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RAPID COMMUNICATION |
1 Center on Aging, University of Connecticut Health Center, Farmington.
2 Baystate Medical Center, Springfield, Massachusetts.
Abstract
Background. The role of sex hormones in the prevention of cognitive decline is uncertain. Animal studies suggest mechanisms for sex hormones including testosterone to maintain optimal cognitive function. But, there are studies to suggest that endogenous testosterone levels are associated with aggression in men with cognitive impairment.
Methods. In this pilot study, 11 men (mean age 80 ± 5 years, range 73–87 years) with early cognitive decline and bioavailable testosterone levels below 128 ng/dl (lower limit for adult normal range) were randomized to receive intramuscular testosterone (200 mg every 3 weeks) or placebo for 12 weeks. Outcome measures included sex hormones (testosterone, bioavailable testosterone, sex hormone binding globulin, estradiol, and estrone), Behave AD Questionnaire, Katz Activities of Daily Living, Geriatric Depression Scale, Digit Span, Clock Face Drawing, Clock Face Perception, Verbal Fluency, Trail-Making B, and International Prostate Symptom Score at baseline, 4 weeks, and 10 weeks.
Results. All men completed the study. Total and bioavailable testosterone, estrone, and estradiol levels increased in men receiving testosterone, but no changes were detected in men receiving placebo. No significant changes were found in behavior following testosterone supplementation, nor was there evidence of change in depression or activities of daily living. No discernable changes were found in any of the cognitive tests. Symptoms of prostate hyperplasia remained unchanged in the testosterone (6.6 + 5.8 to 5.2 + 3.6; p =.39) and placebo (8.8 + 6.4 to 6.4 + 3.8; p =.15) groups, and prostate-specific antigen levels did not change significantly.
Conclusion. No significant changes in behavior, function, depression, or cognitive performance occurred following 12 weeks of testosterone replacement in men with low testosterone levels and early-to-moderate cognitive impairment. This pilot work suggests that testosterone can be given to men with early cognitive impairment without significant concern about worsening aggressive or unwanted behaviors.
Testosterone replacement reverses cognitive deficits in learning and memory in senescence-accelerated prone mouse strains (SAM-P) (11). In younger men with severe testosterone deficiency, sex hormone manipulation improves performance on studies of spatial cognition following testosterone replacement (12). Short-term studies of testosterone replacement in healthy older men demonstrate improvement in spatial cognition, verbal memory, and working memory (13–15). No significant changes in cognitive performance have been seen following long-term replacement of testosterone in healthy older men (16,17), although testosterone did correlate with performance of executive function (17).
A potential concern in the use of testosterone in men with dementia is that testosterone levels have correlated with aggression (18). However, studies of testosterone replacement in young hypogonadal men demonstrated a positive effect on mood (19,20). Cognitively impaired older men and women had decreased aggressive behaviors (21) and psychiatric signs and symptoms (22) after 4 weeks of estrogen therapy. The effects of testosterone on behavior, depression, and cognitive function in men with cognitive impairment have not been evaluated, and studies to address the safety of testosterone replacement in men with impaired cognitive function are required. In this study, we investigate the effects of testosterone treatment on behavior, depression, physical function, and cognitive function in older men with mild-to-moderate dementia.
METHODS
Study Population and Design
Men aged 65 years or older with low serum testosterone levels and mild-to-moderate cognitive impairment were recruited to a randomized, double-blind trial evaluating the effects of 12 weeks of intramuscular testosterone enanthate on behavior, depression, activities of daily living, and cognitive function. Men living in a community- or assisted-living environment with bioavailable testosterone below 128 ng/dl and Folstein Mini-Mental State Exam (MMSE) scores between 14 and 28 were eligible to enter the study. Cognitive impairment was further confirmed using the 124-point cutoff for the Dementia Rating Scale (DRS). Exclusion criteria included a history of prostate cancer, nodule, or prostate-specific antigen (PSA) level >4.0 ng/ml; hematocrit >16.5 gm/dl, or institution of vitamin E or acetylcholinesterase inhibitor therapy in the previous 6 months.
Eleven subjects were randomized to receive either testosterone enanthate (200 mg) or placebo injection intramuscularly at baseline and every 3 weeks for a total of 4 injections. Fasting blood was collected at baseline, 4 weeks, and 10 weeks to assess sex hormone levels including total and bioavailable testosterone, estrone, estradiol, and sex hormone-binding globulin (SHBG). In addition, individuals or their caregivers completed questionnaires on behavior (Behave AD) including the aggression subscale, activities of daily living (Katz ADL), mood (Geriatric Depression Scale), and cognitive performance at baseline, 4, and 10 weeks. Cognitive measures surveyed several domains of cognitive function including attention (Digit Span), visuoconstruction (Clock Face Drawing), visuoperception (Clock Face Perception), abstraction and problem solving (verbal fluency), and executive function (Trail-Making B).
In addition, prostate symptom scores were obtained at baseline, 4 weeks, and 10 weeks, and follow-up prostate exam was performed at the completion of the study.
Biochemical Assays
Total and bioavailable testosterone and SHBG measurements were performed. Testosterone levels were measured by radioimmunoassay, SHBG by competitive binding assay, and bioavailable testosterone by competitive binding of the non-SHBG-bound portion of testosterone following ammonium sulfate precipitation of the SHBG-bound steroid as described by Nankin (23). Intra-assay variability of the testosterone assay was less than 7%, bioavailable testosterone was less than 4%, and SHBG was less than 10%. Samples for off-site assay were shipped on dry ice by overnight mail. Estradiol and estrone were performed in the General Clinical Research Center core laboratory using radioimmunoassay; intra-assay variability <10%. The detection limit of the estradiol assay was 2 pg/ml.
