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Hormone
therapy and heart disease: Is it all in the timing?
(This article was first printed in the June
2006 issue of the Harvard Health Letter.
For more information or to order, please go
to http://www.health.harvard.edu/health.)
For years, doctors believed estrogen was the
key to protecting older women against heart disease.
It started with a basic observation: Heart disease
is rare for women before menopause, when estrogen
levels are high, but becomes much more common
after menopause, when they fall. Findings from
long-term observational studies like the Nurses’ Health
Study added credence to the idea. They showed
that women who took hormones after menopause
had markedly lower rates of heart disease. In
addition, many women said they just felt a whole
lot better when they were on postmenopausal hormone
therapy. The number of prescriptions soared.
Hormones prove risky
Then in July 2002, came the results from the
Women’s Health Initiative (WHI), a randomized
controlled trial of hormone therapy. They showed
a higher rate of heart disease among
women using hormones. Because randomized controlled
trials like the WHI are considered to provide
stronger evidence than observational studies
like the Nurses’ Health Study, many doctors
concluded that the results of the WHI trumped
findings from the observational studies. Since
heart disease is by far the most common cause
of death in women, any protective effects of
hormone therapy against osteoporosis or (possibly)
colon cancer were small next to the apparently
negative effects on heart disease. Use of hormone
therapy plummeted.
The age effect
The WHI was the largest randomized controlled
trial of hormone therapy ever, and it was meticulously
conducted. There is little reason to doubt its
conclusions. However, even the largest and most
carefully done studies of this kind only tell
us the “truth” about the sorts of
people who were enrolled in the study.
The average age of the women who participated
in the WHI was 63, and they had not taken hormones
at the time they entered menopause. But most
hormone therapy prescriptions are written for
women as menopause begins, and the average age
of menopause in the United States is 51. Thus
the women in the WHI were not typical of the
women taking hormones.
In contrast, the Nurses’ Health Study
and others like it included women who took hormones
when menopause started, most often between the
ages of 45 and 60. The question arose: Could
it be that hormone therapy protects the heart
when taken during the years a woman enters menopause
but puts it at risk if taken at a later age?
Flash forward to January 2006. Harvard researchers,
including Dr. JoAnn Manson, reported the results
of a reanalysis of the Nurses’ Health
Study data in the Journal of Women’s
Health. They had taken the important step
of dividing the nurses by when they started hormone
therapy.
An intriguing difference jumped out: Those who
had started taking hormones within about four
years of menopause had about a 30% lower risk
of developing heart disease than those who had
never taken hormones. But there was no cardiovascular
advantage to hormones for women who began hormone
therapy 10 or more years after menopause. The
reanalysis of the Nurses’ Health Study
data was consistent with the possibility that
there might be an age effect.
Would a reanalysis of data from the WHI show
the same trend? Dr. Judith Hsia, a George Washington
University cardiologist; Dr. Manson; and their
colleagues looked at the heart disease results
for women who took estrogen without progestin.
They found that women in their 50s did, in fact,
have lower rates of heart disease. The finding,
published in February 2006 in the Archives
of Internal Medicine, was statistically
iffy because there were so few women in their
40s and 50s enrolled in the study.
No one has published a similar age breakdown
for the combination of estrogen with progestin
that was tested in the WHI. But buried in the
original results for that part of the study is
a trend for “years since menopause” that
hints at favorable effects on the heart if the
hormones are started soon after menopause. As
with the results for estrogen without progestin,
the numbers were small, so the trend didn’t
reach the threshold for statistical significance.
The estrogen paradox
Laboratory research provides some possible explanations
for why estrogen might have heart disease benefits
for younger women but pose a risk to older women.
Atherosclerosis begins in young adulthood, as
tiny deposits of cholesterol begin to accumulate
in the walls of the arteries that supply the
heart. With age, atherosclerotic plaques form
and narrow arteries. In women, most of these
plaques develop after menopause.
Each plaque is a pool of cholesterol sealed
in by a cap of tiny fibers. Most heart attacks
occur when the fibrous caps break open, spilling
inflammatory molecules, cells, and cholesterol
into the bloodstream. That may cause a blood
clot that completely blocks the flow of blood
to a part of the heart.
Estrogen does three important things that slow
the development of atherosclerotic plaque. It
lowers “bad” LDL cholesterol, increases “good” HDL
cholesterol, and tends to widen the inside of
arteries.
But the hormone has a dark side, too, increasing
levels of various sorts of clotting factors and
inflammatory markers, such as C-reactive protein
(CRP) and matrix metalloproteinase (MMP). CRP
and MMP wear away and weaken the fibrous caps
of atherosclerotic plaques, so they are more
likely to rupture. Estrogen also increases the
tendency of blood to form clots.
For a woman in her 50s, higher levels of CRP
and MMP may not matter so much because her blood
vessels are relatively free of plaque. Meanwhile,
estrogen is good for her cholesterol levels and
arteries.
