Perimenopausal use of hormone therapy is associated with enhanced memory and hippocampal function later in life

Abstract

Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This "critical window hypothesis" remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women's Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p<.05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis.

Figure 1. Results of primary region of interest analysis in the medial temporal lobe: increased hippocampal activation and decreased parahippocampal activation in perimenopausal initiators of hormone therapy compared to never users

Sagittal, coronal, and axial projections of medial temporal regions showing significant (p < .01) differences in activation between perimenopausal users of hormone therapy and nonusers. Odd numbered rows show glass brain images of significant findings, and even numbered rows show activations superimposed on a structural anatomical template, with most significant voxel depicted in the cross-hairs. The scale to the right of each pair of figures shows the color scale corresponding to the z-values for that particular analysis. Rows 1 and 2 show significantly decreased activation in perimenopausal estrogen users compared to nonusers in bilateral parahippocampal gyrus. Rows 3 and 4 show significantly increased activation in perimenopausal users compared to never users in the left hippocampus during verbal recognition, and Rows 4 and 5 show a similar effect during verbal match.

Figure 2. Characteristic activations in the medial temporal lobe during performance of verbal tasks

Sagittal, coronal, and axial projections of medial temporal regions showing significant (p < .01) increases in activation across the two groups combined. There were no significant decreases in activation. Odd numbered rows show glass brain images of significant findings, and even numbered rows show activations superimposed on a structural anatomical template. For ease of presentation and reference to HT effects, the cross-hairs reference the regions showing HT effects in the group comparisons, as depicted in Figure 2. The scale to the right of each pair of figures shows the color scale corresponding to the z-values for that particular analysis. Rows 1 and 2 show significantly increased activation in the bilateral parahippocampal gyrus during verbal recognition across the two groups combined (in contrast to the decreased activation seen in perimenopausal HT users in Figure 1). Rows 3 and 4 show significantly increased activation across the two groups combined in the left hippocampus during verbal recognition (in comparison to the increased activation seen in perimenopausal HT users in Figure 1). Rows 4 and 5 show a similar effect during verbal match.