Elsevier

Brain Research

Volume 1379, 16 March 2011, Pages 232-243
Brain Research

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

https://doi.org/10.1016/j.brainres.2010.11.030Get rights and content

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.

Research Highlights

►Use of hormone therapy during the perimenopause confers benefit to hippocampus. ►Benefit is evident during an fMRI verbal encoding and recognition test. ►Verbal memory performance was also enhanced with hormone use. ►Results support “critical window hypothesis” of estrogen use.

Introduction

Before the publication of findings from the Women's Health Initiative (WHI) in 2002 (Rossouw et al., 2002), 17% of women on hormone therapy (HT) in the United States began HT before reaching the final menstrual period, and 65% of women began HT within two years of the final menstrual period (Brett and Chong, 2001). The observational studies of HT prior to the WHI results therefore primarily involved women who initiated treatment in the perimenopausal or early postmenopausal stage. Some evidence suggests that certain forms of HT may confer cognitive benefit when initiated in close temporal proximity to the menopausal transition, whereas later initiation may be neutral or detrimental to cognitive function (see Henderson, 2009, Maki and Sundermann, 2009 for a review). This hypothesis implies a “critical window” for beneficial action of HT (Resnick and Henderson, 2002).

Basic science studies provide support for this hypothesis, particularly as it applies to memory performance and the structure and function of medial temporal lobe structures subserving memory performance (Gibbs, 2000, Silva et al., 2003). Parallel human studies investigating the effects of early HT use on verbal episodic memory and medial temporal lobe function later in life are lacking. A recent neuroimaging study found that early HT use was associated with enhanced medial temporal lobe function during a working memory task, and that enhanced hippocampal and medial temporal activation predicted better working memory (Berent-Spillson et al., 2010). The critical period hypothesis remains a topic of debate, in part because it is not feasible to conduct randomized clinical trials to test the effects of early HT use on cognitive function many years later, when memory problems may appear.

The aim of the present study was to use fMRI to determine the effects of perimenopausal initiation of HT (i.e., during the perimenopausal stage) on hippocampal activation during performance of memory tasks. Participants were a subsample of women from the Melbourne Women's Midlife Health Project, a prospective, population-based study of the natural history of the menopausal transition (Dennerstein et al., 1993). Samples of women who initiated HT before the final menstrual period and healthy controls who never received HT were selected on the basis of prospective daily diaries and study visit data, providing a valid means of verifying the timing of HT initiation in relation to the final menstrual period. Primary outcomes focused on hippocampal activation during performance of a verbal memory test, and secondary analyses focused on nonverbal (figural) memory. The verbal and figural imaging memory tasks were structured to resemble standardized memory tests commonly administered outside the scanner, and included an initial encoding phase followed by a 20-minute delay and then a yes/no recognition test for the words and figures presented earlier in the encoding phase. We hypothesized that women who initiated HT during the perimenopausal stage and continued using HT would show enhanced verbal memory and hippocampal/parahippocampal function in comparison to those who never initiated HT.

Section snippets

Behavioral outcomes

Table 1 shows the demographic and behavioral outcome variables for perimenopausal HT users and never users and shows the results of t-tests comparing the two groups on these variables. T-tests were conducted on the neuropsychological tests administered out of the scanner for the full sample (n = 33) of early versus never users. T-tests were conducted on the imaging memory task on the subsample (n = 25) with valid imaging date (see Neuroimaging outcomes). Groups were well-matched on demographic

Discussion

The aim of this study was to investigate the influence of continuous use of HT from the perimenopausal stage on patterns of hippocampal activation during performance of a verbal memory test. To achieve this aim, we studied healthy midlife women whose timing of exposure to HT was prospectively validated. Seventeen women who initiated HT during the perimenopausal stage were compared with 17 controls who were similar in age, education, depressive symptoms, and estimated verbal intelligence, but

Participants

The sample was drawn from a cognitive follow-up study of women enrolled in the Melbourne Women's Midlife Health Project, a longitudinal population-based study of women's health across the menopausal transition (Dennerstein et al., 1993). Original entry criteria into the longitudinal study included menstruation during the prior 3 months, age 45 to 55, and no history of estrogen-containing HT. Recruitment began in 1991 and was based on random telephone dialing in metropolitan Melbourne. Of 2001

Acknowledgments

This work was supported by the Intramural Research Program of the National Institute on Aging, NIH and by an unrestricted grant from Wyeth Pharmaceuticals. P. Maki received research funding from Wyeth Pharmaceuticals for this investigator-initiated study. Lorraine Dennerstein is currently a consultant/advisory board member for Boehringer-Ingleheim and Bayer Schering Women's Healthcare. She has previously been a consultant/advisory board member for Wyeth. M. Clark, J. Guthrie, V. Henderson, P.

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