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Postmenopausal Hormones: An Update

Posted by medconsumers on March 1, 2002

Postmenopausal Hormones: An Update
by Maryann Napoli

Postmenopausal hormones have been promoted to women (and doctors) for nearly four decades with promises of everything from youthful skin to increased longevity. The currently popular indications-prevention of heart attack and hip fracture-are not supported by good research. Two large trials, which randomly assigned women to take hormones or not, have failed to confirm estrogen’s heart protective effects. And while many randomized controlled trials (RCTs) have proven estrogen’s ability to stop the loss of bone density, none lasted long enough to show that this hormone actually prevents fractures.

Estrogen is still prescribed to women as a treatment for osteoporosis (bone loss), though the Food and Drug Administration removed this indication in 1999 because of lack of evidence. Only one indication for taking hormones is backed up with good research support-the relief of menopausal symptoms, such as hot flashes.

The two large RCTs, which provided the heart-related results, are the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Study (HERS). Together they included about 30,000 participants. The HERS was designed to determine whether hormones can prevent heart attacks in women, aged 44 to 79 years, who have heart disease. And the WHI, which includes healthy women, aged 50-79 years, is exploring the effects of hormone therapy on the prevention of heart disease and osteoporosis-related fractures, and on the risk of breast and uterine cancers. All participants had been randomly assigned to take a placebo (inactive pill) or hormones (estrogen alone for women who had a hysterectomy or estrogen plus progestin for women with an intact uterus).

The data from these and other RCTs are being searched for information about a range of health effects associated with hormone therapy:

Cardiovascular Events: Both the HERS and the WHI found a small increase in the number of heart attacks, strokes, and blood clots in the lungs in the first one to two years of hormone use. Researchers initially thought that this small risk (fewer than 1% altogether) would disappear after two years, but longer follow-up showed otherwise. Last year, the WHI reported a continued increase in heart attacks, strokes, and blood clots in women taking hormones.

Prevention of Another Stroke: Among 652 women (mean age 71 years) who had suffered a non-disabling stroke or a transient ischemic attack, those who had been randomly assigned to take oral estradiol did not show a lower incidence of death or stroke. Worse, the rate of fatal stroke was significantly higher among those taking estradiol (a form of estrogen).

Fractures: The WHI is designed to answer the question of whether hormones prevent fractures, following its participants for eight to 12 years.

Urinary Incontinence: 1,525 women with urinary incontinence participated in the HERS. All were younger than 80 years and had experienced at least one episode of urinary incontinence per week. Incontinence improved in 26% who had been assigned to take a placebo for four years, as compared with 21% assigned to take hormones. Urinary incontinence worsened in 27% of the placebo group, as compared with 39% of the hormone group.

Dry Eye Syndrome: 665 participants of Women’s Health Study, a RCT that began in 1992, found a slight increased incidence of dry eye syndrome in hormone users (past and current), especially among the women on estrogen alone. According to questionnaires completed by the participants: 9% of those taking estrogen alone reported severe symptoms diagnosed by physician, as compared with 7% among the estrogen plus progesterone or progestin, and 6% among those who never used hormones. Dry eye syndrome, a condition with no effective treatment, can damage the surface of the eye.

Urinary Tract Infection: Women in the HERS who had been randomly assigned to take hormones for four years did not have a lower incidence of urinary tract infections.

Gallbladder Disease: The HERS showed gallbladder disease to be 38% higher among those who had been assigned to take estrogen/progestin therapy.

Annoying “Minor” Side Effects: Breast tenderness with uterine bleeding caused 30% to stop taking hormones by the end of one year.

What’s Wrong With Observational Studies?

Many benefits attributed to hormones, such as prevention of Alzheimer’s disease, have yet to be validated in an RCT. Such information comes from less reliable research, known as observational studies. Such research takes a backward look at women who chose to take hormones to determine whether their health status differs from that of women who did not take hormones.

The problem with observational studies is this: Women who take hormones tend to be upper income and well educated. Both characteristics are associated with better heart health and longevity. Susan Love, MD, author of Dr. Susan Love’s Hormone Book, identified the problem: “We don’t know whether hormones made the women healthy, or whether healthy women take hormones.” It is the observational studies that misled so many gynecologists to believe that estrogen prevents heart disease.

An RCT provides more trustworthy results because participants of similar age, health status, etc, are randomly assigned to take the drug or not. Then they are followed for years. Most RCTs are double-blind, which means that neither the participants nor the health professionals monitoring them know who is on the placebo and who is taking the active drug.

Benefits and Risks Yet to Be Confirmed:

Colorectal Cancer: Observational studies have produced inconsistent findings regarding the possibility that hormones lower the risk of colorectal cancer. The results range from no reduction to a 33% reduction in colorectal cancer.

Cognition: Observational studies suggest that hormone therapy may reduce the risk of cognitive decline. A systematic review of all studies, including some RCTs, that explored this topic was published last year in the Journal of the American Medical Association. The participants, who had been taking hormones for the symptoms of menopause, showed improvements in “verbal memory, vigilance, reasoning, and motor speed, but no enhancement in other cognitive functions.” The authors went on to explain that most of these studies had significant limitations.

Alzheimer’s Disease: No RCT has been conducted regarding the risk of dementia. Earlier observational studies suggest that women taking hormones were less likely to develop Alzheimer’s disease, but more recent observational studies did not find this benefit.

Breast Cancer: Does estrogen use increase the risk of developing breast cancer? More than 30 observational studies have been conducted to answer this question. But, here too, the results have been inconsistent. Some found estrogen use to be associated with a reduced risk of developing breast cancer; others found an increased risk of breast cancer beginning after five years of use. And some studies found no risk. The WHI has been designed to provide a reliable answer to the question of whether there is an association between estrogen and breast cancer.

Endometrial (uterine) Cancer: Ever since it became known that estrogen increases a woman’s odds of developing uterine cancer, the drug is now prescribed with another hormone, progestin, to women with an intact uterus. Not all doses of progestin protect the uterus, however. For the results of a review of all trials that determined appropriate doses, see “Protecting the endometrium” by Gibbons and Thorneycroft in the Journal of Reproductive Medicine (2/99).

For More Information About the WHI:

The Women’s Health Initiative is sponsored by the U.S. National Heart, Lung and Blood Institute. Visit its Web site at www.nhlbi.nih.gov/whi/hrt/htm for more information about the progress of this trial.

(March 2002)

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