The effects and safety of testosterone replacement therapy for men with hypogonadism: the TestES evidence synthesis and economic evaluation.

There was no significant difference in cardiovascular and/or cerebrovascular events between testosterone replacement therapy and placebo groups.

• 13 studies were included in this analysis with an odds ratio of 1.07 (95% CI 0.81 to 1.42; p = 0.62)
• Event incidence was 120/1601 (7.5%) in the testosterone replacement therapy group versus 110/1519 (7.2%) in the placebo group
• The analysis was based on individual participant data meta-analysis combined with two-stage meta-analysis

There were too few deaths across included trials to permit a meaningful assessment of the effect of testosterone replacement therapy on mortality.

• 35 trials with 5601 randomised participants were identified
• The limited number of defined mortality events hampered meaningful evaluation
• The paper notes that 'a meaningful evaluation of mortality was hampered by the limited number of defined events'

Testosterone replacement therapy improved quality of life and sexual function in almost all patient subgroups.

• Improvements in quality of life and sexual function were observed across nearly all patient subgroups examined
• No evidence was found that particular subgroups of men benefited more than others from testosterone replacement therapy
• Medical studies often failed to prove that symptoms such as low mood, poor concentration, and lack of energy improved with testosterone replacement therapy

Testosterone replacement therapy was associated with higher serum testosterone and lower serum cholesterol, triglycerides, haemoglobin, and haematocrit compared to placebo.

• Serum testosterone was higher in the testosterone replacement therapy group
• Serum cholesterol, triglycerides, haemoglobin, and haematocrit were all lower in the testosterone replacement therapy group
• No adverse effects on blood pressure, serum lipids, or glycaemic markers were observed

The cost-effectiveness of testosterone replacement therapy was uncertain and dependent on modeling assumptions.

• Cost-effectiveness was dependent on whether uncertain effects on all-cause mortality were included in the model
• Results also depended on the approach used to estimate the health state utility increment associated with testosterone replacement therapy
• The utility increment may have been driven by improvements in symptoms such as sexual dysfunction and low mood
• There is 'too much uncertainty about the benefits of testosterone replacement therapy to accurately estimate its value for money for the NHS'

A qualitative evidence synthesis identified several themes showing how symptoms of low testosterone affect men's lives and their experience of treatment.

• Five qualitative studies were included in the qualitative evidence synthesis
• Men with low testosterone reported having low mood, poor concentration, and lack of energy
• Most medical studies were conducted among white men in North America using questionnaires designed specifically for them, limiting generalizability to other countries and ethnic backgrounds

The evidence base comprised 35 trials with 5601 randomised participants, of which 17 trials (3431 participants) provided individual participant data.

• Major electronic databases were searched from 1992 to February 2021, restricted to English-language publications
• Evidence was considered from placebo-controlled randomised controlled trials assessing any formulation of testosterone replacement therapy in men with male hypogonadism
• 17 of 35 identified trials (3431 participants) provided individual participant data for one-stage meta-analysis
• Definition and reporting of cardiovascular and cerebrovascular events and methods for testosterone measurement varied across trials