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Careful evaluation can help women sort through risks of hormone replacement

This article first appeared in the St. Louis Beacon, Jan. 2, 2009 - When women visit Dr. Andrea Stephens for the first time to discuss menopause symptoms, there's a good chance they have gathered just enough conflicting data to make them nervous about hormone replacement therapy.

"There's a lot of incomplete information," said Stephens, assistant professor of obstetrics and gynecology at the Washington University School of Medicine.

"The perception that most women have is that hormones are dangerous for them," Stephens said. She was referring to drugs that contain estrogen and/or progestin to relieve hot flashes and night sweats. These are the only drugs approved by the Food and Drug Administration for treating symptoms of menopause.

Patients' concerns are caused by a mixture of voluminous and confusing clinical trial data, strong warnings on hormone-therapy drug labels and unproven claims by purveyors of non-drug therapies.

"Women have to beware of people offering an enthusiastic lack of knowledge," Stephens said. "There's a lot of misinformation that isn't evidence-based." Dr. Mitul Shah, assistant professor of obstetrics/gynecology and women's health at the Saint Louis University School of Medicine, sees many patients "who are scared of hormones."

For patients who are amenable to taking hormones and whose health doesn't preclude the drug, she recommends a three-month trial after discussing risks and the daunting set of clinical trial data.

Many of the patients "have heard from friends about 'natural' treatments," she said. "A lot of women are not educated about herbals. They think 'all natural' means it's fine."

Shah won't object to a patient trying a herbal product as long she makes sure the patient doesn't take other drugs or products that interact with the supplement. She recommends the patient try the supplement for a limited amount of time.

"Some herbal products may be helpful in the short-term treatment of symptoms, whereas others are not," says the American College of Obstetricians and Gynecologists. "Others may cause harm."

The National Institutes of Health adds that although some non-drug therapies may provide some relief, "there is very little scientific evidence to support [their] effectiveness" for menopausal symptoms.

Risks and Benefits

The FDA-approved hormone drugs come with multiple red flags for serious side effects. Labels contain black box warnings -- the strongest alert by the Food and Drug Administration -- against using these drugs for preventing heart disease and dementia.

These labels also refer to a federal study that said estrogen-based drugs increase the risk of stroke or clots in leg veins in women over 50. Postmenopausal women 65 and older, the federal study said had a higher risk of developing "probable dementia" if they took estrogen alone or estrogen plus progestin compared to those who took a placebo.

Stephens say a patient's fear of hormones often correlates to the intensity of her menopausal symptoms. "The vast majority of asymptomatic women don't want to take hormones," she explained. "Those with symptoms say 'I'm miserable. Tell me the pros and cons of hormone replacement therapy.' "

The pros include reducing hot flashes and night sweats. Among the cons, the FDA says women shouldn't take hormones if they have vaginal bleeding, have had certain types of cancer, have had a heart attack or stroke in the past 12 months, have had blood clots or have liver disease.

"If women use hormone therapy, they should use them at the lowest dose that helps," the FDA says. "Use them for the shortest time that you need them." Shah and Stephens also will prescribe other drugs, such as antidepressants, for treating menopausal symptoms. The FDA hasn't approved them for these uses; but 'off label' prescribing is legal for any treatment as long as the FDA has approved a drug for a single disease or condition.

If a patient has a sleep disturbance or changes in mood without having hot flashes, Stephens will prescribe an insomnia drug or an antidepressant.

Shah will prescribe antidepressants for women who don't want hormones or who shouldn't take them. They "are pretty good, although they're not as good as [the estrogen drug] Premarin," she said. "I'd say 50 percent to 60 percent get relief."  Doctors won't prescribe hormone drugs for every patient, especially older ones. The average age of menopause onset is 51, and Shah won't recommend hormone therapy for anyone 60 and over.

Age played a role in the controversial 2002 report that triggered the debate over hormone therapy and its risks. A federally funded study, the Women's Health Initiative (WHI), was halted because a safety review board said the risks of invasive breast cancer outweighed the benefits of using a combination of estrogen and progestin.

