As president and chief executive officer of the Society for Women's Health Research, Phyllis Greenberger knows all about the studies showing that women who take hormones after menopause have a greater risk of breast cancer, stroke, heart attack, incontinence and dementia. She is aware that federal health officials recommend that the drugs be taken at the lowest dose for the shortest time possible to treat severe symptoms of menopause such as hot flashes.

But Greenberger has no plans to stop taking the hormones she started at age 50 more than a decade ago, although she has reduced the dose. In her case, she said, she doesn't think the advice is relevant. And she believes the risks of the estrogen-progestin combination have been exaggerated.

"I feel better, I have no side effects and in my case I see no downside," she said, noting that estrogen protects against osteoporosis and colon cancer. "Obviously if I thought it was dangerous, I wouldn't be taking it," Greenberger said.

Greenberger's experience is emblematic of a medical landscape that has shifted dramatically since July 2002, when federal researchers made a stunning announcement: Because of the risks to women taking hormones, they were halting a key arm of the mammoth study known as the Women's Health Initiative (WHI) three years early and advising women taking the drugs to consult their doctors.

For decades, despite little evidence of their safety and effectiveness, post-menopausal hormones had been widely regarded -- and aggressively marketed -- as one of the best ways for women to stave off the ravages that accompany age.

The 2002 bombshell was followed by a spate of studies that seemed to systematically strip the remaining gloss from the rosy view of hormones: They don't prevent dementia or memory problems but in fact may increase them; they don't prevent incontinence but may contribute to it; and there is no evidence they improve skin tone, combat wrinkles or blunt mood swings. These findings contravened the gospel drug companies and many doctors had been preaching since the 1960s.

After the announcement, sales of the estrogen-progestin combination drug Prempro, along with estrogen-only Premarin, both manufactured by Wyeth and tested in the WHI, nosedived off the list of best-selling pharmaceuticals. In the months before the WHI announcement, an estimated 14 million women in the United State were taking hormones. Today the number hovers around 6 million.

Even the name has changed. Hormone replacement therapy been renamed hormone therapy (HT) -- the word "replacement" has been dropped.

Despite the scientific sea change of the past three years, it's unclear to what extent clinical practice has been altered, and whether doctors are prescribing the drugs inappropriately or softpedaling their risks.

Some health advocates say they worry that the dangers of hormone therapy may be obscured by the fog of marketing or lingering doubts among doctors about the validity of the WHI's findings.

"There are clinicians who read the data and say the earth is still flat" or insist that their patients are different, said Amy Allina, program director of the National Women's Health Network, a nonprofit educational group located in Washington.

"I think a lot of doctors have been slow to change," said Diana Zuckerman, president of the Washington-based National Research Center for Women and Families. How many women, she mused, are trading relatively short-term relief for a long-term threat like invasive breast cancer?

A Quiet Return

While women are not returning to the drugs in droves, there has been an uptick in their use to treat the more troublesome symptoms of menopause. Some of the increase seems to have been spurred by the marketing of new, lower-dose formulations of existing drugs.

Two months ago Wyeth launched a television marketing campaign featuring actress Cheryl Ladd. Best known for her role as one of "Charlie's Angels" in the eponymous television series Ladd, 54, discusses her own experiences with menopause. She never mentions a specific drug but advises women to talk with their doctor about how best to cope with hot flashes, night sweats and osteoporosis.

"There seems to be a very strong interest in low-dose hormones," said Wyeth vice president Natalie deVane, citing recent company data showing that 25 percent of women who stopped taking hormones after the WHI was halted are now back on them. A study by Minnesota researchers published earlier this year in the journal Menopause yielded similar results; it found that women in their fifties were more likely than older patients to stay on HT.

Some gynecologists who switched their patients to low-dose pills say they still believe the benefits for many women with severe menopausal symptoms outweigh the small risks, which they regard as hyped and not necessarily applicable to younger, healthier women. The average age of women in the WHI was 63, they note.

"I think the fear factor has definitely calmed down now -- as it should -- and other points of view have come forward," said Anne Brown, chief of obstetrics and gynecology at Inova Loudoun Hospital.

"I think the WHI has unnecessarily scared too many women," said obstetrician-gynecologist Constance Bohon, who practices near Washington's Sibley Hospital. "I tell patients it's a very specific study" of a single drug at a particular dose and let them decide for themselves.

But women's health advocates say the potential risks apply to women of all ages, not just those over 60. The WHI included women between the ages of 50 and 79, including thousands in their fifties.

"The thing about science is that you can always ask another question -- like, 'What about women who are 49?' " said Allina, of the Women's Health Network. The WHI, she said, remains the scientific gold standard.

Zuckerman points to the latest WHI-related study, published two months ago in the Journal of the American Medical Association, which found that more than half of women who had taken hormones to treat hot flashes and night sweats experienced those problems when they stopped taking the drugs. Some women "are taking a risk with their health with the possibility of just dragging this out," she said.

Other advocates say that one reason women return to HT is that nothing else has been shown to work for severe menopausal symptoms.

"Nobody ever said that women who tried other approaches and had miserable hot flashes and couldn't sleep shouldn't take estrogen" for a short time at the lowest dose, said Judy Norsighian, co-founder of the Boston Women's Health Book Collective, which wrote the landmark feminist guide "Our Bodies, Ourselves." But, she noted, women must be properly informed of the potential hazards.

