Testosterone and Male Aging: Faltering Hope for Rejuvenation.

Hopesforhormonal rejuvenationappearperiodically throughout history—with the most prominent attempt occurring around the turnof the20thcenturyonly tovanish in the 1930s following thediscoveryof testosterone,whichdiscredited testis extracts and manipulations. In recent decades, there has been a renewed attempt for hormonal rejuvenation with testosterone in men. Today,8decadessince the first clinicaluseof testosterone,1 the sole unequivocal indication for testosterone treatment is as replacement therapy for men with pathological hypogonadism (ie, organicdisorders of the reproductive system).2Yet despite no proven new indications, global testosterone sales increased 100-fold over the last 3 decades, including increasesof40-fold inCanada and 10-fold in the United States from 2000-2011.3 This was achieved by marketing strategies that circumvented the need for efficacy and safety testing of testosterone for male aging by stretching the definition of the term hypogonadism to encompass virtually any condition associated with low circulating testosterone levels. Promoted under the rubric “low T” (also referred to as andropause or late-onset hypogonadism), this process was facilitated by individual physicians and professional societies that minimized the fundamental distinction between pathological hypogonadism and functional states (including aging) associated with low circulating testosterone levels.4 This issue of JAMA includes the findings from 2 studies that report outcomes from the Testosterone Trials (TTrials), a set of 7 integrated, placebo-controlled randomized clinical trials with overlapping outcomes that tested whether testosterone treatment could ameliorate various aspects of male aging.5 These studies originated from an authoritative 2004 US Institute of Medicine (now National Academy of Medicine) review6 that concluded the paucity of efficacy evidence for testosterone treatment to ameliorate male aging precluded justifying a large-scale, prospective study comparable in scope with the Women’s Health Initiative for estrogen therapy in menopause.7 Responding to the mandate of that review, the National Institutes of Health funded the multicenter TTrials to test the short-term efficacy of testosterone on 7 clinical end points (sexual function, physical function, vitality, cognition, anemia, bone health, and cardiovascular health).5 The article reporting the primary TTrials outcomes8 was based on 790 men (recruited frommillions of invitation letters and resulting in >50000 telephone interviews) who were 65 years or older with low circulating testosterone levels for no apparent reasonother thanage (ie, excludingpathological hypogonadism)whowere randomized to receivedaily testosteronetransdermalgelorplacebogel for 12months.Compared with placebo, testosterone produced a modest increase in sexual function (a 42% relative increase compared with baseline) early in the study before waning by the end of the study, but therewasnoobjectivebenefit for physical function or vitality. The authors concluded that the benefits for sexual function were less robust than those associated with phosphodiesterase5 inhibitors.Anaccompanyingeditorial suggested that the findings were insufficient clinically to justify initiating testosterone use.9 In a report in this issue of JAMA, Resnick and colleagues10 present findings from the TTrials study examining cognitive function based on 493 men with a low testosterone level and age-associated memory impairment at baseline who completed a battery of cognitive function tests at baseline, 6 months, and 12 months, including 247 men in the testosterone group and 246 in the placebo group. The Cognitive Function Trial aimed to detect testosterone-induced enhancement in verbal or other cognitive functions in men with age-associated memory impairment. However, other than some practice (indistinguishable from placebo) effects, the authors found that testosterone produced no benefit in the primary outcome measured on the delayed paragraph recall test or in the secondary outcomes involving visual memory, spatial memory, or executive functions. An exploratory analysis extended to all men in the TTrials (ie, regardless of baselinememory) produced the same findingsofno statistical or clinically significant differences between groups. This is the largest well-controlled study of cognitive effects of testosterone in male aging to my knowledge, but the findings are not surprising because, among placebocontrolled studies, only a single small study ever indicated otherwise11 and a longer (3 years) but smaller study also had negative findings.12 These convincing, unequivocal findings affirm that testosterone treatment does not improve cognitive function in older men. Nevertheless, this does not preclude other possible psychological (eg, mood-elevating) effects of testosterone. In another report in this issue of JAMA, Budoff and colleagues13 present findingsof theTTrials cardiovascular trial involving a subset of 138menwith low testosteronewho completed computed tomographic (CT) evaluation of coronary artery plaque volumebefore and after 12months of testosterone Related articles pages 708 and 717 Opinion