To test the hypothesis that the reduction in serum testosterone levels with aging contributes to an age-related physiologic and functional decline, carefully controlled clinical trials to determine whether testosterone replacement therapy in elderly men can improve physiologic indices and function are needed. Initial studies investigating the effects of testosterone replacement therapy in a small number of healthy elderly men have been reported recently.
In a double-blind, placebo-controlled, crossover study, Tenover found that administering testosterone enanthate, 100 mg a week, for three months to 13 healthy elderly men with low serum total and non-sex hormone-binding globulin bound testosterone levels substantially increased lean body mass, reduced urinary hydroxyproline excretion, increased hematocrit, and decreased the total and low-density lipoprotein-cholesterol without changing high-density lipoprotein (HDL)-cholesterol levels.
Furthermore, 12 of the 13 men experienced behavioral changes (such as increased libido and feelings of well-being) that permitted them to determine correctly whether they were receiving testosterone or placebo, despite the double blind design of the study. No adverse effects or changes in prostate volume or post-voiding residual urine volumes were noted, but serum prostate-specific antigen levels increased slightly during testosterone treatment.
In a preliminary study, Morley and co-workers found that administering testosterone enanthate, 200 mg every two weeks, for three months to eight elderly hypertensive men with low serum bioavailable testosterone levels substantially increased hand-grip strength, serum osteocalcin levels, and hematocrit and decreased total cholesterol without changing HDL-cholesterol levels, compared with six untreated control subjects.
Despite the short-term nature of these studies, testosterone treatment of mildly androgen-deficient elderly men had notable beneficial effects on lean body mass, muscle, and hematocrit and possibly on bone turnover and mood. No significant adverse clinical effects were noted.
As discussed by Swerdloff and Wang, when contemplating the use of testosterone replacement therapy in elderly men with mild androgen deficiency, the possible risks as well as benefits must be considered. Of particular concern is the potential for testosterone treatment to stimulate benign or malignant prostate growth – benign prostatic hyperplasia and prostate carcinoma, respectively – and to reduce HDL-cholesterol levels that may result in an increased risk of coronary artery disease.
Larger and longer term studies are needed to determine both the risks and benefits of androgen replacement therapy in elderly men. To avoid the adverse effects of pharmacologic levels of androgens, a reasonable initial goal of therapy in elderly men is to restore normal testosterone levels. If the late evening to morning rise in serum testosterone levels is found to be physiologically important (for example, in maintaining normal sleep quality), it may also be useful to restore a normal circadian variation of serum testosterone levels. Such truly physiologic testosterone replacement is now possible and practical using recently developed transdermal testosterone delivery systems.
In summary, aging in men is associated with a gradual and progressive decrease in serum testosterone levels and a decline in various physiologic functions. The physiologic importance of lower androgen levels in elderly men and their relationship to age-related decreases in sexual interest and function, muscle mass and strength, and bone mass and alterations in mood and sleep quality remain unclear. Clarification of the functional significance of reduced testosterone levels with aging (“andropause”) awaits carefully designed, long-term, placebo-controlled trials to determine the possible risks and benefits of androgen replacement therapy in selected elderly men.