Questions and Answers About the Women's Health Initiative Memory Study

May 23, 2003

In May 2003, scientists taking part in the Women's Health Initiative Memory Study (WHIMS), part of the Women's Health Initiative, reported new health risks for women over age 65 using a type of combined estrogen plus progestin known as Prempro™. You may have heard reports on the news or seen something in newspapers or magazines or on the Internet. Maybe you have questions. Here are answers to some of the most common questions. Talk with your doctor if you want to know more about what this means for you.

What is this new finding?

The WHIMS scientists found that the number of women over age 65 who began having symptoms of dementia while using this form of estrogen plus progestin was twice as high as those not taking any hormones.

What does this mean?

This finding means that older women should know that

• Using Prempro™ does not keep you from getting dementia. It doesn't slow the start of the symptoms of dementia. In this study, in fact, it increased the risk for dementia. It also does not stop problems with remembering, paying attention, following directions, or using words correctly.
  
• Older women should not take this form of estrogen plus progestin to prevent dementia or to keep an alert mind.

By dementia, do you mean Alzheimer's disease?

Dementia is a disease that happens when the brain stops working correctly. A person with dementia may repeat things, become lost in familiar places, stop taking care of himself or herself, or forget what year it is. Over time a person with dementia is no longer able to live independently. Alzheimer's disease (AD) is the most common form of dementia among older people. Early in the illness AD attacks the parts of the brain that control thinking, memory, and language. Carrying out the daily activities of life, such as cooking or bathing, becomes harder and harder. There are other forms of dementia. Special tests help doctors rule out other possible causes and diagnose "possible" or "probable" Alzheimer's disease.

Will this dementia go away?

We don't know whether the symptoms of dementia will go away when women are no longer taking these hormones. For the rest of the time the follow-up is planned to run, WHIMS researchers will continue to check the health of women who took part in this study to see what happens over time.

Did these scientists learn anything else about mental abilities?

Yes, the scientists found there was no difference between the two groups of women in their chance of having symptoms of mild cognitive impairment (MCI).

What is mild cognitive impairment?

Mild cognitive impairment (MCI) is a condition marked by a loss of mental abilities such as paying attention, remembering, or thinking. This loss is not great enough to make it hard for people to carry out everyday activities. For example, some people with MCI may be forgetful, but they are still able to live on their own, unlike people with dementia. In the WHIMS study, women found to have MCI did not do well on one or more tests of their mental abilities.

What is WHIMS?

WHIMS, the Women's Health Initiative Memory Study, is a research study looking at changes in memory and mental abilities. It is a part of the larger research study called the Women's Health Initiative. Scientists in the WHIMS are looking at whether using menopausal hormone therapy could keep women over 65 from getting dementia and losing the mental abilities that help them perform daily tasks.

What is the Women's Health Initiative?

In 1992 the National Institutes of Health (NIH) began a large research study called the Women's Health Initiative (WHI). Through this study scientists hope to learn how to protect postmenopausal women from heart disease, breast and colorectal (colon and rectum) cancer, and osteoporosis. The scientists also want to better understand the good things and problems that could come from using menopausal hormone therapy to prevent chronic illnesses such as heart disease. Menopausal hormone therapy is using the hormones estrogen plus progestin or estrogen alone to treat the symptoms of menopause and to prevent bone loss after menopause. This treatment used to be called hormone replacement therapy.

More than 27,000 of the more than 161,000 women in the WHI are taking part in the menopausal hormone therapy study. Other women in the WHI are taking part in studies involving changes in diet to reduce the risk of heart disease, breast and colon cancer, and osteoporosis.

What treatment did the women receive in the WHI and WHIMS?

Women were chosen by chance to receive hormones or a placebo. The placebo looks like the hormone pills, but has no hormone in it. There were two groups that received hormones. The first group took Prempro™ every day. This contained 0.625 mg (milligram) of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate, a progestin. The second group took Premarin™ daily. This had just 0.625 mg of conjugated equine estrogens, without the progestin.

These drugs were chosen because at the time the study started they were the ones most often prescribed by doctors in the United States for menopausal hormone therapy. More than six million women used Prempro™ at the time of the study, and around eight million took Premarin™.

