Findings Challenge Hypothesis That Longer Term Exposure to Endogenous Estrogen Protects Against Dementia

March 21, 2001 — A longer reproductive period, thought to be related to a longer exposure to estrogen produced within a woman's body, does not appear to reduce a woman's risk of dementia and Alzheimer disease, according to an article in the March 21, 2001, issue of The Journal of the American Medical Association, a theme issue on women's health.

Mirjam I. Geerlings, Ph.D., of Erasmus University Medical Center, Rotterdam, the Netherlands, and Lenore J. Launer, Ph.D., of the National Institute on Aging, National Institutes of Health, Bethesda, Md., and colleagues studied postmenopausal women to determine whether a longer reproductive period (the time between the onset of menstruation and menopause), as an indicator of longer exposure to endogenous (within the body) estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. Dr. Launer presented the findings at a JAMA media briefing on women's health held on Tuesday, March 20, 2001.

"Our findings do not support the hypothesis that a longer reproductive period reduces risk of dementia in women who have natural menopause," the authors write.

According to background information cited in the article, decreasing estrogen levels have been hypothesized to be associated with increased risk of dementia. Although a number of studies have found an association of exogenous estrogen (estrogen replacement therapy) with reduced risk of dementia and cognitive functions, others have not found a relationship, and some have even suggested that estrogen may have negative effects. To date, no studies have determined whether long-term exposure to endogenous estrogen is related to risk of dementia and AD.

The authors followed 3,601 women aged 55 and older who did not have dementia when they enrolled in the Rotterdam Study in 1990 to 1993, and who had information on the age of their first menstruation, age at menopause, and type of menopause. The women were designated into four groups, based on the length of their reproductive period: less than 34 years, 34 to 36 years, 37 to 39 years, or more than 39 years. DNA testing determined if women carried the apolipoprotein E (APOE) genotype (which is associated with late-onset AD cases and is considered a risk factor for the disease).

Study participants were re-examined in 1993 to 1994 and 1997 to 1999, and were continuously monitored for development of dementia. During a median follow-up of 6.3 years, 199 women developed dementia, including 159 who developed AD.

The authors found that a longer reproductive period was associated with a higher risk of dementia in women with natural menopause, after adjusting for age, education, smoking, alcohol intake, body mass index, hormone replacement therapy, number of children and APOE genotype. "Insofar as reproductive period is a marker of long-term exposure to endogenous estrogen, these findings do not support the hypothesis that high estrogen levels reduce risk of dementia," the authors write.

"Risk of dementia in women with 34 to 36 reproductive years was 1.56 times higher than in women with less than 34 reproductive years; in women with 37 to 39 reproductive years, this risk was 1.64 times higher, and in women with more than 39 reproductive years, it was 1.78 times higher than in women with less than 34 reproductive years," they report.

"For AD the risks showed a similar but not statistically significant pattern of higher risk with longer reproductive period," they continue.

The association of dementia with a longer reproductive period was found primarily in women who carried the APOE epsilon-4 allele. "For dementia, in the group with at least one APOE epsilon-4 allele, the adjusted rate ratio (RR) in the highest quartile compared with the lowest quartile was 4.20 [times higher risk], in the third quartile it was 1.93 [times higher risk], and in the second quartile it was 2.43 [times higher risk], whereas in the group with no APOE epsilon-4 alleles, these RRs were 1.10, 1.29, and 1.29 [times higher risk], respectively," the authors report.