Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.
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 alpha = 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.
Coker
L H
LH
Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. lcoker@wfubmc.edu
Hogan
P E
PE
Bryan
N R
NR
Kuller
L H
LH
Margolis
K L
KL
Bettermann
K
K
Wallace
R B
RB
Lao
Z
Z
Freeman
R
R
Stefanick
M L
ML
Shumaker
S A
SA
D000367:Age Factors; D000368:Aged; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D015984:Causality; D002536:Cerebral Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003627:Data Interpretation, Statistical; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications; D008279:Magnetic Resonance Imaging; D017063:Outcome Assessment, Health Care / Q000379:methods; D012307:Risk Factors
D004967:Estrogens; D004966:Estrogens, Conjugated (USP)