Mitochondria, glycogen, and lipid droplets in skeletal muscle during testosterone treatment and strength training: a randomized, double-blinded, placebo-controlled trial.

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double-blinded, placebo-controlled study, we investigated the effects of six-month testosterone replacement therapy (TRT) and strength training (ST) on mitochondrial, glycogen, and lipid droplet (LD) content in skeletal muscle of aging men with subnormal bioavailable testosterone (BioT) levels. Mitochondrial, glycogen, and LD volume fractions in muscle biopsies were estimated by transmission electron microscopy. Insulin sensitivity (insulin-stimulated Rd) and body composition were assessed by euglycemic-hyperinsulinemic clamp and dual X-ray absorptiometry, respectively. TRT significantly increased total testosterone levels, BioT, and lean body mass (LBM) (p < 0.05), whereas percent body fat decreased (p < 0.05), and insulin sensitivity was unchanged. Baseline mitochondrial volume fraction correlated inversely with percent body fat (ρ = -0.43; p = 0.003). Δ-mitochondrial fraction correlated positively with Δ-total testosterone (ρ = 0.70; p = 0.02), and Δ-glycogen fraction correlated inversely with Δ-LBM (ρ = -0.83; p = 0.002) during six-month TRT, but no significant changes were observed in mitochondrial, glycogen, and LD volume fractions during TRT and ST. In conclusion, in this exploratory small-scale study, the beneficial effects of six-month TRT on total testosterone, LBM, and percent body fat were not followed by significant changes in fractions of mitochondria, glycogen, or lipid in skeletal muscle of aging men with lowered testosterone levels. Six-month ST or combined three-month ST+TRT did not change intramyocellular mitochondria, glycogen, and LD fractions compared to placebo. However, further studies with a larger sample size are needed.

Antipsychotic treatment for children and adolescents with schizophrenia spectrum disorders: protocol for a network meta-analysis of randomised trials.

INTRODUCTION: Antipsychotic treatment in early-onset schizophrenia (EOS) lacks a rich evidence base, and efforts to rank different drugs concerning their efficacy have not proven any particular drug superior. In contrast to the literature regarding adult-onset schizophrenia (AOS), comparative effectiveness studies in children and adolescents are limited in number and size, and only a few meta-analyses based on conventional methodologies have been conducted. METHODS AND ANALYSES: We will conduct a network meta-analysis of all randomised controlled trials (RCTs) that evaluate antipsychotic therapies for EOS to determine which compounds are efficacious, and to determine the relative efficacy and safety of these treatments when compared in a network meta-analysis. Unlike a contrast-based (standard) meta-analysis approach, an arm-based network meta-analysis enables statistical inference from combining both direct and indirect comparisons within an empirical Bayes framework. We will acquire eligible studies through a systematic search of MEDLINE, the Cochrane Central Registry of Controlled Trials, Clinicaltrials.gov and Centre for Reviews and Dissemination databases. Eligible studies should randomly allocate children and adolescents presenting with schizophrenia or a related non-affective psychotic condition to an intervention group or to a control group. Two reviewers will-independently and in duplicate-screen titles and abstracts, complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-relevant efficacy and safety outcomes when possible. ETHICS AND DISSEMINATION: No formal ethical procedures regarding informed consent are required as no primary data collection is undertaken. The review will help facilitate evidence-based management, identify key areas for future research, and provide a framework for conducting large systematic reviews combining direct and indirect comparisons. The study will be disseminated by peer-reviewed publication and conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013006676.

Prescription of antidepressants is increased in Danish patients with polycystic ovary syndrome and is associated with hyperandrogenism. A population-based cohort study.

