pipeline—selective androgen receptor modulators—that act on androgen receptors in a similar manner to testosterone and yet do not appear to be associated with adverse prostate outcomes.

For reasons described throughout this report, research on testosterone and its potential therapeutic use presents challenges to clinical researchers. Any clinical trial or set of trials designed to assess the risks and benefits of testosterone therapy in aging men must account for multiple, complex aspects of health and behavior across the lifespan. Because testosterone is a critical hormone in many physiological and anatomic systems, there are numerous health endpoints that could be studied. Each of these endpoints, in turn, is affected by a complex set of variables other than testosterone, including genetics, environment, lifestyle factors, comorbid conditions, and the use of other medications and therapies.

STRATEGY FOR FUTURE CLINICAL TRIALS IN OLDER MEN

After examining the research on endogenous and exogenous testosterone, and discussing the research questions that remain to be explored, the committee determined that this is an area in which further clinical trials are needed. This chapter provides the committee’s recommendations on future research directions with a focus on clinical trials of testosterone therapy in older men. To guide its recommendations on a research strategy, the committee developed a central hypothesis that provides a general premise for future clinical trials and a set of key conclusions and considerations that serve as a rationale for the recommended research approach.

Central Hypothesis

Aging in men is associated with a progressive decline in median bioavailable testosterone levels such that concentrations in many septuagenarians and especially octogenarians are at or below the levels associated with clear-cut hypogonadism in young men. Aging in men is also associated with progressive declines in fat-free mass (including muscle mass) and an increase in adipose mass, especially central visceral adiposity. Male aging is also associated with a decline in sexual function and, in some individuals, with a decline in affect and cognition. Many of these aging-associated changes begin in middle age and progress with advancing age such that muscular weakness, osteopenia, osteoporosis, sexual dysfunction, depression, and cognitive dysfunction are seen in a number of older men. These multiple deficiencies frequently coexist, resulting in diminished vitality, and often converge to reduce quality of life and lead to frailty, which threatens independence and life in old age.



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