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Weighing the risks of hormone therapy

New data on estrogen/progestin therapy have researchers urging caution

From the September ACP-ASIM Observer, copyright 2002 by the American College of Physicians-American Society of Internal Medicine.

By Margie Patlak

Combined estrogen/progestin and its effect on six diseases

It's been a rough summer for physicians prescribing hormone replacement therapy (HRT) for menopausal and post-menopausal women.

While HRT has a tumultuous history, researchers in July stunned the medical establishment when they abruptly halted a large study of postmenopausal women taking estrogen/ progestin therapy. Officials from the Women's Health Initiative said they were calling the study off because of overwhelming evidence that the drugs caused small increases in breast cancer, heart attacks, strokes and blood clots.

The decision marked the end of a year-long period during which researchers released data and guidelines that called on physicians to exercise more caution when using HRT. Recent clinical trials, for example, showed that HRT (estrogen alone or an estrogen/progestin combination) does not appear to prevent cardiovascular disease.

These studies, as well as the emergence of other options to treat conditions common in older women, led an international panel of experts to question many common uses of HRT. Sponsored by the National Heart Lung and Blood Institute, the panel's comprehensive 13-chapter monograph on women's health and menopause was published in June by the Government Printing Office. "Research results are teaching us to be cautious before assuming that current practice is best," the monograph understated while dropping a bombshell.

Here's a look at some of the most recent research that is leading many clinicians to take a more cautious approach to using HRT, and a look at some alternatives to hormonal therapy.

Cardiovascular disease

A prime example of the changing attitude toward HRT can be seen in how experts' views have changed regarding the therapy to prevent coronary artery disease.

For more than a decade, experts enthusiastically recommended that post-menopausal women take HRT to minimize cardiac problems. Small- and large-scale observational studies had indicated that estrogen alone or an estrogen/progestin combination gave women an edge over the disease, and most expected similar results from subsequent randomized clinical trials.

Several large, randomized studies, however, found that estrogen/progestin combinations actually boosted women's risk of experiencing an adverse cardiovascular event, especially within the first year of taking the therapy. The Women's Health Initiative trial, which is the only large randomized study to test HRT in healthy women, reported in July that combination estrogen/ progestin therapy increased women's risk of developing an adverse coronary heart disease event (mainly heart attacks) by 29% and stroke by 41%. (The Women's Health Initiative continues to test women with prior hysterectomy for the effects of estrogen alone on heart disease, stroke, blood clots, osteoporosis, and breast and colorectal cancer.)

HRT also continues to be dogged by blood clots. Estrogen with progestin doubled the risk of blood clots in both the Heart & Estrogen/progestin Replacement Study and the Women's Health Initiative. Researchers have found that even raloxifene, a selective estrogen receptor modulator (SERM), triples the risk of experiencing blood clots just like standard HRT. Definitive data is pending on how this drug affects cardiovascular disease risk.

As a result, experts are now backpedaling and telling physicians not to prescribe HRT to prevent cardiovascular disease. They say to hold off giving hormones to women who have a history of blood clots. Finally, they urge physicians to think twice before prescribing HRT to a woman with coronary artery disease.

Like everything else in clinical medicine, however, you have to balance these risks with potential benefits on a case-by-case basis, noted Nanette K. Wenger, MACP, editor of the menopause monograph published in June by the National Heart, Lung and Blood Institute.

"If a woman with coronary artery disease tells me, 'I am having such severe menopausal symptoms that life isn't worth living,' I tell her HRT is linked to a small cardiovascular risk," said Dr. Wenger, who is chief of cardiology at Grady Memorial Hospital in Atlanta. "If she decides to go on HRT, I would support her decision. To minimize the risk, I would see that she gets the lowest effective dose for her symptoms, and that she stays on it for the shortest period of time."

Osteoporosis

Experts once touted HRT as a way to prevent osteoporosis in post-menopausal women. But the deeper you dig into this use, the muddier the water becomes.

For example, researchers have found that standard or low-dose estrogen—with or without progestin—can prevent bone loss, which can translate to a reduced risk of fractures. The Women's Health Initiative found that taking combined estrogen/progestin slashed the risk of fractures, including hip and vertebrae fractures, by a quarter.

But other data suggest that women must take estrogen continuously following menopause to preserve their bone density. The bones of older women who have never received estrogen are just as dense as those of women who used estrogen for 10 years and then stopped taking it for another 10 years.

