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Postmenopausal hormone therapy and regional brain volumes

The WHIMS-MRI Study

AUTHORS’ AFFILIATIONS
From the Laboratory of Personality and Cognition (S.M.R.), Intramural Research Program, National Institute on Aging, NIH, Biomedical Research Center, Baltimore, MD; Division of Public Health Sciences (M.A.E., S.A.J.), Wake Forest University School of Medicine, Winston-Salem, NC; Departments of Internal Medicine and Public Health Sciences (C.H.), University of California, Davis, CA; Stanford Prevention Research Center (M.L.S.), Department of Medicine, Stanford University, CA; Chronic Disease Research Group (A.M.M.), Hennepin County Medical Center, Minneapolis, MN; University of Massachusetts (J.O.), Worcester, MA; and Department of Radiology (C.D.), University of Pennsylvania, Philadelphia, PA.

Address correspondence and reprint requests to Dr. Susan M. Resnick, Laboratory of Personality and Cognition, Biomedical Research Center/04B317, 251 Bayview Blvd., Baltimore, MD 21224 susan.resnick{at}nih.gov

Objectives: To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions.

Methods: Brain MRI scans were obtained in a subset of 1,403 women aged 71–89 years who participated in the Women’s Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women’s Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables.

Results: Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm³ lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm³) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90).

Conclusions: Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.

Abbreviations: 3MS = modified Mini-Mental State Examination; AC-PC = anterior commissure–posterior commissure; BMI = body mass index; CEE = conjugated equine estrogens; GM = gray matter; MPA = medroxyprogesterone acetate; WHI = Women’s Health Initiative; WHIMS = Women’s Health Initiative Memory Study; WM = white matter.

Supplemental data at www.nehurology.org

See page 125

*See the appendix for details about the WHIMS-MRI Clinical Centers.

Authors’ affiliations are listed at the end of the article.

The Women’s Health Initiative and WHIMS-MRI Study are funded by the National Heart, Lung, and Blood Institute of the NIH, US Department of Health and Human Services. WHIMS was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA. S.M.R. is supported by the Intramural Research Program, National Institute on Aging, NIH.

Disclosure: Author disclosures are provided at the end of the article.

Received June 27, 2008. Accepted in final form September 26, 2008.

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