Dataset Information

Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials.

ABSTRACT:

Background

The use of testosterone replacement therapy in obese men with low testosterone levels has been controversial. This review aims to analyze the effectiveness of testosterone therapy for weight loss and preventing cardiovascular complications in obese men with low testosterone levels.

Methods

We will perform a systematic review according to Cochrane Methodology of randomized studies, including crossover studies, wherein patients are allocated into one of the two groups: testosterone therapy and control (no treatment or placebo). The primary outcomes analyzed will be: weight loss, adverse events, quality of life, improvement of libido, control of obesity complications, frequency of cardiovascular events, and deaths. Four general and adaptive search strategies have been created for the following electronic health databases: Embase, Medline, LILACS, and CENTRAL. Two reviewers will independently select the eligible studies, assess the risk of bias, and extract the data from included studies. Similar outcomes measured in at least two trials will be plotted in the meta-analysis using Review Manager 5.3. The quality of evidence of the effect estimate of the intervention for the outcomes that could be plotted in the meta-analysis will be generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group.

Results

Although testosterone replacement seems to be an attractive treatment modality for obese men with low testosterone, its potential benefits has been refuted by some studies, whose results have not shown significant differences between treated and untreated patients.

Conclusion

For obese men with low testosterone concentrations, the proposed systematic review aims to answer the following questions: When compared with no treatment or placebo: Is testosterone therapy safe? Is testosterone therapy effective in promoting weight loss, a sustained reduction in body weight and changes in body composition? Is testosterone effective in improving quality of life, libido, and erectile function? Is testosterone therapy effective in controlling obesity complications and in preventing cardiovascular events?

SUBMITTER: Mangolim AS

PROVIDER: S-EPMC5944503 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials.

Mangolim Amanda S AS Brito Leonardo A R LAR Nunes-Nogueira Vania S VS

Medicine 20180401 17

<h4>Background</h4>The use of testosterone replacement therapy in obese men with low testosterone levels has been controversial. This review aims to analyze the effectiveness of testosterone therapy for weight loss and preventing cardiovascular complications in obese men with low testosterone levels.<h4>Methods</h4>We will perform a systematic review according to Cochrane Methodology of randomized studies, including crossover studies, wherein patients are allocated into one of the two groups: te ...[more]

PMID: 29703008

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Project description:Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Project description:BACKGROUND: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. METHODS: A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. RESULTS: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). CONCLUSIONS: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

Project description:Abstract BACKGROUND: In men, obesity is often associated with low testosterone (T) levels, but information is limited as to how body weight affects the pharmacokinetic profile or dosing of testosterone therapy (TTh) in men with T deficiency. Historically, men with body mass index (BMI) >32.4 kg/m2 required higher doses of T 2% gel to achieve physiological T levels than men with BMI ≤29.1 or 29.2–32.4 kg/m2.(1) In a phase 3 trial (N=150) of subcutaneous (SC) testosterone enanthate (TE) administered weekly, concentration-guided dosing raised T levels to within physiological range in 92.7% of patients.(2) Here, we report a post hoc analysis evaluating the association between body weight and serum T levels attained with SC TE. Methods: SC TE was evaluated in an open-label, single-arm, dose-blinded, 52-week phase 3 trial (NCT02159469). Patients self-administered 75 mg SC TE weekly during the titration phase; blinded dose-adjustments in 25 mg increments occurred at pre-defined time points beyond the sixth dose. The primary endpoint of this study was the percentage of patients achieving an average serum T concentration (Cavg0-168h) of 300 to 1,100 ng/dL at week 12. For this post hoc analysis, a linear regression model with weight and dose as independent variables was used to assess differences in mean minimum T concentration (Cmin) and Cavg0-168h at week 12. Results: For this analysis, 137 patients were included. Doses were 50 mg (n=25), 75 mg (n=93), and 100 mg (n=19). The mean weight was 84.4 kg, 102.2 kg, and 112.0 kg for the 50 mg, 75 mg, and 100 mg dose groups, respectively (range, 49.9–146.5 kg). The dose-normalized T Cmin was 9.2 ng/dL, 5.7 ng/dL, and 4.3 ng/dL per 1 mg of SC TE for the 50 mg, 75 mg, and 100 mg groups, respectively. The dose-normalized T Cavg0-168h was 12.0 ng/dL, 7.2 ng/dL, and 5.7 ng/dL per 1 mg of SC TE. In an overall linear regression model, 48.2% (P<0.0001) and 55.0% (P<0.0001) of the total variance in Cmin and Cavg0-168h, respectively, can be predicted from the independent weight and dose variables. Conclusion: Our results show an inverse relationship between body weight and T exposure. Men with higher mean body weights required higher doses of SC TE to achieve physiologic T levels compared with men with lower mean body weights. The available doses provide effective options to reach target exposures. These findings highlight the impact of weight and dose selection on SC TE exposure. References: (1) Dobs et al., J Sex Med 2014;11:857–864; (2) Kaminetsky et al., J Urol. 2019;201:587–94.

Project description:Context: Although androgen treatment increases muscle mass in HIV-infected men, the underlying mechanisms are poorly understood. Analysis of genome-wide microarray data obtained from skeletal muscle biopsies can be used to profile androgen-regulated pathways. Objective: To identify genes and pathways associated with testosterone treatment and myogenesis in the context of HIV-infected men using genome-wide microarray analysis of skeletal muscle biopsies. Results: A significant weight gain was observed in subjects treated with testosterone compared to placebo (+2.05 kgs and â??1.07 kgs, respectively; P = 0.003) as well as gains in DEXA lean; mass (2.93 kgs vs. 0.35 kgs, respectively; P = 0.003). Microarray expression profiles and RTPCR validation of RNA after 14 days of treatment indicated that several gene sets including; transcriptional control, myogenesis, adipogenesis, insulin signaling, apoptosis, cell cycle, chromatin remodeling, and stress response genes were differentially expressed with testosterone treatment. Protein expression analysis of myogenic differentiation and protein synthesis markers (MyoD, Myogenin, phosphorylated p38 MAPK and phosphorylated AKT) in muscle biopsies and skeletal muscle cells treated with DHT confirmed that testosterone engages; a network of pro-myogenic genes. Conclusions: Testosterone-associated gain in muscle mass in HIV-infected men engaged a network of regulatory pathways involved in broad transcriptional control, myogenesis, insulin signaling, chromatin remodeling, and stress response. Further evaluation of precise signaling intermediates within androgen regulated pathways may help to better define improvements in muscle mass, both in healthy and HIV infected patients. Experiment Overall Design: Design, Setting, and Participants: 44 HIV+ men with weight loss were randomized to receive either 300mg testosterone enanthate or placebo injections IM weekly for 16 weeks. Muscle Experiment Overall Design: biopsies were obtained at baseline and on treatment day 14. A random subset of specimens was chosen for microarray analysis; changes in selected genes were confirmed by reverse transcriptase - polymerase chain reaction (RT-PCR), and western blot analysis. Human skeletal Experiment Overall Design: myogenic precursor cells (SkMCs) were cultured in vitro in the presence of dihydrotestosterone (DHT) to evaluate activation of myogenic protein expression. Experiment Overall Design: Main outcome measures: Relative RNA levels in skeletal muscle biopsies were measured by expression profiling with microarrays and expression levels were validated in samples using quantitative RT-PCR. Further confirmation of changes in key myogenic biomarkers was obtained in DHT treated SkMCs.

Dataset Information

Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials.

Background

Methods

Results

Conclusion

Publications

Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials.

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