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Hormone therapy, either estrogen alone or estrogen combined with progestin, has been the subject of numerous studies over the past two decades. Some of the findings have suggested benefits to hormone use; others have suggested risks.

Recently, however, one definitive study has convinced experts that the risks of estrogen plus progestin outweigh the benefits. This large randomized trial, conducted as part of the Women's Health Initiative (WHI) at the National Institutes of Health, was stopped early when it became clear that estrogen plus progestin increased the risk of heart disease, blood clots in the legs and lungs, and breast cancer. More information from the National Cancer Institute about the WHI trial can be found at http://cancer.gov/ClinicalTrials/digest-postmenopausal-hormone-use.

In August 2002, following publication of these results, the Agency for Healthcare Research and Quality (AHRQ) reviewed the available data on the risks and benefits of postmenopausal hormone use. AHRQ also concluded that the risks of long-term use (more than five years) outweighed the benefits. The AHRQ papers, which include a review on cardiovascular disease published in the Annals of Internal Medicine, an overall summary of risks and benefits published in the Journal of the American Medical Association, and summaries of evidence for breast cancer, cardiovascular disease and stroke, dementia, blood clots, and osteoporosis, are available at http://www.ahrq.gov/clinic/3rduspstf/hrt/.

What were the studies that preceded the WHI results and the AHRQ review? Following is a list of major studies and their findings, from 1984 to 2002, grouped under the diseases or health problems that they have addressed: breast cancer, endometrial cancer, ovarian cancer, osteoporosis, coronary heart disease, colorectal cancer, stroke, gall bladder disease, and blood clots.

Background
The use of the hormone estrogen to counteract some of the short-term discomforts of menopause (hot flashes, vaginal drying and thinning) began in the 1940s and increased rapidly in the 1960s. When it became clear in the 1980s that adding progestin, a synthetic form of the natural hormone progesterone, reduced the increased risk of endometrial cancer associated with using estrogen alone, it became increasingly common to prescribe estrogen-progestin replacement therapy for women who had not had a hysterectomy.

Today, anywhere from 20 percent to 45 percent of U.S. women between the ages of 50 and 75 take some form of hormone therapy. According to industry estimates, about 8 million U.S. women use estrogen alone and about 6 million U.S. women use estrogen-progestin therapy. The median duration of use among U.S. women is approximately two years. About 20 percent of hormone users continue for more than five years.

Types of Studies
There are various levels of evidence to evaluate the effects of an exposure on a disease or condition. Some are stronger than others. Two general kinds of studies are used to see whether hormone therapy (estrogen or estrogen-progestin) is linked to various conditions -- observational and experimental studies.

Observational Studies
In observational studies, which are more common than experimental ones, there is no intervention on the part of the investigator. Observational studies can be cohort and case-control.

• Cohort Studies
  The investigator begins with a cohort -- a group of people who have different exposures to hormone therapy. The cohort is followed over time to see whether a disease or condition develops. The investigator is interested in seeing if those with the highest exposure to hormone therapy develop the disease or condition at a higher rate than those with lower exposures.
  
  

• Case-Control Studies
  In case-control studies, the investigator begins with people diagnosed as having a disease (cases) and compares them to people without the disease (controls). Using data from a variety of sources -- personal interviews and medical, hospital, and pharmacy records -- cases and controls are compared with regard to their use of hormone therapy. The purpose is to determine if the two groups differ in the proportion of people who are exposed to hormone therapy.
  
  

• Case-Control vs. Cohort Studies
  Case-control studies are generally used to study rare diseases. Compared to cohort studies, they often have more women with disease (cases). Case-control studies are usually less expensive and require less time to carry out than cohort studies. However, case-control studies rely on participants telling the researchers about events or exposures that have happened in the past. This is a particular problem for people with the disease, because their disease can affect the reliability of their responses (e.g., cases may recollect past events differently than the controls because they are searching for explanations for their particular disease). Sometimes this problem can be overcome by using pharmacy records. Another important problem in case-control studies is that it may be difficult to select controls to "match" the cases so that they are similar to the cases in specific characteristics. For these reasons, case-control studies are generally more subject to bias and tend to provide a lower level of evidence than cohort studies.
  
