NEUROLOGY 2009;72:125-134
© 2009 American Academy of Neurology
Postmenopausal hormone therapy and subclinical cerebrovascular disease
The WHIMS-MRI Study
L. H. Coker, PhD,
P. E. Hogan, MS,
N. R. Bryan, MD,
L. H. Kuller, MD,
K. L. Margolis, MD,
K. Bettermann, MD,
R. B. Wallace, MD,
Z. Lao, MD,
R. Freeman, MD,
M. L. Stefanick, PhD,
S. A. Shumaker, PhD For the Women's Health Initiative Memory Study*
AUTHORS’ AFFILIATIONS
From the Division of Public Health Sciences (L.H.C., P.E.H., S.A.S.), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Radiology (N.R.B.), University of Pennsylvania, Philadelphia; Department of Epidemiology (L.H.K.), University of Pittsburgh, PA; Health Partners Research Foundation (K.L.M.), Minneapolis, MN; Department of Neurology (K.B.), Penn State College of Medicine, Hershey, PA; Department of Epidemiology (R.B.W.), University of Iowa College of Public Health, Iowa City; Eastman Kodak (Z.L.), Rochester, NY; Department of Obstetrics and Gynecology and Women's Health (R.F.), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; and Stanford Prevention Research Center (M.L.S.), Department of Medicine, Stanford University, CA.
Address correspondence and reprint requests to Dr. Laura H. Coker, Division of Public Health Sciences, Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, NC 27157 lcoker{at}wfubmc.edu
Objective: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS.
Methods: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of 
= 0.05 was used.
Results: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo.
Conclusions: Conjugated equine estrogen–based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.
Abbreviations: 3MSE = modified Mini-Mental State Examination; BMI = body mass index; CEE = conjugated equine estrogen; CVD = cerebrovascular disease; HT = hormone therapy; MCI = mild cognitive impairment; MPA = medroxyprogesterone acetate; MRIQCC = MRI Quality Control Center; ROI = region of interest; WHIMS = Women's Health Initiative Memory Study.
Received June 13, 2008. Accepted in final form August 28, 2008.
See page 135
*See the appendix for details about the WHIMS centers.
Authors' affiliations are listed at the end of the article.
The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, US Department of Health and Human Services. The Women's Health Initiative Memory Study was funded in part by Wyeth Pharmaceuticals, Inc., St. Davids, PA.
Disclosure: The authors report no disclosures.
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