OBJECTIVE: Quality of life is impaired in polycystic ovary syndrome (PCOS). In this study, we compared the time to first prescription of antidepressants (ADM) in PCOS vs two control groups. DESIGN: Register-based cohort study. PATIENTS: One thousand and one hundred and twenty-four premenopausal women with hirsutism and/or PCOS, premenopausal women with hypertension (HT, n = 301), and age- and sex-matched population controls (controls, n = 4110). MEASUREMENTS: Prescriptions for ADM on secondary care contacts from regional registers. RESULTS: The median age at cohort entry in PCOS, HT and controls was 29, 34 and 29 years, respectively. Among PCOS, HT and controls, 227 (20%), 74 (25%) and 633 (15%), respectively, had prescriptions of ADM. The median time to first prescription of ADM in the PCOS, HT and control cohorts was 6·8, 6·6 and 7·2 years, respectively. The adjusted hazard ratio for time to prescription of ADM for HT vs PCOS was 1·36 [95% CI (1·02-1·82)], P = 0·039, and for controls vs PCOS, it was 0·75 [95% CI (0·64-0·88)], P < 0·001. Within patients with PCOS, hyperandrogenism contributed significantly to the model, likelihood ratio test P = 0·009. The adjusted hazard ratio for hyperandrogenism vs no hyperandrogenism was 1·97 (1·12-3·45), P = 0·018. CONCLUSION: Patients with PCOS had moderately but significantly decreased time to first prescription of ADM compared with age-matched healthy women, whereas patients with HT had the shortest time to prescription. In PCOS, prescription of ADM was associated with the presence of hyperandrogenism.

Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men.

BACKGROUND: The beneficial effects of testosterone treatment (TT) are debated. METHODS: Double-blinded, placebo-controlled study of six months TT (gel) in 54 men aged 60-78 with bioavailable testosterone (BioT) <7.3 nmol/L and waist >94 cm randomized to TT (50-100 mg/day, n = 20), placebo (n = 18), or strength training (ST) (n = 16) for 24 weeks. Moreover, the ST group was randomized to TT (n = 7) or placebo (n = 9) after 12 weeks. OUTCOMES: Chemokines (MIF, MCP-1, and MIP-1 α ) and lean body mass (LBM), total, central, extremity, visceral, and subcutaneous (SAT) fat mass established by DXA and MRI. Results. From 0 to 24 weeks, MIF and SAT decreased during ST + placebo versus placebo, whereas BioT and LBM were unchanged. TT decreased fat mass (total, central, extremity, and SAT) and increased BioT and LBM versus placebo. MIF levels increased during TT versus ST + placebo. ST + TT decreased fat mass (total, central, and extremity) and increased BioT and LBM versus placebo. From 12 to 24 weeks, MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST + placebo versus placebo. CONCLUSION: ST + placebo was associated with decreased MIF levels suggesting decreased inflammatory activity. TT may be associated with increased inflammatory activity.

Overweight in polycystic ovary syndrome. An update on evidence based advice on diet, exercise and metformin use for weight loss.

AIM: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women affecting 5-10%. Nearly 50% are overweight or obese, which result in a more severe phenotype of PCOS. Weight loss is therefore considered the first line treatment in overweight women with PCOS. The aim of this study was to appoint evidence based and clinically applicable advises on weight loss in overweight women with PCOS. METHODS: A review of the existing literature on weight loss through lifestyle modification and/or metformin treatment in overweight women with PCOS. The primary outcome was weight loss. The clinical manifestations of hyperandrogenism and menstrual cyclicity were secondary outcomes. Metabolic parameters were not included in the present review. RESULTS: Weight loss is most effectively achieved through a 12-1500 kcal/day diet, which results in a clinically relevant weight loss. The type of diet has no implications for degree of weight loss. Physical activity has no significant additive effect on weight loss. Metformin combined with a low calorie diet has subtle additive effect on weight loss and level of androgens when compared to diet alone. CONCLUSION: Weight loss through life style changes, preferably a low calorie diet, should be the first line treatment in overweight/obese women with PCOS. Metformin can be considered as an additional treatment but has subtle additive effect.

Osteoprotegerin levels decrease during testosterone therapy in aging men and are associated with changed distribution of regional fat.

