13 studies (76%) provided IPD for cardiovascular or cerebrovascular events (table 2). We were unable to confirm whether cardiovascular or cerebrovascular events occurred for the remaining four studies.44, 48, 49, 50 Of the 13 studies, two42, 43 reported no cardiovascular or cerebrovascular events. For one study38 outcomes were reported up to 3 years and the date of events could not be confirmed. The rate of cardiovascular or cerebrovascular events was not a primary endpoint in any of the included trials. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report.
The use of testosterone in healthy older men is not an authorised use in the EU. Testosterone-containing medicines are used to replace testosterone in men with hypogonadism. Risk of myocardial infarction in older men receiving testosterone therapy.
Testosterone reduced serum fasting glucose concentrations in cases for which this was recorded, but this effect became non-significant when patients with known diabetes were excluded. More men treated with testosterone had oedema and high haematocrit than treated with placebo. One-stage analysis for secondary outcome of physiological markers
Studies restricted to conditions not resulting from hypogonadism likely to affect cardiovascular or thrombotic risk (eg, cancer, HIV, cirrhosis, Klinefelter syndrome, type 1 diabetes), or studies restricted to men with congenital hypogonadotrophic hypogonadism were not deemed suitable for inclusion. Uncertainty regarding the safety of testosterone might unduly influence decision making regarding the management of men with hypogonadism who could otherwise derive substantial benefits from treatment. The US Food & Drugs Administration (FDA) has mandated a box label warning of potential cardiovascular risks for all testosterone products. Testosterone has potentially favourable effects on cardiovascular risk such as increased lean-to-fat body mass and improved insulin sensitivity and glycaemia.
An important strength of this IPD meta-analysis is its large size compared with individual testosterone trials, which have provided limited and situation-dependent information on cardiovascular safety. Because most trials do not publish details of individual adverse events, the exact frequency of cardiovascular events occurring during testosterone treatment, up until this point, has been unclear. Despite these risk factors, the overall incidence of cardiovascular events was not significantly higher during testosterone treatment than for placebo. For the one-stage meta-analysis, we used a fixed-effects logistic regression model accounting for clustering and allowing a separate intercept per study, with treatment effects presented as odds ratios (ORs) for the primary outcomes due to non-converge of a random-effects analysis.
Male hypogonadism has been increasingly diagnosed and treated in elderly males since the last decade. In addition to being responsible for primary sexual characteristics at birth and puberty (development and changes of sexual organs such as uterus, vagina, penis, and testes), testosterone is also involved in maintaining secondary sexual characteristics. However, a higher incidence of pulmonary embolism, acute kidney injury, and atrial fibrillation was noted in the testosterone group. Of note, a higher incidence of pulmonary embolism, acute kidney injury, and atrial fibrillation was noted in the testosterone group. The primary endpoint occurred in 7% of the testosterone group and in 7.3% of the placebo group.
The risk of study bias was assessed independently by MC and MA-M using the original version of the Cochrane Collaboration's risk of bias tool for randomised controlled trials.33 Follow-up enquiries were made with collaborators providing IPD for cases in which details required were unclear or not reported. All but two eligible studies had durations of 12 months or less; to aid data comparison between studies, secondary outcomes were assessed at 12 months or the time-point closest to 12 months. To address ongoing uncertainly about the safety of testosterone, the Testosterone Efficacy and Safety Consortium was established as a global collaboration of principal investigators of testosterone trials. Long-term safety of testosterone is not yet established; an FDA-mandated study is ongoing. We focused on trials with at least 3-month treatment duration and mean baseline total testosterone of 12 nmol/L or less (or equivalent) before treatment.