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Association of sex steroid hormones with brain morphology and cognition in healthy elderly men

From SRI International (Drs. Lessov-Schlaggar, Swan, and Carmelli, R.E. Krasnow), Menlo Park, CA, Indiana University School of Medicine (Dr. Reed), Indianapolis, University of California at Davis (Dr. DeCarli), Geriatrics Research (Dr. Marcus, L. Holloway), Education and Clinical Center, VA Medical Center, Palo Alto, CA, and Boston University (Dr. Wolf), MA.

Address correspondence and reprint requests to Dr Lessov-Schlaggar, Center for Health Sciences, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025; e-mail: christina.lessov{at}sri.com

Background: There is inconsistent evidence of the presence and direction of the relationship between sex hormone concentrations and cognitive function in older men, and there is little published literature on the relationship of sex hormone concentrations and brain volume as measured by MRI.

Objective: To examine the hypothesis that midlife total serum concentrations of testosterone (T), estradiol, estrone, and sex hormone binding globulin (SHBG) predict cognitive task performance and regional brain volumes at 10- to 16-year follow-up, in a longitudinal sample of World War II veteran twin men.

Methods: Treating twins as individuals, linear regression models were used, adjusting analyses for age, education, depressive symptomatology, blood pressure, alcohol consumption, years of cigarette smoking, and APOE 4 allele status.

Results: There were no significant associations between sex hormone or SHBG concentrations and performance on a series of cognitive tasks measuring global and executive function, visual and verbal learning and memory. Higher midlife T concentrations were associated with larger hemispheric, frontal, and parietal regional brain volumes and with smaller left occipital brain volume. Higher estradiol and estrone concentrations were also associated with smaller right (estradiol) and both right and left (estrone) occipital volumes, but with no other brain regions. Owing to the multiple comparisons conducted, some significant associations may have occurred by chance.

Conclusions: Overall, the pattern of results suggests a role for sex hormones in brain volume that predates potentially observable associations between sex hormones and cognitive task performance.

Supported by HL51429 (D.C.) and internal funds from SRI International (C.N.L.S.).

Presented in part at the annual conference of the American Academy of Neurology, in April 2004, San Francisco, CA.

Dr. Marcus’ current address is Eli Lilly & Company, Indianapolis, IN.

Disclosure: The authors report no conflicts of interest.

Received October 15, 2004.

Accepted in final form August 15, 2005.

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