BERKELEY, CA (UroToday.com) - The use of testosterone in the United States has increased by approximately 400% over the past decade. However, the long-term risks and benefits of testosterone replacement remain unclear because no studies have been large enough or long enough to adequately assess the outcomes.
Low serum testosterone levels are common in aging men and are associated with adverse health conditions such as the metabolic syndrome, diabetes, dyslipidemia, cardiovascular disease, and mortality.[3, 4, 5] Testosterone treatment trials have reported benefits of testosterone treatment such as increased libido and strength,[6, 7, 8, 9, 10, 11] and a recent meta-analysis of testosterone-treatment studies found no increased mortality associated with testosterone treatment.[12, 13] However, the significance of the meta-analysis was limited as most of the studies had small sample sizes and short treatment durations. No epidemiological studies have previously examined the association between testosterone treatment and mortality as a primary outcome. Given the high prevalence of low testosterone levels in men and the increased use of testosterone, an important public health issue is to clarify the risks and benefits of testosterone treatment.
The purpose of our study was to examine if testosterone treatment was associated with early mortality in men with low testosterone levels and whether the relationship between testosterone therapy and mortality was modified by age, prevalent coronary heart disease, or diabetes mellitus. We conducted an observational study of testosterone treatment versus non-treatment in 1 031 male veterans who were older than 40 years (mean age: 62) and had low total testosterone levels (< 250 ng/dl). Mean follow-up was 41 months. Testosterone treatment was initiated in 36% of the men and was associated with decreased mortality compared to non-treatment (9.9% vs. 20.5%; P < .001) in an unadjusted analysis. In multivariable adjusted analyses, testosterone treatment was associated with a 39% decrease in mortality risk with a hazard ratio of 0.61 (95% confidence interval: 0.42-0.88, p=.0008). There was no significant effect modification by age, prevalent coronary heart disease, or diabetes. We performed a propensity-score analysis to adjust for the observational study design and non-randomization to treatment, and we continued to find similar results. There were no significant differences in incident prostate cancer in the testosterone-treated and untreated men (1.9% vs. 2.1%; p=NS), but the sample size was inadequate to detect small differences.
There are several limitations to our study. Subjects were not randomized to treatment, and it is possible that the results were due to differences between groups rather than to testosterone treatment. We attempted to control for this by adjusting for confounders and conducting a propensity score analysis, a technique that minimizes bias in observational studies. However, it is still possible that there were some unmeasured differences between groups that may have influenced the results. Other limitations were that our analysis was based on a single baseline testosterone level, but guidelines recommend two serum testosterone levels before initiation of testosterone therapy. In addition, the clinical data set did not contain information on specific symptoms associated with low testosterone, but we obtained data on diagnoses that might be associated with low testosterone levels (e.g. osteoporosis, sexual dysfunction). Finally, it is unclear how generalizable our results are because the subjects were men with a high degree of chronic medical illness who were treated at Veterans Administration (VA) medical centers. Thus, our results may not be generalizable to healthier men.
Despite these limitations, the significance of this study is that it is the first long-term study to examine the relationship between testosterone treatment and mortality in a large cohort of men followed for several years. This study found that testosterone treatment was associated with decreased mortality in multivariable-adjusted analyses including a propensity-score analysis to adjust for potential selection bias.
Because of the observational study design, these results must be viewed with caution, and they do not imply a causal relationship between testosterone treatment and decreased mortality. However, the results provide some reassurance that testosterone replacement therapy is not harmful. The results also provide the rationale for conducting a large, prospective, long-term trial designed to determine the benefits and risks of testosterone replacement in men. A landmark trial, the Women’s Health Initiative, provided essential information about the effects of sex steroid hormone therapy for postmenopausal women. The Women’s Health Initiative changed clinical practice. A similar trial should be conducted in men.
- FDA. http://www.fda.gov/Drugs/DrugSafety/default.htm; Post Market Review, Volume 2, No 3, 20092009.
- Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. International Journal of Clinical Practice. Jul 2006;60(7):762-769.
- Farrell JB, Deshmukh A, Baghaie AA. Low testosterone and the association with type 2 diabetes. Diabetes Educ. Sep-Oct 2008;34(5):799-806.
- Rosano GM, Sheiban I, Massaro R, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res. Mar-Apr 2007;19(2):176-182.
- Matsumoto AM. Andropause: Clinical implications of the decline in serum testosterone levels with aging in men. Jnl of Gerontology: Medical Sciences. 2002 2002;57A(2):M76-M99.
- Atkinson RA, Srinivas-Shankar U, Roberts SA, et al. Effects of testosterone on skeletal muscle architecture in intermediate-frail and frail elderly men. Journals of Gerontology. Series A, Biological sciences and medical sciences. Nov 2010;65(11):1215-1219.
- Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. Journal of Cinical Endocrinology and Metabolism. Feb 2010;95(2):639-650.
- Shores MM, Kivlahan DR, Sadak TI, Li EJ, Matsumoto AM. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). Journal of Clinical Psychiatry. Jul 2009;70(7):1009-1016.
- Webb CM, Elkington AG, Kraidly MM, Keenan N, Pennell DJ, Collins P. -Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. American Journal of Cardiology. Mar 1 2008;101(5):618-624.
- Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA :The Journal of the American Medical Association. Jan 2 2008;299(1):39-52.
- Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail. Jan 2007;9(1):44-50.
- Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. Jun 2006;91(6):2011-2016.
- Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. Int J Impot Res. Jan-Feb 2009;21(1):9-23.
- Liverman Ce, Blazer De. Testosterone and Aging: Clinical Research Directions, Institute of Medicine. Washington D. C. : National Academy Press; 2004.
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. Journal of Cinical Endocrinology and Metabolism. Jun 2010;95(6):2536-2559.
Molly M. Shores, MD,* Bradford D. Anawalt, MD, and Alvin M. Matsumoto, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
University of Washington
VA Puget Sound Health Care System
Seattle, WA 98108