The Truth About Hormones

By Christine Gorman and Alice Park

Susan Pierres, a Miami photojournalist who just turned 60, is confused and angry. Ten years ago, when she was approaching menopause, her doctor started her on hormone-replacement therapy, or HRT. "I didn't have any symptoms," she recalls, "but he recommended it for general well-being, bones and heart." Many years and pills later, her gynecologist suggested that perhaps it was time to stop. After all, there had been reports that HRT might increase a woman's risk of breast cancer, a disease that had afflicted Pierres' mother and aunt. She turned to several other physicians for advice. They couldn't seem to agree. Now comes word from a really big study that taking HRT for years at a stretch isn't such a great idea after all.

Should Pierres believe these latest results or go back to her doctor for an explanation? Which doctor? It's not as though she's all that eager to get off hormones: "You feel it is your last vestige of youth. What if my skin turns scaly and my hair falls out?" she worries. "These are complicated matters. People like me don't know where to go or whom to listen to."

Whom indeed. For decades, millions of women like Pierres have been told that HRT is a veritable fountain of youth. It kept the skin supple, held back heart disease, boosted old and brittle bones and might even have staved off senile dementia. More than 40% of all women in the U.S. start some form of HRT in their menopause years. Many of them continue well into their 70s and 80s, convinced that the little pills give them a youthful glow.

Like latter-day Ponce de Leons, however, these women are watching their dream of eternal youth fade away. A large, federally funded clinical trial, part of a group of studies called the Women's Health Initiative (WHI), has definitively shown for the first time that the hormones in question--estrogen and progestin--are not the age-defying wonder drugs everyone thought they were. As if that weren't bad enough, the results, made public last week, proved that taking these hormones together for more than a few years actually increases a woman's risk of developing potentially deadly cardiovascular problems and invasive breast cancer, among other things.

As with any major medical announcements, there are caveats and complications. The WHI wasn't designed to look at short-term use during menopause, for instance. But the principal message is this: taking estrogen and progestin for years in the hope of preventing a heart attack or stroke can no longer be considered a valid medical strategy. (For a detailed look at the pros and cons of hormone therapy for various conditions, see the chart on pages 38 and 39.)

Here at last is a rare moment of clarity. The debate over the long-term benefits and risks of HRT has lasted for decades. Now we have at least a few concrete answers.

The findings are so striking that the study was stopped three years short of its scheduled completion. (The other WHI trials, which include a look at how estrogen alone affects women with hysterectomies, are still proceeding.) And the formal scientific report, which is being published in this week's Journal of the American Medical Association, was released a week early at a press conference in Washington.

The phones haven't stopped ringing since. Women across the U.S. immediately started calling their doctors, their mothers, their daughters, their friends. Are you still taking your pills? Do you think plant-based hormones are any better? Would lowering the dosage make it any safer?

"Maybe I've been too trusting. I still don't feel like I have all the facts and details," says Jodi Simma, 55, a homemaker who engaged nine friends in a spirited discussion over salads and lemon dessert in New Richmond, Wis., last week.

"We're all concerned," says Muriel Smith, membership coordinator at the Dave and Mary Alper Jewish Community Center, south of Miami, which is organizing a panel discussion on the topic. "Everyone wants to know what to do."

Some, like Ellen Robinson, 58, a commercial litigator who works in Chicago, have already made up their minds. Robinson decided last week to stop taking her hormones cold turkey. "I haven't had breast cancer, a stroke or a heart attack," she explains, "but now I'm nervous. Everyone has been in the dark about the risks."

Others who were skeptical of hormones all along feel vindicated. "I'm not antiestrogen, but we need to accept menopause as a natural, normal, physiological process," insists Vicki Meyer, founder of a cybercommunity called the International Organization to Reclaim Menopause. The idea that our bodies fail us at menopause, she says, is "ludicrous, extremely sexist and just plain wrong."

Physicians are scrambling to keep up. A gynecologist in Dallas has written a script to help her office staff deal with the deluge of calls. The American College of Obstetrics and Gynecology has created a task force to rethink its guidelines on HRT. "The bubble has burst," says Dr. Isaac Schiff of the Massachusetts General Hospital in Boston, who is chairing the task force. Schiff admits that in the aftermath of last week's news, doctors need as much guidance as their patients. "Some physicians say they are not going to change things in their practice at all and will be as proactive for HRT as they've ever been," he says. "Others say this will change their thinking dramatically."

