In July 2002, the national Womens Health Initiative (WHI) terminated its randomized controlled trial of estrogen and progestin because the health risks of the regimen clearly outweighed the benefits. Its most startling finding--that HT increases the risk of heart disease--seemed to contradict the conclusions of several Nurses' Health Study (NHS) reports. During the 1980s and '90s, that observational cohort and several others showed a significant overall reduction in heart disease risk among women taking HT. The end result is an epidemiologic puzzle that Manson and other researchers have only begun to untangle.
doesnt mean that the observational studies were wrong and the clinical
trials are right," says Manson, who is a professor at both the Harvard
School of Public Health and Harvard Medical School. "Observational
studies have been tremendously helpful in generating hypotheses. They
are often on target, but in this case theres a divergence, and we
need to get a better understanding of why that is."
number of School-affiliated scientists are hot on the trail of this understanding.
Manson joined Assistant Professor of Epidemiology Francine
Grodstein and a non-NHS researcher in penning a February "Sounding
Board" article in the New England Journal of Medicine outlining
some of the possible reasons behind the disparity. Meir
Stampfer, chair of the School's Department of Epidemiology and a NHS
investigator, together with Grodstein, organized a major symposium on
campus earlier this year to explore the scientific issues raised by the
hormone debate. And Dr. Robert Hoover, SD'76, who made the first link
between hormone therapy and breast cancer, has been responding to many
of the same questions as director of the Epidemiology and Biostatistics
Program at the National Cancer Institute (NCI). Their combined efforts
are not only critical for women's health but have enormous implications
for the design and interpretation of epidemiologic studies in general.
has described the theory that estrogen replacement therapy might protect
women from heart disease as a "beautiful hypothesis" generated
by the existence of several viable biological mechanisms related to estrogen
and the observation that women, prior to menopause, seem to be relatively
protected from heart disease. The theory held up when examined through
the lens of the NHS, and other studies indicated possible means for the
protective effect, including improved cholesterol profiles. But ultimately,
those findings didnt translate into protection from coronary heart
disease (CHD) in the WHI.
the results of a randomized controlled trial like the WHI would transcend
the results of an observational study like the NHS outright--and indeed
many doctors and patients have taken its conclusions to heart. But the
NHS is not your typical exercise in epidemiology. Researchers believe
that nurses, as health workers, are more diligent and precise than the
average person in responding to questionnaires and are also more motivated
to participate in a study long term. So NHS findings often carry more
heft with clinicians and policymakers than other studies of its kind.
And more often than not, the results of observational studies correspond
with subsequent clinical trials. For many other endpoints--including fractures,
stroke, pulmonary embolism, and breast and colon cancers--the NHS predicted
the results of the WHI. So why the conflict when it came to CHD?
looking back, Manson points out several possible biological explanations.
Many of the NHS subjects used estrogen alone, while the WHI looked at
women taking estrogen/progestin combination therapy. In addition, the
two populations may have been different. Compared with WHI subjects, women
in the NHS had a lower body-mass index and tended to begin hormones at
the time of menopause. Methodologic limitations may have played a role
as well, she says. The observational studies may have suffered from a
confounding bias--a failure to control adequately for lifestyle or socioeconomic
factors, as well as an inability to capture short-term effects of HT.
"Every effort should be made to collect information about possible
confounders and to control for them carefully in mathematical models,"
she observes. "But sometimes it is very difficult to control for
and Grodstein agree that biology, along with timing, likely contributed
to the difference in the two studies. If the women using hormones in the
NHS were healthier in ways that could not be controlled for, the data
would also have indicated a lower stroke risk. Instead, Grodstein documented
a higher stroke risk among HT users in the NHS, a finding that suggests
that confounding is unlikely. On the other hand, all three researchers
note that the NHS subjects began HT near the onset of menopause, which
usually occurs around the age of 50. In contrast, about two- thirds of
WHI subjects were over the age of 60 when they entered the study. With
that in mind, Stampfer points to animal studies that have shown hormones
to protect newly menopausal monkeys from CHD--a protection that failed
to appear when therapy was delayed.
the result may be due to the fact that younger women are less likely to
have existing coronary artery disease, Stampfer says. "Hormones increase
the production of enzymes that make plaque in the coronary arteries less
stable and can cause an acute heart attack," he observes. "If
you dont have plaque, it may not have a bad effect." Studies
similar to the WHI in women with preexisting heart disease lend support
to this notion, finding that hormone therapy led to more heart attacks,
not fewer. Likewise, in the NHS, Grodstein found that women with heart
disease who used HT were initially at higher risk for subsequent heart
remarks that each research finding must be weighed both on its own merits
and in light of other relevant data. It may mean that hormones protect
some women and are too risky for others, but it is very difficult to extrapolate
findings from one specific group to other populations. Manson agrees:
"One of the lessons here is that researchers need to be very cautious
in how they present the results of their findings, noting the strengths
and limitations of the research."
there are times when those acting on scientific information have marketing
rather than methods in mind. Scientists repeatedly cite the over-promotion
of HT by the pharmaceutical industry as one reason women and their doctors
believed it could prevent a range of illnesses, including CHD. A 1992
review of 109 HT ads in medical journals found that 40 percent included
"unbalanced" information on the drugs' efficacy and side effects,
according to a study in the Annals of Internal Medicine.
his time at the School, alumnus Robert Hoover has been doing his part
to bring a bit more balance to the topic. For his doctoral thesis, he
tracked 1,500 women who had started taking estrogen in their mid-40s.
The result was the first study to make the link between breast cancer
and estrogen, which was published in 1976 in the New England Journal of
Medicine and "sparked a whole lot of enthusiasm to go out and do
similar studies in larger populations," he says.
studies, which came on the heels of research linking estrogen to uterine
cancer, convinced a lot of women to stop taking the drugs. But his role
did not end there. While a combined estrogen/ progestin therapy seemed
to eliminate the uterine cancer risk, Hoover helped determine that the
breast cancer risk of that regimen was even higher than with estrogen
alone. During a FDA hearing on HT cancer risks in the late 1980s, a participant
would make note of his ongoing role in the hormone controversy. "One
of the drug company representatives got up to criticize the study and
said, 'Whenever we see a study that implies HT is bad, somewhere in the
authorship there is this name: Hoover,'" the NCI researcher recalls.
At the same time, biological and epidemiologic studies indicated that
the drugs might protect against heart disease. "The real question
was: do the benefits outweigh the risk?" Hoover says. That
was the driving factor for the WHI."
light of the study's recent results, it would appear that they don't--at
least for women who start hormone use later in life. But that hasn't stopped
Hoover, who still works on questions regarding hormones and cancer. (He
helped launch the NCI's Cohort Consortium, which will use data and blood
samples from a number of large studies--including the NHS. The consortium's
first project will examine the link between gene/hormone interactions
and breast and prostate cancers.) Today, however, women are advised to
take HT only to relieve significant menopausal symptoms and for as short
a duration as possible. "It is one of the most dramatic sea changes
in clinical medicine that I've ever seen," says Manson.
The good news is when it comes to the heart, we have alternatives, according to Stampfer. "The main take-home message is that we have plenty of ways to prevent heart disease without having to resort to hormones," he says, estimating that about 80 percent of CHD could be prevented by simple changes in lifestyle. "In contrast, we have few ways to lower the risk of breast cancer. So, based on all our past research, avoiding long-term use of estrogen plus progestin makes a lot of sense."
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