But by the time a woman is in her 60s and 70s
and is much more likely to have built up some
atherosclerotic plaque, the negative effects
of estrogen may outweigh the positive.
Two studies to keep an eye on
But this is just a plausible explanation for
an age effect, not proof of its existence. And
while the evidence so far from the WHI and the
Nurses’ Health Study is intriguing, it
certainly isn’t conclusive. Two clinical
trials have started that may give some answers.
The Kronos Early Estrogen Prevention Study (KEEPS)
is testing whether starting hormone therapy within
three years of menopause slows atherosclerosis.
Dr. Manson is one of the lead investigators.
The Early versus Late Intervention Trial with
Estradiol (ELITE), funded by the National Institute
on Aging, is comparing the effects of estrogen
started within six years of menopause to the
effects of starting it 10 or more years after.
We’ve posted additional information about
these studies on our Web site.
Women have choices
But the results won’t be available for
years. So what should women do in the meantime?
Dr. Manson points out that the recent results
haven’t changed the fundamental message
about hormone therapy: Cardiovascular protection
is not a reason to be on hormone therapy, which
increases the risk for stroke and blood clots,
regardless of any age, even if the findings about
a heart disease benefit for younger women turns
out to be true. Diet, exercise, weight loss,
diabetes control, statins — there are many
paths open to women who want to reduce their
chances of getting a heart attack or having a
stroke.
For women who are less than 10 years out from
menopause and who need hormone therapy for hot
flashes and other menopausal symptoms, the findings
should be reassuring. Rather than running a cardiac
risk, they may — emphasize may — be
getting some added benefit, just as doctors once
hoped.
“The pendulum had swung from hormones
being good for all women to hormones being bad
for everyone,” says Dr. Manson. “Both
were oversimplifications. The truth lies somewhere
in between.”
Surprise finding:
Estrogen may decrease breast cancer risk
While hormone therapy and heart disease
have had an on-again, off-again relationship,
one thing seemed pretty certain: Taking
the hormones, particularly estrogen,
increased a woman’s chances of
developing breast cancer.
Numerous studies point to such a link,
and based on most everything we know about
the biology of estrogen and breast cancer,
the connection makes sense. Most breast
cancer cells have receptors for estrogen,
and in laboratory conditions, those cells
proliferate when exposed to the hormone.
The first wave of results from the huge
Women’s Health Initiative (WHI) for
combined estrogen and progestin therapy
did little to challenge the conventional
wisdom, although other data quietly seeded
some doubts. (Estrogen by itself increases
a form of uterine cancer, so women who
haven’t had a hysterectomy who are
on hormone therapy usually take estrogen
with progestin, an artificial form of the
progesterone that counteracts estrogen’s
effect on the uterus. Generally speaking,
estrogen-only therapy is for women who
have had a hysterectomy.)
Those doubts blossomed into full-fledged
question marks in April 2006 when WHI investigators
reported the women in the trial who took
estrogen alone, without progestin, did not have
an increased risk for breast cancer. In
fact, the researchers said the data hinted
at a 20% decrease in risk, although that
result fell shy of statistical significance
and could have been by chance.
Researchers have several explanations
for the surprising results for estrogen.
Although seven years is a long time for
a randomized controlled study, the WHI
may have been too short to detect the increased
breast cancer risk that comes from estrogen.
Harvard researchers have seen a pattern
in the Nurses’ Health Study of estrogen
protecting against breast cancer early
on, but the risk increasing with longer
use.
The WHI researchers noted that about 45%
of the women in the study were obese (a
body mass index of 30 or more). Fat tissue
makes estrogen, so it’s possible
that additional estrogen from hormone therapy
didn’t add much risk.
Another complicating factor may be Premarin,
the type of estrogen pills used by women
in the WHI. Premarin, which is made from
horse’s urine, is actually a mix
of estrogens. Maybe that particular mix,
or some part of it, affects breast cancer
risk? Dr. Manson says it is unclear whether
the WHI findings are specific to Premarin
or whether estradiol and other forms of
estrogen have the same effect.
Finally, some doctors think the WHI points
the finger at progestin. Estrogen is a
neutral factor, or even protective against
breast cancer, they say. But add progestin,
and breast cancer risk goes up.
There’s good biological evidence
for this point of view. Most breast cancer
cells have receptors for progesterone,
not just estrogen, and progesterone stimulates
the growth of such cells.
Moreover, a number of epidemiologic studies
support the notion that progesterone may
have more influence on breast cancer risk
than estrogen. Dr. Manson says more research
is needed into hormone therapy that minimizes
women’s exposure to progestin. |
(This article was first printed in the June
2006 issue of the Harvard Health Letter.
For more information or to order, please go
to http://www.health.harvard.edu/health.)
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