That finding, along with HRT's newly-discovered side effects, has tarnished the once-popular notion that doctors could stave off osteoporosis by starting their menopausal patients on HRT and keeping them on it for several years—or even for the rest of their lives. Don't bother giving a post-menopausal woman estrogen, experts now say, unless she is experiencing disruptive menopausal symptoms or has markedly reduced bone mass.

Many post-menopausal women do eventually develop severe enough osteopenia to justify treatment. But there are other options besides estrogen to prevent further loss. Bisphosphonates have been shown to preserve bone density about as well as estrogen. And in randomized trials, bisphosphonates also cut the risk of hip and other fractures nearly in half for osteoporotic women. (Researchers are still collecting data on whether these drugs can prevent fractures in low-risk women.) For now, there is more evidence to support using bisphosphonates to prevent fractures than estrogen, noted epidemiologist Deborah Grady, MD, in an article in the April 24, 2002, Journal of the American Medical Association.

Bisphosphonates, however, have downsides. They can trigger gastrointestinal side effects that many women find intolerable. But new formulations can be taken once a week, and researchers are currently testing an intravenous bisphosphonate that is given once a year.

Raloxifene is another drug that can help prevent bone loss. This agent prevents spinal fractures by about 40%, but not hip or other fractures, one large study found. In 10% to 20% of patients, however, raloxifene prompts hot flashes, making it an unpopular choice for women with both osteopenia and menopausal symptoms. The drug is an option for those not prone to hot flashes, however. By slowly increasing the dosage of raloxifene, physicians can reduce patients' flushing.

When it comes to preventing osteoporosis, plant sources of estrogen fare even worse than animal sources. In clinical trials, researchers found little or no benefit to ingesting reasonable amounts (20 to 25 g) of soy protein each day. A synthetic version of a plant estrogen, ipriflavone, failed to improve bone density or reduce fracture risk in a large clinical study of women with osteoporosis.

HRT myths and concerns

Estrogen has been promoted as a panacea to prevent or cure many other conditions that commonly occur in older women, but researchers have proven that estrogen is no fountain of youth.

Initial small studies suggested that taking estrogen prevents the development of Alzheimer's disease. But a large, randomized clinical trial recently ruled out that possibility. Studies have also shown that estrogen doesn't help with memory loss or urinary incontinence.

The finding that HRT boosts the incidence of gallbladder disease by 40% is a concern, particularly in women with a family or personal history of the disorder. Taking statins or aspirin appears to reduce that risk.

Menopausal symptoms

Experts do support using HRT for one purpose: relieving the hot flashes, insomnia and vaginal dryness that often accompany menopause. But they note that clinical trials on HRT have not proven hormones to be effective in relieving other supposed menopausal symptoms such as moodiness or decreased sex drive.

Both standard-dose (.625 mg of equine estrogens or equivalent) or low-dose estrogen (half or two-thirds of the standard dose) very effectively relieve hot flashes and the sleep problems that often accompany it.

Other drugs can offer some relief, such as progestogens, selective serotonin reuptake inhibitors (SSRIs) like venlafaxine and paroxetine, clonidine, and the dopamine antagonist veralipride. These options pale, however, next to estrogen and progestin.

"There is no question that hormones have no peers when it comes to managing menopausal symptoms," Dr. Wenger said.

Most clinical trials have found that plant estrogens and other botanicals such as evening primrose oil and dong quai were unable to stem hot flash symptoms significantly better than placebo.

To avoid excessive and unnecessary exposure to estrogen, some experts recommend gradually increasing patients' doses until they experience symptom relief, then gradually reducing the doses when patients are ready to stop the therapy. HRT can be tapered by lowering doses or by asking patients to take hormones fewer times per week.

In clinical trials, topical estrogen appears to be better at relieving vaginal dryness than oral preparations. It also exposes women to less estrogen.

Most experts recommend prescribing estrogen for just a few years to relieve menopausal symptoms. At that point, women can usually stop taking HRT without experiencing a resurgence of symptoms. You can move patients to an SSRI or another drug to offer some symptom relief if need be.

"In the past, doctors had the estrogen-forever approach, especially when we thought it was good for your heart," noted Atlanta internist Sandra Adamson Fryhofer, MACP, a past President of the College who specializes in women's health. "If a woman was doing well on it, we would just leave her on it. But now it's the estrogen-now-and-let's-wait-and-see-for-how-long philosophy. Every year, when a woman who is on estrogen comes into the office, you have to ask why is she still on it."

Cancer risk

Looming over HRT is the concern that the therapy might increase breast cancer risk. Until recently, however, no large, randomized trial had shown that using HRT boosts breast cancer risk.

