Risks of testosterone therapy in elderly men

Testosterone supplementation therapy (TST) is a widely used treatment for men with late onset hypogonadism. The benefits seen with TST, such as improved libido and energy level, beneficial effects on bone density have been well documented. Although hypogonadism remains an independent risk factor for mortality, recent studies have examined the association between testosterone therapy and cardiovascular risk.

Vigen et al. 1 examined the association between testosterone supplementation and cardiovascular morbidity in men older than 60 years. They performed a retrospective national cohort study of men with low testosterone levels (<300 ng/dL) who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011. The absolute rate of atherosclerotic events (myocardial infarction, stroke and mortality) was 19.9% in men who did not receive testosterone vs 25.7% in the men who were treated with testosterone. Men on testosterone supplementation were reported to have higher risk of adverse events than men not on testosterone, despite being younger and having less comorbidity.
One of the most important messages to glean from the study is that hypogonadism could be an adverse prognostic factor for cardiovascular and cerebrovascular morbidity and mortality. This message is also found in other studies about hypogonadism, including a large study on male veterans that showed that hypogonadism could be an important risk factor for increased mortality 2 . Further, in men with hypertension 3 , low testosterone levels were shown to be associated with increased risk of major cardiovascular adverse events.
In the Vigen et al. study men who received testosterone had lower pre-therapy testosterone levels, suggesting that they were even more hypogonadal than men who did not start testosterone therapy. In addition, it is unclear how much testosterone the men in the treatment arm actually received. Based on prescription refills, most men were on testosterone therapy for less than one year, and their mean post-treatment testosterone level was 332 ng/dL. With serum testosterone less than 300 ng/dL defined as biochemical hypogonadism by the Endocrine Society 4 , we are concerned that a significant proportion of men could have remained hypogonadal, in spite of testosterone treatment.
Additionally, the reasons for starting testosterone therapy cannot be determined from this retrospective analysis. Because of the uncertain reasons for starting therapy in some hypogonadal men and not in others, and because of the variability in the amount of total testosterone that the patients actually received, there may be confounding factors that could also explain the higher risk of adverse events in men treated with testosterone. It is unclear whether the minimal exposure to testosterone in this elderly population (as evidenced by the post-treatment levels and duration of treatment) was responsible for such a dramatic difference in mortality and morbidity.
The association between testosterone therapy and mortality has remained controversial with studies demonstrating conflicting results 5,6 . Until larger randomized studies demonstrate clear causation, physicians prescribing testosterone therapy to elderly men with co-morbidities should use it prudently with close follow-up.
Author contributions RR chose the article for correspondence and evaluated the data in the manuscript. JD wrote a part of the commentary. JK wrote the abstract and introduction. LIL supervised the process and critically edited the manuscript. All authors discussed the implications and commented on the manuscript at all stages.

Competing interests
Ranjith Ramasamy, James M. Dupree and Jason R. Kovac do not have any competing interests to disclosure. Larry I. Lipshultz has reported being a clinical trials participant, consultant, and speaker for Auxlium and Endo.

Grant information
The author(s) declared that no grants were involved in supporting this work.
Dr. Ramasamy and colleagues present a well-researched brief summary on a topic which has received great attention among physicians treating low testosterone. The authors provide a nice summary of a newsworthy publication by in JAMA in late 2013. The concerns presented with the Vigen et al. methodology of this article, primarily regarding the efficacy of likely sub-therapeutic testosterone replacement therapy in an elderly veteran population, are relevant and worthy of further study. Given the conflicting studies within the literature, further research is required to clearly delineate the cardiovascular risks (or lack thereof) in elderly men receiving testosterone replacement therapy.
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