Victor W. Henderson, MD, MS, NCMP


August 07, 2009


Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72:1850-1857.

Abstract copyright © Lippincott, Williams, and Wilkins. All rights reserved. Used with permission.

Background: There is almost no longitudinal information about measured cognitive performance during the menopause transition (MT).
Methods: We studied 2,362 participants from the Study of Women's Health Across the Nation for 4 years. Major exposures were time spent in MT stages, hormone use prior to the final menstrual period, and postmenopausal current hormone use. Outcomes were longitudinal performance in three domains: processing speed (Symbol Digit Modalities Test [SDMT]), verbal memory (East Boston Memory Test [EBMT]), and working memory (Digit Span Backward).
Results: Premenopausal, early perimenopausal, and postmenopausal women scored higher with repeated SDMT administration (p < or = 0.0008), but scores of late perimenopausal women did not improve over time (p = 0.2). EBMT delayed recall scores climbed during premenopause and postmenopause (p < or = 0.01), but did not increase during early or late perimenopause (p > or = 0.14). Initial SDMT, EBMT-immediate, and EBMT-delayed tests were 4%-6% higher among prior hormone users (p < or = 0.001). On the SDMT and EBMT, compared to the premenopausal referent, postmenopausal current hormone users demonstrated poorer cognitive performance (p < or = 0.05) but performance of postmenopausal nonhormone users was indistinguishable from that of premenopausal women.
Conclusions: Consistent with transitioning women's perceived memory difficulties, perimenopause was associated with a decrement in cognitive performance, characterized by women not being able to learn as well as they had during premenopause. Improvement rebounded to premenopausal levels in postmenopause, suggesting that menopause transition-related cognitive difficulties may be time-limited. Hormone initiation prior to the final menstrual period had a beneficial effect whereas initiation after the final menstrual period had a detrimental effect on cognitive performance.

Commentary by Victor W. Henderson, MD, MS, NCMP

SWAN is a landmark multicenter, multiethnic, community-based observational study of the menopause transition within the United States. At cohort inception, women were pre- or perimenopausal with an intact uterus and not currently using hormone therapy (HT). Cognitive assessment was initiated 3 years after cohort inception, at which time the mean age was 50 years, and 8% of the women in the sample were still premenopausal. Participants were administered brief cognitive measures of processing speed (SDMT; a 90-second task in which women call out numbers corresponding to one of nine pictured symbols depicted on a printed key), verbal memory (EBMT; a 36-word story presented for immediate and delayed recall), and working memory (the familiar digit span backward test). Results of these three tasks administered annually over an additional 4 years form the basis of the report by Greendale et al.

Test score changes over time were modeled as a function of reproductive stage (pre-, early peri-, late peri-, and postmenopause) and HT use. Analyses considered use of HT prior to SWAN enrollment and, among postmenopausal women, current use of HT. Analyses excluded premenopausal and perimenopausal women during the time they used HT (including oral contraceptives).

One important result was the absence of any significant difference in test scores at time of initial testing, when women in the early peri-, late peri-, and postmenopause groups were compared to the premenopause group. A second finding was that test score trajectories within each reproductive stage improved with repeated administration, although the magnitude of improvement was not always significant. Third, test score trajectories of early peri-, late peri-, and postmenopausal women did not differ significantly from that of premenopausal women. The study conclusion that perceived memory difficulty during perimenopause is associated with "a decrement in cognitive performance" is based on positive trajectories that were "marginally different" from the slope of the premenopausal referent.

HT, however, did have significant effects. For SDMT and EBMT, prior HT users scored significantly better at cognitive baseline than women who had not used HT in the past. Conversely, prior HT use was associated with significantly lower trajectories in test score change on these tasks. Comparisons between postmenopausal users and postmenopausal nonusers showed significant differences in slope trajectories on immediate and delayed recall components of the EBMT (worse trajectories for HT users). Test trajectories were also significantly lower among postmenopausal current users in comparison to premenopausal nonusers for SDMT and for EBMT delayed recall.

These new, interesting, and important findings from SWAN investigators are consistent with cross-sectional and longitudinal observations in other cohorts that the natural menopause transition is not accompanied by overall change in cognitive skills.[1,2,3,4] However, there may be "marginal" decrements in trajectories of test score improvement during perimenopause that resolve after postmenopause is reached. Also interesting is that prior HT users showed a cognitive advantage at the time of initial testing. Whether differences were due to biological effects of prior HT use or to unrecognized confounding is not easily decided with observational data. Because prior hormone users showed less tendency to improve with practice, these differences were attenuated or eliminated during the course of the menopause transition, and current HT use after menopause was associated with lower cognitive trajectories in the present study.

Effects of HT on midlife cognitive outcomes can best be answered through well-designed clinical trials in this age group, such as are beginning to emerge.[5]

From the NAMS First to Know e-newsletter released June 23, 2009

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