Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men

doi:10.1016/j.psyneuen.2006.10.008

Psychoneuroendocrinology

Volume 32, Issue 1, January 2007, Pages 72-79

https://doi.org/10.1016/j.psyneuen.2006.10.008 Get rights and content

Summary

Background

It has been suggested that cognitive changes in response to T supplementation may occur within an ideal range. The objective of this study was to compare the cognitive responses of older, eugonadal men in whom moderate or large increases in serum testosterone levels was induced by exogenous testosterone supplementation.

Design

Randomized, double-blind, placebo-controlled study with subsequent grouping of participants according to average increase in circulating T from baseline.

Setting

Community dwelling participants.

Participants

Fifty-seven healthy, eugonadal, community dwelling male volunteers,

mean age 67 years (±11 years).

Interventions

Participants were randomized to receive weekly intramuscular (I.M.) injections of either 50, 100 or 300 mg T enanthate or placebo (saline) injection for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, weeks 3 and 6 of treatment and after 6 weeks of wash-out.

Main outcome measures

Performance on cognitive tests of verbal and spatial memory.

Results

Men with moderate increases in serum T and/or its metabolites demonstrated significant improvements in verbal and spatial memory. In contrast, men with large or low increases in circulating T levels, failed to demonstrate significant changes in memory.

Conclusion

These results suggest that in healthy older men, beneficial changes in cognitive function induced by T supplementation are most evident with moderate changes in cognition from moderate to high T supplementation increases in T levels. Large or no to low increases in T levels do not appear to appreciably effect cognition.

Introduction

Age-related decline in testosterone (T) is associated with several physiologic changes including decreased muscle mass and strength, osteoporosis and reduced sexual activity (Matsumoto, 2002; Swerdloff and Wang, 1993). The age-related decline in T is also associated with a progressive decline in cognitive abilities. Several retrospective epidemiological studies have found declines in bioavailable or free testosterone to be associated with decrements in cognitive functioning (Barrett-Connor et al., 1999; Moffat et al., 2002; Yaffe et al., 2002).

Studies examining T supplementation in older men have found evidence for a beneficial effect on cognition (Cherrier et al., 2001, Cherrier et al., 2003, Cherrier et al., 2005; Gray et al., 2005; Janowsky et al., 1994, Janowsky et al., 2000; Kenny et al., 2002). In contrast, other studies have found no support for beneficial effects on cognition (Kenny et al., 2004; O’Connor et al., 2001; Sih et al., 1997; Wolf et al., 2000). It has been suggested that a positive relationship between testosterone and cognition may exhibit an inverted U shape dose–response, such that beneficial effects on cognition occur within a moderate dose range but not at high or low levels (Gouchie and Kimura, 1991; Hampson and Moffat, 1994; Hogervorst et al., 2005; Moffat and Hampson, 1996; Muller et al., 2005; Shute et al., 1983). In the present study, we directly examined the role of dose effects of T supplementation on cognition in a sample of healthy older men.

Section snippets

Participants

Participants were healthy older men between the ages of 50 and 90 mean age 67 years (±11 years) recruited from the community through flyers. The study protocol was approved by the University of Washington Institutional Review Board and approved informed consent procedures were followed. Participants underwent a screening visit to determine eligibility including a physical exam, psychiatric and laboratory evaluation to exclude any significant physical or medical illness. This included tests of

Results

Sixty five men gave informed consent and were screened for the study. Five participants evidenced an elevated PSA, one participant evidenced an elevated calcium level, two subjects declined to continue after screening visit due to scheduling or other conflicts. Fifty-seven men with a mean age of 67±11 years (range 50–85) met screening criteria and were randomized. Mean education level was 16 years ±2 years (range 12–19) and mean DRS score was 140 points±3 points (range 137–144). There were no

Discussion

In this study of brief T supplementation, improvements in verbal and spatial memory were evident in men who demonstrated moderate increases in T levels during exogenous T administration. In men with moderate increases, T levels were raised to the normal to high-normal range for young men. Significant changes in cognition were not observed for the groups with large or no to low increases in T levels. Serum T levels in the large increase group were raised into the supraphysiological range (Table 1

Acknowledgements

This research was supported in part by NIA award #K01AG00858, American Federation for Aging Research, and Veterans Administration Puget Sound Health Care System. Serum T and E samples were processed in Dr. William Bremner's laboratory at University of Washington. A portion of this work was conducted through the General Clinical Research Center at the University of Washington and supported by the National Institutes of Health, grant M01RR-00037.

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Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men

Summary

Background

Design

Setting

Participants

Interventions

Main outcome measures

Results

Conclusion

Introduction

Section snippets

Participants

Results

Discussion

Acknowledgements

Horm. Behav.

J. Psychiatr. Res.

Psychoneuroendocrinology

Brain and Cognition

Maturitas

Psychoneuroendocrinology

Neuropsychologia

Exp. Gerontol.

Biol. Psychiatry

Endogenous sex hormones and cognitive function in older men

J. Clin. Endocrinol. Metab.

Risks versus benefits of testosterone therapy in elderly men

Drugs Aging

Testosterone dose–response relationships in healthy young men

Am. J. Physiol. Endocrinol. Metab.

Testosterone supplementation improves spatial and verbal memory in healthy older men

Neurology

Cognitive effects of short term manipulation of serum sex steroids in healthy young men

J Clin. Endocrinol. Metab.

Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report

J. Androl.

The role of aromatization in testosterone supplementation: effects on cognition in older men

Neurology