Detailed Questions and Answers about the Women's Health Initiative And the Women's Health Initiative Memory Study

May 22, 2003

What is the Women's Health Initiative?

The Women's Health Initiative (WHI) is a National Institutes of Health (NIH)-sponsored study of more than 161,000 women, ages 50-79, to gather information on ways to prevent and reduce heart disease, breast and colorectal (colon and rectum) cancer, and osteoporosis in postmenopausal women, as well as to identify the benefits and risks of using menopausal hormone therapy (MHT) to prevent these chronic diseases. Menopausal hormone therapy involves the use of the hormones estrogen plus progestin or estrogen alone to treat the symptoms of menopause such as hot flashes and to prevent bone loss after menopause. This therapy was formerly called hormone replacement therapy (HRT)

More than 27,000 of the women in the WHI are taking part in the menopausal hormone therapy portion of the study. Participants were to be followed for 8 to 12 years. Some took combined estrogen plus progestin, some just estrogen alone, and some took a placebo, a pill that looked like the hormone pill, but had no active ingredient.

Wasn't WHI in the news in 2002?

In July 2002, WHI investigators announced that they had stopped the part of their study involving combined estrogen plus progestin because they found that the possible risks of this therapy exceeded the safety limits established at the beginning of the study. That is, the health risks of this combination exceeded the benefits. Those risks were an increase in heart attacks, breast cancer, strokes, and blood clots in women taking estrogen plus progestin compared to those receiving the placebo. They also found some benefits—fewer hip fractures and less chance of colon cancer. All WHI participants taking estrogen plus progestin were told to stop their study pills. Those taking estrogen alone were allowed to continue.

What were the actual increases in risk?

The increase in risk and decrease in risk (benefit) were described in two ways. One, relative risk, compares the chance that a woman using estrogen plus progestin (EPT) 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 study involving estrogen plus progestin:

What is WHIMS?

WHIMS is the Women's Health Initiative Memory Study, a "substudy" of the WHI trial. It was designed to test whether using menopausal hormone therapy – either the combination of estrogen and progestin or estrogen alone – would reduce the risk of cognitive decline and dementia in women over the age of 65. All WHI studies using combination therapy, including WHIMS, were halted in July 2002. Some 4,500 women participated in the combination therapy arm of WHIMS, with about half taking combination therapy and half on placebo.

What hormones did women in the WHI and WHIMS take?

Women who were randomly selected to receive hormones were taking Prempro™, 0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate, a progestin, continuously (every day), or Premarin™, 0.625 mg of conjugated equine estrogens daily without the progestin. Prempro™ was given to women who have a uterus to protect them from endometrial hyperplasia and, rarely, endometrial cancer. Premarin™ is only given to women whose uteri have been removed. 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 were the main findings in the WHIMS study of the effects of estrogen plus progestin on cognition?

Compared to women taking placebo pills, the number of women over age 65 who developed dementia was greater in women taking estrogen plus progestin.

What are the conclusions from these findings?

The main conclusions are:

• The estrogen plus progestin combination studied in WHIMS does not prevent dementia or slow progression toward dementia over time. In addition, it did not prevent general cognitive decline.
  
• Older women should not take estrogen plus progestin to prevent dementia or to preserve cognition.

What are the increased cognitive risks for women taking estrogen plus progestin?

• The number of older women taking estrogen plus progestin who developed dementia was greater than the number of older women taking placebo pills who developed dementia.
  
• The risk for developing dementia in older women taking estrogen plus progestin was double the risk for developing dementia in older women taking placebo pills.
  
• The risk for mild cognitive impairment was the same for older women taking estrogen plus progestin as it was for older women taking placebo pills.
  
• Some older women taking estrogen plus progestin did not do as well on cognitive tests compared to older women taking placebo pills. This indicated an adverse effect on cognitive function in some older women.

What is the actual increased risk?

In one year in every 10,000 older women using this estrogen plus progestin treatment, 45 women might develop dementia, compared to 22 women in every 10,000 older women using no hormones. That is an increase of 23 additional women who developed dementia for every 10,000 older women treated each year. The relative risk was 2.05 or 105% increased risk of dementia.

By dementia, do you mean Alzheimer's disease?

Dementia is a brain disorder that eventually makes carrying out the daily activities of life impossible. Memory lapses become more common as people age, and many worry that forgetfulness is the first sign of a type of dementia known as Alzheimer's disease (AD). AD is the most common form of dementia among older people, but not the only form. AD affects the parts of the brain that control thought, memory, and language in the early stages of the disease. This often leads to problems carrying out everyday activities. Through special tests doctors can rule out other possible causes and make a diagnosis of "possible" or "probable" AD. Fifty percent of the dementia found in the estrogen plus progestin group and 57 percent of the dementia in the placebo group were Alzheimer's disease, although there were also various other forms of dementia, such as vascular dementia.

What is mild cognitive impairment?

Mild cognitive impairment (MCI) is a condition marked by a loss of mental abilities, but not severe enough to be dementia. Most people with MCI may be forgetful and confused, but are still able to carry on independently with their everyday activities. In the WHIMS study, women diagnosed with MCI showed below normal performance in one or more cognitive tests, not necessarily including memory.

When did the increased risk of developing dementia in women taking estrogen plus progestin compared to women taking placebo pills began to occur?

The first cases of dementia began to be seen around one year after women began using this estrogen plus progestin treatment, but the trend became apparent over a number of years. These results from WHIMS suggest that instead of slowing the onset of dementia, this estrogen plus progestin actually shortens the time before symptoms first appear.