THE ESTROGEN EXPRESS

To understand how we got to this point, it helps to know a little medical history. About 40 years ago, attention was focused on just one female hormone, estrogen. Its greatest popularizer was a gynecologist named Robert Wilson, who thought the hormone could serve as an all-purpose rejuvenator for women of a certain age. There was, it must be admitted, more than a little sexism, not to mention ageism, in his point of view. In his hugely successful book, Feminine Forever, published in 1966, Wilson wrote of menopause as a "living decay" in which women descended into a "vapid cow-like" state. Supplemental estrogen, Wilson insisted, would almost magically transform the dull cow into a supple, younger-looking wife and mother. She would not only feel better but also make those around her feel better--especially, it was implied, her partner in bed.

Those were different times, of course. But the idea that a single pill might turn back the clock quickly caught the popular imagination. It didn't hurt that the hormone's No. 1 manufacturer, Wyeth Pharmaceuticals, launched an aggressive marketing campaign. Thank goodness today's spots have been updated to feature the dulcet tones of singer Patti LaBelle and have abandoned patronizing messages like the one in a 1975 ad--"Almost any tranquilizer might calm her down...but at her age, estrogen may be what she really needs."

Over the years the medical arguments for prescribing estrogen were also updated. "The vapid cowlike state was gone, and there was very scientific language about bone density and heart disease," explains Cynthia Pearson, executive director of the National Women's Health Network, a longtime skeptic of HRT.

It all seemed so logical and convincing. Women are much less likely than men to suffer heart attacks and strokes in their 30s and 40s. But when natural estrogens stop flowing after menopause, women's risk quickly catches up to men's. Clearly estrogen has some kind of positive influence. And sure enough, a number of studies in the 1980s showed that women who took the hormone at menopause had lower levels of LDL cholesterol, the so-called bad cholesterol, and higher levels of HDL, the so-called good cholesterol, than those who didn't. The benefits of supplemental estrogen couldn't be more obvious.

Biology, alas, is rarely so straightforward. Researchers came to realize that it wasn't safe to give estrogen alone to a woman with an intact uterus. Unopposed estrogen, as it is called, dramatically increases the chances that a woman will develop uterine cancer. (Obviously, this isn't a problem for women who have undergone hysterectomies.) The addition of progestin, another female hormone, seemed to take care of that problem.

The conviction that long-term HRT was beneficial became so entrenched that doctors who delved into the issue more closely were surprised to discover how thin the evidence was. In the early 1990s, Dr. Deborah Grady of the University of California at San Diego was asked to help write guidelines on HRT use for the American College of Physicians. She remembers growing increasingly uncomfortable as she sifted through the scientific literature. None of the studies were definitive. Most were observational studies that showed that women who took HRT lived longer and with fewer health problems than those who didn't. Perhaps HRT was the real reason, or perhaps women on HRT were simply more health conscious than their counterparts. No one could say for sure.

Even the studies that showed that estrogen improved a woman's cholesterol profile weren't ultimately all that satisfying. After all, plenty of women with normal cholesterol levels still have heart attacks. What was needed was a hard-core clinical trial so rigorously designed that no one could contest the results.

Former U.S. Congresswoman Pat Schroeder remembers arguing for such studies. At the end of the 1970s, she recalls, the largest study done by the National Institute on Aging "didn't have one woman in it. They didn't know anything about osteoporosis, menopause, anything. They wouldn't do anything for women but throw pills at us." With a shove from Schroeder, other female legislators and women's groups, the WHI was launched in 1991. The giant investigation was designed to get some precise answers to the hormone debate and determine the best strategies for preventing the diseases of aging, including heart disease, cancer and osteoporosis.

SOME ANSWERS AT LAST

More than 160,000 American women are enrolled in the WHI, which is divided into five major studies that look at everything from the role of diet in determining a woman's health as she ages to the role of hormones in that process. More than 16,000 healthy women, ages 50 to 79, volunteered for the study on estrogen and progestin.

Half of these women were randomly assigned to receive the hormone combination, and the other half were given a placebo, or dummy pill. Neither the women nor their doctors knew who was taking the active medication. This type of study, called a double-blind, randomized, controlled trial, is the most rigorous type of investigation scientists know how to conduct. It's a long, difficult path to take to get an answer, but at least you can be certain of the results.

The plan was to follow the women for an average of eight years and record how many suffered from heart attacks, strokes, blood clots, hip fractures or colon cancer. From the outset, a safety board monitored the data to ensure that the study would be stopped before its scheduled ending in 2005 if there was evidence of such a clear benefit that it would be unethical to withhold the drug treatment from those women in the control group. It would also be stopped if, conversely, the risks of HRT so obviously outweighed the benefits that women in the treatment group should stop taking the drugs.

