American College of Physicians: Internal Medicine — Doctors for Adults ®

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Research spurs new thinking on hormone therapy

WHI data have changed the risk-benefit conversation with menopausal patients

From the July-August ACP Observer, copyright © 2006 by the American College of Physicians.

By Janet Colwell

Like many physicians, Nancy C. Dolan, FACP, a general internist and associate professor of medicine at Northwestern University’s Feinberg School of Medicine in Chicago, found the number of estrogen prescriptions she was writing slowing to a trickle in the wake of 2002 findings from the Women’s Health Initiative (WHI).

Once almost routinely prescribed, hormone therapy (HT)—in the form of estrogen plus progestin—had been found by WHI researchers to increase women's risk of breast cancer, heart attack, stroke, and leg and lung clots. Those findings were given high-profile coverage in the consumer press.

Dr. Dolan immediately recommended that patients stop using hormones if they were taking them only for assumed benefits, such as heart disease prevention. She also recommended that women taking HT for menopausal symptoms try tapering off, especially if they had been on hormones for more than three to five years (at which time the risk of breast cancer starts to increase) or if they had any risk factors for heart disease or stroke.

“I became much more likely to recommend that patients with mild hot flashes and night sweats try to ride out their symptoms or consider alternative treatments,” said Dr. Dolan. And she noted that the risks would be lower for her menopausal patients who are generally younger than the women in the study. "If their symptoms are severe, alternative treatments aren’t working, and they are not at increased risk for cardiovascular disease, thromboembolism, or breast cancer," she said, "I talk to them about estrogen.”

In the past five years, estrogen has gone from a miracle drug with the power to ward off deadly diseases to a suspected cause of those same conditions. But the pendulum may now be swinging back toward judicious use of estrogen, widely acknowledged as the single most effective treatment for hot flashes during menopause.

The WHI—which conducted both an estrogen plus progestin and an estrogen alone trial—also provided a clearer picture of hormones' long-term risk-benefit profile.

“We no longer use estrogen or estrogen-progestin therapy routinely as long-term therapy,” said Carolyn J. Crandall, FACP, associate professor of medicine at the University of California, Los Angeles School of Medicine. “For those who have risk factors, such as history of heart disease, stroke, blood clots or high risk for breast cancer, they may think twice about hormones even for short-term.”

In talking to patients about HT, there are two certainties, said Katherine D. Sherif, FACP, associate professor of medicine and director of the Center for Women’s Health at Drexel University College of Medicine in Philadelphia: Estrogen is effective for menopausal symptoms, and it should never be given to anyone who has had breast cancer.

“After that," Dr. Sherif said, "it is not easy.”

Sifting through the results

Established in 1991 by the National Heart, Lung, and Blood Institute, the WHI was the largest randomized controlled trial to date on hormones. (The WHI concurrently ran two other randomized trials that also produced controversial results, one on dietary modification and the other on dietary supplementation. See "Diet, supplements findings suggest sticking with status quo."

More than 27,300 women participated in the HT trial, including 16,608 postmenopausal women with intact uteri who took either estrogen plus progestin or placebo for slightly more than five years.

The trial was halted early in July 2002 when it was discovered that an increased risk of heart attacks, strokes, breast cancer and blood clots outweighed a decreased risk of colorectal cancer and hip fracture. In 2003, a subset of the study involving women age 65-79 concluded that estrogen plus progestin also boosted women’s risk of dementia.

When the results of the WHI hormone trials began being published in 2002—in the July 17, 2002 issue of Journal of the American Medical Association (JAMA)—the central message filtered through the popular press was that HT increased the risk of serious disease. Much less attention was paid to the different types of trials and characteristics of the participants, which are central to understanding what the risks really mean to individual women.

Here are some factors to consider:

Age of participants. WHI participants were not selected based on whether they had menopausal symptoms, and were generally older (mid-60s) than the typical age 50-59 women actively seeking relief from menopausal symptoms.

“Recently menopausal women who have low baseline risk of heart disease may have a more favorable balance of benefits and risks than older women,” noted JoAnn E. Manson, FACP, a WHI investigator and chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School in Boston.

The issue of age and how early in menopause women are prescribed HT may also have implications for cardiovascular benefit.

Harvard University’s Nurses Health Study, an observational study on HT use that followed 28,835 female nurses between 1976 and 2000, suggested that hormones may protect against heart disease in younger women.

