Does testosterone treatment exacerbate serious injury risk?

Initiation of prescription testosterone treatment does not appear to further increase the risk of serious injury for patients beyond the already high baseline risk, a study has shown.

“Given the popularity of testosterone treatment, quantitative knowledge about the risk of serious injury also adds to existing research about thromboembolism risks to help improve informed patient choices, public policy, and clinical decision-making,” the researchers said.

A self-matched individual-patient exposure-crossover analysis was conducted to compare injury risks before and after initiation of testosterone. A total of 64,386 adults treated with testosterone (median age, 52 years; 89 percent men) in Ontario, Canada, from 1 October 2012 to 1 October 2017 (enrolment) and continued until 1 October 2018 (follow-up) were selected. The primary outcome was an acute traumatic event requiring emergency medical care.

Overall, 34,439 serious injuries were identified during the baseline interval before starting testosterone treatment (584 per month) and 7,349 serious injuries during the subsequent interval after initiating therapy (565 per month). [Am J Med 2021;134:84-94.E6]

Rates of injuries were higher than the population norm in both intervals without a substantially increased risk after starting testosterone (relative risk [RR], 1.00, 95 percent confidence interval [CI], 0.96–1.04; p=0.850). The unchanged risk was also seen in diverse patients, for different formulations, and applied to all injury mechanisms.

On the other hand, testosterone treatment correlated with a 48-percent increased risk of subsequent thromboembolic events, including ischaemic stroke, myocardial infarction, and pulmonary embolism (RR, 1.48, 95 percent CI, 1.25–1.74; p<0.001).

The upper bound of most observed CIs indicated the exclusion of a clinically important increased risk of serious injury from testosterone treatment, according to the researchers.

“Trial data are unlikely to contradict this result given the tendency of such trials to preferentially enrol healthy, cooperative, and safety-minded participants; moreover, our study is 10 times larger than the most recent meta-analysis of randomized trials of patients,” they said. [BMJ 2012;344:e1004; Ann Intern Med 2020;172:105-118]

Furthermore, the current study suggested other risk factors that should be prioritized for targeted interventions to reduce injury risk, particularly substance use disorder. [BMJ Open 2018;8e023776]

“The findings also help in clarifying the distinction between illicit supraphysiologic doses and clinical physiologic doses that may have different risks of violence because some patients who are prescribed testosterone would experience serious injury even without initiating treatment,” the researchers said. [Biol Psychiatry 2017;82:249-256; Horm Behav 2020;123104644]

The current study had several limitations, including the lack of many clinical details (eg, results of hormone testing, increases in haemoglobin, measures of adherence, etc.) and of data on illicit testosterone use. [BMJ Open 2017;7e015284; J Clin Endocrinol Metab 2018;103:1715-1744; Scand J Med Sci Sports 2011;21:e247-e259]

In addition, the databases did not provide information on distinct subgroups such as transgender adults, body builders, or those receiving supratherapeutic doses. Information on the indications for treatment, possible benefits, and less severe cases of injury that did not require emergency care were also lacking. [Transgend Health 2017;2:119-128; N Engl J Med 2016;374:611-624]