Estrogen Replacement and Cognition: Ready for Prime Time?

While estrogen replacement therapy shows promise in helping post-menopausal women preserve important cognitive abilities such as memory, its effectiveness is still being questioned. In studies at the National Institutes of Health and at the University of California, Los Angeles, researchers have demonstrated that in some women, this hormone alters brain blood flow and improves performance on certain mental tests. But other studies are not as definitive, suggesting that improved cognitive abilities could be associated with a decrease in menopausal symptoms. "The epidemiologic data we have is not that mature," says Stanley Birge, clinical director of the Older Adult Health Center at Washington University. "But I think if you add up the negative studies and the positive studies, it does fall to the side of recommending. It probably is effective in preserving the brain." Courtesy of Pauline MakiLeft: Pauline Maki But don't advise treatment right now, some researchers say. "Not yet," says Pauline Maki, an investigator with the National Institute on Aging. "There haven't been any [looks] at large numbers of women on cognitive outcomes." Natalie Rasgon, assistant professor of psychiatry at UCLA and director of the menopause-related mood disorders research program, shares Maki's opinion. "It will take us some, probably a few more years to tease it out. But as a researcher I believe there are niches for estrogen. We just haven't hit on them," she says. In a two-year imaging study of women over 55,1 Maki found that those receiving estrogen replacement showed greater blood flow in the brain regions connected with memory while taking standard mental tests than did nontreated women. The estrogen users also scored better on memory tests. Estrogen does more than increase blood flow. "Estrogen has very large and diverse effects on the central nervous system," Maki says. For instance, animal studies have shown that estrogen increases dendritic spines, structures that help nerve cells communicate in the hippocampus, a part of the brain involved in memory.2 "That suggests the microstructure in the brain changes in response to estrogen," she says. Estrogen also stimulates neurotransmitters such as serotonin and acetylcholine, which are important in memory, adds Birge. Though Maki's study is the first longitudinal look at estrogen's effect on regional blood flow in the brain, other imaging studies have also found that estrogen enhances blood flow. Rasgon and her colleagues reported that women using estrogen showed increases in glucose metabolism in the brain.3 Pediatrics professor Sally Shaywitz at Yale University and her colleagues found PET images of post-menopausal women receiving estrogen showed increased brain activity during memory tasks; but these women did not perform better on memory tests.4 A meta-analysis of nine randomized case-control trials and eight cohort studies by Erin Le Blanc, Oregon Health Sciences University, and her colleagues conclude that women, given post-menopausal estrogen who had experienced menopausal symptoms, "improved cognitive performance especially in tests of verbal memory, vigilance, reasoning, and motor speed." But it wasn't necessarily the estrogen that was helping, the researchers note. A decrease in symptoms, such as hot flashes, might have improved performance, say the authors. The studies did not show consistent results when visual recall, complex attention, and verbal functions were measured.5 This "well done" analysis, says Rasgon, demonstrates the uncertainty about estrogen's impact and value. "Maybe estrogen has a beneficial effect in certain populations, which are not well defined, and on selective memory functions and not on cognition overall. We can't really be quite sure of what is going on with estrogen and cognition in humans," she asserts. A better understanding might come in a few years. An ongoing study known as WHISCA, women's health initiative study of cognitive aging, a double-blind, placebo-controlled ERT study, involves 2,900 women. Maki, who is working on the study with Wake Forest University researchers, says WHISCA is part of the NIH Women's Health Initiative. The study, its results due in 2005, will assess estrogen's effect on the cognition tests that Maki used in her earlier research. "That's when we should have a much better sense of whether or not hormone replacement therapy is a good idea," she says. In the meantime, whether a post-menopausal woman should take estrogen to help her cognitive abilities is a decision to be made with her physician, says Birge. "Although estrogen at any time may delay the progression of the loss of cognitive function, there is data which would suggest that the optimal efficacy of that estrogen depends on starting the estrogen at the time of the menopause." Courtesy of Morrie GelfandAbove: Morrie Gelfand Meanwhile, research is also focusing on the possible neuroprotective effects of testosterone. Morrie Gelfand, professor of obstetrics and gynecology at McGill University, and his colleagues found that physiological doses of testosterone prevented the death of brain neurons in cultured fetal tissue. After 48 hours, the cells started to die, but at a 60 percent lower rate than in the hormone's absence. The form of testosterone used was one in which its conversion to estrogen was blocked.6 Gelfand says he is now researching the mechanism by which testosterone protects the neurons. Harvey Black (73773.2227@compuserve.com) is a freelance writer in Madison, Wis. References 1. P.M. Maki, S.M. Resnick, "Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition," Neurobiology of Aging, 21:373-383, 2000. 2. E. Gould et al., "Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood," Journal of Neuroscience, 10:1286-91, 1990. 3. N. Rasgon et al., "Estrogen use and brain metabolic change in older adults: A preliminary report," Psychiatry Research: Neuroimaging, 107:11-8, 2001. 4. S. Shaywitz et al., "Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks," Journal of the American Medical Association (JAMA), 281[13]:1197-1202, 1999. 5. E. LeBlanc et al., "Hormone replacement therapy and cognition," JAMA, 285[11]:1489-99, 2001. 6. J. Hammond et al., "Testosterone mediated neuroprotection through the androgen receptor in human primary neurons," Journal of Neurochemistry, 77[5]:1319-26, 2001. Supplemental Materials Chart: Change in Hamilton Depression Rating Scale scores over an 8-week trial of ERT alone or ERT with Fluoxetine (SSRI) in perimenopausal depressed women.

Estrogen Replacement and Cognition: Ready for Prime Time?

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