Gary A. Wittert

Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis

CONTEXT Low testosterone levels have been associated with outcomes that reduce survival in men. OBJECTIVE Our objective was to perform a systematic review and meta-analysis of published studies to evaluate the association between endogenous testosterone and mortality. DATA SOURCES Data sources included MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), and reference lists. STUDY SELECTION Eligible studies were published English-language observational studies of men that reported the association between endogenous testosterone and all-cause or cardiovascular disease (CVD) mortality. A two-stage process was used for study selection. 1) Working independently and in duplicate, reviewers screened a subset (10%) of abstracts. Results indicated 96% agreement, and thereafter, abstract screening was conducted in singlicate. 2) All full-text publications were reviewed independently and in duplicate for eligibility. DATA EXTRACTION Reviewers working independently and in duplicate determined methodological quality of studies and extracted descriptive, quality, and outcome data. DATA SYNTHESIS Of 820 studies identified, 21 were included in the systematic review, and 12 were eligible for meta-analysis [n = 11 studies of all-cause mortality (16,184 subjects); n = 7 studies of CVD mortality (11,831 subjects)]. Subject mean age and testosterone level were 61 yr and 487 ng/dl, respectively, and mean follow-up time was 9.7 yr. Between-study heterogeneity was observed among studies of all-cause (P < .001) and CVD mortality (P = 0.06), limiting the ability to provide valid summary estimates. Heterogeneity in all-cause mortality (higher relative risks) was observed in studies that included older subjects (P = 0.020), reported lower testosterone levels (P = 0.018), followed subjects for a shorter time period (P = 0.010), and sampled blood throughout the day (P = 0.030). CONCLUSION Low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, but considerable between-study heterogeneity, which was related to study and subject characteristics, suggests that effects are driven by differences between cohorts (e.g. in underlying health status).

Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.

IMPORTANCE Obesity is a risk factor for atrial fibrillation. Whether weight reduction and cardiometabolic risk factor management can reduce the burden of atrial fibrillation is not known. OBJECTIVE To determine the effect of weight reduction and management of cardiometabolic risk factors on atrial fibrillation burden and cardiac structure. DESIGN, SETTING, AND PATIENTS Single-center, partially blinded, randomized controlled study conducted between June 2010 and December 2011 in Adelaide, Australia, among overweight and obese ambulatory patients (N = 150) with symptomatic atrial fibrillation. Patients underwent a median of 15 months of follow-up. INTERVENTIONS Patients were randomized to weight management (intervention) or general lifestyle advice (control). Both groups underwent intensive management of cardiometabolic risk factors. MAIN OUTCOMES AND MEASURES The primary outcomes were Atrial Fibrillation Severity Scale scores: symptom burden and symptom severity. Scores were measured every 3 months from baseline to 15 months. Secondary outcomes performed at baseline and 12 months were total atrial fibrillation episodes and cumulative duration measured by 7-day Holter, echocardiographic left atrial area, and interventricular septal thickness. RESULTS Of 248 patients screened, 150 were randomized (75 per group) and underwent follow-up. The intervention group showed a significantly greater reduction, compared with the control group, in weight (14.3 and 3.6 kg, respectively; P < .001) and in atrial fibrillation symptom burden scores (11.8 and 2.6 points, P < .001), symptom severity scores (8.4 and 1.7 points, P < .001), number of episodes (2.5 and no change, P = .01), and cumulative duration (692-minute decline and 419-minute increase, P = .002). Additionally, there was a reduction in interventricular septal thickness in the intervention and control groups (1.1 and 0.6 mm, P = .02) and left atrial area (3.5 and 1.9 cm2, P = .02). CONCLUSIONS AND RELEVANCE In this study, weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity and in beneficial cardiac remodeling. These findings support therapy directed at weight and risk factors in the management of atrial fibrillation. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12610000497000.

Pericardial fat is associated with atrial fibrillation severity and ablation outcome.

