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Men who start testosterone treatment may face an increased risk of venous thromboembolism (VTE) that peak within 6 months and then gradually decline, according to German researchers.

In a case-control study of more than 2.2 million men in the U.K., in the first 6 months of testosterone treatment, there was a 63% increased risk of VTE among current testosterone users, corresponding with 10 additional VTEs above the base rate of 15.8 per 10,000 person years, reported Carlos Martinez, MD, of the Institute for Epidemiology, Statistics and Informatics GmbH in Frankfurt, and colleagues.

However, the risk declined substantially after more than 6 months' treatment, as well as after treatment ended, they wrote in .

"The use of testosterone, especially in middle-aged and older men without pathological hypogonadism, may encounter a transient risk of venous thromboembolism when starting testosterone treatment," Martinez told MedPage Today.

The study followed a , which required that all approved testosterone products display a warning about the risk of VTE. While previous research investigated the association between testosterone treatment and risk of VTE in men, Martinez's group wanted to explore the timing of the risk.

Failure to investigate the timing of VTE in relation to the duration of testosterone use "could result in masking of an existing transient association," the author stated in a press release.

They collected data on 2.92 million men registered with the from January 2001 to May 2013. They compared 19,215 patients with confirmed VTE -- comprising both deep vein thrombosis and pulmonary embolism -- with 909,530 age-matched controls, and estimated their exposure from all prescriptions for a testosterone product issued before the index date.

Three mutually exclusive testosterone exposure groups were identified:

• No treatment in the previous 2 years.
• Recent but not current treatment.
• Current treatment of >6 months or <6 months.

Using conditional logistic regression to calculate estimates of the incidence rate ratios, the authors found that starting testosterone treatment, regardless of whether or not for the first time, was associated with an increased risk of VTE that initially peaks and declines gradually thereafter.

The adjusted rate ratio (RR) of VTE for current versus no testosterone treatment was 1.25 (95% CI 0.94-1.66). The RR after more than 6 months' treatment was 1.00 (95% CI 0.68-1.47), and after treatment cessation was 0.68 (95% CI 0.43-1.07).

Additionally, increased RRs within the first 6 months of treatment were observed for patients with and without pathological hypogonadism (1.52, 95% CI 0.94- 2.46 vs 1.88, 95% CI 1.02-3.45), as well as those with and without a known risk factor for venous thromboembolism [RR 1.41, 95% CI 0.82-2.41 vs 1.91, 95% CI 1.13-3.23).

The result "provides the first evidence for a differential in an adverse effect of testosterone treatment in men with and without pathological hypogonadism, which peaks in the first 6 months and declines thereafter."

But they also stressed that the study was an observational study, so no firm conclusions could be drawn regarding causation. Another study limitation was the chance of residual confounding or hidden bias.

Martinez told MedPage Today that "the mechanism for the transient increased risk due to testosterone treatment is uncertain. It may involve effects on thrombosis via decreased fibrinolysis and an interaction with previously undiagnosed thrombophilia-hypofibrinolysis, and/or with the higher underlying cardiovascular risk associated with erectile dysfunction. The initial increased risk of venous clotting might provoke a secondary response with more fibrinolysis, which tends to dissolve clots and eventually neutralizes the risk."

His group stated that "future research is needed to confirm this temporal increase in the risk of venous thromboembolism and to investigate the risk in first time testosterone users and confirm the absence of risk with long term use."

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