Earlier this year an independent state-of-the-science panel convened by the National Institutes of Health (NIH) called for the "demedicalization of menopause" and warned doctors and patients to use hormones sparingly. The panel also noted that it is difficult to distinguish between symptoms of menopause, which are usually transitory, and those of normal aging.

"Little is known about major adverse events that could be associated with three- to five-year exposures to low-dose estrogen and progestins," including breast cancer that occurs five to 10 years after the drugs are taken, the panel said. Its members warned against the overuse of "treatment approaches that are known to carry serious risks."

Feminine Forever

It's been nearly 40 years since New York gynecologist Robert Wilson published "Feminine Forever," a book that fueled the popularity of estrogen and the notion that menopause is a medical problem that needs to be fixed.

Wilson warned that women were doomed to become shriveled, sexless, sickly hags unless they took supplemental estrogen, which could keep them looking and feeling better.

"I vividly remember one ACOG meeting when we were told we should start all our post-menopausal women on estrogen unless they had advanced breast cancer -- it was that good," recalled Bohon of a meeting sponsored by the American College of Obstetricians and Gynecologists.

By the early 1990s, noted Isaac Schiff, chief of obstetrics and gynecology at Massachusetts General Hospital in Boston, "it was almost malpractice not to offer it to women for the prevention of heart disease," although previous studies had linked it to uterine cancer. Schiff chairs ACOG's task force on hormone therapy.

Results from the ongoing Nurses Health Study, a huge study involving 120,000 women begun in 1976, found that women who took hormones had lower rates of heart disease than women who did not, seemed to underscore the benefits of estrogen. Because it was an observational study, however -- one in which an association between the drug and the benefits was found, but no cause-and-effect relationship established -- critics led by the National Women's Health Network said that the benefits could be due to factors other than drugs.

In an attempt to definitively answer the question, NIH funded the landmark WHI, which employed the most rigorous scientific methodology: a randomized, double-blind, placebo-controlled study that involved more than 68,000 women.

The Prempro arm of the study, which involved 16,000 women, was halted in 2002 after researchers decided the risks of continuing were too great. (Two years later, a trial of estrogen-only Premarin involving women who'd had hysterectomies was also stopped early for the same reason.)

For every 10,000 women taking Prempro, there were eight more cases of breast cancer, eight more women had strokes, seven more had a heart attack and 18 more had blood clots, compared with women taking a placebo, researchers found. There was a modest reduction in hip fractures -- five fewer in the Prempro group -- and six fewer colon cancers.

The risk of breast cancer rose significantly after the fourth year, while the risk of cardiovascular problems increased immediately in the hormone group.

"There's really no safe period" of time the drug can be taken without risking side effects, Jacques Roussouw, acting director of the WHI, said at the time.

Serious Symptoms

While most women experience at least some symptoms of menopause, no one knows how many suffer from the most severe, debilitating problems -- drenching night sweats, hot flashes, mood swings and vaginal dryness that makes sex painful -- or how long symptoms typically last. Those are among the questions being examined by a large, long-term NIH-funded study known as SWAN (Study of Women's Health Across the Nation). Mass General's Schiff said that estimates of the most severely affected range from 10 to 25 percent.

"I still prescribe hormones for symptomatic women," Schiff said, "as long as they understand the risks and benefits." Some patients, he said, say they simply cannot function without the drugs; among these patients is a corporate executive whose face repeatedly turned crimson and sweat-drenched during business meetings. Others, he said have told him, "I know I'm going to be the person who gets breast cancer, and I want to stop right now."

Inova's Brown, whose mother has taken hormones for 20 years, said she tries to reassure patients who find they can't go off the drugs without feeling awful.

Brown, who described herself as a "huge hormone fan" before the WHI, said she no longer prescribes the drugs as preventive medicine but tries to reassure jittery younger patients who decide to take hormones that their risk of harm is probably small.

"Who are we to deny them their quality of life?" Brown asked.

One 65-year-old Leesburg woman, who agreed to be interviewed on the condition that her name not be published, decided her quality of life was worth the risk.

Three months after stopping the drugs she had taken for 10 years, "I was miserable, breaking out in hot flashes, sobbing, and my hair was falling out," she said, so she asked her doctor to renew her prescription.

"Most of my friends who took them are still taking them," she said, adding, "Breast cancer is always in the back of my mind. Sometimes I wish I'd never gone on them."

Isidra "Sheila" Munoz, a 57-year-old nurse at Sibley Hospital, said she decided last month to see if she could live without her hormone regimen of 10 years. "I'm fine," said Munoz, who has experienced only minor hot flashes.

Greenberger, head of the Society for Women's Health Research, said she had such severe symptoms when she cut her dose that she doesn't plan to stop taking hormones. Her group receives funding from more than 18 drug companies, including Wyeth, according to its Web site.

She said she hopes future studies will further refine the risk-benefit calculation, and thinks hormones may be beneficial in ways not yet discovered.

"There are still questions that need to be answered and more research that needs to be done," she said.



Phyllis Greenberger, president of the Society for Women's Health Research, says the federal government's advice about limiting hormone therapy doesn't apply to her.