  

Experimental Studies or Intervention Trials (Randomized Trials)
In experimental studies or intervention trials, the investigator varies the exposure to a factor -- in this case, hormone treatment -- to see its effect on disease. The investigator tries to control all experimental conditions so that any difference between study participants can be attributed only to the factor being studied.

The highest level of evidence for a causal association between hormone exposure and disease or condition is achieved with a randomized, controlled, blinded, clinical trial. In this type of trial, the criteria of who will be included and excluded from a study are carefully spelled out; a particular age range, previous health history, or medication use might be specified. Once the criteria are decided, trial participants are randomly assigned to a treatment group; the group receiving the new treatment may be compared to a group receiving either placebo (an inactive substance that looks the same and is administered in the same way as the hormone treatment) or standard care. Randomization will not only increase the likelihood that the groups will be comparable in terms of sex, age, and race, for example, but also in terms of variables that may not be recognized. Clinical trials are often double-blinded, meaning neither patients nor researchers know whether individuals are in the placebo group or the treatment group. Blinding is necessary to ensure that the two groups are not treated differently during follow-up and that outcomes are not reported or interpreted differently. This type of trial ensures that, at the end of the trial, any difference between the two groups was caused by the therapy.

A data and safety monitoring board is set up before a clinical trial begins to ensure patient safety. The trial may be stopped when harmful effects arise or when beneficial effects are clear. A plan is established in advance to weigh the risks and benefits and guide the board in interpreting the data.

Randomized trials are used to evaluate agents for the prevention or treatment of disease, but, for practical or ethical reasons, cannot be used in some situations, such as to test suspected cancer-causing substances. So, for example, it would not be ethical to design a trial to test the potential harmful effects of hormone therapy, such as breast cancer and stroke, first suggested by observational trials. However, observational trials also indicated potential benefits of hormone therapy, such as possible protection against heart disease and osteoporosis. Therefore, randomized trials were designed to evaluate and compare both the risks and the benefits of the therapy.

Observational Studies vs. Intervention Trials
Researchers almost always begin the study of a health issue with observational studies. Observational studies can provide definitive answers for risk factors like smoking or exposure to harmful agents. For new treatments or protective agents, they provide preliminary answers without raising the ethical issues associated with random assignment to a treatment and blinded follow-up and can usually be completed much more quickly than trials. Treatments and preventive interventions that look promising in observational studies are generally followed by randomized trials to provide definitive evidence.

Some observational studies have the advantage of being able to look at the effect of an exposure over a longer period of time than is typical of a randomized clinical trial, since most trials last only a few years. However, there are particular problems with observational studies that are not present in randomized trials when studying hormone therapy. One of the major problems is that women who choose to take hormone therapy are different than the non-users; compared to non-users, those on therapy are often healthier, have a higher level of education, better access to medical care, and are more willing to comply with a prescribed therapy. So, if a difference is seen in observational studies between those on hormone therapy compared to those not on therapy, it is not clear whether the difference is due to the therapy or to some other difference between the two groups. Researchers usually try to control these differences using statistical methods, but it is not always possible to do so completely. For these reasons, a randomized clinical trial is considered the strongest level of evidence for testing whether an agent prevents a disease or condition.

Evidence of Benefits and Risk
The tables below summarize the available evidence on the risks and benefits of hormone therapy. Included are all randomized trials and meta-analyses (a re-evaluation of the combined results of several studies) looking at incidence or mortality of diseases or conditions. Inclusion of observational studies was dependent on size: case-control studies with 500 or more cases and cohort studies with at least 2,000 women are included here.

Tables
Click the title to view the table.

Breast Cancer	Colorectal Cancer
Endometrial Cancer	Stroke
Ovarian Cancer	Gallbladder Disease
Osteoporosis	Blood Clots (Venous Thromboembolism)
Coronary Heart Disease

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