Objective: Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels. Design: Meta-analysis. Methods: An extensive Medline search was performed including the following words: 'testosterone', 'diet', 'weight loss', 'bariatric surgery', and 'males'. The search was restricted to data from January 1, 1969 up to August 31, 2012. Results: Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery. Overall, both a lowcalorie diet and bariatric surgery are associated with a significant (P!0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51-10.95) vs 2.87 (1.68-4.07) for bariatric surgery and the low-calorie diet, respectively; both P!0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (BZ2.50G0.98, PZ0.029). Conclusions: These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.

Several studies suggest that type 2 diabetes mellitus (T2DM) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in T2DM has not been completely clarified. The aim of the present study was to analyse systematically the relationship between androgen levels and T2DM by reviewing and meta-analysing available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was performed. An extensive Medline search was performed including the following words: 'testosterone', 'type 2 diabetes mellitus' and 'males'. Of 742 retrieved articles, 37 were included in the study. In particular 28, 5 and 3 were cross-sectional, longitudinal and interventional studies, respectively. A further unpublished RCT was retrieved from http://www.clinicaltrials.gov. T2DM patients showed significantly lower testosterone plasma levels in comparison with non-diabetic individuals. Similar results were obtained when T2DM subjects with and without erectile dysfunction were analysed separately. Meta-regression analysis demonstrated that ageing reduced, while obesity increased, these differences. However, in a multiple regression model, after adjusting for age and body mass index (BMI), T2DM was still associated with lower total testosterone (TT) levels (adjusted r = -0.568; p < 0.0001). Analysis of longitudinal studies demonstrated that baseline TT was significantly lower among patients with incident diabetes in comparison with controls (HR = -2.08[-3.57;-0.59]; p < 0.001). Combining the results of RCTs, TRT was associated with a significant reduction in fasting plasma glucose, HbA1c, fat mass and triglycerides. Conversely, no significant difference was observed for total and high-density lipoprotein cholesterol, blood pressure and BMI. The meta-analysis of the available cross-sectional data suggests that T2DM can be considered independently associated with male hypogonadism. Although only few RCTs have been reported, TRT seems to improve glycometabolic control as well as fat mass in T2DM subjects.

Objective: To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs). Design: Meta-analysis. Methods: An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011. Results: Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-b estradiol (E 2 ) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E 2 levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)Z0.763 (0.744-0.783) and HRZ1.015 (1.014-1.017), respectively, for each increment of total testosterone and E 2 levels; both P!0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall-and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E 2 levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. Conclusions: Lower testosterone and higher E 2 levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.

Introduction Metabolic syndrome (MetS) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in MetS has not been completely clarified. Aim To systematically analyse the relationship between androgen levels and MetS we performed a review and meta-analyses of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was also performed. Methods An extensive Medline search was performed including the following words “testosterone,” “metabolic syndrome,” and “males”. Main Outcome Measures Out of 323 retrieved articles, 302 articles were excluded for different reasons. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and RCTs, respectively. Another unpublished RCT was retrieved on http://www.clinicaltrials.gov. Results MetS patients showed significantly lower T plasma levels, as compared with healthy individuals. Similar results were obtained when MetS subjects with and without erectile dysfunction were analyzed separately or when NCEP-ATPIII MetS criteria were compared with other definitions. Meta-regression analysis demonstrated that type 2 diabetes (T2DM) increased the MetS-associated T fall. In a multiple regression model, after adjusting for age and BMI, both T2DM and MetS independently predicted low testosterone (adj. r = −0.752; P &lt; 0.001 and −0.271; P &lt; 0.05, respectively). Analysis of longitudinal studies demonstrated that baseline testosterone was significantly lower among patients with incident MetS in comparison with controls (2.17 [−2.41;−1.94] nmol/L; P &lt; 0.0001). Combining the results of RCTs, TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed. Conclusions The meta-analysis of the available cross-sectional data suggests that MetS can be considered an independent association of male hypogonadism. Although only few RCTs have been reported, TRT seems to improve metabolic control, as well as central obesity.

Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulphonylureas deserves further investigation.

SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high-density lipoprotein (HDL)-cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT-2 inhibitors appear to be well tolerated.

Aims: Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods:A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Conclusions:Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms.

The present meta-analysis seems to exclude any relevant short term effect of DPP4i on the incidence of cancer and suggest a possible protection from cardiovascular events. This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short, and the characteristics of patients included could be different from routine clinical practice.