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 http://www.alzheimers.org.