The Women's Health Initiative, however, changed all of that earlier this summer. Officials said that of 2,000 women taking combined estrogen/progestin for five years, eight more women will develop invasive breast cancer compared to the control group. (Researchers also found that seven more will have a heart attack, eight more women will have a stroke and 18 more will have blood clots.)

Several smaller studies have also found that estrogen therapy lasting more than five years, with or without progestin, increases breast cancer risk by 30% to 60% in post-menopausal women. Experts note that because physicians tend to hold off prescribing HRT to women at high risk of breast cancer, the actual boosted risk for breast cancer among hormone users could be higher than what was seen in those studies.

Another recent study also found that HRT tripled the risk of women developing lobular breast cancer, which is more difficult to detect than the more common ductal carcinoma.

Further confusing matters is the fact that some estrogen-like drugs, such as raloxifene and tamoxifen, actually appear to decrease the risk of breast cancer. Large, randomized studies found that women who took raloxifene or tamoxifen for four years reduced their risk of developing breast cancer by 65% or 50%, respectively.

These findings have prompted some physicians to prescribe these drugs to post-menopausal women at high risk for breast cancer. Others wait for more definitive data from two large clinical trials whose results won't be available for three years or more.

(Recent guidelines from the U.S. Preventive Services Task Force, however, say that the downsides of tamoxifen and raloxifene may outweigh the potential benefits in women who are not high-risk candidates for breast cancer. In the July 2, 2002, Annals of Internal Medicine, the task force pointed to evidence that the drugs increase the risk of thromboembolic events like strokes, as well as side effects like hot flashes.)

Women with breast cancer who take tamoxifen for five years are less likely to have a recurrence. Researchers, however, found that those who continued taking the drug for an additional five years had a greater chance of recurrent cancer than those who stopped after the first five years. It is unclear what this means for women without prior breast cancer or who take raloxifene for more than five years.

Tamoxifen, unlike raloxifene, substantially boosts women's risk of uterine cancer. There is also weak evidence from a few observational studies that HRT boosts ovarian cancer risk. No one questions, however, the fact that long-term unopposed estrogen use markedly increases a woman's risk of endometrial cancer.

On the plus side, both observational studies and the large, randomized Women's Health Initiative study found that HRT lowers colon cancer risk-by as much as 40%.

Indications and risk factors

Some say that for many years, the benefits of HRT were oversold and the risks unknown or ignored. "Physicians told menopausal women, 'Take hormones, you'll feel better, you'll look better, you'll be young again,' " said Dr. Wenger. "Now we have to tell each patient why the therapy is being prescribed and indicate the risks and benefits for her individually at this particular time.

"There is no simplistic, one-size-fits-all approach to caring for menopausal women," Dr. Wenger continued. "You have to individualize treatment."

But figuring out the option that works best can be tricky if a woman has both indications and contraindications for HRT. What do you do if a patient has coronary artery disease and osteopenia, but can't tolerate bisphosphonates? How do you treat a woman who has had breast cancer, yet can't wean herself off of HRT because of severe menopausal symptoms? Although the experts might disagree on which therapy is best for each of these scenarios, they all agree on who must make the final decision—the patient.

"You have to get your patient involved, because she's the one who has to take the medicine," noted Dr. Fryhofer. While the physician must inform a woman about the risks and benefits of each option, she pointed out, each patient will weigh these risks and benefits differently. A woman with severe menopausal symptoms, for example, may be more willing to accept a slightly increased heart attack risk than one whose symptoms are mild.

Finally, you need to keep an eye on the literature for future changes in the science on HRT. As research continues, views on HRT's benefits and risks will continue to be in flux in the near future. This may be frustrating to some patients, who view their doctors' advice as gospel truth.

Dr. Fryhofer said she offers those patients this reassurance: "It's an exciting time to be a woman because we're moving from the art of medicine to having clinical trial evidence of what's best to do. We want to do the right thing that works, not just what people think might work."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

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

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Combined estrogen/progestin and its effects on six diseases

Alzheimer's disease

  • No proven benefit.

Cancer

  • Increases risk for breast cancer, particularly lobular breast cancer.
  • May increase risk of ovarian cancer, though evidence is not yet strong.
  • Reduces risk of colon cancer.

Cardiovascular disease

  • Increases risk for heart attack and coronary death.
  • Increases risk for blood clots.
  • Increases risk for stroke.

Gallbladder disease

  • Increases risk.

Menopause symptoms

  • Reduces hot flashes, insomnia and vaginal dryness.
  • No proven effect on moodiness or sex drive.

Osteoporosis

  • Reduces bone loss and fractures.

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