Menopause medicine: Custom-fit quandary

No woman wants hot flashes. But fixing an annoying problem probably isn't worth risking a fatal one. Risk/benefit studies on HT leave physicians searching for individual solutions for individual patients.

By Stephanie Stapleton, AMNews staff. July 21, 2003.

Single medical research studies rarely throw wrenches into everyday clinical practice. But that's exactly what happened last July. A Women's Health Initiative review panel ceased its estrogen plus progestin study because a statistically significant increase in breast cancer risk emerged. Almost overnight, the way doctors interacted with patients in managing menopause was altered.

"The biggest thing about this study -- it impacted women's faith," said Audrey Curtis, MD, the director of women's health for Kaiser-Permanente Northwest in Portland, Ore. "There was a breakdown in the system." Doctors had been telling women that these drugs were good for them, and in many respects, they weren't.

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Absolute risk

Dementia risk

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Combination hormone therapy, widely prescribed and viewed as a proverbial fountain of youth, was suddenly transformed into a perplexing set of risks and benefits. Physicians now must help women figure out how to manage sometimes debilitating symptoms while also confronting concerns about breast cancer, bone loss and even heart disease.

Many agree that the experience has marked a sea change in menopause medicine -- a switch from a one-size-fits-all presumption to individualized therapy.

"It's been really dramatic," Dr. Curtis said.

In the months since the news broke, she said, the clear pattern among her patients is that there is no pattern. They are different ages and have different concerns, different family histories and different degrees of willingness to take risks.

No longer automatic

The WHI study was the first of its kind -- a prospective, randomized trial of more than 16,000 healthy, postmenopausal women between 50 and 79. Participants received either combined HT or placebo. The goal was to determine the effects in terms of coronary heart disease and stroke, breast and colorectal cancer, and bone fractures. It was halted three years early because the breast cancer risk was perceived as exceeding benefits. A WHI estrogen-only trial is ongoing.

Considered on an individual basis, the risk for taking combination therapy was relatively small -- an increase of eight cases per 10,000 per year more than placebo. However, on a populationwide basis, it was considered significant because of the sheer number -- about 38% -- of American women using combination therapy at that time.

Finding the right amount of hormone therapy requires trial and error.

Other findings announced last year included a slight increase in blood clots, strokes and coronary heart disease and a decrease in fractures and the development of colon cancer. And more recently, a component of the study evaluating women 65 or older found that the combination therapy did not improve cognitive function, and when compared with placebo, actually increased the risk of Alzheimer's disease and other types of dementia.

"The WHI provided a lot of information that helped physicians decide how and when to use hormone therapy," said Julia Johnson, MD, professor and vice chair of gynecology at the University of Vermont College of Medicine, Burlington. It also triggered a lot of anxiety, especially among primary care physicians. "Before, we thought it was very simple -- that everyone would benefit."

Then, some doctors reacted by deciding not to prescribe it -- period. But that left in a lurch patients who were struggling with debilitating hot flashes. Other physicians felt the media made too much of the risks.

"What we've known all along we still know: HT is protective of the bone and good for managing symptoms," said Martin Keltz, MD, director of reproductive endocrinology at St. Luke's-Roosevelt Hospital in Manhattan, N.Y. The breast cancer risk should not have been news, he said. "The problem is that people were trying to use HT regardless. The WHI squashed this -- and appropriately so."

New guiding principle

Most physicians now take the approach that women who do not experience symptoms -- hot flashes, sleep disturbances, depression, vaginal changes -- need not bother with hormone replacement. "You have to look at use when indicated. It leads to an individualization of hormone therapy," Dr. Johnson said.

"They have to know what they are using it for," agreed Donna Shoupe, MD, a professor of obstetrics and gynecology and director of the women's health center at University of Southern California, Los Angeles. Almost all of Dr. Shoupe's patients come in asking about HT. Her response is to give them an overview -- the absolute numbers in terms of risk. She considers the incidence of risk very low and worries that the media attention might have cast doubts on estrogen's value.

Recent studies on hormone therapy have discredited benefits.

"I am concerned about 30 years of a woman's life with low estrogen. These changes are not good." The hormone's presence affects skin thickness and vaginal and urological functions, among other things. She also argues that it offers protection to the brain -- though this point is now more controversial. For her patients who want to go forward, she recommends low-dose therapy.

This approach has become part of an new guiding principle: Use therapy only when needed and only as long as necessary at the lowest possible dose. Finding this magic amount requires trial and error, Dr. Johnson said. She starts at the standard dose and then reduces it to determine the lowest level that still addresses symptoms. It usually takes months, and varies from patient to patient.

According to Malcolm Pike, PhD, USC professor of preventive medicine and expert on hormones and cancer risk, this approach may not be a complete answer. He agrees that using HT for a shorter time will reduce potential for harm, but thinks it is also possible that the reduced but still effective amount of progestin involved will not succeed in lowering breast cancer risk. Any changes in HT dosing should be tested for their effect on mammographic densities, an easily measured cancer risk marker. Only if there is little or no impact on this marker should one assume that the therapy is likely to be less harmful, he said. "If we have no evidence on what is happening, we can't assume that it is an improvement."

Duration also is an important consideration now. Some experts say that most women's hot flashes improve after two years, while the associated breast cancer risk has been shown to increase after four. Short-term HT might be an answer for these patients.