The first hint that all was not well came late in 1999, when the monitoring board detected an unexpected increase in the risk of blood clots and heart attacks in women on combination-hormone therapy. Although the absolute risk was small, it came as a shock. Most doctors believed that hormone replacement offered protection against cardiovascular disease. Investigators informed participants and their doctors of their findings early in 2000 but decided to continue the study to see if the negative effect persisted. Perhaps, they reasoned, it takes longer for cardiovascular benefits to appear.

By the spring of this year, however, a new danger emerged from the data. Not only were women who took estrogen and progestin more likely to suffer heart attacks and blood clots in the lungs and legs, but they also had a slightly increased risk of developing breast cancer. That was just enough to tip the scale. Though the women on HRT suffered fewer hip fractures (1 woman per 1,000 per year vs. 1 1/2 women per 1,000 per year), the benefit wasn't great enough to warrant the risk. Because the trial was designed to look at women who were already healthy, the safety bar was set fairly high. Given the criteria that the monitoring board had developed before the WHI study began, this part had to be stopped.

Intriguingly, the part of the WHI study that focuses on the long-term benefits of estrogen alone among women who have undergone hysterectomies is ongoing. So far, the safety board has not detected any excess risk of breast cancer in this group. Apparently, estrogen plus progestin has a negative cumulative effect on the breast that estrogen by itself seems not to have.

SOME QUESTIONS STILL

So much for the major conclusions. Now for the caveats and complications. The WHI study looked at the most popular brand of estrogen and progestin, which is called Prempro and is made by Wyeth. Technically speaking, the WHI findings do not apply to other products. Some doctors have speculated that lower-dose hormones or estrogen-progestin patches and creams might somehow avoid some of the risks associated with Prempro. That has yet to be proved. Even so-called natural hormones (those derived from plants) aren't necessarily risk free. For one thing, they haven't been as carefully tested as Prempro. There is preliminary laboratory evidence, says Dr. Wulf Utian, who heads the North American Menopause Society, that natural hormones may promote tissue growth in the breasts and thereby contribute to a cancer risk.

There is also a chance that certain estrogen-like compounds may be developed that will capture all the hormone's benefits without any of its risks. One such drug, raloxifene, has been shown to prevent fractures, so far without increasing a woman's risk of breast cancer. But a number of women suffer hot flashes and even blood clots while on raloxifene, making it an unlikely candidate to replace estrogen completely.

Though last week's news raises big questions for anyone on hormone-replacement therapy, women taking birth-control pills shouldn't panic. True, these pills also contain estrogen and progestin, but most women take them before menopause, when their bodies are making more of their own hormones. So it's quite possible that their bodies are better able to handle the excess. In any case, it's impossible to extrapolate from the WHI study.

Nor should women panic if they are using HRT for short-term relief of menopausal miseries. For in a strange sort of way, the study brings HRT back to the basics, doing what it always did best--alleviating intense hot flashes, night sweats and mood swings during the limited period in which they occur. "Estrogens," says Dr. Howard Judd of UCLA, one of the WHI principal investigators, "are still the best, and in many ways the only, way of treating menopause."

Is it worth a very slight, short-term risk of blood clots to battle hot flashes? You bet, says Christine Fulbright, 53, who runs her own hair salon in Venice, Calif. Fulbright's menopausal symptoms, which started a year ago, were so bad she thought she was dying. "I was aching all over and crying all the time," she recalls. "At one point I was cutting a man's hair when, out of the blue, I had to fight back tears." Fulbright tried alternative remedies, like yam creams, but relief came only when she tried Prempro four months ago. "It was like a miracle," Fulbright says. "I was back to my normal self."

The tricky part is going to be figuring out just how long women like Fulbright need to stay on HRT, how best to wean them off the treatment and then how to protect them from osteoporosis and other ravages of age without resorting to old-fashioned hormones. "The world of menopause management," says Utian of the North American Menopause Society, "has just become a lot more complex."

And part of that complexity is dealing with the emotional attachment that some women have to their HRT regimen. Many like the way they look and feel on the stuff. Change is scary.

And that, perhaps, is why Susan Pierres, the angry and frustrated Miami photojournalist, has yet to make her move in the wake of last week's news. Along with so many other women, she continues to fret over whether she really has to part with her pills. --With reporting by Amanda Bower/New York, Wendy Cole/Chicago, Jeanne DeQuine/Miami and Jeanne McDowell/Los Angeles

With reporting by Amanda Bower/New York, Wendy Cole/Chicago, Jeanne DeQuine/Miami and Jeanne McDowell/Los Angeles