These were the headlines women woke up to on the morning of July 10, 2002. It was the day after researchers at the National Heart, Lung and Blood Institute (NHLBI) announced that they had stopped the largest randomized clinical trial of one of the most popular prescribed forms of hormone replacement therapy. Part of the NHLBI’s Women’s Health Initiative (WHI), the trial ended early because women taking the hormones had an increased risk of developing breast cancer compared to women on placebo.
The response was swift: Menopausal women ditched their hormones. In 1999, U.S. doctors wrote 90 million prescriptions for hormone replacement therapy. Within a year after the trial ended, that number dropped by a third and continued to fall. In 2010, about 30 million prescriptions were filled.
Yet not all of those women needed to give up the medication, according to experts. In 1941, the U.S. Food and Drug Administration (FDA) approved hormone replacement therapy—estrogen for women whose uteruses had been surgically removed or estrogen plus progesterone (to protect against endometrial cancer) for women with uteruses— and calls it the “most effective FDA approved medicine” to alleviate hot flashes, night sweats, and vaginal dryness, which frequently occur during menopause. The WHI, however, was investigating whether the drugs could also prevent cardiovascular disease in older women who were on average 63 years old and 12 years past menopause.
These are two very different uses of the drugs, but that subtlety was lost in the original media reports, says Robert Langer, M.D., M.P.H., medical director of the Jackson Hole Center for Preventative Medicine in Wyoming. “Doctors as well as women got really confusing, mixed messages,” he says.
Over the past decade, with the release of additional follow-up data, doctors now have a better picture of the risks and benefits of hormone replacement therapy, now called menopause hormone therapy or MHT.
“In the past 10 years, after the initial alarm, a much more reasonable approach is being taken,” says Virginia Miller, Ph.D., a professor of surgery and physiology at the Mayo Clinic College of Medicine.
Medical associations like The Endocrine Society and the North American Menopause Society (NAMS) agree that menopause hormone therapy is an effective treatment for menopausal symptoms. Adverse effects are low for relatively young, healthy women, so these organizations recommend prescribing the therapy to women in their 50s, or those within 10 years of menopause. However, women with certain medical histories are not good candidates for treatment. According to NAMS, “If you have had blood clots, heart disease, stroke, or breast cancer, it may not be in your best interest to take hormone therapy.”
In general, these medical societies advise that women stay on the treatment for the shortest period possible. For example, no more than three to five years for estrogen plus progesterone. However, because the Women’s Health Initiative evaluated an older population of women, the risks of long-term hormone use in younger menopausal women are unclear.
“What the trials didn’t answer is if a woman started in her 50s and took it into her 70s that the risk would go up,” says Howard Hodis, director of the Atherosclerosis Research Unit at the University of Southern California Keck School of Medicine. “There are no data in the Women’s Health Initiative that can say that.” In fact, no data from any randomized clinical trial are available to answer that question.
Some doctors think there’s still a chance that the longterm use of menopause hormone therapy, started when a woman is young enough, may be not only safe but beneficial. “There are observational studies where women have taken these things for 20, 30, or 40 years and clearly still have reduced [coronary] events and mortalities,” Hodis says. But this belief remains one of the most controversial aspects of menopause hormone therapy.
Risks versus Benefits
Menopause hormone therapy for the treatment of chronic conditions is not an FDA-approved use of the drugs. The Women’s Health Initiative chose to look at the potential preventive benefits of the treatment because of the dozens of observational studies that indicated hormones might protect the heart. There had never been a large, long-term randomized clinical trial of the treatment. In 1993 to 1998, 16,608 women between the ages of 50 and 79 years enrolled in the estrogen-plus-progestin (a synthetic progesterone) trial and 10,739 women enrolled in the estrogen-only trial. These trials were supposed to run for 8.5 years, but the estrogen-plus-progestin trial ended about five years early, in 2002, after the researchers determined the treatment group had a 26 percent increased risk of developing breast cancer. The estrogen-only trial continued until 2004, when an increased risk of stroke was found in the group taking the hormone.
