Oxidative stress, testosterone, and cognition among Caucasian and Mexican-American men with and without Alzheimer's disease

Abstract

Background: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal.

Objective: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone's neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load.

Methods: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer's Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone.

Results: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 μmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans.

Conclusion: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

Keywords: Androgens; Mexican American; antioxidants; homocysteine; luteinizing hormone.

Figure 1. Total testosterone and oxidative stress levels by ethnicity

Mexican-American men had significantly higher total testosterone levels than Caucasian Men. Total testosterone levels significantly decreased as a function of age, regardless of ethnicity (A). SHBG levels were not altered by total testosterone, regardless of ethnicity (B). Oxidative stress increased as a function of age in only Caucasian men not Mexican-American men. This effect of oxidative stress in Mexican-American men may be due to testosterone’s preconditioning effects in younger Mexican-American men (C).

Figure 2. CDRSUM, a measure of cognitive dysfunction, and the influence of oxidative stress and testosterone

In the low oxidative stress condition, testosterone levels did not alter CDRSUM scores in either Caucasian or Mexican-American men (A). In the high oxidative stress condition, testosterone significantly increased CDRSUM scores in Caucasian men, but significantly decreased CDRSUM scores in Mexican-American men (B). Testosterone significantly increased CDRSUM in Caucasians diagnosed with Alzheimer’s disease (C). * vs. hypogonadal Caucasian men and # vs. borderline and hypogonadal Mexican-American men.

Figure 3. SOD and the influence of oxidative stress and testosterone

Testosterone did not alter SOD levels in either Caucasians or Mexican-Americans, regardless of oxidative stress.

Figure 4. GST and the influence of oxidative stress and testosterone

In low oxidative stress, Mexican-American men had significantly higher GST levels than Caucasian men. Testosterone increased GST levels in Caucasian men (A). In high oxidative stress, Mexican-American men had significantly higher GST levels than Caucasian men. Testosterone significantly decreased GST levels in Mexican-American men (B). # vs. Caucasian men, * vs. hypogonadal men.

Figure 5. Luteinizing Hormone (LH) and cognition

Testosterone did not alter LH levels in either Caucasians or Mexican-American men. However, Mexican-Americans have significantly higher LH levels than Caucasians (A). In Caucasians, LH is higher in men diagnosed with Alzheimer’s disease and Mild Cognitive Impairment compared to cognitively intact men. No association between LH and disease status in Mexican-Americans (B). In a high oxidative stress condition, increased LH significantly increased CDRSUM (cognitive dysfunction) only in Caucasians (C). # vs. Caucasian men, + vs. Alzheimer’s disease and cognitively intact Caucasian men, $ v. cognitively intact Caucasian men, * vs. Caucasian men with normal LH.