Low Free Testosterone Concentration as a Potentially Treatable Cause of Depressive Symptoms in Older Men

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Context  Serum concentrations of gonadal hormones have been associated with various measures of well-being, but it is unclear whether their association with mood is confounded by concurrent physical morbidity.

Objective  To determine whether the association between serum testosterone concentration and mood in older men is independent of physical comorbidity.

Design  Cross-sectional study.

Setting  Community of Perth, Western Australia.

Participants  A community sample of men aged 71 to 89 years.

Main Outcome Measures  We used the 15-item Geriatric Depression Scale (GDS-15) to assess depressed mood. Clinically significant depression was defined a priori as a GDS-15 score of 7 or greater. Physical health was assessed using the weighted Charlson index and the Physical Component Summary score of the 36-Item Short Form Health Survey.

Results  Of 3987 men included in the study, 203 (5.1%; 95% confidence interval [CI], 4.4%-5.8%) had depression. Participants with depression had significantly lower total and free testosterone concentrations than nondepressed men (P < .001 for both). However, they were also more likely to smoke and to have low educational attainment, a body mass index categorized as obese, a Mini-Mental State Examination score less than 24, a history of antidepressant drug treatment, and greater concurrent physical morbidity. After adjusting for these factors and for age, men with depression were 1.55 (95% CI, 0.91-2.63) and 2.71 (95% CI, 1.49-4.93) times more likely to have total and free testosterone concentrations, respectively, in the lowest quintile.

Conclusions  A free testosterone concentration in the lowest quintile is associated with a higher prevalence of depression, and this association cannot be adequately explained by physical comorbidity. A randomized controlled trial is required to determine whether the link between low free testosterone level and depression is causal because older men with depression may benefit from systematic screening of free testosterone concentration and testosterone supplementation.

Depression is a leading cause of disability worldwide,1 affecting 2% to 5% of the population at any point in time.2 The prevalence of depression is higher in women than in men throughout the lifespan, but sex differences all but disappear after age 65 years.3 The results of several experimental and observational studies and randomized trials suggest that gonadal corticosteroids might be partly responsible for such a sex-related phenomenon.4– 6 Currently available evidence suggests that estradiol has clinically relevant antidepressant properties,6– 10 but data in support of a potential role for testosterone in the modulation of mood remain scant.

Testosterone binds to an intranuclear androgen receptor that is ubiquitously distributed throughout the body, including the central nervous system.11 This receptor, in turn, binds to DNA and affects the production of messenger RNA, which modifies protein synthesis by the cell.11 The androgen receptor has a polymorphic CAG microsatellite coding for a variable length of glutamine residues, and men with shorter sequences of CAG repeats who have higher total testosterone levels seem to be less prone to experiencing clinically significant depressive symptoms.12 In target cells, testosterone can also be converted to 2 active metabolites: dihydrotestosterone, a highly potent activator of androgen receptors, and estradiol.13 It seems plausible, therefore, that low concentrations of testosterone will result in reduced androgen receptor activation and a decline in the concentration of estradiol in the brain. In addition, preliminary evidence14 suggests that testosterone has short- and long-term γ-aminobutyric acid (GABA)-ergic properties, and these actions may further contribute to the modulation of mood in men.

Pope et al15 found that 8 of 50 men aged 20 to 50 years treated with high doses of testosterone developed symptoms of hypomania. Moreover, testosterone levels have been inversely correlated with depression scores,16,17 and preliminary evidence suggests that men with depression have deficient testosterone secretion.18 Depression scores seem to increase with chemical castration19 and typically decrease with testosterone supplementation,20– 22 which is consistent with a possible causal link between the two. However, the association between testosterone and health outcomes is not specific to depression. Total testosterone and free testosterone levels decline with increasing age, but the concentration of free testosterone declines more markedly.23– 26 The resulting relative androgen deficiency in later life has been linked to decreased lean mass and increased fat mass, osteopenia, decreased muscle strength, fatigue, decreased hematocrit values, systemic illness and increased risk of coronary heart disease, and poor concentration, among other problems.27,28 This raises the possibility that the association between low testosterone concentration and depression in later life might be due to the presence of concurrent poor physical health.

We designed this study to examine the association between depressive symptoms and testosterone concentrations in older men. We hypothesized that men with clinically significant depression would have lower concentrations of free testosterone than nondepressed men and that this association would be independent of poor physical health.

Article Source: http://archpsyc.jamanetwork.com/article.aspx?articleid=482640

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