Analysis
All measures were checked for skewness and heterogeneity of variance with basic descriptive analyses. One-way analysis of variance (ANOVA) or Chi-square analysis was used to test the difference in baseline characteristics between the treatment groups. Repeated measure ANOVA was used to assess change between groups over time. Differences in percent change of sex hormones, behavior, activities of dailt living, and cognitive function between groups were compared by ANOVA. All analyses were done using SPSS version 11.0 (SPSS, Inc., Chicago, IL).
RESULTS
Eleven men were randomized to the study. No men discontinued the study, although one man (placebo treatment) suffered a cerebral vascular accident in week 11 of the study. The baseline characteristics of the study participants are presented in Table 1; the testosterone treatment had significantly higher baseline scores on measures of cognitive function including Folstein MMSE and DRS.
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We found no change in behavior, physical function, or cognitive abilities during a short-course of testosterone replacement in men with early-to-moderate cognitive impairment. This pilot work suggests that testosterone can be given to men with early cognitive impairment without significant concern about worsening aggressive or unwanted behaviors. Previous correlational studies demonstrate conflicting results concerning the level of aggression associated with exogenous testosterone levels (24). There are few studies in men with dementia assessing the association between aggression and testosterone. Two studies of older men with dementia have shown an association between increase aggression with endogenous testosterone levels (25) and decreased aggression with higher estrogen levels (26). Replacement studies are few. Studies of eugonadal and hypogonadal young men found no increase in aggression and an improvement in negative affect found in hypogonadal men (27). Our study, the only study we know of to date, of testosterone replacement in men with cognitive impairment found no change in behaviors or the aggression subscale in a survey developed for individuals with dementia. We found significant increases in both testosterone and estrogen levels in men receiving testosterone replacement. It is not known whether behavior or mood are dependent on testosterone, estrogen, or a balance of the sex hormones, and further investigation is warranted to study the effects of sex hormones on behavior in individuals with dementia.
We found no change in depression scores in the men in this study. There are few controlled studies assessing depression scores in men receiving testosterone, and, overall, they have not found changes in scores of depression (16,28), although a recent study did find improvement in depressive scores in men with depression treated with testosterone (29). We may have missed an effect on depressive symptoms since the men were not selected for depression; however, further studies to specifically assess the effects of testosterone on depression are required.
There is evidence of cognitive improvement associated with higher testosterone levels in the literature. Epidemiologic and cross-sectional studies have found that older men with higher testosterone levels had better scores on cognitive tests (30–32). Studies of testosterone replacement in healthy older men have found improvement in spatial cognition (13,14), working memory (15), and verbal memory (13), but not all studies have found significant improvement (16,17). We may have missed changes in cognition in this study for several reasons. Our sample size was small, and large improvements would have been required to detect change. The tests of cognitive performance, while validated, may not have been sensitive enough to detect subtle changes in cognitive function. Finally, testosterone, if beneficial, could be given prior to cognitive decline, as has been suggested by studies of estrogen replacement in women with cognitive impairment (33,34).
While we found no changes in this study, animal studies suggest mechanisms that support the biological plausibility of a protective effect of testosterone on the brain to prevent Alzheimer's disease. Alzheimer's disease is histologically characterized by senile plagues and neurofibrillary tangles consisting of beta-amyloid and hyperphosphorylated tau, respectively. In a recent study, testosterone was found to prevent the heat shock-induced hyperphosphorylation of tau (5). Testosterone has also been shown to reduce neuronal secretion of beta-amyloid peptides (7). Finally, testosterone up-regulates the P75 nerve growth factor (NGF) receptor in the forebrain and increases NGF levels in the hippocampus, septum, and occipital cortex (6). NGF is known to play a crucial role in cognitive functions and neuropathologic dysfunction (35,36).
Conclusion
This pilot study of testosterone replacement in hypogonadal older men with early cognitive decline found no worsening in aggressive behavior but failed to find a beneficial effect on depression or cognitive performance. Larger trials of testosterone replacement are required to address the effect of testosterone on depression and cognition, but may be considered given our lack of increase in problem behaviors.
Acknowledgments
This work was supported by the General Clinical Research Center (MO1-RR06192), Claude Pepper OAIC (5P60-AG13631), and a small grant from the Brookdale Foundation. Dr. Kenny was supported with a fellowship from the Paul Beeson Faculty Scholar Program and Dr. Fabregas by a fellowship from the American Federation for Aging Research. In addition, we wish to thank Bertha Robbins, RN, for her assistance in completing the trial, Alison Kleppinger for her assistance with data management, and the physicians at the University of Connecticut Center on Aging for assisting with recruitment of the gentlemen who agreed to participate in the study.
Address correspondence to Anne Kenny, MD, Center on Aging, MC-5215, University of Connecticut Health Center, Farmington, CT 06030-5215. E-mail: kenny{at}nso1.uchc.edu
Received January 24, 2003
Accepted February 3, 2003
References
This article has been cited by other articles:
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  P. H. Lu, D. A. Masterman, R. Mulnard, C. Cotman, B. Miller, K. Yaffe, E. Reback, V. Porter, R. Swerdloff, and J. L. Cummings Effects of Testosterone on Cognition and Mood in Male Patients With Mild Alzheimer Disease and Healthy Elderly Men Arch Neurol, February 1, 2006; 63(2): 177 - 185. [Abstract] [Full Text] [PDF]
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