DIMENSIONS Winter 2000


by Julie Cleveland

The relationship between estrogen and cognition among postmenopausal women remains controversial. Also uncertain is whether the proposed association varies between women on unopposed estrogen (estrogen taken without progestin) and those on estrogen combined with a progestin.

There are many proposed mechanisms by which estrogen may slow memory loss (preserve cognitive function). Estrogen may act as an antioxidant and protect brain cells from toxic molecules (free radicals). Estrogen appears to improve communication between brain cells by stimulating neuronal growth and stimulating the synthesis of the neurotransmitter acetylcholine. In addition, estrogen appears to improve blood flow to the brain.

Alternately, estrogen may simply make women feel better and therefore perform better on memory tests. Estrogen has been shown to reduce hot flashes and improve mood.

Many scientists believe that estrogen doesn't really influence cognition. They state that the reason we see less memory loss in women who take estrogen is because these women are generally healthier to begin with. That is, healthy women are more likely to choose to take estrogen. Thus, it may be something besides the estrogen that slows memory loss.

At the UW, researchers have looked at this relationship between estrogen and cognition in the KAME Project, a research study of Japanese Americans aged 65 years and older living in King County, Washington. Dr. Eric Larson is the principal investigator for this study. This study conducted by Dr. Madeline Rice and colleagues compared cognitive performance in 837 women over a two-year period-in women who had never taken estrogen, were taking estrogen in the past, were currently taking estrogen, or currently taking estrogen and progestin. Cognitive performance was measured at baseline and two-year follow-up. On cognitive testing, women who had never taken estrogen showed slight improvement over two years. This improvement was somewhat greater in women who had taken estrogen in the past. Test scores for women currently taking unopposed estrogen improved significantly, while women currently taking estrogen and progestin actually showed a decline on test scores.

These findings support a modest beneficial association between current unopposed estrogen use and the rate of cognitive change. The researchers also observed a modest detrimental association between current estrogen-progestin use and the rate of cognitive change.

One reason for this negative association may be because many women report more negative moods when they are on combined estrogen-progestin therapy compared to unopposed estrogen. Therefore, women on unopposed estrogen may simply feel better, thus performing better on cognitive tests. In addition, certain progestins, such as medroxyprogesterone acetate (MPA) may blunt some of the beneficial effects on estrogen on blood lipids and glucose tolerance, which may influence cognition. All of the women in the KAME study who were on estrogen-progestin therapy were on MPA.

"Another explanation" says Dr. Rice, "may be that this finding simply occurred by chance. No other studies have observed this difference between unopposed estrogen and estrogen-progestin on cognitive function. So this finding should be interpreted cautiously." She adds, "It is very important to note that women who still have a uterus should take combined estrogen-progestin therapy since unopposed estrogen greatly increases a women's risk of uterine cancer. The addition of a progestin counters this effect of estrogen on the uterus."

Although the differences in memory loss between women on estrogen and not on estrogen were modest, these findings led KAME researchers to ask whether women with several risk factors for cognitive decline may reap a greater benefit from unopposed estrogen use. In a follow-up study, six risk factors for cognitive decline modified the estrogen/cognitive change association: low income; family history of memory problems; mild cognitive impairment; history of depression; history of hypothyroidism; physical inactivity. Overall, most women showed slight improvements in their cognitive performance test score over the two-year period. Among women with none or only one of the six risk factors for cognitive decline, women on unopposed estrogen improved more than women who had never taken estrogen. Among women with two or more risk factors, this improvement was increased eight-fold. These data suggest that the proposed beneficial association between estrogen and cognitive change may be greatest in women who are at an increased risk of cognitive decline.

KAME researchers are continuing their research efforts on estrogen and cognition. They are performing a follow-up study that will follow the KAME subjects for eight years, to further examine estrogen use and rates of cognitive change. In addition, they are beginning to research estrogen use and the incidence of Alzheimer's disease and other dementias.

Women who are thinking about taking estrogen and want to learn more should consult their physician about the potential benefits and risks of estrogen replacement therapy. Rices states: "There are many different forms of estrogens and progestins and a physician can tailor a woman's therapy based on her personal profile." Also, women can obtain information from the North American Menopause Society by calling (440) 442-7550, or visiting their website at http://www.menopause.org/

For additional information on KAME research regarding estrogen use and cognitive change, contact Dr. Madeline Rice at (206) 326-2421 or madrice@u.washington.edu.

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