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Hormone therapy's rise and fall: Science lost its way, and women lost out

By Stephen Smith

Reprinted from The Boston Globe

July 20, 2003

The year was 1991, and hormone replacement therapy pills sat like pastel candies inside the medicine cabinets of middle-aged women from coast to coast. They were easy to use, widely available, and touted as the pharmaceutical embodiment of Ponce de Leon's fountain of youth, promising youthful vigor, sharper thinking, and softer skin for women confronting menopause and the years after.

But Bernadine Healy, who became the first woman to lead the National Institutes of Health that year, was convinced that the rush to put hormones into the hands of every woman over 50 was a reckless pursuit based on insufficient science.

''We were on a fast train to putting estrogen and progestin in every woman's drinking water,'' she recalled. ''The train was moving so fast that I felt guilt because my mother and mother-in-law had never been placed on hormone replacement therapy. But we just didn't have the necessary data.''

To settle the matter, she began a landmark study known as the Women's Health Initiative that would prove the undoing of pills that for much of the 1990s were the top sellers of all drugs in America's pharmacies.

The stellar rise and spectacular fall of hormone replacement therapy ranks among the biggest medical mistakes in history, fueled by a combination of weak science, relentless hype, the herd mentality of doctors, and women's dawning redefinition of menopause from an inevitable ''change of life'' to a manageable condition.

Now, a year after the first of a series of bombshell studies demolished widely held beliefs about hormone replacement, physicians and patients alike continue to reel from the reality that the pills cause some of the very problems they aim to prevent, including heart disease and impaired mental skills.

Rise and fall of hormone therapy

The result has been a 42 percent plunge in sales in just one year and the filing of class action lawsuits representing hundreds of clients seeking redress from Wyeth Pharmaceuticals, maker of the most popular varieties of hormone therapy.

In the process, millions of women glimpsed an unsettling side of medicine in America. They learned that doctors were prescribing hormones for uses never even reviewed by federal regulators.

Plus, many of the physicians didn't know enough about basic data analysis to see through the entreaties of hormone boosters such as the New York gynecologist who wrote a popular book urging their widespread use or the marketing pitch of drug company representatives.

''It was just an incessant drumbeat, the marketing of the hormone replacement stuff,'' said former US representative Patricia Schroeder, who led a Capitol Hill charge in the late 1980s and early 1990s to expand the study of hormone therapy. ''They made it sound like it was the answer to cancer, the answer to Alzheimer's, the answer to everything. I remember at some time thinking, `Surely all of these people aren't prescribing it without having the scientific background to support it.'

''But that's exactly what they were doing.''

Hormone replacement therapy debuted more than 60 years ago, with estrogen harvested from the urine of pregnant mares and made into a pill called Premarin. It was designed to be given to women in the throes of menopause, the time when menstruation ceases, which typically happens between ages 45 and 55.

But it was in the 1960s that hormones as a panacea for a variety of ailments began to gain currency.

Leading medical journals, including The New England Journal of Medicine and The Journal of the American Medical Association, published studies that appeared to validate estrogen's potential. But it was research based on old, sometimes unreliable medical records, a method far less rigorous than the methods that define the medical canon today.

For example, the records frequently did not indicate the strength of the pills women were swallowing, or whether they contained just estrogen or a combination of estrogen and another hormone, progestin. The experiences of those women would then be compared with the records of women who hadn't taken hormones, a tricky proposition because the women who chose to take hormones tended to be more health-conscious and to avoid risky behaviors. Such reviews are known as observational studies.

''In those early studies of hormones, we had whole mixed bags of women on different combinations of drugs and different doses,'' said Dr. Maureen Lowery, a University of Miami cardiologist who was a principal investigator of a hormone study called HERS -- the Heart and Estrogen/Progestin Replacement Study -- in the '90s. ''It's not like when we do trials today, and we carefully recruit participants and data is meticulously gathered and scrutinized.''

So while those early human trials, along with tests in animals, suggested hormones prevented heart disease and improved quality of life, they were clearly inferior to the more detailed reviews done years later.

But Dr. Robert Wilson, a New York gynecologist, ignited a fervor for hormones as a way of stilling the consequences of menopause. In his 1966 tome ''Feminine Forever,'' he branded menopause as a ''horror of living decay'' demanding aggressive medical intervention.

