The menopause transition, prior hormone use, and current postmenopausal hormone use were each related to measured cognitive performance, but the patterns of these relations varied by cognitive domain. An MT-related cognitive disadvantage was most apparent in the domain of processing speed: while premenopausal, early perimenopausal, and postmenopausal women manifested significant gains in SDMT scores with repeated testing, late perimenopausal women did not. Perimenopause was also disadvantageous to verbal episodic memory: although scores for premenopausal and postmenopausal participants improved with repetition of the EBMT-delayed test, scores for early and late perimenopausal women did not. Former hormone use, taken prior to the FMP, was associated with better processing speed and verbal memory: initial SDMT scores were approximately 6% higher and initial EBMT-immediate and delayed scores were roughly 4%–5% greater among prior hormone users. In contrast, current hormone use among postmenopausal women predicted worse processing speed and verbal episodic memory performance over time compared to premenopausal performance.
The relation between MT stage and cognitive performance has been the subject of only two longitudinal studies.4,5
The first was a cohort of 573 Chinese women with average age of 46 years and average education of 6.5 years. On the Rey Auditory Verbal Learning Test, those who transitioned to perimenopause had significantly less improvement than those who remained premenopausal, similar to the EBMT results of perimenopausal SWAN participants. The second was a SWAN site-specific cognitive substudy that began at SWAN cohort baseline. With 2 years of follow-up in ~800 women aged 42–52 years, adjusting for social and demographic variables, small time-related improvements were observed but no MT effects were identified.5
Our observation that perimenopause negatively impacted cognitive performance likely differs from the substudy's findings because the current sample size is three times larger, follow-up is twice as long, and the substudy did not account for the effects of prior and current hormones. Unlike prior reports, the current study modeled time in MT stage as its primary exposure.
The disturbance in cognitive performance during perimenopause was subtle, manifested by lack of improvement over time rather than an overt decline. Although there are limited longitudinal data in this age range, improvement with repeated testing is believed to be the norm. In the Baltimore Longitudinal Study of Aging, among men and women aged 55–90 years, annual gains on the California Verbal Learning test were observed until subjects reached their mid 60s; the authors postulated that in young persons, the absence of improvement with serial testing may be an indicator of abnormal cognitive function.18
Our participants ranged in age from 49 to 61 years, thus would be expected to improve with repeated tests. Further support that the absence of improvement observed during perimenopause was related to MT stage and not to chronological aging comes from the finding that improvement resumed in postmenopause.
Prior hormone users (prior to the FMP) had better baseline processing speed and verbal memory relative to women in equivalent MT stages who had not used hormones. Conversely, current hormone use during postmenopause was detrimental to performance in these domains. These discordant effects may be reconciled by the critical timing hypothesis, which predicts that early hormone initiation would benefit cognition (higher initial scores) but late initiation would be detrimental to it (less improvement in postmenopausal hormone users).19–21
Critical timing for cardiovascular disease (CVD) was reported in the Women's Health Initiative: women <10 years postmenopause at hormone initiation did not have increased risk of CVD and those aged 50–59 years at hormone startup had regression of vascular calcifications.22,23
The SWAN results suggest that critical timing applies to cognitive performance, but that the critical period may be substantially earlier than that for CVD. Mechanisms underlying critical timing have been reviewed.19–21,24,25
Poorer cognitive performance among postmenopausal hormone users could also result from confounding. Symptomatic women are more likely to use hormones; if MT symptoms lead to poorer cognition, it could appear that hormones cause poorer performance. However, this thesis does not fit with the observed benefit of hormones prior to the FMP because these women were probably using hormones for MT symptoms.26
The effects of perimenopause and prior and current hormone use were apparent for processing speed (SDMT) and verbal episodic memory (EBMT). These findings are consistent with theories about cognitive aging and cognitive function during the MT. Slowed processing speed is considered one of the earliest indicators of cognitive aging.9,27
We also expect MT and hormone effects on verbal memory because the hippocampus and prefrontal cortex, brain areas that serve these functions, are rich in estrogen receptors.6,7
We posit that MT effects were picked up by the delayed, but not the immediate, EBMT because the delayed assessment was slightly more difficult. Contrary to expectation, we witnessed no MT effects on working memory (DSB), a cognitive domain also served by estrogen receptor–rich brain regions.9,27
Also unexplained is the lack of improvement in this domain. DSB scores decline very little with age in cross-sectional studies28
and other longitudinal data show that men and women substantially older than our cohort learn with repeated DSB administration.29
Limitations of this study include the small cognitive battery and that many participants started with maximum verbal memory scores, precluding improvement over time. Whether menopause symptoms (e.g., hot flashes) mediate the cognitive difficulties observed during perimenopause and whether endogenous sex steroids are related to cognition during the MT remain important questions that are beyond the scope of this analysis, but will be the subjects of future work.