Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00097058.

Figure 1. Study Subject Flow.

Figure 2. 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.

Color voxels shown above have significance of p<0.001.

Figure 3. Subjects who discontinued 17β-E demonstrated significant decline in the precuneus/posterior cingulate (green arrows in part A), while this was not seen in subjects that continued 17β-E (green arrows in part B).

Subjects who continued CEE underwent significant declines in the primary visual cortex and precuneous/posterior cingulate (blue and green arrows in part C, respectively). In a difference of differences analysis, the primary visual cortex was the region of most significant difference between subjects who continued on CEE versus 17β-E (blue arrow in part D). All color voxels are significant at p<0.005. (Differential effect between women discontinuing estradiol versus those discontinuing CEE was observed in precuneus/posterior cingulate cortex at p<0.01, not shown here.)

Figure 4. Subjects that discontinued E opposed by progesterone and stayed off HT for two years demonstrated decline in the medial frontal gyrus, while subjects that discontinued unopposed E and stayed off HT for two years demonstrated decline in the precuneous and dorsofrontal cortex.

Color voxels shown above have significance p<0.01.

Figure 5. HT+ women continuing on 17β-E with concurrent progesterone demonstrated decreased metabolism with the statistical cluster mapping from the lateral parietotemporal cortex, extending medially through the brain into the posterior cingulate.

The posterior cingulate was the most significantly different metabolic area between subjects continuing use of opposed 17β-E versus subjects on unopposed 17β-E. Color voxels shown above have significance of p<0.01 with crosshairs.