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The estrogen-plus-progestin combination that for decades has been a frontline of defense against menopausal symptoms was dealt a blow in 2002 when the massive WHI stopped study trials on the common hormone replacement regimen. The project’s primary focus was to determine if hormone replacement prevented a number of chronic diseases in post-menopausal women. But this part of the randomized clinical trial was halted early when it became apparent that the opposite effect was occurring: study participants taking the estrogen-plus-progestin combination were suffering more breast cancer, heart attack, stroke and blood clots than the group taking a placebo. And an ancillary study showed hormone use increased the risk of dementia in women 65 and older.

“All of a sudden you had a huge number of women stopping their hormones without talking to us,” recalls Eisenberg. Even though the WHI was not meant to evaluate the risks and benefits of the short-term use of hormone replacement to alleviate menopausal symptoms, the startling study results prompted some women to stop taking the medication for that problem and others to avoid starting it, says Eisenberg. But some patients – struggling with night sweats, hot flashes, vaginal dryness and other bothersome symptoms – stuck with the treatment, she says.

Using hormone replacement to help alleviate menopausal symptoms – a use it was approved for by the U.S. Food and Drug Administration – requires the physician and patient to look at the balance between benefits and risks, says Eisenberg. She sees the threat of increased disease for an individual woman using hormones for this reason as “very low.”

“Women who have symptoms want to feel better,” she says, adding that taking hormone medication still is the most effective treatment for many people.

Science trumps the common wisdom
Up until the WHI trial the combination of estrogen-plus-progestin had achieved something akin to anointment as a magic potion for post-menopausal women. The results of some observational studies, in which groups of women taking and not taking hormones reported their lifestyle and heath experiences, touted it as a potential protective against cardiovascular disease and dementia. These findings elevated hormone replacement during the 1990s into the category of a prescription that prevented disease, far beyond its FDA-approved use to control debilitating menopausal symptoms and ward off the bone-thinning disease osteoporosis. By the mid-1990s, physicians’ professional organizations and the American Heart Association supported the recommendation of hormone replacement to older women for both heart and bone health. By 2001, millions of women had hormone prescriptions, and many were older women taking the pills solely to promote better health and long life.

But Lisa A. Mendes, M.D., assistant professor of Medicine at the Vanderbilt Heart and Vascular Institute, says some studies prior to the WHI had narrowed the window for using hormone replacement for heart health. The Heart and Estrogen/Progestin Replacement Study (HERS) reported in 1998 that the use of estrogen-plus-progestin in post-menopausal women with previous heart disease did not prevent another heart attack or death from heart disease, but did raise the risk of blood clots and gallbladder disease.

“The results of this study were completely opposite to what the investigators expected,” Mendes said.

Then in 2002 the WHI, the first large randomized prevention study, provided a bigger picture, reporting that estrogen-plus-progestin did lower the risk for developing osteoporosis, since fewer hip and other fractures were reported. Taking the hormones also was linked to a reduction in risk for colorectal cancer. However, the risk of breast cancer, heart attack, stroke, and blood clots in the legs and lungs were all higher among the women taking the hormones, as was dementia in women 65 and older.

“The risk was generally small, but it was still a real difference,” says Mendes. “I think it was a shock to a lot of people.”

And while a companion study found that middle-aged women without a uterus taking estrogen alone may be able to use the drug without incurring increased risks for breast cancer and heart disease, Mendes says she believes the days of suggesting hormone replacement as a heart-healthy prescription probably are past.

Hormone use drops and so does breast cancer
The results of the WHI study shook up a lot of women taking the drugs. But perhaps even more startling was what happened when millions of women abandoned the drug regimen after that news broke in 2002.

The annual incidence of breast cancer dropped dramatically in the two years after the WHI study was halted, when millions of women stopped taking the hormones. Researchers have linked the disease decline, particularly in estrogen receptor-positive breast cancers, to the drop in hormone use, and are continuing to monitor the statistics to learn more about the trend.

Julie Means-Powell, M.D., of the Vanderbilt-Ingram Cancer Center, says research on breast cancer already had hinted at a link to higher levels of estrogen and other hormones naturally produced in the body. Post-menopausal women who have breast cancer tend to have higher levels of endogenous estrogen, she says. The same is true of women who have more menstrual cycles in their lives – therefore, a longer exposure to hormonal fluctuations.

“So, obviously, women who take hormone replacement increase their exposure to estrogen,” says Means-Powell, a medical oncologist and assistant professor of Medicine in the Division of Hematology/ Oncology. “I don’t think it was surprising.”

Even though the incidence of breast cancer declined, she says some people aren’t convinced that can be attributed to the precipitous drop in hormone use. But Means-Powell anticipates an even further decline as behavior continues to adjust in light of the WHI findings.

“It was important information,” she says. “It sort of changed the paradigm of how we approach post-menopausal women.” As for her cancer patients, they continue as before to be counseled against taking hormones if they have had estrogen receptor-positive tumors or a family history or disease profile that suggests an increased risk for developing breast cancer. As for others, she suggests hormones should have limited usage for a targeted population.

No new insight into short-term hormone use
Since she has a special interest in treating patients with difficult menopausal symptoms, Eisenberg has been in the eye of the WHI storm. Even though the study was not designed to evaluate the risks and benefits of short-term hormone replacement to relieve menopausal symptoms, the well-publicized results have complicated the decision for many women.

“Some women who were concerned stopped their medication. Some women said they didn’t want to go on hormones,” she explained. But other patients, suffering debilitating menopausal symptoms, want to take hormone replacement, she says.

“When you have symptoms you have a different balance of benefits and risks,” she says.

The WHI-randomized hormone therapy trials enrolled 68,132 post-menopausal women from 50 to 79. The hormone used was the most commonly prescribed pill form of estrogen-plus-progestin, which leaves unanswered questions about the possible disease preventive benefits of hormone replacement using other delivery methods, dosage levels and treatment formulations.

The safety and effectiveness of alternative nonprescription supplements for “change of life” symptoms – such as soy-based products, botanical black cohash and red clover – have not yet been proven. And bioidentical hormones – formulated to have the same chemical structure as the hormones made by the human body – also have not been conclusively studied. These compounds are made by pharmacists for each individual based on hormone deficiencies identified through saliva samples.

Research is under way to learn more about some of these alternative treatments and supplements. These alternatives are not under the oversight of the FDA, although the mainstream drug industry is pushing for regulatory intervention from that agency.

So, for now, as the FDA guidelines counsel, Eisenberg advises patients who need relief from menopausal symptoms to take the lowest effective hormone dose for the shortest possible time. The target use is no more than five to seven years. She tells her patients they can reassess the prescription over time and reduce the dosage or stop the treatment if it’s no longer needed.

“The decision must be made one patient at a time, thinking about the individual patient in front of you,” she said. VM

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