Circulating concentrations of androgens decline gradually with aging before menopause and, unlike estrogen levels, do not decrease precipitously during the menopausal transition.112 In contrast, androgen levels decline sharply by ˜50% after surgical or medical oophorectomy (e.g., induced by administration of gonadotropin-releasing hormone [GnRH] analog). Estrogen replacement therapy also suppresses circulating free testosterone levels and probably contributes to postmenopausal symptoms of androgen deficiency (i.e., reduced libido and sexuality). Among surgically and spontaneously menopausal women with significant sexual dysfunction, androgen replacement therapy stimulates libido and improves the feeling of well-being and sexuality.105,112,113 and 114 Androgen treatment may also increase bone formation and density (see earlier). The major identifiable risk of androgen treatment in women is the potential for masculinizing side effects (e.g., acne, hirsutism, hair loss, and deepening of the voice). The effects and consequences of androgen therapy on body adiposity, fat distribution, muscle mass and strength, and risk of coronary artery disease and breast cancer are unknown.

With increasing age, otherwise healthy men experience a gradual decline in testicular function, and in total and free testosterone concentrations, so that levels in a significant proportion of elderly men (˜30%) fall below the normal range for young men.115 Testosterone production is compromised further by conditions such as illness, administration of some medications (e.g., glucocorticoids, CNS-acting drugs), and malnutrition, which occurs commonly in aging men. In addition to the decrease in testosterone levels, aging is associated with a functional decline in a number of androgen-dependent tissues, which results in diminished libido and erectile function; increased adiposity; reduced muscle mass and strength; decreased bone mass; increased risk of fractures; mood changes; diminished vigor; and alterations in sleep quality.115,116 Therefore, the age-related decrease in testosterone concentrations may contribute to these functional declines with aging. Short-term preliminary studies of the administration of testosterone enanthate to mildly androgen-deficient elderly men have revealed beneficial effects on lean body mass, muscle strength, bone turnover, libido, and mood, without significant adverse clinical effects, notably on either the prostate or serum lipid profiles, except polycythemia.117,118 and 119b Larger longer-term, randomized, placebo-controlled studies are needed, however, to determine the benefits and risks of androgen replacement therapy in elderly men (especially effects on the prostate and cardiovascular risk).

The demonstration that testosterone increases fat-free muscle mass and strength both in hypogonadal men receiving androgen replacement therapy and in eugonadal men who were using supraphysiologic dosages (matched for diet and exercise) has renewed interest in studying the anabolic effects of androgen administration in clinical states associated with muscle wasting (sarcopenia) and protein catabolism.63,64,120,121 These states include AIDS, cancer, chronic illness (e.g., end-stage renal disease, COPD), conditions due to use of medications (e.g., glucocorticoids), normal aging, muscle disease, autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus), major trauma and surgery, burns, immobilization, and zero-gravity conditions during space travel. Many patients with these conditions also have low serum testosterone concentrations, providing a further rationale for considering androgen treatment to increase muscle mass and strength, and most important, to improve muscle performance, physical function, and quality of life.