“Women in the study who started therapy with estrogen alone or estrogen with progestin near menopause had about a 30% lower risk of coronary heart disease [CHD] compared with postmenopausal women who never used hormones,” said Dr. Manson, also one of the lead authors of the Nurses’ Health Study. According to findings published in the January 2006 issue of Journal of Women's Health, women who began therapy 10 or more years after menopause had no reduced CHD risk.

Those findings, while not based on clinical trials, generally corroborate WHI investigators’ more indepth analyses of the estrogen-alone study data, which also suggested that initiating estrogen close to menopause may reduce CHD. (See "Conjugated Equine Estrogens and Coronary Heart Disease" in the Feb. 13, 2006, issue of Archives of Internal Medicine.)

“The bottom line is that HT still should not be used for prevention of cardiovascular disease in either the primary or secondary prevention setting,” Dr. Manson said. “But the overall benefits may outweigh the risks for recently menopausal women with moderate-to-severe vasomotor symptoms and they may even get a delay in atherosclerosis.”

Differentiating trials. Many media reports glossed over the fact that “the trials involving women with and without a uterus were pretty different,” said Karen L. Margolis, FACP, a WHI investigator and senior clinical investigator for HealthPartners Research Foundation in Minneapolis. “When people talk about the risks, they are mostly thinking about the estrogen plus progestin trial.”

The estrogen-alone trial was likewise stopped early—in February 2004—due to an increased risk of stroke among women in the hormone group. Preliminary findings published in the April 14, 2004, issue of JAMA noted that higher stroke risk, as well as reduced risk of hip fracture, no effect on heart disease risk,and no increased risk of breast cancer.

However, the Nurses' Health Study found that women who have undergone hysterectomies can safely take estrogen alone for up to 15 years without significantly increasing their risk of breast cancer, said Wendy Y. Chen, MD, MPH, a study author and oncologist at Boston's Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. While the study was not as scientifically rigorous as a randomized trial, the findings gave hope to women who require longer-term treatment, such as those who undergo premature surgical menopause before age 40. Those results must be balanced against the higher risk of stroke found in the WHI studies.

What works?

Chicago's Dr. Dolan said she now follows recommendations made by the Food and Drug Administration in response to the WHI findings: She prescribes estrogen at the recommended lowest possible dose for the shortest possible duration for women who have a uterus. According to Dr. Dolan, that timeframe is typically three to five years.

Dr. Sherif said she often prescribes alternative forms of estrogen, such as gels, creams and patches. “Cream or tablets in the vagina can be used very safely and not much is absorbed into the body,” she said. This works for vaginal dryness, lack of mucous, irritation or burning.

After WHI, many women stopped their hormones and experienced worse symptoms than they had before starting them, said Marcia L. Stefanick, PhD, a WHI investigator and professor of medicine at Stanford University School of Medicine in Stanford, Calif. That suggests that a woman might be better off just "riding it out", since hot flushes and night sweats subside or at least become more tolerable for most women within a year. Physicians are also trying natural hormones and other prescription drugs, said Dr. Stefanick, who gave an update on WHI and hormones at Annual Session in April.

Options include different forms of estrogen, such as patches, vaginal rings and topical emulsions, as well as some antidepressants, she said. For milder symptoms, physicians can suggest practical measures such as paced respiration, dressing in layers, avoiding alcohol and spicy foods, and natural therapies such as “bioidentical” hormones derived from plants.

However, a recent review of trials involving nonhormonal therapies for menopause published in the May 3, 2006, issue of JAMA found that none of the commonly used alternatives was very effective and all had their own side effects. Several antidepressants, as well as clonadine and gabapentine, provided some relief from hot flashes, the authors said. But natural remedies such as red clover and soy isoflavone extracts had no impact on symptoms.

The real problem for many women is trying to decide where they fit in on the scale of severity of symptoms.

“A lot of women start having hot flashes while they are still having menstrual periods in their 40s," noted Dr. Margolis. "My rule of thumb for treating vasomotor symptoms is when the woman is experiencing significant discomfort or disruption of sleep that is interfering with her quality of life."

However, she continued, physicians should explain to women that there is a risk that symptoms may recur when HT is stopped and that estrogen alone and estrogen plus progestin both carry small but real risks. "The older the woman, the more I would encourage non-hormonal options," she said, "because of the higher absolute risks of heart disease, stroke and dementia."

