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Date of release: 16 February, 2009

New insights into mechanisms contributing to increased dementia risk in the WHI


The Women’s Health Initiative Memory Study (WHIMS) was an ancillary study to the Women’s Health Initiative (WHI) that investigated the impact of hormone therapy on risk for dementia in women 65 years of age and older [1,2]. Among naturally menopausal women (n = 4532), the hazard ratio for probable dementia among women receiving conjugated equine estrogen (CEE) (0.625 mg/day) plus medroxyprogesterone acetate (MPA) (2.5 mg/day) compared with those assigned to placebo was 2.05 (95% confidence interval (CI), 1.21–3.48; p = 0.01). Among surgically menopausal women (n = 2947) randomized to CEE alone versus placebo, the hazard ratio was 1.49 (95% CI, 0.83–2.66, non-significant). Hormone therapy (HT) also increased the risk of decline on the Mini-Mental State Exam in the WHI [3,4]. 


 


Two new reports from the WHIMS Magnetic Resonance Imaging (MRI) Study shed new light on mechanisms that might contribute to this cognitive decline. Both studies used data from a subset of 1403 women participating in the two arms of WHIMS. Neither study included pretreatment baseline measures. For the CEE/MPA group, MRI outcomes were collected on average 3 years post-trial and after an average of 4 years of on-trial treatment. For the CEE-alone group, outcome variables were collected on average 1.5 years post-trial and after an average of 5.6 years. The mean age of women at the time of the MRI assessments was 78 years. Thus, these results address the impact of long-duration hormone therapy in elderly women.


 


The first study examined subclinical cerebrovascular disease [5]. Counter to predictions, mean ischemic brain lesion volumes did not differ significantly between women randomized to hormone therapy versus placebo.  


 


The second study investigated the impact of hormone therapy on regional brain volumes [6]. Total brain volume, ventricle volume, hippocampal volume and frontal lobe volume were measured. In pooled analyses, but not in each arm individually, frontal lobe volume was significantly reduced among women randomized to receive hormone therapy. Subanalyses examined whether the magnitude of decline in brain volume varied with pretreatment cognitive status and with the magnitude of ischemic lesion volume. Hippocampal volume varied with baseline cognitive status, with the greatest volume loss evident in women with the poorest cognitive status. Total brain volume, hippocampal volume and frontal lobe volume were each reduced more among women with relatively high ischemic brain lesion volumes compared with women with relatively low ischemic brain volumes.

Comment

Prior to the publication of these two companion papers, it was widely believed that the mechanism by which hormone therapy increased dementia risk in older women in WHIMS was vascular. Subclinical vascular disease is a risk factor for dementia [7], and hormone therapy increased the risk of stroke in WHI [8,9]. The new report from WHI MRI suggests that a vascular mechanism does not appear to explain the increased risk for dementia in WHIMS. 
 
Instead, the findings of Resnick and colleagues pointed to loss of brain volume as a possible contributing factor. In some ways, the primary analyses are somewhat surprising. First, despite high statistical power due to an unusually large sample size, the volumetric differences were evident only in the pooled analysis of 1403 women, not in the individual study arms. Second, although hippocampal volume loss, rather than frontal volume loss, is an early predictor of dementia due to Alzheimer’s disease, the hippocampal volume loss only approached statistical significance (p = 0.05) whereas frontal volume loss was greater (p = 0.004). Perhaps more consistent with the clinical findings and more informative were the subanalyses. The first of these notable findings was that hippocampal brain volume decreased as pretreatment cognitive status decreased. This is consistent with the finding that the HT-related risk of cognitive decline was most prominent among women with poor cognitive function at enrolment in WHIMS [3]. The second of the more impressive findings was that HT had no impact on brain volume in women who were relatively free of ischemic brain lesions (below the 25th percentile) but negatively impacted brain volume in other women. This pattern of findings is consistent with the healthy cell bias of estrogen, which suggests that estrogen exerts protective effects on healthy cells but negative effects on unhealthy cells [10]. The mechanism by which hormone therapy causes brain volume loss in older women is unknown.
 
So what do these findings mean for the clinician? It is rare for women to initiate hormone therapy after age 65, so the question arises as to whether these effects are observed in younger postmenopausal women or in older postmenopausal women who have been on HT since the menopausal transition. Smaller-scale clinical studies suggest that hormone therapy may spare brain volume or, at minimum, does not lead to brain volume loss in those groups of women [11-14]. On the other hand, in younger postmenopausal women, CEE/MPA (but not other hormone formulations) has been shown to decrease performance on a memory task that is dependent on the hippocampus [15]. Further investigations are needed to evaluate the impact of various formulations of hormone therapy on brain volume in women who are more representative of women who use hormone therapy. The recent findings, however, do shed important light on a new reason why women should not initiate CEE/MPA or CEE alone after age 65.

Comentario

Pauline Maki
Associate Professor of Psychiatry and Psychology, Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, USA

    References

  1. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Womens Health Initiative Memory Study. JAMA 2004;291:2947-58.
    http://www.ncbi.nlm.nih.gov/pubmed/15213206

  2. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Womens Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62.
    http://www.ncbi.nlm.nih.gov/pubmed/12771112

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    http://www.ncbi.nlm.nih.gov/pubmed/15082697

  10. Brinton RD. Investigative models for determining hormone therapy-induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci 2005;1052:57-74.
    http://www.ncbi.nlm.nih.gov/pubmed/16024751

  11. Eberling JL, Wu C, Haan MN, et al. Preliminary evidence that estrogen protects against age-related hippocampal atrophy. Neurobiol Aging 2003;24:725-32.
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  13. Erickson KI, Colcombe SJ, Raz N, et al. Selective sparing of brain tissue in postmenopausal women receiving hormone replacement therapy. Neurobiol Aging 2005;26:1205-13.
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  14. Resnick SM, Maki PM, Golski S, et al. Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance. Horm Behav 1998;34:171-82.
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  15. Maki PM, Gast MJ, Vieweg AJ, et al. Hormone therapy in menopausal women with cognitive complaints: a randomized, double-blind trial. Neurology 2007;69:1322-30.
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