OBJECTIVES The aim of this study was to characterize the relationship between pericardial fat and atrial fibrillation (AF). BACKGROUND Obesity is an important risk factor for AF. Pericardial fat has been hypothesized to exert local pathogenic effects on nearby cardiac structures above and beyond that of systemic adiposity. METHODS One hundred ten patients undergoing first-time AF ablation and 20 reference patients without AF underwent cardiac magnetic resonance imaging for the quantification of periatrial, periventricular, and total pericardial fat volumes using a previously validated technique. Together with body mass index and body surface area, these were examined in relation to the presence of AF, the severity of AF, left atrial volume, and long-term AF recurrence after ablation. RESULTS Pericardial fat volumes were significantly associated with the presence of AF, AF chronicity, and AF symptom burden (all p values <0.05). Pericardial fat depots were also predictive of long-term AF recurrence after ablation (p = 0.035). Finally, pericardial fat depots were also associated with left atrial volume (total pericardial fat: r = 0.46, p < 0.001). Importantly, these associations persisted after multivariate adjustment and additional adjustment for body weight. In contrast, however, systemic measures of adiposity, such as body mass index and body surface area, were not associated with these outcomes in multivariate-adjusted models. CONCLUSIONS Pericardial fat is associated with the presence of AF, the severity of AF, left atrial volumes, and poorer outcomes after AF ablation. These associations are both independent of and stronger than more systemic measures of adiposity. These findings are consistent with the hypothesis of a local pathogenic effect of pericardial fat on the arrhythmogenic substrate supporting AF.

Antenatal lifestyle advice for women who are overweight or obese: LIMIT randomised trial

Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women. Design Multicentre randomised trial. We utilised a central telephone randomisation server, with computer generated schedule, balanced variable blocks, and stratification for parity, body mass index (BMI) category, and hospital. Setting Three public maternity hospitals across South Australia. Participants 2212 women with a singleton pregnancy, between 10+0 and 20+0 weeks’ gestation, and BMI ≥25. Interventions 1108 women were randomised to a comprehensive dietary and lifestyle intervention delivered by research staff; 1104 were randomised to standard care and received pregnancy care according to local guidelines, which did not include such information. Main outcome measures Incidence of infants born large for gestational age (birth weight ≥90th centile for gestation and sex). Prespecified secondary outcomes included birth weight >4000 g, hypertension, pre-eclampsia, and gestational diabetes. Analyses used intention to treat principles. Results 2152 women and 2142 liveborn infants were included in the analyses. The risk of the infant being large for gestational age was not significantly different in the two groups (lifestyle advice 203/1075 (19%) v standard care 224/1067 (21%); adjusted relative risk 0.90, 95% confidence interval 0.77 to 1.07; P=0.24). Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g (lifestyle advice 164/1075 (15%) v standard care 201/1067 (19%); 0.82, 0.68 to 0.99; number needed to treat (NNT) 28, 15 to 263; P=0.04). There were no differences in maternal pregnancy and birth outcomes between the two treatment groups. Conclusions For women who were overweight or obese, the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.

OBJECTIVE: Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17β-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY).METHODS: Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations.RESULTS: Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized.CONCLUSION: Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

Long-term effects of a high-protein, low-carbohydrate diet on weight control and cardiovascular risk markers in obese hyperinsulinemic subjects.

OBJECTIVE: To compare the long-term compliance and effects of two low-fat diets differing in carbohydrate to protein ratio on body composition and biomarkers of cardiovascular disease risk in obese subjects with hyperinsulinemia.DESIGN: Outpatient, parallel, clinical intervention study of two groups of subjects randomly assigned to either a standard protein (SP; 15% protein, 55% carbohydrate) or high-protein (HP; 30% protein, 40% carbohydrate) diet, during 12 weeks of energy restriction (∼6.5 MJ/day) and 4 weeks of energy balance (∼8.3 MJ/day). Subsequently, subjects were asked to maintain the same dietary pattern for the succeeding 52 weeks with minimal professional support.SUBJECTS: A total of 58 obese, nondietetic subjects with hyperinsulinemia (13 males/45 females, mean age 50.2 y, mean body mass index (BMI) 34.0 kg/m2, mean fasting insulin 17.8 mU/l) participated in the study.MEASUREMENTS: Body composition, blood pressure, blood lipids, fasting glucose, insulin, CRP and sICAM-1 were measured at baseline and at weeks 16 and 68. Urinary urea/creatinine ratio was measured at baseline, week 16 and at 3 monthly intervals thereafter.RESULTS: In total, 43 subjects completed the study with similar dropouts in each group (P=0.76). At week 68, there was net weight loss (SP −2.9±3.6%, HP −4.1±5.8%; P<0.01) due entirely to fat loss (P<0.001) with no diet effect. Both diets significantly increased HDL cholesterol concentrations (P<0.001) and decreased fasting insulin, insulin resistance, sICAM-1 and CRP levels (P<0.05). Protein intake was significantly greater in HP during the initial 16 weeks (P<0.001), but decreased in HP and increased in SP during 52-week follow-up, with no difference between groups at week 68, indicating poor long-term dietary adherence behaviour to both dietary patterns.CONCLUSION: Without active ongoing dietary advice, adherence to dietary intervention is poor. Nonetheless, both dietary patterns achieved net weight loss and improvements in cardiovascular risk factors.