''The concept became very pervasive that menopause was something that required treatment,'' said Dr. JoAnn Manson, a principal investigators of the Women's Health Initiative study of hormones and chief of preventive medicine at Brigham and Women's Hospital. ''It was the concept that by popping a pill, you could be useful, you could have a great sex life, you could be more attractive.''

Wilson blazed a path across the nation, seeking converts to his belief about the power of pills to keep women feminine. But his son, Ronald Wilson, said the drug makers themselves gave Wilson his public platform. Ronald Wilson said in an interview last week that his father's work was underwritten by Wyeth, the drug company that made the leading hormone.

The son, who lives in North Carolina, said the pharmaceutical giant paid for the writing of ''Feminine Forever,'' opened a Park Avenue office in New York for the doctor, and sponsored speeches.

''But he totally, totally believed in everything he said about hormones, even though much of it was glamorized,'' Ronald Wilson said. ''There were no lies on his part, although there was some exaggerating. He would be devastated if he knew what the outcome of today's findings were.''

Wyeth spokesman Douglas Petkus said no evidence exists in company files of a financial arrangement with the gynecologist, who died in 1981.

Hormone therapy suffered its first round of scientific setbacks as early as 1975, when researchers reported that women using estrogen alone ran a significantly higher risk of developing uterine cancer. So the search began for an alternative for women whose uteruses were still intact. The result: a pill that combined estrogen with a chaser of progestin, which negated the cancer threat.

The new medicine, marketed as Prempro, became an overnight hit, with sales soaring to $888 million globally by 2001.

Prempro and other hormone replacement medicines were widely prescribed as a way of preventing heart disease and restoring quality of life, even though the US Food and Drug Administration had only approved their use to stop menopause symptoms such as hot flashes and to prevent osteoporosis.

Doctors are allowed to stray outside the borders of a drug's approved purpose, a practice known as off-label use. And that's what physicians did with the hormones, prescribing the pills by the millions to erase wrinkles and boost mental functioning in women.

''There certainly is a culture that physicians respond to. If they see that other physicians are doing something, then it adds to their decision-making as to whether to do it,'' said Judith K. Ockene, chief of preventive and behavioral medicine at the University of Massachusetts Medical School in Worcester and a principal investigator of the Women's Health Initiative. ''They don't look at the data and say, `How strong is that data?' ''

So, by the 1990s, 6 million US women at any given moment were taking combination hormone replacement therapy, some for just a few months to ease menopause, others for years to slow the advance of aging.

But both federal investigators and the company making the pills sought more conclusive evidence that the medicine lived up to its billing. In fact, Wyeth executives were confident enough in their product that they paid for the HERS trial, which was designed to see if hormone therapy could prevent the recurrence of heart disease in women.

Separately, the Women's Health Initiative aimed to discover whether hormones could prevent disease and improve quality of life among the healthy by tracking roughly 16,000 postmenopausal women between the ages of 50 and 79, with half taking the hormone combination and the rest taking placebo pills.

Those studies conformed to what is now regarded as the gold standard of scientific investigation, the randomized clinical trial. Researchers divide study participants into one group that gets the medicine under study, another that downs a dummy pill, and, sometimes, a third that receives an entirely different treatment. Usually, neither participant nor researcher knows who got what pill until the research is complete.

Wyeth researchers admit they'd held fervent hope that HERS would validate the belief that hormones could prevent the return of heart disease.

''It was not just Wyeth's hope,'' said Dr. Victoria Kusiak, Wyeth's North American medical director. ''It was the hope of the medical community because it would have been a good thing.''

But the HERS study in 1998 released findings that showed cardiovascular problems actually increased among women on hormones during their first year of taking the pills.

Conclusions from the more damning Women's Health Initiative began emerging last July, with each piece of bad news lighting up phone lines in the offices of gynecologists. The NIH was so concerned by the outcome that it put an early halt to the review once researchers found that the pills increased a woman's risk of breast cancer, blood clots, and heart disease.

This March and May, further results from the Women's Health Initiative found that not only did combination hormone therapy not improve the quality of life, it doubled the risk of dementia.

''I really do believe that the hormone therapy saga is the most dramatic sea change in medicine that has occurred in the past few decades, perhaps ever,'' Manson said. ''A medication was perceived as a magic bullet and then the randomized trial evidence suggested almost the very opposite.''

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