01), BMI Z‐score (P < 0·05), insulin (P < 0·01) and leptin (P < 0·05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls. Conclusions Relative to controls of similar age and BMI Z‐score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI‐matched 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.     

Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study

Context Ghrelin regulates energy homeostasis and may contribute to the development of the metabolic syndrome (MS) in the elderly. Objective To study the relationship between ghrelin and the MS, IGF‐I and life style factors over a 2‐year follow‐up. Design Longitudinal population‐based study, starting from 2002; 2 years follow‐up. Participants Three hundred and thirteen (153 men/160 women) individuals living independently older than 70 years. Results MS was found in 54·9% of men and 61% of women. In the 229 subjects available at follow‐up, ghrelin was higher in men than in women at basal (P = 0·002) and 2‐year follow‐up (P = 0·004). Ghrelin decreased over time in both genders (P < 0·01). Ghrelin was lower in individuals showing MS compared to non‐MS (P = 0·08), but this difference was more evident at 2‐year follow‐up (P = 0·016), mostly due to men with MS (P = 0·002) and even after adjustment for BMI, gender and age. Individuals with MS had an OR of 1·67 (95% CI: 1·0–2·78) for low ghrelin (< first tertile); when adjusting by BMI, gender and age, only high triglycerides with OR 1·8 (1·0–3·3), remained statistically significant among the MS components. IGF‐I showed a positive correlation with ghrelin only in individuals without MS (r_s 0·403, P < 0·001) with no gender differences; this relationship was not found in MS (r_s 0·120, P = 0·129). A positive association of ghrelin was found with academic level, alcohol consumption and smoking. Conclusions Ghrelin is higher in old men in comparison to women and decreases over time with a steeper decline in subjects with MS; moreover, in these subjects ghrelin/IGF‐I correlation is lost.     

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.     

Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis

Background To date, no systematic review or meta‐analysis has been published of direct head‐to‐head studies comparing clomiphene citrate (CC) vs. metformin, or the combination of both drugs as first‐line therapy in anovulatory polycystic ovary syndrome (PCOS) patients seeking pregnancy. The aim of the current paper was to define, if possible, the best evidence‐based recommendations regarding the use of CC and/or metformin as the initial treatment of PCOS women with anovulatory infertility. Design Systematic review and meta‐analysis of the head‐to‐head randomized controlled trials (RCTs) available in the literature. Methods A bibliographic search was performed using the following bibliographic databases: Medline, EMBASE, Biological Abstracts, Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews. Reference lists of included studies, other relevant review articles and textbooks were checked for additional citations of interest. Results Four head‐to‐head RCTs were identified and qualified for inclusion in the analysis. No difference in fertility improvement was observed comparing CC with metformin (OR = 1·22, 95% CI 0·23–6·55, P = 0·815), whereas a significant (P < 0·0001) heterogeneity was observed. Homogeneous data showed no difference in fertility improvement between the combination treatment and CC monotherapy (OR = 0·99, 95% CI 0·70–1·40, P = 0·982), but a significant difference in comparison with metformin monotherapy (OR = 0·23, 95% CI 0·14–0·37, P < 0·0001). Conclusions In PCOS patients with anovulatory infertility and not previously treated, the administration of metformin plus CC is not better than monotherapy (metformin alone or CC alone), whereas to date no specific recommendation can be given regarding the use of CC or metformin as first‐step drug.     

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.     

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.     

Primary hyperparathyroidism is associated with marked impairment of GH response to acylated ghrelin

Background Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH‐releasing action, mainly at the hypothalamic level. Objective To evaluate secretory response of GH to ghrelin in PHP patients. Patients Fifteen patients [11 women/4 men, mean age 54 years, range 32–70 years, body mass index (BMI) 25·0 ± 0·7 kg/m²] affected with PHP due to single parathyroid adenoma and 35 normal age‐matched subjects (23 women/12 men, mean age 58 years, range 35–68 years, BMI 24·1 ± 1·1 kg/m²). Methods A measure of 1 µg/kg body weight i.v. acylated ghrelin or 1 µg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0·5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. Results Mean serum GH peak after GHRH + ARG was 32·6 ± 7·8 and 17·4 ± 4·0 µg/l, in controls and PHP patients, respectively (P < 0·05). Mean serum GH peak after ghrelin was 70·4 ± 31·5 and 16·8 ± 1·9 µg/l, in controls and PHP patients, respectively, (P < 0·001). Using ROC curves, a serum GH peak > 22 µg/l after ghrelin stimulation might be considered as a cut‐off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF‐1, PTH or ionized calcium concentrations. Conclusions The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients.     

