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
Highlights
Estrogen has been shown to exert both neuroprotective and neuropathological effects in a variety of in vitro and in vivo models of brain disorders [1,2]
The Women’s Health Initiative Memory Study (WHIMS) findings have resulted in the broad interpretation that hormone therapy (HT) fails to protect against dementia in postmenopausal women [11], though this conclusion conflicts with the majority of data showing beneficial effects of estrogen HT in the aging female brain [13]
2) Women who discontinued 17-b estradiol (17bE)-based HT, as well as women who continued on conjugated equine estrogen (CEE)-based HT exhibited significant decline in the posterior cingulate/precuneus area, whereas women who continued 17bE-based HT and those discontinuing CEE had no observable metabolic change in this area
Summary
Estrogen has been shown to exert both neuroprotective and neuropathological effects in a variety of in vitro and in vivo models of brain disorders [1,2]. Many of the studies on HT that have found beneficial effects have included 17-b estradiol (17-bE)-based HT formulations [6,7,8,9,10], while the Women’s Health Initiative Memory Study (WHIMS), which recruited women 65 and older, found an increased risk of dementia with conjugated equine estrogen (CEE) compared to placebo [11,12]. The WHIMS findings have resulted in the broad interpretation that HT fails to protect against dementia in postmenopausal women [11], though this conclusion conflicts with the majority of data showing beneficial effects of estrogen HT in the aging female brain [13]. There may be a ‘‘window of opportunity’’ for beneficial effects of HT, as the observational studies based on typical prescription patterns (usually initiated during menopausal transition for treatment of vasomotor symptoms) of estrogen HT suggest a decreased risk for dementia with initiation of treatment on or around the time of menopause [3,4]
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