February 23, 2000
Estrogen replacement therapy (ERT) does not improve the memory or function of hysterectomized women with mild to moderate Alzheimer's disease, according to a new research report. The findings, from the largest and longest clinical trial to date examining the effects of estrogen therapy on AD, suggest that estrogen should not be used to treat the dementia once the disease is established in women who have had a hysterectomy.
Scientists involved in the study emphasize, however, that estrogen therapy may still play an important role in fighting AD in women at an earlier point in the disease process. A number of epidemiological studies have indicated that estrogen therapy might prevent AD or delay its onset. Clinical trials to validate the usefulness of estrogen to prevent or delay AD are now underway.
This study on estrogen therapy for women with mild to moderate dementia appears in the February 23, 2000, issue of the Journal of the American Medical Association. The research was conducted by Ruth Mulnard, R.N., D.N.Sc., University of California, Irvine, and colleagues from 32 Alzheimer's Disease Cooperative Study (ADCS) sites across the U.S. The National Institute on Aging (NIA) supports the ADCS, a consortium of academic medical centers and others involved in AD clinical trials.
"A negative finding, particularly one from a study of this size and scope, is critically important in our search for treatments," says Neil Buckholtz, Ph.D., who directs NIA's Dementias of Aging program. "We need to determine where estrogens may or may not be effective for people with AD. This study clearly turns our attention to how estrogens may help protect women who, at the start of therapy, are cognitively healthy. It is also not clear at this time whether estrogen therapy may be effective in women with AD who have an intact uterus."
The 120 hysterectomized women age 60 and above involved in the study had mild to moderate AD. They were divided into three groups of women taking 0.625 mg (milligrams) per day of estrogen, 1.25 mg of estrogen, or placebo pills that looked like the estrogen medication. The women were followed for 15 months (12 months on estrogen therapy with 3 months of additional followup); researchers tested for cognitive or functional changes at 2, 6, 12, and 15 months. Primarily, the scientists were examining the overall rate of change the women may have experienced on a scale developed by the ADCS for pinpointing clinical changes in patients with the disease. In addition, they looked for specific effects on mood; certain cognitive functions such as memory, attention, and language; motor function; and standard measures of activities of daily living.
At the end of the study, no significant differences were seen in any of the areas studied, indicating that the ERT had no effect. Estrogen did not, as it has in smaller studies, improve cognitive function, nor did it delay progression of the disease by any of the measures used by Mulnard's group.
Mulnard said that the positive effects of ERT seen in smaller and shorter studies might have been due to short-term effects that estrogen might have had on neurotransmitters in the brain, as seen in animal studies. But, according to Mulnard, the short-term effects could not be sustained over a longer period of time.
Basic research on the etiology of AD may help explain ERT's failure to make a difference in women who already have AD, Mulnard said. Studies on the mechanisms of the disease have indicated that AD may have at least two phases, one called an "initiation" phase and the another a "propagation" phase when the disease has been set in motion. Cell culture studies show that the actions of estrogen may only be effective against some of the mechanisms of the disease, effectively countering those that occur earlier in the disease process. Estrogen receptors, for example are concentrated in the regions of the brain affected first by AD, and ERT may work best before these brain regions are compromised. Mulnard also points to research indicating that estrogen is a relatively weak antioxidant when compared with vitamin E, which has been shown to have some effect at later stages of the disease.
"Research on the basic mechanisms of AD and a range of diseases shows that certain things happen at certain stages," Mulnard notes. "We may find that some therapies, possibly estrogens, may only work during selective phases of the disease process."
The NIA, the National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), and the National Institute of Nursing Research (NINR) within the National Institutes of Health (NIH), support the AD Prevention Initiative, which funds much of the ongoing clinical research on AD, including additional studies of the preventive possibilities of estrogens. In addition, Wyeth-Ayerst Laboratories is sponsoring a memory study component of NIH's national Women's Health Initiative to test the use of estrogens for preventing AD.
For more information on federally funded AD research and the possibility of participating in a study, contact the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center at 1-800-438-4380, or adear@alzheimers.org. You can view information on AD and on clinical trials specifically on the ADEAR website at www.alzheimers.org.