Ghrelin and the differential regulation of des-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT)

Objectives Ghrelin, an important central acting orexigenic hormone, is predominantly secreted in the gastrointestinal tract. However little is known about the action of ghrelin in human adipose tissue (AT). Aim To study the expression of ghrelin in AT, the effects of octanoyl–(OTG) and des‐acyl (DSG) ghrelin on lipolysis and lipogenesis, leptin release and potential peripheral signalling through the Y1 receptor. Methods Ex vivo human AT was obtained from women undergoing elective surgery (46 (mean ± SD) 6·8 years, body mass index (BMI): 25·6 ± 5·0 kg/m², n = 20). Abdominal‐subcutaneous (AbdSc) adipocytes were isolated and treated with recombinant human (rh) OTG and DSG to assess lipid metabolism leptin release and the influence of Y1‐receptor blocker. Results Ghrelin was expressed in AbdScAT and negatively correlated with BMI (lean: 3·6 ± 0·74 optical‐density‐units (OD), obese: 1·64 ± 0·45OD, *P < 0·05). Only DSG significantly suppressed glycerol release (Control (C): 286 ± 58 µl/l; DSG 1 nm : 224 ± 38 µl/l↓*; DSG 100 nm : 172 ± 13 µl/l↓*,*↓P < 0·05, n = 7) and reduced hormone sensitive lipase expression (C: 1·0 ± 0·3OD; DSG 1 nm : 0·8 ± 0·3OD↓*; DSG 100 nm : 0·6 ± 0·1OD↓*, n = 4). However, both isoforms increased lipoprotein lipase expression (C: 1·0 ± 0·3OD; DSG 100 nm : 0·2 ± 0·4OD↑*; OTG 100 nm : 2·5 ± 0·3OD↑*, n = 4), whilst blockade of Y1 eliminated this effect in both. Leptin was down‐regulated by DSG only (DSG 1 nm : 5·3 ± 0·7 ng/ml; DSG 100 nm : 4·1 ± 0·7 ng/ml*) and was significant after BMI adjustment (P = 0·029). Conclusion Ghrelin was expressed in human AbdSc AT. In vitro, both OGT and DSG appear to mediate fat deposition with the lipogenic effects in part mediated by the Y1 receptor, whilst the influence of DSG affected lipolysis, lipogenesis and leptin secretion. Taken together, these studies support a local action for ghrelin isoforms on lipid and adipokine metabolism that further supports a cross talk between organs.     

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.     

The antioxidant alpha-lipoic acid improves endothelial dysfunction induced by acute hyperglycaemia during OGTT in impaired glucose tolerance