The study wanted to know if hormone therapy in postmenopausal women could prevent heart disease. The study of healthy women had been scheduled to continue until 2005. The average follow-up review for patients was just over five years.

The study found "increases in coronary heart disease, stroke, and pulmonary embolism" among hormone therapy patients versus those who were taking a placebo. However, the average age of the women studied was 63, or more than 10 years older than the average age of menopause onset. At the time, the WHI director said hormones for "short-term relief" of symptoms "may be reasonable to continue since the benefits are likely to outweigh the risks."

Since then, there have been more studies. Last year, a WHI study said women who use hormones closer to the onset of menopause "tended to have" a reduced heart-disease risk versus women who had experienced menopause long ago.

The report, which said its statistical analysis was "not definitive," said total mortality was reduced among women ages 50 to 59. The results, it added, offer "some reassurance that hormones remain a reasonable option for the short-term treatment of menopausal symptoms."

In March, another WHI report said that three years after halting the use of hormone therapy in 2002, there was no significant difference in cardiovascular disease between women taking the combination hormone therapy and women taking a placebo. However, women who took the combination hormone therapy pills "continue to be at increased risk of breast cancer, even years after stopping therapy."

As new studies are published, physicians have had to adjust their approach to hormone replacement therapy - or at least to their patients' reactions.

"There was huge fear-mongering in 2002," said Dr. Wulf Utian, executive director of the North American Menopause Society, which provides scientific, medical practice and consumer information about women's health. "You had a lot of confusion."

This summer, his group updated its recommendation. "Recent data support the initiation of [hormone therapy] around the time of menopause to treat menopause-related symptoms," it says. "The benefit-risk ratio ... is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women."

Lawsuits and Sales

Patient concerns remain stoked in part by lawsuits against Wyeth, which makes Premarin, an estrogen drug, and Prempro, a combination of estrogen and progestin. These drugs were used in the Women's Health Initiative study.

By late October, Wyeth had been cited as a defendant in approximately 7,800 personal injury lawsuits filed by about 11,000 women, says a Wyeth filing with the Securities and Exchange Commission. The suits allege the drugs caused breast cancer, ovarian cancer, stroke and heart disease.

Of the 30 hormone therapy cases alleging breast cancer that have been resolved after being set for trial, Wyeth has prevailed in 24 through verdicts, summary judgments or voluntary dismissal by plaintiffs.

Three other cases were settled. Wyeth is appealing two verdicts; and one verdict was dismissed by a judge, who ordered a new trial. "Additional cases have been voluntarily dismissed by plaintiffs before a trial setting," Wyeth said.

Despite its courtroom success, Wyeth has never regained the sales of Premarin and Prempro that occurred before the WHI report. Sales peaked in 2001 at $2.1 billion. By 2004, sales fell to $880 million.

Annual sales crept up to $1.06 billion last year. For the nine months that ended Sept. 30, Wyeth recorded sales of $809 million, or a 2 percent gain over the same period last year. Premarin and Prempro aren't the only hormone replacement drugs. Sagient Research, a San Diego firm that tracks drug and biotech developments, says the FDA has approved seven other brand-name drugs that contain estrogen alone, progestin alone or a combination.

These drugs can be administered orally, via a skin patch or through a spray to the skin. At Washington University, Stephens prefers to try non-pill therapies first. She says they don't raise the risk of stroke as hormone pills do.

The newest FDA-approved drug is the skin-spray Evamist. It is applied once a day to the forearm to treat moderate to severe hot flashes after menopause.

Vivus, a small California company, developed the estrogen-based drug and has licensed it for manufacturing and marketing to St. Louis-based KV Pharmaceutical. Although the FDA approved Evamist in July 2007, KV only began shipping it in April 2008.

Seeking More Choices

Several drug companies are testing non-hormone drugs, but none has been approved by the FDA.

