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EDITORIAL Testosterone Deficiency, Supplementation, and Prostate Cancer: Maintaining a Balanced Perspective Sir William Osler once stated, “The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow.” Although this may apply to many aspects of medical science, perhaps one topic it fits particularly well is testosterone (T) replacement therapy. Since the early pioneering work on T in the 1930s, acquired testosterone deficiency syndrome (TDS) has experienced several “pendulum swings” in regard to diagnosis and treatment. Initial excitement surrounded T therapy, which, much like the early entry of steroids into clinical medicine, purported to be a cure-all for many age-related ailments, even being referred to as a modern-day fountain of youth. Despite the fervor, subsequent clinical experience and data suggested that the actual benefits of therapy were significantly less than originally claimed and that it could even harm in certain conditions, such as prostate cancer [1]. As clinical experience mounted, the once groundbreaking therapy declined in popularity. More recently, TDS has experienced a resurgence of interest among patients, physicians, industry, and The Journal of Sexual Medicine ( JSM). From 2001 to 2011, the number of patients diagnosed with TDS in the United States has more than tripled, with Australia and the UK also demonstrating similar significant increases [2]. Subsequently, prescription T sales have risen exponentially from $18 million in 1988 to $1.6 billion in 2011 [3]. While this increase may reflect several factors, such as physician and public awareness, it may also signify a trend toward medical overdiagnosis and overtreatment. Low T remains a challenging condition to identify and treat for several reasons, including an absence of reliable standardized questionnaires, lack of consensus on a true chemical or clinical definition, nonstandardized assays, and poorly defined objective therapeutic end points. Each of these factors limits a clinician’s ability to accurately identify appropriate patients as well as to objectively define treatment failures and successes. Arguably, nearly all physicians who treat TDS have encountered asymptomatic patients with low © 2013 International Society for Sexual Medicine

T levels and symptomatic patients with normal or high T levels. Given this clinical disparity, some have elected to treat purely based on symptomatic improvement, regardless of T level. This practice is relatively indistinguishable from the administration of performance-enhancing substances, which similarly result in clinical and symptomatic improvements. These limitations have similarly restricted the extent and quality of conducted research and must be taken into account when interpreting reported outcomes. Despite these shortcomings, it is clear that a sizable percentage of men with TDS experience significant improvements in quality of life following T supplementation. As with any therapy, an appropriate balance must be achieved that weighs the anticipated risks and benefits of therapy. T has repeatedly been associated with multiple comorbid conditions, including obesity, diabetes, osteoporosis, dyslipidemia, anemia, and cardiovascular morbidity, among others. Even more significant, the association between low T and increased mortality is commonly cited [4]. Although these studies appear to give compelling evidence for the benefits of T replacement, they frequently represent a low quality of evidence (retrospective or observational studies) and only identify correlations. In contrast, several meta-analyses of trials (including randomized controlled trials [RCTs]) evaluating T replacement therapy in eugonadal and hypogonadal males have demonstrated no evidence for improved mortality, with modest improvements in diabetic indices, lipid profiles, sexual function, libido, and body composition [5–10]. Results from these studies suggest that although low T correlates strongly with several comorbid conditions, the effect of supplementation on these conditions is relatively limited. As such, T may be better understood as an indicator of overall health, rather than a causative factor. As with any therapy, it is always important to maintain broader perspective and ensure that anticipated benefits far outweigh any potential risks. Although T therapy undoubtedly results in J Sex Med 2013;10:2879–2881

2880 clinical improvements in select cohorts of patients with TDS, its role in men with existing and/or treated prostate cancer remains poorly defined. Exogenous T supplementation is well recognized to result in progression of metastatic prostate cancer, with currently available guidelines recommending against T therapy in men with existing prostate cancer [11–15]. Among men undergoing surgical resection of localized prostate cancer (including low and intermediate stages), micrometastatic disease has been identified using sensitive assays, with subsequent delayed development of biochemical recurrence in these patients [16,17]. Given the elevated recurrence rates observed in higher-grade and higher-stage tumors, increased rates of micrometastatic disease would also be expected in this population [18]. As microenvironmental triggers for the development of prostate cancer from micrometastases have not been defined, the role and threshold of T concentrations have not been adequately studied [19]. These observations provide a physiologic basis for the potentially detrimental effect of T in prostate cancer, and at a minimum, they suggest the need for further assessment of safety prior to routine use in men with existing or previously treated prostate cancer. One challenge in assessing the safety and/or efficacy of any therapy for prostate cancer is the large number of patients and length of follow-up required. One meta-analysis reported that in order to detect a 20% increase in prostate cancer rates (in men undergoing T supplementation) with 80% power and 5% significance (two-tailed), an estimated 85,862 men would need to be enrolled over a 12-month period [7]. Given these numbers, studies of small cohorts would be unable to detect the impact of T therapy on prostate cancer. Hence, studies with small patient numbers concluding safety with T therapy in men with prostate cancer are at an exceedingly high risk of reporting type II statistical errors, in which the null hypothesis (i.e., safety of T therapy) is accepted, when in fact, it may be false. This is particularly relevant with prostate cancer, which requires long follow-up periods to detect clinically meaningful differences. With this background in mind, several studies have evaluated the effect of T supplementation in prostate cancer. One recent retrospective analysis of 13 men with TDS and untreated prostate cancer concluded that T replacement did not result in cancer progression at a median follow-up interval of 2.5 years [20]. Similarly, other recent retrospecJ Sex Med 2013;10:2879–2881

Editorial tive series with limited follow-up (all

Testosterone deficiency, supplementation, and prostate cancer: maintaining a balanced perspective.

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