Testosterone Supplementation Therapy for Older Men: Potential Benefits and Risks

Abstract

Serum testosterone levels decline gradually and progressively with aging in men. Many manifestations associated with aging in men, including muscle atrophy and weakness, osteoporosis, reduced sexual functioning, and increased fat mass, are similar to changes associated with testosterone deficiency in young men. These similarities suggest that testosterone supplementation may prevent or reverse the effects of aging. A MEDLINE search was performed to identify studies of testosterone supplementation therapy in older men. A structured, qualitative review was performed of placebo-controlled trials that included men aged 60 and older and evaluated one or more physical, cognitive, affective, functional, or quality-of-life outcomes. Studies focusing on patients with severe systemic diseases and hormone deficiencies related to specific diseases were excluded. In healthy older men with low-normal to mildly decreased testosterone levels, testosterone supplementation increased lean body mass and decreased fat mass. Upper and lower body strength, functional performance, sexual functioning, and mood were improved or unchanged with testosterone replacement. Variable effects on cognitive function were reported, with improvements in some cognitive domains (e.g., spatial, working, and verbal memory). Testosterone supplementation improved exercise-induced coronary ischemia in men with coronary heart disease, whereas angina pectoris was improved or unchanged. In a few studies, men with low testosterone levels were more likely to experience improvements in lumbar bone mineral density, self-perceived functional status, libido, erectile function, and exercise-induced coronary ischemia with testosterone replacement than men with less marked testosterone deficiency. No major unfavorable effects on lipids were reported, but hematocrit and prostate specific antigen levels often increased. Based on these results, testosterone supplementation cannot be recommended at this time for older men with normal or low-normal testosterone levels and no clinical manifestations of hypogonadism. However, testosterone replacement may be warranted in older men with markedly decreased testosterone levels, regardless of symptoms, and in men with mildly decreased testosterone levels and symptoms or signs suggesting hypogonadism. The long-term safety and efficacy of testosterone supplementation remain uncertain. Establishment of evidence-based indications will depend on further demonstrations of favorable clinical outcomes and symptomatic, functional, and quality-of-life benefits in carefully performed, long-term, randomized, placebo-controlled clinical trials.

Are declining testosterone levels a major risk factor for ill-health in aging men?

“…63 Overviews of randomized controlled trials of testosterone therapy in men without or with underlying chronic illness using a variety of testosterone formulations report improvements in body composition with increased lean body mass and reduced fat mass, but limited benefit in physical capabilities and equivocal improvements in quality of life measures, including general well-being and fatigue. [64][65][66] However, the studies reported tend to be of limited size and duration, with a lack of large-scale trials with extended long-term follow-up. Thus, additional studies have been recommended incorporating vitality, well-being and/or quality of life as end points.…”

“…Trials of testosterone therapy generally have not been designed or adequately powered to detect effects on clinically significant cardiovascular events. 16,[64][65][66]119,120 Although randomized controlled trial data are lacking, there are observational data which support a relationship between low testosterone and fatal cardiovascular events. Lower testosterone levels have been associated with increased overall and cardiovascular-related mortality in middle-aged and older men.…”

Dihydrotestosterone treatment rescues the decline in protein synthesis as a result of sarcopenia in isolated mouse skeletal muscle fibres

“…This finding has fuelled many trials in the use of TRT as a possible treatment for sarcopenia. However, in E men, TRT reverses some but not all the effects of sarcopenia 17, 22. It is also associated with several side effects including an increase in the risk of developing prostate cancer and gynecomastia, alterations in the composition of plasma lipids, and increased cardiovascular events.…”

“…For example, treating adult female rats,13 hypogonadal men,14 and E men with low testosterone (T) concentrations15 with T or any of its many derivatives for several weeks increases lean body mass and decreases fat content, suggesting that sex steroids are essential for the maintenance of skeletal mass and may be important in the management of sarcopenia. Although the concentration of free T in plasma decreases with age in both men and women,16 and T supplementation has been shown to increase lean body mass, T is not the most potent sex steroid in the body 17. Instead, in target tissues such as the skin, prostate, and brain, it is irreversibly metabolized to dihydrotestosterone (DHT) by the enzyme 5α‐reductase 18.…”

Androgens and male aging: current evidence of safety and efficacy

“…In hypogonadal men, testosterone replacement was associated with improved mood and well-being, and reduced fatigue and irritability [103][104][105]. Randomized controlled trials of testosterone therapy in men without or with underlying chronic illness using a variety of testosterone formulations, report equivocal improvements in QoL measures, including general well-being and fatigue [106,107]. For patients with major depression and/or dysthymia, improvement was equal to that achieved with standard antidepressants with significant improvement in the depression inventory score.…”