Increased Incidence of Diagnosed Depressive Illness in Hypogonadal Older Men
Shores MM, Sloan KL, Matsumoto AV, Moceri VM, Felker B and Kivlahan DR ;
Commented by , 24 Mar 2004
Background
Age associated testosterone deficiency occurs in 30% of men over 55, and is associated with reduced libido, memory problems, anorexia, fatigue, dysphoria and irritability. While these symptoms overlap with depression, the association between hypogonadism and depression remains unclear.
Purpose
Explore the longitudinal relationship between hypogonadism and 2-year incident depression in older men.
Methods
A historical cohort study using computerized clinical records from the Veterans Affairs Puget Health Care System, validated by manual record review. Subjects were 278 men older than 45 with no history of depression and repeated testosterone levels (baseline and during a 2-year follow-up period). Hypogonadism was defined by total and free testosterone levels ≤ 200ng/dL and ≤0.9ng/dL, respectively.
Depression was determined by ICD-9-CM codes recorded by clinicians in outpatient and inpatient settings. Because of circadian variation of testosterone levels, phlebotomy times were recorded. Main outcome measures included incidence and time to a diagnosis of depression.
Results
During the 2-year follow-up period, hypogonadal men had a significant increase in incident depression compared with eugonadal men (21.7% vs 7.1%; χ2=6.0, p=0.01). Lower total testosterone thresholds were associated with increased incident depression: 29% incidence ≤ 150ng/dL, compared to 13% using the least stringent threshold ≤ 350ng/dL. There was a significant increase in incident depression for all total testosterone thresholds ≤ 280 ng/dL.
Hypogonadal men had a significantly shorter time to depression diagnosis, using a Kaplan-Meier survival analysis (p=0.008). Controlling for all covariates (age, race, number of clinic visits, alcohol use disorders, prostate cancer, medical comorbidity), the adjusted hazard ratio for depression with a low testosterone level was 4.2 (95% confidence interval, 1.5-12.0; p=0.008) using Cox proportional hazards regression models. There were no between group differences in phlebotomy times.
Discussion
Previous studies evaluating the relationship between hypogonadism and depression have yielded mixed findings. In this first study examining the relationship longitudinally, a 4-fold increase in incident depression was found in hypogonadal men. While a provocative finding, the results should be viewed as preliminary given the inherent limitations of the study’s historical design.
A selection bias may have occurred in this population of men having repeated testosterone levels ordered. The diagnosis of depression based on codes recorded in routine care raises concerns about diagnostic validity. Finally, the results were based on total testosterone levels, which appears to be a poor indicator of hypogonadism in older men compared to other assays (ref. 1,2).
While these findings represent an important contribution, the association between hypogonadism and depression remains far from clear. Despite the uncertainty of the association, testosterone treatment or augmentation studies in depression have already been underway, with mixed results (ref. 2,3). With the marketing efforts of industry, these small studies can have a powerful impact on prescribing practices. There is a paucity of long-term safety data on testosterone replacement in older men.
Reported adverse effects include gynecomastia, irritability, acne, hair loss, worsening of sleep apnea, increases in hematocrit and platelet aggregation; these latter changes raising concerns about cerebro- and cardiovascular events. Additional potential risks include prostate cancer and aggression
(ref. 3). Given the potential for serious adverse effects, prospective, well-designed studies are necessary to further establish the relationship between hypogonadism and depression before moving ahead with treatment studies, and moreover considering testosterone treatment or augmentation in the treatment of depression.
References
1. Morley JE, Patrick P, Perry III HM. Evaluation of assays available to measure free testosterone. Metabolism 2002;51:554-559
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2. Morley JE. Testosterone and behavior. Clinics in Geriatric Medicine 2003;19(3):605-616
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3. Sternbach H. Age-associated cognitive decline in men: clinical issues for psychiatry. American Journal of Psychiatry 1998;155:1310-1318.
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