Is this reversible?

We don't know whether the cognitive decline seen in this study will improve when women are no longer taking the drug. WHIMS investigators will continue to monitor the women who participated in the study to see what happens over time.

Is there an increased risk of dementia 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 Data and Safety Monitoring Board (DSMB) is an independent board of medical researchers who are responsible for ensuring the safety of the WHI volunteers and the proper conduct of the study. The DSMB reviews all of the study data every 6 months. The Board includes 12 outstanding medical researchers with expertise in aging, behavioral science, cancer, cardiology, ethics, gynecology, nutrition, osteoporosis, statistics, and women's health. The Board reports to the Director of the National Heart, Lung, and Blood Institute (NHLBI), NIH. NHLBI provides the principal support for the WHI program. Thus far, the DSMB has decided that the estrogen only portion of the WHIMS study can continue.

Each WHIMS Clinical Center also has a separate review committee called an Institutional Review Board (IRB). The local IRB is responsible for making sure that participants are kept fully informed about the study and that their safety is protected.

What happened to younger women on the hormones?

All WHIMS participants are women ages 65 and older. Women younger than 65 at the start of the WHI study did not receive the detailed cognitive testing used in WHIMS.
There is some evidence in laboratory animals and other types of studies involving women under 65 that the age at which menopausal hormone therapy is started may make a
difference in how effective it may be in preventing both heart disease and Alzheimer's disease. However, much more research is needed.

Why did they think estrogen plus progestin would prevent cognitive decline and dementia?

Research in tissue culture cells and in animals has shown that estrogen has a number of beneficial effects on the brain. Some studies observing certain groups of women for several years suggested that those women using menopausal hormone therapy kept their memory and thinking abilities longer than those not on such treatment.

Why are these WHIMS results so different?

The WHI is a randomized controlled clinical trial. Most of the earlier studies were not. Trials such as the WHI are believed to provide more reliable results than other types of research projects. In addition, many of these earlier animal studies and some of the human studies did not use the type of estrogen and progestin studied in the WHI. Future analyses of estrogen plus progestin in animals and humans may explain these unexpected results.

How long did the women in the study take Prempro™? Are they still taking Prempro™?

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—is the cause of cognitive impairment? 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. (BA) When those trials end and scientists are able to analyze and compare the results of the studies, they may be able to answer this question.

Do other types of estrogen and progestin also cause cognitive decline?

Without a similar type of trial, we cannot assume that the safety of different estrogens and progestins is the same as or different from the safety of those hormones used in WHI/WHIMS. Since the WHI was designed, more types of estrogens and progestins are available, including estradiol, the principal estrogen produced in a woman's body before menopause, and micronized progesterone, chemically identical to natural progesterone.

Are "natural" hormones safer than Prempro™?

Again, until the same types of studies are conducted with "natural" hormones, conclusions about better safety or effectiveness cannot be made.

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

We also do not have information about hormones women take in lower dosages or in different ways, such as patches or creams instead of pills.

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 duration to reach treatment goals.

How were WHIMS participants notified of these results?

They were notified by letter explaining the study results.

Can they withdraw from the study?

As with any research study, they can withdraw 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 medication when the larger WHI estrogen plus progestin clinical study was stopped.

I am taking prescription hormones. What should I do?

Schedule a visit with your health care provider to talk about your own health risks, any menopausal symptoms you may be having, and your treatment options.

How does all of this new information affect my decision to use menopausal hormone therapy for relief from hot flashes?

Short-term menopausal hormone therapy is still approved by the Food and Drug Administration for controlling the symptoms of menopause and for protecting women from bone loss that could lead to osteoporosis. Remember, however, in the WHI estrogen plus progestin trial, the increase in breast cancer did not develop until after 4 years of use, but the increase in heart disease, stroke, and blood clots began within the first two years after starting estrogen plus progestin. In the WHIMS estrogen plus progestin study, the change in cognition also developed very quickly in these women, who were age 65 and older. That is why it is important to discuss your entire health picture with your health care provider.

Where can I get more details about this study?

The scientific report of the study findings is being published in the May 28, 2003, issue of the Journal of the American Medical Association (JAMA). Background information on menopausal hormone therapy and the Women's Health Initiative is available through the NIH home page, www.nih.gov, by 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 may be viewed at www.alzheimers.nia.nih.gov, the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center. The public may also call the ADEAR Center toll free at 1-800-438-4380 for information and publications. General information on menopause and aging may be viewed at www.nia.nih.gov in "Health Information," and publications may be ordered by calling the NIA Information Center toll free at 1-800-222-2225.

I take oral contraceptives. What does this study mean for me?

Oral contraceptives, which are prescribed for younger women than those in WHI/WHIMS, contain different estrogens and progestins than those used in these trials. Therefore, we do not know if the results of this trial can be applied to premenopausal women. Users of 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 hope to study WHI participants for several years in order to learn about any long-term effects of using menopausal hormone therapy.

Are more findings expected from the WHI?

When the estrogen-only trial of the WHI ends, the investigators will be to analyze and compare the results of both studies and then publish the findings. Before then, more detailed analyses of estrogen plus progestin data may be published from time to time. Also, scientists in other parts of the WHI, separate from the randomized clinical trial, will be reporting in the future.

What did the WHIMS cost?

The entire funding for both parts of WHIMS (estrogen plus progestin and estrogen alone) was provided by Wyeth Pharmaceuticals, Collegeville, PA.