The cardiovascular effects of testosterone treatment are debated. Osteoprotegerin (OPG) is an independent marker of cardiovascular risk. We investigated the effect of testosterone therapy on OPG levels in aging men with low normal bioavailable testosterone levels. A randomized, double-blinded, placebo-controlled study of 6 months testosterone therapy (gel) in 38 men aged 60-78 years with bioavailable testosterone <7.3 nmol/l and waist circumference >94 cm was performed. Clinical evaluation, OPG, and C-reactive protein (CRP) measurements were carried out. Lean body mass (LBM), total fat mass, and bone mineral density (BMD) were established by dual X-ray absorptiometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured by magnetic resonance imaging. Power calculation was based on an increase in LBM during testosterone therapy and responders were defined as testosterone treated patients with increased LBM (Δ LBM positive), n=14. Data are presented as median (interquartile range). Testosterone therapy decreased total fat mass and SAT, whereas VAT was unchanged (n=38). OPG levels decreased during testosterone therapy (from 2.0 (1.9-2.5) to 1.9 (1.6-2.2) ng/ml, p<0.05 vs. placebo), whereas CRP levels were unchanged (n=38). In responders to testosterone therapy (n=14), ΔOPG levels were inversely associated with ΔSAT (r= - 0.60, p=0.03) and positively associated with ΔVAT (r=0.56, p=0.04). OPG levels decreased during testosterone therapy suggesting decreased cardiovascular risk. Decreased OPG levels were associated with changes in regional fat distribution and future studies are needed to further evaluate the association between OPG and regional fat mass distribution.

Plasma osteoprotegerin is associated with testosterone levels but unaffected by pioglitazone treatment in patients with polycystic ovary syndrome.

OBJECTIVE: Increased osteoprotegerin (OPG) levels are associated with increased cardiovascular risk and decreased bone resorption. Pioglitazone treatment reduces the inflammatory state but may decrease bone mineral density (BMD). OPG levels during pioglitazone treatment have not previously been evaluated in polycystic ovary syndrome (PCOS). RESEARCH DESIGN AND METHODS: Plasma OPG levels were measured in 30 PCOS patients before and after randomized treatment with 30 mg pioglitazone/placebo for 16 weeks. Fourteen age- and body mass index-matched healthy women were included as controls. Clinical and hormonal evaluations and whole body dual-energy X-ray absorptiometry scans were performed in all participants. RESULTS: OPG levels were comparable in PCOS patients [12.0 (10.5-14.6) ng/ml] and controls [12.9 (11.7-14.9) ng/ml]. In PCOS patients (no.=30), OPG levels were positively associated with testosterone (r=0.43), PRL (r=0.47), Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (r=0.43), and hip BMD, whereas inverse associations were found between OPG levels and triglyceride (r=-0.49) and free fatty acid levels during euglycemic clamps (r=-0.38), all p<0.05. Pioglitazone treatment significantly decreased inflammatory markers, insulin sensitivity, and BMD without affecting OPG levels. CONCLUSIONS: OPG levels were comparable in PCOS patients and controls and unchanged during insulin sensitizing treatment with pioglitazone. OPG levels were associated with BMD in PCOS. Future studies need to evaluate OPG as a marker of cardiovascular disease in PCOS.

Age associated differences in prevalence of individual rotterdam criteria and metabolic risk factors during reproductive age in 446 caucasian women with polycystic ovary syndrome.

Clinical manifestations and metabolic risk factors may differ according to age in patients with polycystic ovary syndrome (PCOS). Therefore, a retrospective trans-sectional study in academic tertiary-care medical center was designed. A cohort of 446 premenopausal, Caucasian women (age range 15-49 years) with PCOS were divided into 4 subgroups according to age: group 1 (15-19 years, n=42), group 2 (20-29 years, n=180), group 3 (30-39 years, n=187), group 4 (40-49 years, n=37) and underwent clinical evaluation (Ferriman-Gallwey score, BMI, waist, blood pressure), hormone analyses (sex hormones, fasting lipids, insulin, glucose), transvaginal ultrasound, oral glucose tolerance tests (OGTT) (n=234), and ACTH tests (n=201). BMI, waist, Ferriman-Gallwey score, blood pressure, and lipid profile were higher in older vs. younger age groups whereas androgen levels were lower. Measures of insulin resistance were unchanged between age groups, but glucose levels were significantly higher in older age groups. Rotterdam criteria: The prevalence of PCO and biochemical hyperandrogenism decreased in the oldest age group whereas clinical hyperandrogenism increased. Young patients are characterized by PCO and biochemical hyperandrogenism, whereas older patients are more obese with more severe hirsutism and more cardiovascular and metabolic risk factors.