Future directions

The Kronos Early Estrogen Prevention Study (KEEPS) sponsored by the Phoenix-based nonprofit Kronos Longevity Research Institute may help clarify the risk and benefits of estrogen plus progestin. The trial is looking at the effects of estrogen replacement on the progression of atherosclerosis in recently menopausal women—and was specifically designed to explore issues raised by the WHI, including the role of age.

To be eligible for the study, women must have an intact uterus, be between ages 42-58, and had their last menstrual cycle within the previous six months to three years. The KEEPS trial will also compare oral vs. transdermal administration of estrogen with cyclical micronized progesterone, said Dr. Manson, a KEEPS principal investigator.

“Further research is needed on selective estrogen receptor modulators, lower doses of estrogen and other hormone formulations," she said. Until results come in from rigorous randomized clinical trials, she said, hormone therapy is suitable for only a small subgroup of women and for limited duration.

In the meantime, WHI investigators are continuing to follow participants through 2010 and will eventually provide data on the long-term effects of hormones as those women age. The next findings on hormones are expected to be published by 2007, said Dr. Margolis. That will include three years of follow-up data after women in the estrogen plus progestin trial stopped therapy.

WHI not only provided a basis for future research on treating menopausal symptoms, said Dr. Margolis. It also illustrated the hazards of basing treatment decisions on assumptions that are not backed by clinical trial evidence.

“We went into the whole WHI hormone trial kind of optimistic that we would find a preventive effect for heart disease and stroke,” she observed. “The use of HT to treat vasomotor symptoms was not something we set out to assess—but it turns out to be the one incontrovertible benefit of these medications.”

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.

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Diet, supplements findings suggest sticking with status quo

The hormone therapy data published by the Women’s Health Initiative (WHI) weren't the only controversial study findings. More recent data related to the WHI's diet and supplement trials also prompted new discussions between women and their physicians.

The low-fat diet study, which included 48,835 postmenopausal women age 50-79, was designed to test the effect of lowering total fat on the risk of cancer and heart disease. The findings, published in three articles in the Feb. 8, 2006, issue of Journal of the American Medial Association, reported that lowering total fat and increasing intake of fruits, vegetables and whole grains did not significantly reduce women's risk of breast cancer, colorectal cancer, stroke or heart disease.

But that doesn't mean that lowering fat is useless, experts warn. Consider, for example, that the WHI study did not separate out saturated from unsaturated fats, which is the basis of current recommendations.

Carolyn J. Crandall, FACP, associate professor of medicine at the University of California, Los Angeles School of Medicine, noted a positive trend toward decreased coronary heart disease rates as the low-fat trial progressed, even though the numbers did not reach statistical significance. Women in the trial also had a borderline decrease in risk for breast cancer and a significant decrease in colon polyps, suggesting that benefits may show up in follow-up years.

A potential 'crisis'

Another WHI trial looked at the effect of calcium and Vitamin D supplements on women’s risk for hip fractures and colon cancer. Investigators reported a small improvement in hip bone density in the group taking 1,000 mg of calcium plus 400 IU of Vitamin D daily for seven years. However, the supplements had no effect on risk of colon cancer or hip fractures and caused a slight increase in risk for kidney stones.

The publicity surrounding these findings created a potential “crisis” that physicians must help head off, Dr. Crandall said. The results do not alter current recommendations, she said, because women in the study were already taking recommended dosages, meaning that the trial actually compared taking 1,200 mg of calcium and 400 IU of Vitamin D with taking 2,200 mg of calcium and 800 IU of Vitamin D. There was no control group.

“It’s possible that once you get to 1,200 mg or so of calcium, there is a threshold effect,” said JoAnn E. Manson, FACP, a WHI investigator, chief of the division of preventive medicine at Boston's Brigham and Women’s Hospital and professor of medicine at Harvard Medical School. Another factor that may have skewed results: Half of the participants were obese and half were taking estrogen, both of which protect bone density.

Bolstering these theories, Dr. Crandall pointed out, is the fact that thinner women in the trial who were taking less-than-average calcium at the beginning of the study were the ones most likely to benefit from additional supplements. Dr. Manson also pointed out that 40% of the women in the study were not taking their pills regularly—but among those who took at least 80% of their supplements, the risk of hip fractures was reduced by 29%.

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