Prospective Randomized Trial to Assess Effects of Continuing Hormone Therapy on Cerebral Function in Postmenopausal Women at Risk for Dementia

<div><p></p><p>The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT−) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-β estradiol (17βE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's disease.</p><p>Trial Registration</p><p><a href="http://ClinicalTrials.gov" target="_blank">ClinicalTrials.gov</a><a href="http://clinicaltrials.gov/ct2/show/NCT00097058" target="_blank">NCT00097058</a></p></div

Study Sample Demographics and Clinical Characteristics (N = 45).

<p>Study Sample Demographics and Clinical Characteristics (N = 45).</p

Bilateral medial frontal metabolism (first row) and left temporo-occipital metabolism (second row) were significantly preserved in HT+ women who were ApoE-ε4 negative, compared to HT− women who were ApoE-ε4 negative.

<p>Color voxels shown above have significance of p<0.001.</p

Study Subject Flow.

<p>Study Subject Flow.</p

Impact of hormone therapy on telomere dynamics is APOE-dependent.

<p>Initial evidence that the impact of the APOE-ε4 risk allele on cell aging is modulated by HT use in mid-life women. Among women who were randomized to stay on HT (n = 26) for the two year study period, no significant difference in TL attrition was detected between ε4-carriers and non-carriers. Among women who went off HT (n = 16), those carrying the risk allele exhibited telomere shortening, while non-carriers exhibited telomere maintenance/growth. Values represent mean TL change (base pairs) adjusted for study covariates. Error bars represent S.E.M, ** p≤.005.</p

Characteristics of the study sample by HT randomization.

<p>Values represent mean (SD) or % as noted.</p>*<p>p<0.05.</p

APOE-ε4 genotype and telomere attrition.

<p>Dot plot illustrating age-adjusted change in leukocyte telomere length (TL) in carriers of the APOE-ε4 risk allele and non-carrier controls. APOE-ε4 carriers had significantly greater age-adjusted LTL shortening over the 2 year study period than non-carrier control participants [<i>F</i>(1,39) 4.89, <i>p</i> = .03].</p