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Requests for reprints should be addressed to G. Caleb Alexander, MD, MS, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street W6035, Baltimore, MD 21205.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MdCenter for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MdDivision of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, Md
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MdCenter for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, Md
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MdCenter for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, Md
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MdCenter for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, Md
Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, MdDivision of General Internal Medicine, Department of Medicine, Johns Hopkins Medicine, Baltimore, Md
We sought to evaluate whether exogenous testosterone therapy is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo.
Methods
Study selection included randomized controlled trials (RCTs) and observational studies that enrolled men aged 18 years or older receiving exogenous testosterone for 3 or more days. The primary outcomes were death due to all causes, myocardial infarction, and stroke. Secondary outcomes were other hard clinical outcomes such as heart failure, arrhythmia, and cardiac procedures. Peto odds ratio was used to pool data from RCTs. Risk of bias was assessed using Cochrane Collaboration tool and Newcastle and Ottawa scale, respectively. The strength of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation Working Group approach.
Results
A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs). Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision, and inconsistency.
Conclusions
We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone.
Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% confidence interval [CI], 0.39-1.93; 16 randomized controlled trials [RCTs]), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs).
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Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision, and inconsistency.
Sales of exogenous testosterone products, available since the 1950s, have increased substantially during the past 15 years. For example, the prevalence of commercially insured US men aged 40 years and older receiving androgen replacement therapy tripled over 10 years, from 0.81% in 2001 to 2.9% in 2011.
These increases have been attributed to factors such as the emergence of more convenient routes of delivery, such as gels and patches, as well as marketing of “low T” to middle-aged and elderly men with symptoms suggestive of hypogonadism.
among males with low testosterone levels, but these trials have been underpowered to evaluate safety. Early suggestion of potential cardiovascular risks with exogenous testosterone arose from the prematurely terminated Testosterone in Older Men with Mobility Limitations (TOM) trial.
In September 2014, a US Food and Drug Administration (FDA) advisory committee found insufficient evidence to confirm an association between cardiovascular events and testosterone, while in March 2015, the FDA issued a Drug Safety Communication cautioning that the use of testosterone was not approved for men with age-related low testosterone levels, and should be prescribed only to men with low testosterone levels caused by certain medical conditions after assessing the risk/benefit balance for each patient due to possible cardiovascular side events.
U.S. Food and Drug Administration FDA Drug Safety Communications: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use 2015.
Since early evidence of potential risk, additional observational studies have given rise to uncertainty about these signals, with some investigations suggesting decreased cardiovascular risk with these products.
We undertook our review to update previous analyses as well as to apply a more comprehensive literature search and more detailed evaluation of the quality of included studies. Also, in contrast to the previous systematic reviews, we used meta-analytic techniques appropriate for rare events and examined the risks of events such as myocardial infarction or stroke separately rather than as a single aggregate outcome representing all cardiovascular events. Thus, this systematic review and meta-analysis assessed whether exogenous testosterone therapy with any formulation, whether injection, oral, or topical, is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo.
Methods
Our review protocol (Appendix 1, available online) is published in the PROSPERO International Prospective Register of Systematic Reviews (Registration No. #CRD42015019259). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist is shown (Appendix 2, available online).
Study Selection
We included both randomized controlled trials (RCTs) and observational studies. Among them, we excluded: crossover trials and observational studies without any comparators; case reports; case series; and cross-sectional designs. Detailed selection criteria are provided in Appendix 3 (available online). Our included studies enrolled men aged 18 years or older, with a minimum of 10 participants in each group, who received exogenous testosterone, compared with either placebo, an active comparator, or another testosterone formulation or dose, for 3 days or longer. We excluded studies among patients with cancer, HIV, schizophrenia, end-stage renal disease, or primary hypogonadism.
Outcomes Extracted
Our primary outcomes for this systematic review were death due to all causes, myocardial infarction, or stroke. Secondary outcomes included other cardiovascular end points like arrhythmias, coronary angiography, pulmonary embolism, or venous thrombosis. We included studies that reported any of these outcomes as an adverse event, reason for withdrawal of patient from study, or effect estimates, such as hazard ratios (HR) or odds ratio (OR). We also included studies with zero events as long as they reported that there were “no cardiovascular events.”
Data Sources and Searches
We used a combination of controlled vocabulary terms and relevant free text keywords to search PubMed, MEDLINE, EMBASE, Cochrane Collaboration Clinical Trials, www.clinicaltrials.gov, and the FDA's Web site through August 28, 2015 (Appendix 4, available online). There were no language restrictions applied. We also hand searched the reference lists of previous systematic reviews. Two independent reviewers evaluated the abstracts for potential inclusion, categorizing them into “include,” “exclude,” and “unclear,” and a third reviewer adjudicated discordant pairs. We then compiled full text files for potentially eligible abstracts and reviewed these a second time using the same procedure to derive our final sample of eligible scientific reports.
Data Extraction and Quality Assessment
We used Microsoft Access (Microsoft Corporation, Redmond, Wash) to create separate data extraction forms for RCTs and observational studies. We extracted data on demographic characteristics, details of treatment, and control groups, as well as additional trial characteristics such as randomization method employed, adequacy of masking, and the funding sources. Wherever available, we identified the number of relevant cardiovascular events in both the treatment and control groups for RCTs and observational studies or the effect estimate, as well as the corresponding 95% confidence interval for the main analysis and any subgroup analyses performed.