Myocardial response to a triathlon in male athletes evaluated by Doppler tissue imaging and biochemical parameters.

The aim of this study was to examine cardiac dysfunction following ultra-endurance exercise in male athletes. Fourteen athletes (mean+/-SD, age 39+/-8 years) were evaluated before and after the European Championship in Triathlon 2003 using echocardiogram (ECG), cardiac markers [cardiac troponin T (cTnT) and pro-brain natriuretic peptide (pro-BNP)] and echocardiography. Conventional echocardiography techniques and new Doppler tissue imaging (DTI) modalities were applied before and immediately after the competition. Blood samples were drawn 1 week before, immediately after and 12-24 h post-competition. CTnT significantly increased immediately, but decreased to within normal limits 12-24 h post-competition. Pro-BNP was significantly increased immediately post-race (27+/-21 vs 7+/-2 pmol/L pre-race, P < or = 0.007), which 12-24 h later, decreased to 19+/-14 pmol/L (P = 0.07 vs pre-race). During echocardiography, no significant differences were found in regional or global systolic parameters. Early diastolic peak flow velocity (9+/-2, P = 0.04) and E/A ratio (2+/-1, P = 0.004) were increased pre-race and decreased significantly toward normal values. In one athlete, cTnT levels increased significantly and systolic velocities decreased, thus suggesting reversible cardiac fatigue. When using cardiac markers and echocardiographic findings, a triathlon was found to have no significant negative effects on left ventricular function or myocardial tissue in male athletes.

Significantly higher adrenocorticotropin-stimulated cortisol and 17-hydroxyprogesterone levels in 337 consecutive, premenopausal, caucasian, hirsute patients compared with healthy controls.

OBJECTIVE: To investigate whether elevated ACTH-stimulated 17-hydroxyprogesterone (17OHP) levels are caused by CYP21 genetic defects or by a general adrenal hyperresponsiveness in hirsute patients. METHODS: A total of 337 hirsute patients were evaluated by Ferriman-Gallwey score, serum testosterone, ACTH-stimulated 17OHP, and cortisol during the follicular phase. A cutoff value of 16 nmol/liter for maximum ACTH-stimulated 17OHP (M17OHP) responses was defined as the upper limit of the 95% confidence interval (CI) for the 97.5 percentile in 42 female controls. All patients were offered total screening of the CYP21 gene, and 252 healthy, premenopausal women with regular menses underwent genetic screening. RESULTS: Patients were divided into idiopathic hirsutism (IH) (n = 180) and polycystic ovary syndrome (PCOS) (n = 157) groups. M17OHP levels were significantly higher in IH [geometric mean value (nmol/liter +/- 2 sd) 12.2 (4.6-32.3)] and PCOS [11.9 (5.3-27.2)] compared with controls [8.5 (5.1-14.2)] (P < 0.001). A similar percentage of IH and PCOS patients had elevated M17OHP (20.5 vs. 20.8%, not significant), and these also had significantly higher 30-min cortisol levels compared with controls (P < 0.05). The prevalence of CYP21 mutations in patients was 8.6% compared with 6.3% in controls (P = 0.38). Ten of 19 carriers had M17OHP levels below the cutoff limit. CONCLUSION: The significantly higher ACTH-stimulated levels of cortisol and 17OHP in hirsute patients indicated adrenal hyperresponsiveness in IH and PCOS. CYP21-carrier status could not explain the observed high prevalence of abnormal ACTH-stimulated 17OHP levels in the hirsute population.

[A rare cause of osteomyelitis. A case of Mycobacterium bovis in a wrist]. / En sjaelden arsag til osteomyelit. Et tilfoelde af Mycobacterium bovis i et håndled.

A cases of longstanding infection with Mycobacterium bovis is described in 79 year-old retired butcher presenting with broad erosions of the right wristbones. Further investigations revealed a chronic infection with Mycobacterium bovis present for 58 years. The patient was treated with antibiotics. The importance of having tuberculosis in mind when investigating lytic bone destruction is discussed.