Is Testosterone Replacement Safe?

Dear Patients,
Recently there has been a great deal of press regarding the safety of Testosterone replacement. Two recent studies have suggested that Testosterone replacement therapy is associated with a higher risk of heart attack and stroke. The first study was first reported in November of 2013. This study was debated at the Sexual Medicine Society of North America’s meeting shortly after it was published. The conclusions by some of the most noted authorities in the country is reproduced for you below. It suggests that the study was poorly designed and fraught with technical errors. It was my suggestion at the time that patients on testosterone replacement therapy should continue on with their treatment.
A new study has just been published last week, that again claims that T replacement can be harmful to patients with heart disease. Like the previous study, it will have to be examined for its credibility. I will update you as soon as we have a consensus of opinion from medical experts in the field of T therapy.
Yours in good health,
George Carroll MD

Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels, Editorial Commentary by Ravi Kacker, MD and Abraham Morgentaler, MD

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BERKELEY, CA (UroToday.com) – Considerable concern has been expressed regarding the safety of testosterone (T) therapy since the recent publication in JAMA of a study alleging increased risk of death, and cardiovascular events in men who received testosterone. However, a careful reading of this study by Vigen, et al. reveals this concern is misplaced, and that the data appear to support the opposite conclusion.
The authors retrospectively investigated rates of death, myocardial infarction (MI), and stroke in a large cohort of men in the VA hospital system who had undergone coronary angiography and had a documented serum T < 300ng/dl.[1] The authors reported that men who were treated with T therapy had a greater risk of events than untreated men.
To anyone familiar with the testosterone field, this conclusion was surprising as it contradicts a rich literature spanning more than 20 years demonstrating a beneficial effect of T on cardiovascular function.[2] The discrepancy between the conclusion of this study and prior literature is explained by the highly statistical nature of the paper, and by a serious methodological error.
The raw data was as follows. Among 1 223 men who received T therapy, there were 67 deaths, 23 MIs, and 33 strokes for an event rate of 10.1% (123 of 1 223 men). For 7 486 men who did not receive T therapy, there were 681 deaths, 420 MIs, and 486 strokes for a rate of 21.2% (1 587 of 7 486 men), or roughly twice the rate of events for men on T therapy. Despite this, the authors wrote, “The absolute rate of events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group” at 3y following angiography. This is mathematically impossible, and the authors have since been obligated to revise their article, replacing “absolute risk” with “Kaplan-Meier estimated cumulative percentages with events.” The significance of this change is that it accurately reflects the fact that the conclusion was based on statistical estimates rather than compelling raw data. By the end of the study, the estimated event rate was approximately 30% for the T-group, a threefold multiple of what actually occurred, greatly magnifying potential errors.
The rationale for such a high degree of statistical manipulation becomes evident when one looks at the study design. All men began in the no-T group until some of them filled a prescription for testosterone, at which point they were assigned to the T group. However, men in this group also contributed survival data to the no-T group for the period prior to initiating T therapy. There was also a significant delay (mean 531d) in initiating treatment. An MI was attributed to the T group if a man filled his testosterone prescription the same day, but to the no-T group if he hadn’t yet filled it. Moreover, the two groups were dissimilar in important ways at baseline, with greater coronary artery disease burden in the no-T group, and lower serum T concentration in the T-group, each of which could influence outcomes. Clearly, a sophisticated statistical approach was necessary to accommodate these and other complex issues, causing the investigators to adjust for more than 50 variables. While understandable, this degree of complexity undermines the reliability of the results.
However, our greatest concern is the incorrect exclusion of 1 132 men who were placed on T therapy after MI or stroke. For the purposes of the study, once the event occurred it was irrelevant what happened subsequently to these men. All these events should have been attributed to the no-T group, which would have increased events in that group by 71.8%. Corrected for that serious methodological error, it seems likely that the results of this study would be consistent with two previous reports showing a substantial reduction in mortality with T therapy.[3, 4]
Shores, et al. also investigated the use of T therapy in a VA population of men with T< 300ng/dl. In that study, mortality in T-treated men was 10.3% compared with 20.7% in untreated men (P < 0.0001). Muraleedharan, et al. performed a similar investigation in diabetic men with T< 300ng/dl, and reported mortality of 8.4% in T-treated men and 19.2% in untreated men (P=0.002).
Defining the cardiovascular risk of T therapy is important, and will ultimately require a large, prospective trial. In the meantime, we must make do with available data, indicating on the whole that men with T deficiency are at increased risk for diabetes, metabolic syndrome, cardiovascular disease, and mortality.[5, 6] The conclusions of Vigen et al notwithstanding, early retrospective results suggest that T therapy may actually reduce cardiovascular events and mortality.
References:
  1. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA : The journal of the American Medical Association. Nov 6 2013;310(17):1829-1836.
  2. Traish AM, Kypreos KE. Testosterone and cardiovascular disease: an old idea with modern clinical implications. Atherosclerosis. Feb 2011;214(2):244-248.
  3. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. Journal of Clinical Endocrinology and Metabolism. Jun 2012;97(6):2050-2058.
  4. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. European Journal of Endocrinology / European Federation of Endocrine Societies. 2013;169(6):725-733.
  5. Tajar A, Huhtaniemi IT, O’Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). The Journal of Clinical Endocrinology and Metabolism. May 2012;97(5):1508-1516.
  6. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. Apr 2000;23(4):490-494.
Additional Recommended Reading:
  • Carson CC, 3rd, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. The Journal of Sexual Medicine. Jan 2012;9(1):54-67.
  • Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. The Journal of Endocrinology. Jun 2013;217(3):R47-71.
Written by:
Ravi Kacker, MD and Abraham Morgentaler, MD, Men’s Health Boston, Brookline, MA USA
JAMA Nov 6 2013;310(17):1829-1836
doi: 10.1001/jama.2013.280386
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