  • Pristiq, from Wyeth, is the closest to market as it was approved by the FDA in late February for treating depression in adults. In July 2007, Pristiq received a conditional approval by the FDA for treating moderate-to-severe hot flashes and night sweats. To get the final OK, however, Wyeth must conduct a clinical trial to assess potential cardiovascular and liver side effects. The test of 2,000 women started in July 2008 and is expected to take 18 months.
  • DM-5689 from Depomed, of Menlo Park, Calif., is in late-stage clinical testing. This is an extended-release version of gabapentin. When sold in an immediate-release form, gabapentin is approved by the FDA to treat epilepsy and nerve pain associated with shingles. Immediate-release gabapentin, now a generic, is the scientific name for Pfizer's Neurontin.
  • Mesafem is in a mid-stage clinical trial. Developed by Noven Pharmaceuticals, of Miami, Fla., it is a low-dose version of the antidepressant Paxil, a GlaxoSmithKline drug that has lost patent protection. Noven also has a joint venture with Novartis that makes and markets hormone replacement drugs delivered via a skin patch.
  • Menerba is an experimental estrogen pill from Bionovo, of Emeryville, Calif. The company recently completed a midstage clinical trial. Bionovo is trying to determine whether the drug can effectively treat hot flashes and reduce the number of dangerous side effects linked to current hormone replacement therapies.
  • Aprela combines Premarin and the experimental bazedoxifene. Wyeth expects to submit its menopause application to the FDA in the second half of 2009. Wyeth also is seeking FDA approval of bazedoxifene for treating and preventing postmenopausal osteoporosis.

Different Rules

The makers and sellers of dietary supplements and herbal products aren't subject to the same rules required of prescription drug developers.

A drugmaker must prove a compound is safe and effective before the FDA will approve it for marketing. For herbal products, the FDA must prove they are dangerous, when taken as directed, before the agency can try to remove it from the market.

Sellers of herbal products aren't required to do the same testing as drug manufacturers, and their products aren't approved by the FDA.

"There are many different types of products that vary widely," says the American College of Obstetricians and Gynecologists. "Because of this wide variety, it is hard to set a standard dose. What works for some women may not work for others. For many of these products, there are limited facts available."

The natural-products companies have no incentive to conduct the lengthy, expensive testing that drug companies must do to get FDA approval. Why spend hundreds of millions of dollars testing a herb that lacks patent protection?

"Very little well-designed research has been done" on herbal products and dietary supplements, says the National Institutes of Health. Small, published studies have research flaws so their results "are not strong enough for scientists to draw any conclusions."

However, the NIH has done some testing using the standards applied to prescription drugs. In December 2006, NIH said a 12-month study showed the popular herb black cohosh failed to relieve hot flashes.

The NIH says other studies of black cohosh provide conflicting conclusions and data, partly because these studies have run less than six months and partly because "different amounts of black cohosh from different sources were used in the various studies and their outcome measures were different."

In July 2006, the Archives of Internal Medicine analyzed 70 statistically controlled trials of non-drug treatments for menopausal symptoms.

"Forty-eight studies of phytoestrogens and other biologically based agents showed mixed results," said the report financed by the Oregon Health & Science University, the NIH and the Portland (Ore.) Veterans Affairs Medical Center. Phytoestrogens are natural estrogens found in certain foods such as soybeans and chickpeas.

"Smaller numbers of studies using mind-body, energy, manipulative, and body-based therapies and whole medical systems showed little benefit," the authors said. "Although individual trials suggest benefits from certain therapies, data are insufficient to support the effectiveness of any complementary and alternative therapy in this review for the management of menopausal symptoms," the authors concluded.

More information

FDA Office of Women's Health

National Institutes of Health: menopausal hormone therapy information

American College of Obstetricians and Gynecologists

North American Menopause Society

Women's Health Initiative

Robert W. Steyer is a freelance business journalist living in New York. To reach him, contact Beacon health editor Sally J. Altman.

Robert W. Steyer special to the Beacon