Validity of the Included Studies
To assess the validity of the included RCTs, we evaluated risk of bias using the Cochrane Collaboration assessment criteria.
We evaluated the clinical and methodological heterogeneity of the studies to determine whether it was appropriate to pool the RCTs and observational studies for quantitative meta-analysis. Statistical heterogeneity was assessed using I2 statistic, with I2 values of >50% representing substantial heterogeneity, which would preclude quantitative synthesis.
Meta-Analysis and Assessment of Publication Bias
We employed fixed-effects models to calculate summary Peto odds ratios (POR) with 95% confidence intervals using StatsDirect version 3.0. In contrast to conventional meta-analytic methods such as DerSimonian and Laird random-effects models, this approach provides least biased estimates with good confidence interval coverage when modeling sparse outcomes.
We set statistical significance at 2-sided P value of .05, and a continuity correction of 0.05 was added to trials with zero events in either arm. We used an intention-to-treat analysis and included all participants, including dropouts, to minimize bias due to differential loss to follow-up across treatment arms in individual trials. The unit of analysis was individuals with cardiovascular events. We did not impute missing data; however, in 5 cases, we contacted the authors in order to get more information; Crawford et al
responded with sufficient details to include their study in the quantitative evidence synthesis. We evaluated publication bias using funnel plots as well as Eggers and Beggs-Mazumdar tests, when 10 or more studies were eligible for inclusion.
We separately analyzed studies including patients with preexisting cardiovascular disease or type 2 diabetes mellitus/metabolic syndrome. We tested the stability of our estimates with sensitivity analyses using both a fixed- and random-effects model for the OR and relative risk method, respectively. We applied 3 different continuity corrections: 0.5 continuity correction, reciprocal of the treatment arm continuity correction, and 0.01 continuity correction for studies with zero events in one arm.
Grading the Strength of Evidence
We assessed the strength of evidence using the major domains of risk of bias, imprecision, inconsistency, indirectness, and publication bias following the recommendations of the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE Working Group).
We initially evaluated 21,903 citations, of which 949 were considered for potential inclusion after screening of abstracts (Appendix 5, available online). Three RCTs and one observational study were identified from previous systematic reviews and hand searching, and included for full text screening. After full text screening, 39 RCTs were considered potentially eligible for inclusion in the systematic review
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Treatment group taken from men who were treated with testosterone in 40 low T centers in the US; Control group - Kaiser for myocardial infarction and Northern Manhattan Registry for stroke
Testosterone (mainly intramuscular)
T: 19,968 patients
T: 87% below 55 y of age
N/A
Myocardial infarction and stroke
C: For myocardial infarction – 821,725 hospitalization; For stroke – 117,000 residents
C: For myocardial infarction - 69 ± 14 y; For stroke – 74% below 55 y
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
included 5451 men, 3230 of whom were randomized to receive some formulation of exogenous testosterone and 2221 to receive placebo (Table 1). The trials varied in size ranging from 29 men
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
The mean ages of the participants in most of the RCTs were 50-60 years, and the cut-off of total serum testosterone levels for inclusion in the RCTs ranged from 300 ng/dL
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Most of the indications studied in included RCTs were symptoms of hypogonadism such as sexual dysfunction, depressive symptoms, or loss of bone mass and muscular strength.
Intervention and Comparison
Thirty-four trials compared one testosterone treatment group with placebo, and 4 trials compared treatment groups with different formulations vs placebo.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
did not have a placebo group but compared injection vs transdermal patch. Of the 34 trials with a single treatment group, 17 evaluated intramuscular injections, 14 evaluated topical preparations, and 3 evaluated oral tablets.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Overall, of 3230 patients randomized to receive testosterone, 69 were reported to have any primary event of interest, while 53 of 2221 patients randomized to placebo reported any primary event of interest. In many studies, reporting of the cardiovascular events was not detailed with events such as “cardiovascular complaints” or “cardiac adverse events” being mentioned. A list of all reported primary and secondary cardiovascular outcomes is provided in Appendix 6 (available online). Additionally, few RCTs reported that they had predecided criterion or definitions of cardiovascular safety end points.
Risk of Bias Assessment of RCTs
The design and methodology of the studies were poorly reported (Figure 1; Appendix 7, available online). For example, the randomization sequence generation and concealment of treatment allocation were not explicitly mentioned in 18
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
mentioned that the study was “double blind” without explicitly mentioning who was masked. Fourteen trials had more than 15% of the randomized participants who were lost to follow-up.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
For 30 of 39 RCTs that evaluated testosterone against a placebo, we performed meta-analysis separately for the 3 primary outcomes as well as composite outcome of myocardial infarction (16 trials), stroke (9 trials), and mortality (20 trials). In 3 studies that had more than one testosterone group compared with placebo, the treatment groups were combined to create a single pairwise comparison.
Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial.
Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study.
were excluded from the meta-analysis as they did not report on the outcomes of interest or failed to specify the distribution of events across the groups. Raynaud et al
Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.
Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study.
included in meta-analysis for myocardial infarction showing no statistically significant increased risk (POR 0.87; 95% CI, 0. 39-1.93; I2 = 36.4%; Figure 2A). There were 9 trials
Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial.
Effects of long term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).
that reported on stroke. There was no statistically significant increased risk of stroke (POR 2.17; 95% CI, 0.63-7.54; I2 = 29.9%; Figure 2B). There were 20 trials
Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.
Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial.
A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up.
Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study.
Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.
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