Testosterone deficiency is a clinical syndrome characterized by low serum testosterone levels and a cluster of signs and symptoms that includes decreased libido, erectile dysfunction, decreased energy, depressed mood, and decreased sense of well-being. Data in the literature over the past 20 years have generally revealed an association between low testosterone levels and an increased risk for atherosclerosis, cardiovascular risk factors, and mortality. Numerous interventional studies on testosterone have consistently reported improvements in metabolic risk factors for cardiovascular disease including fat distribution, blood pressure, and glucose homeostasis 1. Randomized, placebo-controlled trials have documented reductions in the carotid intima-media thickness with testosterone therapy, raising the possibility that normalizing serum testosterone levels may counter atherosclerosis in the critical vascular beds 2. In addition, two large recent studies, one in a Veterans Administration population 3 and the other in men with diabetes 4, have reported reductions in mortality among participants with testosterone deficiency who were treated with testosterone therapy compared with untreated men. By contrast, two large retrospective studies found that testosterone therapy increased the risk for cardiovascular events 5,6, although the methodological analyses of these studies have attracted heavy criticism. Nonetheless, the controversy that these articles generated gained widespread media attention. This view was captured by an article published in the January 2014 issue of the New York Times entitled ‘New Concern About Testosterone and Heart Risks’ (http://well.blogs.nytimes.com/2014/01/29/study-adds-to-concern-about-cardiac-risks-for-older-men-taking-testosterone/?_r=0). Since the publication of that article, any person who watches US television regularly or has opened up a web browser would have probably come across the publicity generated by plaintiff attorneys seeking cases of myocardial infarction and stroke among men on testosterone therapy for a class action lawsuit and seeking monetary compensation.
The impact of these studies on patient management and the ensuing public attention has been substantial. Clinicians seeing patients on testosterone therapy have been criticized for starting patients on testosterone and putting their health at risk; this has resulted in some clinicians stopping the prescription of or refusing to prescribe testosterone products altogether. Several articles have been published cautioning the way in which testosterone deficiency is diagnosed and the appropriate use of testosterone therapy in older men and in men with a history of coronary artery disease. This has prompted the US Food and Drug Administration and the Endocrine Society to issue a call for more extensive and detailed assessments of the risks and benefits of testosterone therapy in older men with declining testosterone levels. More recently, the Food and Drug Administration has also mandated a labeling change in testosterone products to inform the public of the possibly increased risk for stroke and heart attack.
In the absence of adequately powered placebo-controlled, randomized clinical trials on testosterone therapy in older men with an age-related decline in testosterone levels, the long-term cardiovascular health implications of testosterone therapy in this patient population remain unclear 7. In response to the studies by Vigen et al.5 and Finkle et al.6, and the resultant controversy and publicity, we invited the authoritative reviews that comprise this special issue of Cardiovascular Endocrinology. Leading experts in the field have provided timely and practical guidance founded on knowledge of the metabolic and cardiovascular effects of testosterone-replacement therapy on cardiovascular risk among men. We would like to thank the contributors for their insightful articles that provide clinicians with a state-of-the-art perspective on this complex and highly controversial topic.
Conflicts of interest
There are no conflicts of interest.
1. Kim C, Halter JB. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women. Curr Cardiol Rep 2014; 16:467.
2. Saad F. Androgen therapy in men with testosterone deficiency: can testosterone reduce the risk of cardiovascular disease? Diabetes Metab Res Rev 2012; 28 (Suppl 2):52–59.
3. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97:2050–2058.
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. Eur J Endocrinol 2013; 169:725–733.
5. Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al.. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310:1829–1836.
6. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al.. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9:e85805.
7. Yuen K. Testosterone and cardiovascular disease: controversy or wake up call? Cardiovasc Endocrinol 2014; 3:117–122.