Article Title: Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels

Authors: Rebecca Vigen, Colin I. O’Donnell, Anna E. Barón, et al

Date of Publication: November 6, 2013

A November, 2013 article in JAMA pointed to increased heart risks for individuals on testosterone therapy.  Since many teens and men with XXY rely on testosterone therapy, we asked Dr. Wylie Hembree, previous member of AXYS’s Board of Directors, to put this article in perspective for those we serve.

Dr. Hembree’s comments:

“Over the years, the question of safety of testosterone treatment of men has been evaluated.  Appropriate diagnosis and treatment of men with testosterone has been well demonstrated in the two Endocrine Society Clinical Practice Guidelines and they have pointed out the risks as well as benefits. A few studies have demonstrated the vulnerability of older men – especially frail older men – to testosterone treatment.  All of us are very careful about treatment of testosterone deficient older men, especially those with hypertension, heart disease, prostate disease and diabetes. No one should be treated with testosterone without a complete evaluation that clearly demonstrates both clinical and laboratory evidence of testosterone deficiency and carefully assesses the risks of the treatment.  Careful monitoring thereafter is essential, especially in men with the above mentioned conditions and older men in general. There is no evidence that testosterone treatment is responsible for prostate cancer but in older men monitoring for prostate cancer is much more difficult.

The JAMA article was not a clinical trial (none of the patients were ever seen by the investigators – the data came from the excellent computer record system of the VA). Nothing was randomized.  The criteria for giving testosterone was not mentioned or known. Most importantly, a significant number of the “testosterone group” were given only one prescription and probably did not take any testosterone or, if so, took it only for a short time.  The average time it could be documented that testosterone may have been given was less than half the duration of the study.  Thus, it was unclear whether those men (whose outcome and follow-up statistically differed from the control group not on testosterone) were actually on testosterone for the duration of the study.  Also, the number of men evaluated each period of time decreased enormously and only after half the duration of the study did the statistical difference between the two groups actually become significant.

The data do demonstrate a small significant difference, probably of clinical significance only in the “death” group, between those “assigned” to take testosterone and those not known to be given testosterone.  However, they do not have data that proves that the study group actually took testosterone.  It is not known how many took testosterone at all or whether any actually took it throughout the study. Thus, any difference in the groups cannot be ascribed to testosterone – unless exposure to testosterone for a short period of time increases rates of death, heart disease and stroke – unlikely but not verifiable by this study.

Another difficulty with the study is the reality known to all of us in practice.  We see and treat VA patients who receive care outside the VA system without knowledge of the VA. Thus, we have no clue how many controls may have been taking testosterone since there was no direct assessment of any patients by those who conducted the study.

It is an important study because it emphasizes the critical importance of caution, thorough pre-treatment evaluation and careful follow-up. Its existence charges all clinicians with caution in treating older men with testosterone – not a new thought.  However, the study has nothing to say about the safety of testosterone in younger men or in older men who clinically were NOT thought to  need coronary angiography (all men in the study “needed” angiography – maybe).  Hypogonadism is not an easy condition to diagnose precisely.  Proper diagnosis and treatment is complex in many people and always requires caution.  This study does not change the indication for proper testosterone treatment.”

Read more