Estrogen use and brain metabolic change in postmenopausal women

Abstract

Objective: We used positron emission tomography to evaluate cerebral glucose metabolic change in postmenopausal women in a naturalistic observational study. Method: Women estrogen users (n=11) and non-users (n=9) were studied at baseline and 2 years later. Analyses focused on glucose metabolism in regions previously reported to decline in older persons at risk for Alzheimer’s disease (AD) (posterior cingulate and lateral temporal cortex). Results: Region of interest (ROI) analysis at baseline showed no regional differences between women estrogen users and non users. ROI follow-up analysis revealed that women non-users declined significantly in the posterior cingulate cortex (P=0.04). Statistical parametric mapping (SPM) analysis confirmed a significant decrease in metabolism of the posterior cingulate cortex among non-users at 2-year follow-up (P=0.004). In contrast, women estrogen users did not exhibit significant metabolic change in the posterior cingulate. Conclusions: Estrogen use may preserve regional cerebral metabolism and protect against metabolic decline in postmenopausal women, especially in posterior cingulate cortex, the region of the brain found to decline in the earliest stages of AD.

Introduction

Healthy human aging is accompanied by changes in brain function, which vary by sex. Women are higher risk for Alzheimer’s disease (AD) than men, and this gender difference may be due to a significantly greater age-related atrophy in the brain regions implicated in AD. Estrogen use, however, may enhance cerebral and cognitive function [20], [22], [24] and lower the risk for AD in postmenopausal women [16]. Because estrogens interact with neuronal networks at many different levels and affect brain development and aging, they significantly affect the function of brain regions, which are crucial to higher cognitive function and implicated in AD.

Positron emission tomography (PET) [26], [36] with 2-deoxy-2-[${}^{18}\text{F}$]fluoro-d-glucose (FDG) allows the non-invasive determination of local cerebral glucose metabolic rate in humans through the use of a tracer kinetic model [9], [27]. Previous PET studies have demonstrated activational estrogen effects on cerebral function in temporal and parietal regions in reproductive-aged and healthy postmenopausal women (for review see [18]). Same regions (i.e. lateral temporal and posterior cingulate) exhibit the greatest magnitude of metabolic decline after 2 years in middle-aged and older persons at risk for AD [33], [34]. In our pilot analyses of metabolic changes between genders, women, estrogen users demonstrated increased metabolism in the lateral temporal cortical regions compared to women non-users and men [23]. Such observations led us to hypothesize that estrogen use, indeed, may be the defining variable in observed metabolic differences.

In the present study, we aimed to validate such findings in a larger subject cohort and to compare regional metabolic activity between postmenopausal women estrogen users and non-users. We postulated that estrogen use will be associated with preserved regional metabolism. We also extended the previous analyses to include voxel-by-voxel analysis throughout the entire brain volume, testing for preservation of regional metabolic activity associated with estrogen use.

It should be noted that although we use the term “estrogen use” in ours and reviewed studies, preparations used by our subjects consisted of plant-derived 17-β estradiol, or conjugated equine estrogens in a combination of with progesterone or its derivatives. Nevertheless, biological effects have been attributed thus far to estrogen, as the role of progesterone compounds in the brain remains not clearly elucidated. Therefore, throughout this text, we will use the term “estrogen use” to describe the effects of hormonal preparations that subjects received.