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Effect of sex and estrogen therapy on the aging brain: a voxel-based morphometry study

Lord, Catherine PhD1; Engert, Veronika PhD2; Lupien, Sonia J. PhD3; Pruessner, Jens C. PhD2

doi: 10.1097/gme.0b013e3181e06b83
Special Section: Menopause, Cognition and Mental Health

Objective: It is still a matter of debate whether estrogen can have a protective effect on brain integrity and against age- and Alzheimer-related assaults. Evidence points toward selective sparing of gray matter (GM) in postmenopausal women using hormone therapy. In the current study, the effect of sex and estrogen therapy (ET) exposure on GM density using voxel-based morphometry was assessed.

Methods: High-resolution structural magnetic resonance imaging scans of 46 healthy participants were analyzed using voxel-based morphometry. A total of 15 men and 31 healthy postmenopausal women were included: 15 ET-naive women (never users) and 16 current ET users with an average duration of use of 11 years.

Results: Sex differences were found in fronto-temporo-parietal areas, with postmenopausal women having greater GM concentration in the medial prefrontal cortex, temporal cortices, angular gyrus, and precuneus, whereas the men had greater GM density in the superior frontal, inferior temporal gyri, and inferior parietal lobules. ET users compared with never users had greater GM density in the superior frontal gyrus and less GM density in the posterior part of the hippocampus and parahippocampal gyrus, posterior cingulate, and angular gyri. In the group of ET users, a negative association was found between duration of ET use and posterior hippocampus and parahippocampal GM density, whereas a positive association was found in the hypothalamus, striatum, precunei, and inferior parietal lobules.

Conclusions: These results point toward a potential regional- and duration-dependent estrogen exposure effect on cerebral areas known to be involved in age-related cognitive functions and Alzheimer and Parkinson diseases.

This study identifies new plausible regions sensitive to estrogen exposure, such as the inferior parietal lobule, angular gyri, and precunei, which would have been difficult to assess using manual segmentation protocols. Results suggest a specific effect of estrogen exposure on frontotemporoparietal brain structures.

From the 1Women's Health Concern's Clinic, St. Joseph's Healthcare, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada; 2McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada; and 3Laboratory of Psychoneuroendocrinology of the Centre for Studies on Human Stress, Fernand-Seguin Research Centre, University of Montreal, Montreal, Quebec, Canada.

Received January 22, 2010; revised and accepted March 29, 2010.

This study was performed after approval by the Montreal Neurological Institute research ethics committee.

Funding/support: This study was supported in part through a grant from the Alzheimer Society of Canada to J.C.P. and from the Canadian Institutes of Health Research (CIHR) Institute of Aging, (grant 134254) to S.J.L. An Investigator Award from the CIHR Institute of Aging supports the work of S.J.L. C.L. was holding Canadian Graduate Scholarships doctoral awards administered by the CIHR and a fellowship from the Behavioural, Gene, and Environment Training Grant administered by the Douglas Hospital Research Center.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Catherine Lord, PhD, Women Health Concerns Clinic, St. Joseph's Healthcare, Fontbonne Building, 301 James Street South, Hamilton, ON, Canada L8P 3B6. E-mail:

©2010The North American Menopause Society