Chronic inhibition of endopeptidase 24.11 in essential hypertension : evidence for enhanced atrial natriuretic peptide and angiotensin II

Aim: To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension Methods: Two groups of 12 white male patients with essential hypertension were treated with candoxatril at 25 mg every 12 h (group 1) or at 200 mg every 12 h (group 2) for 5 days in double-blind, placebo-controlled, crossover studies Results: Candoxatril enhanced natriuresis over the initial 48 h of treatment. Twenty-fourhour diurnal hormone profiles (day 4) showed modest elevations in plasma atrial natriuretic factor (ANF) concentrations and more clear-cut increases in plasma and urinary cyclic CMP. Plasma angiotensin II and aldosterone concentrations were also significantly increased. Plasma catecholamine concentrations were significantly increased by the higher dose of candoxatril. Blood pressure (day 4, 24-h intra-arterial recordings) fell significantly with both doses. The infusions of exogenous ANF and angiotensin II on day 5 showed that candoxatril impaired the metabolic clearance of both ANF and angiotensin II with consequent enhancement of the biological effects of both effector peptides Conclusions: Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension. However, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity. The blood pressure response to endopeptidase inhibition in hypertensive patients may depend on the relative effects on humoral vasodilator (including ANF) and vasoconstrictor (including the angiotensin-aldosterone and sympathetic) systems

Obesity and testicular function.

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.

Circulating leptin concentrations in polycystic ovary syndrome : relation to anthropometric and metabolic parameters

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS).

Effect of a high-protein, energy-restricted diet on weight loss and energy expenditure after weight stabilization in hyperinsulinemic subjects

OBJECTIVE: To determine the effect of replacing some dietary carbohydrate with protein, during energy restriction, on weight loss, total energy expenditure (TEE), resting energy expenditure (REE), respiratory quotient (RQ), and the thermic effect of feeding (TEF) in subjects with hyperinsulinemia.DESIGN: Parallel, clinical intervention study of 12 weeks energy restriction (6.5 MJ/day) and 4 weeks energy balance (8.2 MJ/day) in two groups of subjects randomly assigned to either a high-protein (HP) diet (27% of energy (%E) as protein, 45%E as carbohydrate) or a lower-protein (LP) diet (16%E as protein, 57%E as carbohydrate).SUBJECTS: A total of 36 obese nondiabetic volunteers with hyperinsulinemia (10 males/26 females, aged 34–65 y, BMI 28–43 kg/m2, fasting insulin 12–45 mU/l).MEASUREMENTS: Body weight and composition, TEE, REE, and RQ were measured at baseline and at week 16. In addition, the TEF to an HP or LP meal was determined for 3 h, at baseline and at week 16.RESULTS: After 16 weeks, weight loss was similar in response to each diet; the overall decrease was 7.9±0.6 kg (P<0.001), of which 6.8±0.5 kg was fat (P<0.001). REE fell similarly with each diet; the overall decrease was 719±106 kJ/day (P<0.001). The TEF was 2% greater after the HP than after the LP meal at baseline (P<0.01) and 0.8% greater at week 16 (P=0.35). After 16 weeks, the TEF was not reduced in either dietary group. There was no change in TEE after 16 weeks.CONCLUSION: In subjects with hyperinsulinemia an energy-restrictive diet containing an increased protein-to-carbohydrate ratio does not enhance weight loss or significantly affect energy expenditure. Caloric restriction, rather than the macronutrient composition of the diet, is the most important determinant of weight loss.