Introduction

Up to 20% of aging men may have significant hypogonadism, but little is known about the psychiatric implications of this condition. A recent review has addressed this topic, describing the normal changes with age in testosterone physiology, their relationship to behavior, and possible associations to depressive illness. The effects of testosterone replacement treatment on depressive symptomatology are also discussed.

Physiology

Testosterone, the primary androgen hormone, is secreted mainly by the Leydig cells of the testis, under the influence of the hypothalamic-hypophyseal-luteinizing hormone system. It binds to intranuclear androgen receptors situated throughout the body, including the limbic and cortical tissue of the central nervous system. Once within the target cell, testosterone is converted to dihydrotestosterone and estradiol; the former produces male sex effects, and the latter estrogenic effects in the CNS.

Free and total (i.e. including protein bound hormone) testosterone plasma concentrations peak around age 20. Then free testosterone declines throughout adult life at a rate of 1.2% per year, while total testosterone remains unchanged until about age 50, and then declines at about 0.6% per year. The rate of decline is faster in healthy men, as opposed to men with any illness. Declining levels are primarily due to reduced Leydig cell functioning. However, symptomatic hypogonadism cannot be directly related to a threshold plasma level of testosterone.

In adult males, testosterone secretion is both a cause and an effect of social interaction. Its most obvious action is on sexual behavior, but other effects - irritability, impulsiveness, aggression, violence - are not necessarily sex-related.

The effects of testosterone deficiency are quite similar to those of the aging process - increased body fat, and decreases in musculoskeletal mass, hematocrit, facial hair, appetite, libido, and memory. Testosterone replacement is able to reverse such changes in young hypogonadal patients and, to a lesser extent, in aging men. No trials have been reported, however, on the psychiatric benefits of testosterone replacement in older men with depressive symptoms.

Depressive illness in men

There is increasing evidence of an association between testosterone levels and male depression. Two epidemiological studies examined this relationship, with inconclusive results. Observational studies comparing the mean testosterone levels of groups of depressed men with those of non-depressed controls have also yielded discrepant findings. In both types of studies diurnal, seasonal situational and age-related variability in testosterone secretion may have contributed to the inconsistent results.¹,²

One relevant study measured afternoon testosterone in 12 men with major depression and in 12 age-matched controls.³ Although no difference in testosterone levels between the two groups was found, there was a significant negative correlation between hormone level and age in the depressed patients, but not in the controls. This suggests that depressed men may be more sensitive to the normal age-related decline in testosterone levels. Other studies summarized in the review corroborate this suggestion. However, the significance of a low testosterone level in the setting of depressive illness remains unclear.

Testosterone administration in depression

Administration of androgens to hypogonadal men has clear-cut effects on mood: increased friendliness, energy and well-being, with decreased nervousness, irritability, sadness and anger.⁴ The effects of testosterone administration in patients with established depression have not, however, been systematically investigated. Earlier, poorly designed studies suggested dramatic, if anecdotal, improvements. However, the reviewers summarize 7 trials that used DSM diagnostic criteria for major depression in which testosterone (or its androgenic metabolite mesterolone) was given with apparent beneficial results. Unfortunately the study designs employed do not allow a determination of whether the benefits seen are related to testosterone replacement, a direct effect on depressive symptoms, or are non-specific placebo effects.

Adverse effects of testosterone administration

Reduced plasma HDL-cholesterol, increased erythropoiesis and stimulated growth of an existing prostate carcinoma are known adverse effects of androgen treatment. There is less certainty regarding theoretical effects such as polycythemia, worsening coronary artery disease, and benign prostatic hypertrophy.

Comment

The available data on benefits of exogenous testosterone in male depression were not obtained specifically in aging men, and further research is clearly needed to address this. Until such studies have been completed, the authors are unwilling to recommend the use of testosterone treatment for late-life depression in men, particularly in view of the known adverse effects.