More clinical data collected from thousands of patients are needed to better understand the association between venous thromboembolism (VTE) and testosterone therapy. However, accumulating that kind of data may not be possible, according to endocrinologist Charles J Glueck, MD, of the Jewish Hospital-Mercy Health in Cincinnati, Ohio. Clinicians are prescribing testosterone therapy with increasing frequency, but there is a growing concern about potential adverse events. Dr Glueck contends that currently available randomized studies are too underpowered to detect a relationship between VTE and testosterone.

He noted that without large randomized trials to assess risk for cardiovascular disease, VTE, prostate cancer, and all-cause mortality due to testosterone replacement therapy, there would be persistent controversy over whether testosterone therapy is “good, bad, or indifferent.” The optimal study would parallel the Women’s Health Initiative and would be prospective, placebo controlled, and double blind, with thrombotic and cardiovascular disease endpoints.

“Such a trial would be difficult to fund and carry out, since Onasanya and colleagues1 concluded that any randomized controlled clinical trial aimed at detecting a difference in cardiovascular risk between testosterone therapy and placebo groups would require at least 17,664 participants in each trial group. Houghton and colleagues2 similarly calculated that 15,613 subjects would be required in testosterone therapy and placebo groups,” Dr Glueck told Hematology Advisor.

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A Lack of Good Evidence

A recent system review and meta-analysis by Damon Houghton, MD, of the department of cardiovascular diseases, division of vascular medicine and department of internal medicine, and division of hematology/oncology at the Mayo Clinic in Rochester, Minnesota, and colleagues found that although current evidence provides little certainty, it does not support an association between testosterone use and VTE in men. The researchers included 6 randomized controlled trials (2,236 patients) and 5 observational studies (1,249,640 patients) in their analysis. Five of the randomized controlled trials were performed in men with documented hypogonadism, and the 5 observational studies were varied. They included 2 case control studies, 2 retrospective cohorts, and 1 retrospective cohort with a nested case control study.

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Houghton and colleauges found no evidence of a statistically significant association between VTE and testosterone therapy (odds ratio = 1.41). However, the researchers concluded that there is a scarcity of high quality research, and this prevents clinicians from arriving at any definitive conclusions. “It is very important to look beyond the overall summary statistic of our analysis and understand the significant heterogeneity in study populations and study quality which limits the strength of the conclusion. Additional high quality studies will be essential to more completely understand this possible risk [associated with] testosterone supplementation,” Dr Houghton told Hematology Advisor.

Samuel Denmeade, MD, co-leader of the prostate cancer program at the Johns Hopkins Kimmel Cancer Center and a professor of oncology and urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, said this systematic review is important because it provides clinicians with a better overall picture, even with its inherent limitations. “The conclusions were reasonable, given the data available for analysis. [The researchers] selected appropriate trials, randomized and observational, to include in the meta-analysis, and they had larger number of patients included across all the studies,” said Dr Denmeade.