May 27, 2003
Treatment with the widely used hormone duo of estrogen and progestin--popularly known as combination hormone replacement therapy, or HRT--appears to do little to ward off the devastating memory loss that occurs with Alzheimer's when the hormones are started in women aged 65 and older. One study, still unconfirmed, suggests that combination HRT may actually increase your risk of developing the disease. The findings were published in two reports in the May 28, 2003 issue of the Journal of the American Medical Association, a highly respected medical journal for physicians.
"These major 'gold standard' studies show that combination estrogen/progestin begun at age 65 or later does not protect against Alzheimer's," says Samuel E. Gandy, M.D., Ph.D., Chairman of the Scientific Advisory Board, Fisher Center for Alzheimer's Research Foundation. "One of the studies showed it may even slightly increase your risk."
Earlier research had found that combination hormone therapy does nothing to reverse or slow the progression of Alzheimer's in women who already had memory loss and other symptoms of the disease. However, it was unknown whether the medicine may afford protection against Alzheimer's in healthy women whose memories are functioning normally. Many women take estrogen in pill form, with or without progestin (or other forms of the female sex hormone progesterone), to combat the severe hot flashes and other symptoms of menopause. The treatment is commonly referred to as hormone replacement therapy.
Data from the study, compiled from a subset of the very large and rigorous trial known as the Women's Health Initiative, revealed that healthy women aged 65 and older who took Prempro, a popular combination of estrogen and progestin, had twice the rate of dementia, including Alzheimer's, as women who did not take the medication. Alzheimer's is the most common form of dementia, a conditioned marked by severe confusion and memory and cognitive loss.
The findings also showed that combination hormone replacement did not protect against a milder form of memory loss called mild cognitive impairment, (MCI). MCI is characterized by memory lapses that can accompany aging and, in some cases, eventually lead to Alzheimer's.
A second report, also in the Journal, found that on memory tests to assess concentration, language, memory, and abstract reasoning, women taking the combination hormones had slightly lower general cognitive status than those on a dummy pill. The differences between the two groups, however, were very small.
"Because of possible harm in some areas and lack of a demonstrated benefit in others, we have concluded that combination hormone therapy should not be prescribed at this time for older, postmenopausal women to maintain or improve cognitive function," advises Judith A. Salerno, M.D., deputy director of the National Institute on Aging (NIA), part of the National Institutes of Health (NIH).
"It is important to note that the possibility remains that estrogen-only replacement (ERT) might afford protection against Alzheimer's, especially if administered perimenopausally [at or around the onset of menopause] rather than many years later," Dr. Gandy comments. "In fact, estrogen-only treatment is more similar to most of the basic literature on hormone protection. However, unopposed estrogen replacement is only available for women who have had hysterectomies. If these women are indeed found to have a diminished risk of Alzheimer's, that will fuel the search for brain-specific estrogen-like molecules that can protect the brain but spare the side effects on the reproductive tissues."
Hormone Replacement: A Difficult Choice
These findings are only one additional component to be weighed when women are deciding whether to start or continue on hormone replacement therapy. For years, hormone replacement therapy was widely touted for staving off the symptoms of menopause, and many older women still swear by it for dampening hot flashes and other symptoms of menopause.
Last July, however, women who were taking the combination treatment as part of the Women's Health Initiative were suddenly taken off the drugs after the combination treatment was found to increase the risk of heart attacks, strokes, blood clots and breast cancer. Researchers felt that these risks outweighed the possible benefits, including stronger bones and a lower risk of colon cancer.
The new findings, a five-year follow-up memory component of the Women's Health Initiative called WHIMS (Women's Health Initiative Memory Study), add new fuel to the debate over hormone replacement therapy. Among the results:
- Women who were taking estrogen and progestin pills (Prempro) were twice as likely to develop dementia as those who were taking a dummy pill.
- Most of the cases of dementia were attributed to Alzheimer's disease. The second most common form of dementia was linked to blood circulation problems in the brain.
- Women receiving hormone replacement were no more likely to develop milder types of memory loss than those taking a dummy pill.
It is important to keep these risks in perspective. Out of 4,500 women in the study, only 61 developed dementia. Forty of those cases occurred in those on hormone replacement (20 were deemed to be Alzheimer's diseases), while 21 cases of dementia (including 12 cases of Alzheimer's) occurred in those on a placebo.
These results confirm that the vast majority of older women who take estrogen will not develop dementia, just as they will not develop breast cancer or have a heart attack as a result of the medicines. There risk, however, is still slightly increased, and women will want to continue to discuss the pros and cons with their doctors.
The Allure of Estrogen
Many other questions remain unanswered. This study looked at women age 65 and older, and it remains unknown what effects hormone replacement might have on younger women.
In addition, this trial used a particular type of combination of estrogen and progestin. As noted by Dr. Gandy, it is uncertain whether estrogen alone, or different forms of estrogen and progesterone, might have different results. As part of the ongoing WHIMS study, about 3,000 women have had hysterectomies and are taking estrogen alone continue to be assessed for the effects on memory. (These women do not need to take progesterone as part of their hormone regimen, since that hormone is added to reduce the risk of uterine cancer.)
Earlier research has offered tantalizing clues on the brain-boosting benefits of estrogen. For example, animal studies from the Fisher Center for Alzheimer's Research at The Rockefeller University, led by Nobel Prize winner Paul Greengard, Ph.D., found that the hormone lowers production of amyloid, the toxic protein that builds up in the brains of those afflicted with Alzheimer's, and has other memory-enhancing effects as well. Other large trials that surveyed the health habits of women over many years similarly reported that estrogen appears to foster thinking and memory skills in people, too.
Scientists were hopeful that analysis of the Women's Health Initiative might reveal that estrogen has memory-protecting benefits, but that was not the case in the current round of reports.
Still, promising clues remain. Researchers speculate, for example, that some women may carry genes that may make them more susceptible to the benefits of estrogen on memory. Others are looking into different types of estrogen delivery, such as a skin patch rather than a pill, different doses and dosing schedules, and alternative combination regimens. The search continues to develop more effective and safer forms of hormone replacement and other therapies to combat the ravages of Alzheimer's disease.
The WHIMS study was funded by Wyeth Pharmaceuticals, the maker of Prempro, and the National Institutes of Health.
By Toby Bilanow, Medical Writer, for www.ALZinfo.org, The Alzheimer's Information Site. Reviewed by Samuel E. Gandy, M.D., Ph.D., Chairman of the Scientific Advisory Board, Fisher Center for Alzheimer's Research Foundation.