What are estrogen and progestin?

Estrogen and progesterone are two hormones that are made by a woman's body before menopause. Progestin is a man-made progesterone. When estrogen alone is given to a woman with a uterus, she often has a thickening of the lining of the uterus. This can cause irregular bleeding. Rarely this thickening can lead to cancer of the lining of the uterus. So, Prempro™ is given to a woman who has a uterus to protect her from changes in the lining of the uterus. Premarin™ is only given to a woman whose uterus has been removed.

Didn't I hear about the WHI before?

In July 2002, scientists in the Women's Health Initiative stopped the part of their studies looking at combined estrogen plus progestin. This is because they found that women taking this combination had more illnesses than women taking the placebo. These illnesses included more heart attacks, breast cancer, strokes, and blood clots. You may have heard that this combination had some good effects too—fewer hip fractures and less chance of colorectal cancer. Even so, the scientists believed the risks were greater than the benefits. So, all women taking estrogen plus progestin in the WHI studies, including WHIMS, were told to stop their study pills. Women taking estrogen alone were allowed to keep taking their pills because that group did not seem to face the same risks as women taking the combination.

What risks and benefits did the WHI scientists find?

An increase in risk and decrease in risk (benefit) can be described in two ways. One, relative risk, compares the chance that a woman using estrogen plus progestin will have a health problem like a heart attack to the chance that a woman not using any menopausal hormone therapy will have the same problem. The other, absolute risk, gives the actual number of health problems that happened or are prevented because of this estrogen plus progestin. An explanation of relative and absolute risk is available at www.niapublications.org/tipsheets/risk.asp.

Following are the relative risks and absolute risks found in the WHI and WHIMS studies involving estrogen plus progestin:

Why are the WHIMS results important?

Large trials such as the WHI, which includes WHIMS, are believed to give more reliable results than other types of research projects. Some earlier studies of women using estrogen plus progestin suggested that these hormones might prevent loss of mental abilities, and other studies found the opposite. Scientists decided a special type of large study, known as a randomized controlled clinical trial, was needed. This might help them find the answers to many such questions about the effects of using estrogen and progestin. The Women's Health Initiative was begun and included WHIMS. Some earlier studies also used different types of these hormones than were studied in the WHI. Future studies of estrogen plus progestin in animals and humans may help scientists understand why the findings from WHI and WHIMS differed from some earlier results.

The women in WHIMS took Prempro™ for 5 years or less. They were told to stop their study medications in July 2002.

Which hormone—estrogen or progestin—causes this dementia? Or is it the combination?

That is not clear from the results of this study. The other part of WHI and WHIMS, using estrogen alone, is continuing with careful monitoring for safety by the National Institutes of Health. When those trials end and scientists are able to compare the results of the studies, they may be able to answer this question.

Do other estrogens and progestins also cause dementia?

Since the WHI was first planned, more types of estrogens and progestins have become available. These include some that are almost identical to the hormones made by a woman's body. Researchers would have to do similar types of large trials with these other types of hormones to know whether they are safer than the ones used in the WHI and WHIMS. The same is true for other forms of hormones—skin patches or creams, for example, rather than pills.

Are "natural" hormones safer than Prempro™?

Again, until the same types of studies are done with "natural" hormones, experts cannot say whether they are safer or more effective.

What if I cut my pills in half and take a smaller dose—does my risk go down?

We do not have information about hormones women take in lower dosages.

What about the new low-dose versions of Premarin™ and Prempro™?

In spring 2003, the Food and Drug Administration (FDA) approved low-dose Premarin (0.45 mg of conjugated equine estrogens) and Prempro (0.45 mg of conjugated equine estrogens and 1.5 mg of medroxyprogesterone acetate). These may be used for treating menopausal symptoms (hot flashes, night sweats, and vaginal dryness). FDA continues to remind consumers that estrogens and estrogens with progestins should be used at the lowest doses for the shortest length of time needed to reach treatment goals.

What happened in women taking estrogen alone?

