Endogenous and Exogenous Estrogen, Cognitive Function, and Dementia in Postmenopausal Women: Evidence from Epidemiologic Studies and Clinical Trials

Elizabeth Barrett-Connor, M.D.; Gail A. Laughlin, Ph.D.


Semin Reprod Med. 2009;27(3):275-282. 

In This Article

Surrogates of Endogenous Estrogen

Surrogates of endogenous estrogen offer an alternative to measured estrogen, without the limitations of single assays or assay sensitivity. These studies include investigations of cognitive function and bone mineral density, reproductive stage (pre menopause vs. peri menopause and postmenopause), and duration of estrogen exposure based on lifelong reproductive period (age at menopause minus age at menarche, with or without an adjustment for pregnancy).

Three large studies have looked at lifetime estrogen exposure based on reproductive period and various measures of cognition. The Australian PATH Project[17] and the Melbourne Women's Midlife Health Study[18] found no association of reproductive period or a multifactorial index of estrogen exposure with cognitive performance in older women. In the Rotterdam Study of 3600 postmenopausal women, a greater number of reproductive years (longer exposure to endogenous estrogen) increased the risk of incident dementia, but only in women with at least one ApoE ε4 allele.[19] None of these studies support the hypothesis that estrogen delays cognitive decline or lowers dementia risk.

A study of bone does. In the Study of Osteoporotic Fractures, women with osteoporosis based on baseline bone mineral density, bone loss, or vertebral fractures had poorer cognitive function and a greater risk of cognitive deterioration.[20,21] Bone mineral density and fracture risk are thought to be markers of cumulative estrogen exposure.

If endogenous estrogens influence cognitive function, this effect might be more apparent during the menopausal transition when estrogen levels are decreasing dramatically and 60% of women report memory problems.[22] The Study of Women's Health Across the Nation (SWAN) found no association between phase of the menopausal transition (or estradiol levels) and several tests of cognitive performance[23] in agreement with a smaller Swedish study.[24] In two other cross-sectional studies among premenopausal, perimenopausal, and postmenopausal women, premenopausal women outperformed postmenopausal women on some, but not all, cognitive tests.[25,26] Similarly, women in early versus late postmenopause had better executive function independent of age, but no difference in attention, verbal fluency, or memory.[27] Again the data are too inconsistent to draw definitive conclusions.


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