But a significant number of women have hot flashes for five to six years, and as many as a third have them for a decade or longer, said Charles Hammond, MD, immediate past president of the American College of Obstetricians and Gynecologists, speaking at a June 20 media briefing. "These statistics show there are populations that aren't going to do well on short-term therapy." For them, the benefit/risk estimate becomes even more acute. "You have to look at each patient you see to balance this."

Physicians have observed that when it comes to finding this balance, women now expect to talk more -- both with their physicians and among their peers.

"It is more [open] than it used to be," Dr. Johnson said. "Everyone is so different. Some women have nothing to deal with. Some face the extremes. It helps to find people who are having similar experiences. It reinforces variability -- gives ideas. Women get input."

Dr. Curtis agreed that women in the menopausal age range now need more time to contemplate their course of action. "It takes more than a 15-minute office visit." Kaiser-Permanente Northwest offers classes to help menopausal patients better understand their individual risks and what they can do to protect their overall health. The concept grew out of a series of public forums Dr. Curtis and colleagues held after the initial news reports made a splash. Similar sessions have popped up across the country.

The idea is to give women a solid background in preparation for deciding about HT. The topics also involve other approaches. "Patients want to know what else there is," Dr. Curtis said.

For example, some antidepressants -- selective serotonin reuptake inhibitors -- have been associated with a decrease in moderate hot flashes.

Also on the list are alternative medicines such as black cohosh or soy. For patients who want to try soy, Dr. Johnson recommends dietary changes rather than tablets. She notes that in most studies, these interventions worked at best only slightly better than placebo.

There's a range of other options -- usually over the counter, often alternative, and many times not embraced by traditional medicine. Still, patients ask about them. "It takes education," said Dr. Curtis.

Not the magic pill

The HT debate affects more than symptom management. WHI findings dashed the hope that this therapy would function as a panacea for all of women's aging-related health problems.

Take, for instance, risks related to osteoporosis and fractures. There's no doubt that estrogen offers protection, but the WHI made it clear that risks outweighed benefits in this regard. So what to do now?

Bones take a "what have you done for me lately" position, said Ethel Siris, MD, a professor of clinical medicine at Columbia University. "Once you stop hormone therapy, whether you took it for many years or for a short time, bone loss will resume. The prior protection is quickly eroded."

Physicians should immediately assess patients' skeletal health. "The fact that we have a series of [non-hormone] therapies that are somewhat different from each other means we should individualize osteoporosis treatment to the woman sitting in front of us," said Dr. Siris, speaking at the June media briefing.

Cardiovascular health is also a critical consideration.

Despite expectations based on observational studies, the WHI demonstrated that HT offered no primary preventive benefit for heart disease. Earlier research found no secondary preventive benefit. Still, heart disease among women is a grave concern and is the No. 1 cause of death. Thus, experts say it is important to address well-established cardiovascular risk factors -- hypertension and high blood pressure, high cholesterol, diabetes -- through medication and lifestyle changes.

"There used to be some perception that you didn't have to pay as much attention to some aspects of overall health, that the hormones were going to take care of it, going to smooth the path," said Judith Hsia, MD, a professor of medicine at George Washington University in Washington, D.C., and a WHI principal investigator, about behavioral changes.

"It would have been nice [if HT would have accomplished all it was presumed to]," agreed Dr. Johnson. "What the study said is that no, it doesn't. It makes a healthy lifestyle even more key."

This is a difficult reality. Patients often want a pill or patch to fix the problem. And, indeed, it's easier for a doctor to write a prescription than to engage in the long process of prevention education and the frustration of counseling lifestyle modification.

But for the immediate future, there's no quick fix. The fallout from the WHI findings underscores the importance of continued attention to the basics -- maintaining a healthy diet and weight, exercising at least 30 minutes a day, avoiding tobacco use.

"[There is] no easy answer," Dr. Johnson said. "HT doesn't prevent long-term health problems. We have to do that ourselves."

ADDITIONAL INFORMATION:

Absolute risk

Studies often explain risks in relative terms. But what follows are absolute risks, based on the Women's Health Initiative.

That study saw the following results (per 10,000 women per year) among women who took estrogen plus progestin therapy, as compared with those who took placebo:

7 more coronary heart disease events
8 more invasive breast cancers
8 more pulmonary emboli
8 more strokes
5 fewer hip fractures
6 fewer colon cancers

Source: JAMA, July 17, 2002

Dementia risk

The Women's Health Initiative memory study offered evidence that estrogen plus progestin therapy does not maintain or improve cognitive function in older women.

Women participating in the five-year study were 65 or older.

The risk for dementia among those taking combination hormone therapy was twice that of women taking placebo.

Data showed an increase from 22 women per 10,000 at risk of dementia in the placebo group to 45 women per 10,000 in the combination therapy group.

A total of 61 cases of dementia were diagnosed among the study's 4,500 women; 66% occurred among those on combination therapy.

Weblink

Findings from the Women's Health Initiative (www.nhlbi.nih.gov/whi)

"Questions and Answers on Hormone Therapy," American College of Obstetricians and Gynecologists, August 2002 (www.acog.org/from_home/publications/press_releases/nr08-30-02.cfm)

The Hormone Foundation, the public education affiliate of The Endocrine Society (www.hormone.org)

The North American Menopause Society (www.menopause.org)

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