Postmenopausal hormone therapy and subclinical cerebrovascular disease The WHIMS-MRI Study

Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Neurology (Impact Factor: 8.3). 02/2009; 72(2):125-34. DOI: 10.1212/01.wnl.0000339036.88842.9e
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "WHIMS-MRI was designed to compare neuroradiologic outcomes post-trial among participants who were assigned to hormone therapy versus placebo arms at 14 of 39 WHIMS sites (Resnick et al., 2009; Coker et al., 2009). On average, scans were performed 8.0 years (for CEE + MPA) and 8.0 years (for CEE-alone) following randomization; 3.0 (for CEE+MPA) and 1.4 years (CEE-alone) after termination of the WHI-HT trials. "
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    ABSTRACT: Late-life depressive symptoms (DS) increase the risk of incident mild cognitive impairment and probable dementia in the elderly. Our objectives were to examine the relationship between elevated DS and regional brain volumes including frontal lobe subregions, hippocampus and amygdala, and to determine whether elevated DS were associated with increased subclinical cerebrovascular disease in postmenopausal women. DS were assessed an average of 8years prior to structural brain MRI in 1372 women. The 8-item Burnam regression algorithm was used to define DS with a cut-point of 0.009. Adjusting for potential confounders, mean differences in total brain, frontal lobe subregions, hippocampus and amygdala volumes and total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter outside the basal ganglia were compared between women with and without DS. Depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. After full adjustment, DS at baseline were associated with smaller superior and middle frontal gyral volumes. Hippocampal and amygdala volumes, and ischemic lesion volumes were similar in depressed and non-depressed women. Depression was not assessed based on semi-structured interview, and MRI scans were obtained cross-sectionally rather than longitudinally. Longitudinal MRI assessments will be necessary to define the temporal relationships between DS and frontal lobe volumes. Elevated DS were associated with lower volumes in certain frontal lobe subregions but not in the medial temporal lobe structures. Our findings support the role of frontal lobe structures in late-life DS among women.
    Journal of Affective Disorders 02/2011; 132(1-2):275-84. DOI:10.1016/j.jad.2011.01.020 · 3.71 Impact Factor
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    • "Risk factors for Alzheimer's disease and vascular disease overlap substantially (Stampfer, 2006), and cerebrovascular disease potentiates clinical manifestations of Alzheimer neuropathology (Schneider et al., 2007). However, here is no direct evidence that adverse vascular consequences of hormone therapy led to dementia in the WHIMS trials (Coker et al., 2009). Clinical evidence supporting the critical window hypothesis for cognitive outcomes remains limited. "
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    ABSTRACT: Metabolic derangements and oxidative stress are early events in Alzheimer's disease pathogenesis. Multi-faceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a woman's endogenous and exogenous estrogen exposures during midlife and in the late post-menopause might favourably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older post-menopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimer's disease symptoms. As suggested by the 'critical window' or 'healthy cell' hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a woman's health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials [Early Versus Late Intervention Trial with Estradiol (ELITE), Kronos Early Estrogen Prevention Study (KEEPS)] will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late-life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimer's disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.
    Progress in brain research 01/2010; 182:77-96. DOI:10.1016/S0079-6123(10)82003-5 · 5.10 Impact Factor
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    • "Our results can also be interpreted within the context of an ancillary study of the WHI that examined the effect of CEE with or without MPA treatment on volumetric measurements of the hippocampus and prefrontal cortex in more than 1400 women over 65 years of age (Resnick et al., 2009; Coker et al., 2009). In this large study, women receiving CEE alone or in combination with MPA displayed reduced prefrontal and hippocampal volume. "
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    ABSTRACT: The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or limited window of opportunity, exists for hormone treatment to protect against neurocognitive. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared with peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for a limited window of opportunity for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain.
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