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
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
''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
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
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
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
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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DISCLAIMER: All information, data, and material contained, presented, or provided here is for general information purposes only and is not to be construed as reflecting the knowledge or opinions of the publisher, and is not to be construed or intended as providing medical or legal advice. The decision whether or not to vaccinate is an important and complex issue and should be made by you, and you alone, in consultation with your health care provider.
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