Experiment with Rats Models Earlier Results with Humans

WASHINGTON -- Postmenopausal women with Alzheimer's disease who undergo long-term estrogen replacement therapy (ERT) may make their memory loss worse, according to a new study from researchers at the University of Arizona.

The study in the October issue of Behavioral Neuroscience, a journal published by the American Psychological Association (APA), used female rats to study the effect of ERT on memory. The findings are transferable to humans because the conditions reproduced in the study are analogous to that of postmenopausal women who have existing brain inflammation caused by a neurodegenerative illness like Alzheimer's or by head trauma and then choose to undergo long-term ERT.

G. L. Wenk, Ph.D., and colleagues at the Arizona Research Laboratories at the University of Arizona had 40 rats perform a water maze task to look at the interaction of two conditions known to exist within the brains of female Alzheimer's patients, 1) the presence of chronic neuroinflammation, and 2) having too much or not enough estrogen. Both of these conditions are likely to precede the onset of symptoms associated with Alzheimer's. As part of the experiment, some of the rats were ovariectomized (had their ovaries surgically removed) to mimic the changes seen in postmenopausal women. Aged rats do not undergo an ovarian failure but ovariectomized rats experience both the ovarian failure and the alterations in gene expression within the hypothalamus that appear in women in menopause.

The researchers found that the removal of the rats' ovaries was not enough to impair performance in the water maze task. However, the introduction of either sustained estrogen replacement therapy or chronic brain inflammation did impair memory performance in the ovariectomized rats. Furthermore, the combined occurrence of both conditions (sustained estrogen replacement therapy and longer term brain inflammation) significantly worsened cognitive performance beyond that produced by either condition alone.

"A therapy designed to mimic the natural cycle of hormone fluctuation may provide a more effective therapy to slow the progression of Alzheimer's disease in postmenopausal women," according to the researchers. They add that their findings were confirmed by a 2000 study in the Journal of the American Medical Association (JAMA) involving a long term, placebo-controlled study that examined the effects of estrogen replacement therapy on cognitive function in a large groups of women with mild to moderate Alzheimer's. The effects of ERT were initially beneficial, but the performance of women receiving sustained ERT declined more than that of women receiving the placebo treatment.

"When considered together, the results of this and other clinical trials suggest a pattern of beneficial effects on cognitive function after relatively short-term ERT; however, this beneficial effect is attenuated, and possibly reversed, after much longer treatment regimens," say the authors. "Although a comparison between humans and rodents must be made with caution, it is interesting that continuous long-term estrogen therapy immediately after ovariectomy in the present study parallels the detrimental cognitive effect seen in postmenopausal Alzheimer's disease women who receive continuous, long-term ERT decades after the onset of menopause."

Article: "Long-Term Estrogen Therapy Worsens the Behavioral and Neuropathological Consequences of Chronic Brain Inflammation," L.K. Marriott, B. Hauss-Wegrzyniak, R.S. Benton, P.D. Vraniak and G.L. Wenk, University of Arizona; Behavioral Neuroscience, Vol. 116, No. 5.

Full text of the article is available at http://www.apa.org/journals/bne/press_releases/october_2002/bne1165902.html.

The American Psychological Association (APA), in Washington, DC, is the largest scientific and professional organization representing psychology in the United States and is the world's largest association of psychologists. APA's membership includes more than 155,000 researchers, educators, clinicians, consultants and students. Through its divisions in 53 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting human welfare.

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