Objective Impaired glucose tolerance (IGT) is considered a transitional phase in the development of type 2 diabetes, and is also independently associated with the occurrence of cardiovascular disease. Endothelial dysfunction (ED) represents a very early step in the development of atherosclerosis. The aim of the present study was to examine ED in the fasting state and after a glucose challenge as well as after administration of an antioxidant agent. Patients and methods The study subjects included 42 IGT patients and 26 healthy individuals (control group). The IGT patients were randomly divided into two groups, 21 in each group (the alpha‐lipoic acid group and the placebo group). In the alpha‐lipoic acid group, 300 mg of alpha‐lipoic acid was administrated before an oral glucose tolerance test (OGTT); in the placebo group, 250 ml of 0·9% sodium chloride was administrated before the OGTT. In addition, 250 ml of 0·9% sodium chloride was also administrated to the control subjects before the OGTT (control group), and then vascular function was examined in the fasting state and repeated 1 and 2 h after the glucose load. High‐resolution ultrasound was used to measure flow‐mediated endothelium‐dependent arterial dilation (FMD) and glyceryltrinitrate (GTN)‐induced endothelium‐independent arterial dilation. Results In the fasting state, and at 60 and 120 min, FMD in both the placebo and alpha‐lipoic acid groups was significantly lower than in the controls (P < 0·01). In the control group, FMD tended to decrease at 60 min after glucose loading and returned to the baseline levels at 120 min (P > 0·05). In the placebo group, FMD decreased significantly at 60 min after glucose loading (P < 0·01) and increased markedly from 60 to 120 min (P < 0·01). The alpha‐lipoic acid‐treated patients showed FMD values intermediate between the control subjects and the IGT patients treated with placebo, at both 60 and 120 min, and the differences were significant (P < 0·01). In multiple regression analysis, FMD was significantly correlated to fasting blood glucose (FBG), low density lipoprotein cholesterol (LDL‐C), lipoprotein (a) [Lp(a)], C‐reactive protein (CRP), thiobarbituric acid reactive substances (TBARS) and age in IGT patients at baseline (P < 0·01). Spearman's analysis showed a significant negative correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients (placebo group) (P < 0·01). There was also a significant correlation between FMD and plasma glucose levels, and between FMD and TBARS during the OGTT in IGT patients treated with alpha‐lipoic acid (P < 0·05), although the power of association decreased. Conclusion In subjects with IGT, FMD was impaired both in the fasting state and after a glucose challenge, probably through increased production of oxygen‐derived free radicals. The ED observed after a glucose challenge is related to the extent of hyperglycaemia and TBARS, and an antioxidant agent can improve the impairment of endothelial function induced by acute hyperglycaemia.     

Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study

Objective To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery. Methods A cross‐sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1‐84)] and 25‐hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m²] men and women (age 20–64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks. Results Serum 25OHD was low (mean 45 ± 22 nmol/l) and was inversely associated with BMI (r = ?0·36, P < 0·01). Each BMI increase of 1 kg/m² was associated with a 1·3 nmol/l decrease in 25OHD (P < 0·01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0·0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0·001), whereas PTH(1‐84) declined significantly in subjects treated with cholecalciferol (P < 0·007) and tended to decrease following ergocalciferol (P < 0·09). Conclusions In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at‐risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.     

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.     

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.     

Effects on metabolic variables after 12-month treatment with a new once-a-week sustained-release recombinant growth hormone (GH: LB03002) in patients with GH deficiency

Introduction GH substitution in GH deficiency (GHD) must be subcutaneously administered daily. A new sustained‐release formulation of GH (LB03002) has been developed, which has to be injected once a week. As a substudy to the phase III study, we performed this prospective study to evaluate the influence of LB03002 on metabolic variables and hormones. Methods Eleven patients with GHD [four women/seven men, 58 years (29–69 years)] without GH therapy were included in the study. Eight patients were treated with LB03002 for 12 months and three patients received placebo for 6 months followed by LB03002 for 6 months. A 3‐h oral glucose tolerance test (OGTT) was performed at study entry and at study end. Additionally, IGF‐I, cholesterol, LDL, HDL, triglycerides, leptin, ghrelin, HbA1c and C‐peptide were measured. Body composition was evaluated by dual‐energy X‐ray absorptiometry (DXA), and waist/hip ratio (WHR) and waist/height (WHtR) ratio were measured by tape and scale. Results Multiple of upper limit of normal (xULN) of IGF‐I (0·23 (0·09–0·4) vs 0·71 (0·4–1·04), P < 0·01), WHR (0·98 (0·86–1·04) vs 1·01 (0·86–1·05), P < 0·05) and ghrelin levels [119·8 ng/l (67·7–266·6) vs 137 ng/l (67–289·5), P < 0·05] were significantly higher, whereas fat mass (FM) [34·7% (20·4–49·2) vs 32·4% (16·7–48·5), P < 0·05] and leptin [11·2 μg/l (3·3–55·7) vs 7·05 μg/l (2·4–54·3), P < 0·05] were significantly lower at study end. Glucose, insulin, HOMA‐IR, ISI, HOMA‐β, C‐peptide and HbA1c during OGTT were not significantly different before and after GH substitution, neither were BMI, WHtR, bone mineral density and lipid variables. Conclusion Substitution with LB03002 showed statistically significant reduction in FM, which reduces leptin levels and increases ghrelin levels but does not seem to influence glucose and lipid metabolism.