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
Objective: The Women’s Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials re-
ported 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 re-
ported 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 lin-
ear 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 signifi-
cantly 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 impair-
ment 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 consis-
tent within each trial and in pooled analyses across trials. Neurology®2009;72:125–134
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.
Dementia is increasing due to an aging population.1Clinical stroke is often considered the first
sign of cerebrovascular disease (CVD), but silent stroke and white matter lesions are more
prevalent and commonly predate clinical CVD.2Large cohort studies of older adults indicate
that clinical and subclinical CVD increase the risk of cognitive decline3,4and dementia.5
The Women’s Health Initiative Memory Study (WHIMS) reported that hormone therapy
(HT)—conjugated equine estrogen 0.625 mg/d (CEE) with or without medroxyprogesterone
2.5 mg/d (MPA)—increased the risk for dementia6,7and global cognitive decline in women age
65 and older.8,9The WHI reported that both CEE ? MPA and CEE-Alone were associated
with an increased risk of clinical stroke.10-12These results question whether HT increased the
prevalence of subclinical CVD as a possible mechanism for cognitive decline in WHIMS. The
main objective of the WHIMS Magnetic Resonance Imaging Study (WHIMS-MRI) was to
See page 135
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
*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.
Copyright © 2009 by AAN Enterprises, Inc.
determine whether HT compared to placebo,
randomly assigned at enrollment to the WHI
hormone trials, was associated with volumetric
subclinical CVD on post-trial brain MRI.
The primary outcome measure of WHIMS
MRI was total ischemic lesion volume on brain
the white and gray matter outside the basal gan-
that women randomized to CEE-based HT
would have significantly increased ischemic le-
sion volumes on brain MRI. A companion arti-
cle by Resnick at al.13reports whether regional
and total brain volumes differed by WHI treat-
METHODS The ClinicalTrials.gov Identifier for this study is
Design of WHI and WHIMS. The WHI randomized HT
trials were designed to evaluate postmenopausal HT and pre-
vention of disease, with coronary heart disease the primary
outcome. Hip fracture, other fractures, other cardiovascular
disease, and endometrial, colorectal, and other cancers were
secondary outcomes.14A geographically diverse group of post-
menopausal women aged 50–79 were enrolled in the parallel
CEE?MPA (n ? 16,608) or CEE-Alone (n ? 10,739
women with prior hysterectomy) randomized placebo-
Ancillary to the WHI, WHIMS followed women from these
two trials to examine the effects of postmenopausal CEE-based
HT on the risk of all-cause dementia and global cognitive func-
tioning in healthy women who were 65–79 years old at WHIMS
enrollment. Of age-eligible participants who were approached,
4,532 (92.6%) consented to participate in the WHIMS
CEE?MPA trial and 2,947 (92.1%) consented to participate in
the WHIMS CEE-Alone Trial. The WHIMS study designs, eli-
gibility criteria, and recruitment procedures were described pre-
viously.16WHIMS participants underwent cognitive screening
with the modified Mini-Mental State Examination (3MSE)17at
enrollment and annually. Women who scored below an
education-adjusted cutpoint on the 3MSE underwent a more
comprehensive cognitive evaluation,18assessment of mood, and a
neuropsychiatric examination. If probable dementia was sus-
x-ray computerized tomography of the brain. Final classifications
(normal, mild cognitive impairment [MCI], or probable dementia)
were adjudicated at the WHIMS Clinical Coordinating Center at
the Wake Forest University Health Sciences.
The WHI hormone trials were terminated earlier than planned
due to significantly more non-cognitive adverse events associated
with HT compared to placebo.10,11As a consequence, the ancillary
WHIMS CEE?MPA and CEE-Alone trials were also prematurely
terminated.6-9Post-trial follow-up of participants continued annu-
ally for cognitive assessment and adjudication of MCI and probable
dementia in the WHIMS Extension Study.
Design of WHIMS-MRI. WHIMS-MRI was designed to
compare neuroradiologic outcomes among women with an aver-
age on trial HT exposure of 4.0 years (CEE?MPA) or 5.6 years
(CEE-Alone). Brain scanning was conducted, on average, 8.02
years (CEE?MPA) or 7.97 (CEE-Alone) years following ran-
domization and 3.0 years (CEE?MPA) or 1.4 years (CEE-
Alone) after termination of the WHIMS HT trials.
WHIMS-MRI was conducted in 14 of the 39 WHIMS clin-
ical sites. Following Institutional Review Board approval,
WHIMS-MRI recruitment began in January 2005 and was com-
pleted in April 2006. Women who provided consent underwent
screening to determine if they were acceptable candidates for
MRI. Exclusion criteria included the presence of items that
would make the MRI procedure hazardous (pacemakers, prohib-
ited medical implants, and foreign bodies); shortness of breath or
inability to lie flat; and conditions that can be exacerbated by
stress (anxiety panic disorders, claustrophobia) severe enough to
WHIMS participants who enrolled in WHIMS-MRI tended
to be younger and more highly educated than those who did not;
they also had been relatively healthier at the time they enrolled in
the WHI and tended to have experienced less on-trial decline in
MRI protocol. The MRI scanning protocol was developed
by investigators at the MRI Quality Control Center
(MRIQCC) in the Department of Radiology, University of
Pennsylvania. Scanning and reading were done by individuals
masked to treatment assignment. The scans were conducted
by a standardized protocol; scanning pulse sequences were
performed in the following order:
• Series one: three-plane gradient echo localizer for position-
• Series two: sagittal T1-weighted spin echo midslice image
to demonstrate anatomic location of the AC/PC for slice
angle and slice position.
• Series three: oblique axial spin density/T2-weighted spin
echo images from the vertex to skull base parallel to the
• Series four: oblique axial FLAIR T2-weighted spin echo
images matching slice positions in series three.
• Series five: oblique axial three-dimensional T1-weighted
gradient echo images from the vertex to the skull base
parallel to the AC/PC plane. The field of view was 22 cm
and the acquisition matrix was 256 ? 256 for series three,
four, and five. Scans obtained in series three, four, and five
were used for analyses of ischemic lesions.
The WHIMS-MRI technologist at each site immediately re-
viewed all scans for protocol compliance and technical problems.
Imaging data were transmitted by an encrypted DICOM image
transfer mechanism to the permanent study archive via the Web.
WHIMS-MRI primary outcome measure. The primary
outcome measure for WHIMS-MRI is total ischemic lesion vol-
ume, measured in cubic centimeters, detected from a standard-
ized imaging and reading protocol. Secondarily, ischemic lesion
volumes in the basal ganglia and the cerebral white and gray
matter outside the basal ganglia were measured.20
Ischemic lesion volume defined and identified by this
methodology generally corresponds to what has been called
small vessel ischemic disease (ischemic white matter disease
and lacunar infarctions). Basically unknown before the ad-
vent of MRI, this process is now accepted as a non-necrotic,
ischemic effect on myelin that is secondary to the effects of
aging, hypertension, and other small vessel pathologic pro-
cesses of the brain.21,22The earliest reports of this vasculopa-
thy were by anecdotal observations which were quickly
superseded by semiquantitative, human observer scoring sys-
Neurology 72 January 13, 2009
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