Recently the U.S. Preventive Services Task Force, an independent panel of experts, reviewed the original Women’s Health Initiative studies, follow-up data, and other clinical trials investigating menopause hormone therapy since 2002. The task force published its preliminary findings in July in the Annals of Internal Medicine. The panel considered menopause hormone therapy’s effects on a range of chronic conditions. For many ailments, the treatment either had no effect or raised the risk of developing the condition. Only in some instances did hormones offer some preventive benefits.
“It’s kind of a mixed bag about which risk factors are pulling in different directions,” says task force leader Heidi Nelson, M.D., M.P.H., a research professor of medical informatics and clinical epidemiology and medicine at the Oregon Health and Science University.
Both forms of therapy led to a statistically significant increased risk of stroke, deep venous thrombosis, gallbladder disease, and urinary incontinence. Estrogen plus progestin also raised the risk of dementia, pulmonary embolism, and invasive breast cancer.
However, both forms of treatment protected against spine and hip fractures due to bone loss. Estrogen-only therapy actually lowered the risk of invasive breast cancer and breast cancer deaths.
Although it might be tempting to conclude the progestin explains the difference between the two groups, other factors, such as the women’s risks for breast cancer and cardiovascular disease, also differed, Nelson says.
Even though the absolute risk of developing breast cancer or suffering a stroke because of menopause hormone therapy was low (less than 1 case per 1,000 women)—and no higher than cholesterol-lowering statins, Hodis notes—the results indicate that neither therapy offered any cardiovascular benefits. “There’s no need for women to take estrogen therapy to prevent a heart attack,” Nelson says.
Some doctors theorize that the women in the WHI study did not experience cardiovascular benefits because they missed the “window of opportunity” when taking estrogen can help prevent coronary heart disease. Estrogen is thought to help maintain proper blood flow. After the decline of the hormone at menopause, the lining of the carotid arteries thickens and arteries harden, leading to blockages and heart attacks.
“Once established, you can’t prevent it or change it,” Hodis says. “But if you can prevent it before it gets a foothold, you can potentially prevent progression and maybe even [coronary] events.”
Furthermore, Langer says, starting estrogen within that window may prevent some of the risks associated with menopause hormone therapy. After menopause, the body’s cell receptors that latch on to estrogen become misshapen with disuse. If estrogen is reintroduced later, the hormones won’t fit properly with those receptors, causing damaging inflammation, Langer adds.
Hormones and Heart Trial
A recent randomized clinical trial investigated how starting menopause hormone therapy early affects cardiovascular disease and other chronic conditions. The Kronos Early Estrogen Prevention Study (KEEPS), sponsored by the Kronos Longevity Research Institute in Phoenix, was a four-year study of nearly 730 healthy women, ages 42 to 58 years. The results, announced in October, show no adverse effects, such as increased incidences of breast cancer, stroke, heart attack, or decline in cognitive function, associated with menopause hormone therapy, which suggests younger, healthy women can safely take the drugs for at least four years. In addition to treating typical menopausal symptoms, the researchers found other benefits such as higher levels of high-density lipoproteins (“good” cholesterol) and reported improvements in depression, anxiety and memory. But the therapies had no effect on the progression of the hardening of the carotid arteries.
“What we can’t say is that estrogen is going to protect women against heart disease,” says Kronos Director Mitch Harmon, M.D., Ph.D.
Another study—Early Versus Late Intervention Trial With Estradiol (ELITE), funded by the National Institute on Aging—concludes at the end of the year. The ELITE trial is looking at 643 women for an average of five years and comparing the effects of starting hormone therapy early (six years within menopause) or late (10 years after menopause). Like KEEPS, ELITE is monitoring the thickness and hardening of the arteries and cognitive function.
However, even these trials are not big or long enough to demonstrate whether menopause hormone therapy actually reduces the number of heart attacks or deaths. “Even if you show changes in coronary artery calcium, that doesn’t mean there’s a reduction in risk,” says Jacques Rossouw, M.D., chief of the Women’s Health Initiative. The question of estrogen’s heart-protective benefits may never be answered to everyone’s satisfaction.
Even short-term use to relieve menopausal symptoms may not be appropriate for all women, says Margery Gass, M.D., executive director of the North American Menopause Society. “Hormone therapy will always be a mixed picture of benefits and risks, and that’s why it’s important for a woman to work with her provider to determine what’s in her particular best interest.”
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