Testosterone in older men after the Institute of Medicine Report: where do we go from here?

Despite nearly a half-century of research on aging and sex steroids in men, answers to key questions that would allow us to confidently assess risk:benefit ratios for androgen replacement in older men with the partial androgen deficiency of aging men (PADAM) syndrome remain uncertain. Although it is now reasonably clear that a significant percentage of otherwise healthy older men have decreases in testosterone and bioavailable testosterone to levels consistent with hypogonadism, the clinical implications of this change remain uncertain. Data suggest that low testosterone in older men is correlated to varying degrees with loss of lean body mass and muscle strength, and increased total and central body fat. Less certain, but suggestive, are data relating low testosterone levels to decreased bone density, loss of insulin sensitivity, and cognitive and affective deterioration, as well as reduced sexual function. Replacement of testosterone in older men has shown some positive effects on each of these variables, but findings have been inconsistent, perhaps because studies have employed different preparations and doses of androgens, treated for various durations, and defined their target populations in different ways. As important as beneficial effects is the potential for adverse effects, which may be greater in older men. Possible problems include sleep apnea, erythrocytosis, dyslipidemia with acceleration of atherosclerosis, and, of greatest concern, prostate cancer or hyperplasia. Studies to date have suggested that these outcomes are not major risks, but, in the absence of a large, randomized trial or trials, definitive information is not available. The US National Academies Institute of Medicine's recent report recommends that the National Institutes of Health support small efficacy trials aimed at treatment of androgen deficiency-related clinical conditions, but not a large, randomized trial to elucidate risk:benefit ratios. This recommendation, if adhered to, is likely to delay, rather than foster, progress in this important area.