Menopause Management in Light of the Women's Health Initiative Study

In the July 17, 2002, issue of The Journal of the American Medical Association (JAMA), an article about a clinical trial to assess the risks and benefits of estrogen/progestin treatment for postmenopausal women was published. The Hormone Foundation has prepared this question-and-answer document to help patients understand the recent announcement.

What is the Women's Health Initiative Study?

The study, called the Women's Health Initiative (WHI), was a prospective, randomized trial of more than 16,000 healthy, postmenopausal women between the ages of 50 and 79, who received estrogen plus progestin (if they had a uterus), estrogen alone if their uterus had been removed (by hysterectomy), or placebos (sugar pills) to assess their effects on a variety of health issues. These included cardiovascular disease (coronary heart disease and stroke), breast and colorectal cancer, and bone fractures. The study was not designed to assess the effects on hot flashes or vaginal dryness and irritation Ñ common symptoms that occur after menopause. The study also did not assess the effects on dementia and Alzheimer's disease.

How long was the estrogen plus progestin study originally scheduled to last?

The estrogen plus progestin trial was originally designed to last 8.5 years, and was to have been completed in 2005. However, the estrogen plus progestin component of the study, but not the estrogen alone, was halted after 5.2 years primarily because of an increased risk of invasive breast cancer in the women who received the estrogen/progestin combination, and the perception that risks exceeded benefits.

What is the status of the estrogen-only portion of the WHI study?

In the estrogen-only arm of the study, there was not a statistically significant difference in the incidence of breast cancer between the women receiving estrogen compared to those receiving placebo, so that arm of the study is planned to continue for a total of 8.5 years. There also was no statistically significant difference between the mortality rates in any of the groups.

Why was the estrogen plus progestin study halted early?

Although the increased risk of breast cancer was relatively small for any individual woman (an increase of eight cases per 10,000 per year more in women taking the combination than in those receiving the placebo), because of the large number of postmenopausal women taking this combination (approximately 38 percent of postmenopausal women in the United States use hormone replacement therapy), the physicians and scientists monitoring the study decided to discontinue it.

A press conference to discuss the study was held on June 9, 2002, in Washington, D.C., at which members of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and statisticians involved with the WHI discussed the findings. The article also was placed on the JAMA Web site. Stories about the study appeared in most of the leading newspapers including USA Today and The New York Times , and on radio stations throughout the United States.

What other effects did the estrogen plus progestin have on the women?

The estrogen plus progestin study results demonstrated a decrease in fractures and in development of colon cancer, and a slight increase in blood clots, strokes and coronary heart disease. Compared to the women receiving placebos, for every 10,000 women receiving combined hormone treatment for a year, there would be six fewer colon cancers and five fewer hip fractures, eight more strokes and eight more blood clots that went to the lungs (pulmonary emboli).

For the most part, the results of the WHI study are consistent with previous studies dealing with estrogen/progestin combination treatment. The increased risk of breast cancer with increasing length of use and the reductions in risk of colon cancer and fractures have been found in previous studies, as have the increased risk of blood clots. At least two previous studies have demonstrated that the addition of the progestin used in the WHI study (medroxyprogesterone acetate) to estrogen increased the risk of developing breast cancer compared to the use of estrogen alone, particularly in thinner women. It will be of interest to determine the incidence of breast cancer in the women who are taking estrogen only when that arm of the WHI study is completed. (A progestin is usually given with estrogen only in women who have not had their uterus removed, as this prevents the increased risk of uterine cancer in women who take only estrogen.)

The risk of stroke and blood clots continued during the five years of treatment, whereas most of the risk of coronary heart disease was limited primarily to the first year of treatment, as has been found previously. Previous observational studies had indicated that the use of estrogen and estrogen/progestin treatment reduced the risk of coronary artery disease by 30 percent to 50 percent in postmenopausal women. However, the WHI study, which was a prospective, placebo-controlled double-blind study, did not bear this out. This was perhaps the most surprising finding in the WHI study.

Did the WHI estrogen plus progestin study examine all aspects of how the combination affected the women?

The study did not address the effects of hormone treatment on hot flashes and vaginal dryness, common and sometimes very troubling symptoms, particularly during the first few years following the menopause, for which estrogen is the most effective treatment. In the July report, there was no analysis of effects on dementia and Alzheimer's disease.

What should women who are currently taking estrogen plus progestin do with this new information?

The Hormone Foundation recommends that each postmenopausal woman discuss with her caregiver the optimal treatment management for her, taking into account her medical and family history.

The Foundation also recommends appropriate nutrition, weight reduction when indicated, adequate exercise, alcohol in moderation and no smoking, as these are very important in maximizing health promotion and disease prevention.

Are there alternative treatments for some of the known and suggested benefits of estrogen/progestin treatment?

There are alternative treatments for prevention and treatment of bone loss and cardiovascular disease, and for some of the other suggested benefits particularly of estrogens:

1. For prevention and treatment of bone loss Ñ
   1. Compounds called bisphosphonates, which decrease the rate of bone loss. These are specifically for prevention and treatment of bone loss.
   2. Selective Estrogen Receptor Modulators (SERMs). This class of compounds also specifically targets bone, but may be useful in reducing the risk of breast cancer. They also reduce the levels of low density lipoprotein (LDL) cholesterol and total cholesterol, which have been associated with increased risk of cardiovascular disease.
   3. Calcitonin Ñ This agent also is specifically for minimizing bone loss, and usually is given in an intranasal preparation.
   4. Just approved is a form of a hormone, called parathyroid hormone. When administered on an intermittent basis, it appears to be very potent in adding additional bone to the skeleton. It probably will be used primarily for treatment of severe osteoporosis. Please remember that accompanying all of these treatments, it is important to take adequate quantities of calcium and vitamin D.
      
2. For prevention of cardiovascular disease Ñ
   1. A group of compounds called 'statins.' These lower lipids in the blood and have been shown to decrease the risk of cardiovascular disease in individuals with abnormal circulating lipids and those with a family history of heart disease.
   2. Aspirin. Several observational studies indicate that small doses of aspirin on a daily basis reduce the risk of heart disease.
      
3. For treatment of hot flashes Ñ To date, no treatment has been found to be as uniformly effective as estrogen. However, the following medications have been found to be helpful in many women:
   1. A group of compounds called SSRI's (Selective Serotonin Reuptake Inhibitors)
   2. Megace (progestin-like compound)
   3. Clonidine (medication used to reduce blood pressure)
      
4. For vaginal dryness and painful intercourse Ñ
   1. Small amounts of vaginal estrogen, in the form of a vaginal cream or ring are effective, with only small amounts absorbed in the blood stream
   2. Vaginal lubricants, which can be purchased without a prescription, offer some relief, but do not cause the vaginal lining to thicken, as estrogen does
      
5. For reducing the risk of colorectal cancer Ñ
   1. Testing for blood in the stool
   2. Periodic colonoscopy or sigmoidoscopy