WHIMS includes a study using estrogen alone (without a progestin). This is the type of menopausal hormone therapy used in a woman whose uterus has been removed. At present this trial is continuing. The safety of the women in this study is reviewed regularly. These women and the scientists will be given any new information that might affect their continued involvement in the trial.

Who protects the women in this study?

The Women's Health Initiative studies are watched over by a group of experts from many areas of medicine. They make sure the women volunteers are safe and that the studies are run properly. This group, called a Data Safety Monitoring Board, reports to the Director of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH). NHLBI provides most of the NIH funds for the WHI programs. However, the entire cost for both parts of WHIMS (estrogen plus progestin and estrogen alone) was covered by Wyeth Pharmaceuticals, Collegeville, PA.

Each research location in the WHIMS study also has a separate committee called an Institutional Review Board. This Board's job is to make sure that the volunteers are kept up-to-date about what is happening in the study and that their safety is protected.

They received a letter explaining the study results.

Can the participants withdraw from the study?

Yes, they can leave at any time. However, it is important to remember that the women in the WHIMS estrogen plus progestin trial have not used the hormones since July 2002. They were told to stop taking the pills when the larger WHI estrogen plus progestin clinical study was stopped. Participants have been asked to continue their visits with the WHIMS doctors. This is important in order to watch for any changes in the women's health and to keep on adding information to what we have already learned from this study.

Did younger women in the study get dementia?

All women in WHIMS are age 65 and older. Women who were younger than 65 at the start of WHI did not take part in the tests of mental abilities used in WHIMS. So, scientists don't know the effect of estrogen plus progestin on the mental abilities of these younger women.

I want to use menopausal hormone therapy to relieve my hot flashes. What does this new information mean for me?

Using menopausal hormone therapy for just a short time is still approved by the Food and Drug Administration to control the symptoms of menopause and to protect women from bone loss that could lead to osteoporosis. However, remember three things. First, in the WHI estrogen plus progestin trial, the increase in breast cancer did not happen until after 4 years of use. Second, in the same trial, the increase in heart disease, stroke, and blood clots began within the first 2 years after starting estrogen plus progestin. Third, in the WHIMS estrogen plus progestin trial, the mental changes also occurred very quickly in these women, who were age 65 and older. That is why it is important to talk to your health care provider about your entire health picture.

I take oral contraceptives. Am I at risk for dementia?

Oral contraceptives are prescribed for women younger than those in WHI/WHIMS. They use different estrogens and progestins than those in these trials. Therefore, scientists do not know if the results of this study are important for premenopausal women. Women who use oral contraceptives should be aware, however, that these pills carry their own increased risk of heart attacks, stroke, and blood clots.

Will there be a follow-up study to make sure this result is correct?

Scientists will follow WHI participants for several years in order to learn about any long-term effects of using this menopausal hormone therapy.

Are more findings expected from the WHI?

When the estrogen-only trial of the WHI ends, the scientists will be able to compare the results of that trial with those from the estrogen plus progestin study and publish the findings. Before then, more details about the estrogen and progestin studies may be published from time to time. Also, scientists in other parts of the WHI, separate from the hormone therapy trial, will be reporting in the future.

Where can I get more details about this study?

The scientific report of the study findings is published in the May 28, 2003, issue of the Journal of the American Medical Association (JAMA). You can learn more about menopausal hormone therapy and the Women's Health Initiative by going to the NIH home page, www.nih.gov, and clicking on the link to "Menopausal Hormone Therapy." The WHI Memory Study website is www.wfubmc.edu/whims. Information on memory and Alzheimer's disease can be found at www.alzheimers.nia.nih.gov. That's the National Institute on Aging (NIA)'s Alzheimer's Disease Education and Referral (ADEAR) Center. You may also call the ADEAR Center toll free at 1-800-438-4380 for information and publications. General information on menopause and aging is on the NIA website, www.nia.nih.gov, in "Health Information," and you can order publications by calling the NIA Information Center toll free at 1-800-222-2225.

I am taking prescription hormones. Now that I know all this, what should I do?

Set up a visit with your health care provider. You can talk to him or her about your risk for health problems, any menopausal symptoms you may be having, and possible treatments.