The United States has
had a decline in overall mortality from cardiovascular disease (CVD)
over the past 20 years, but the rate of decline has been slower in women
than men. Although awareness of CVD in women has increased in this
period, this has not resulted in a decline in their rate of
cardiovascular death. On the contrary, as the population ages, the
percentage of women increases along with the absolute number of
cardiovascular deaths in women.
disease, including coronary artery disease and stroke, is the leading
cause of death in women. Over 500,000 women die from CVD each year.
However, compared with men, the initial manifestation of CVD in women is
delayed by an average of 10 years. Women in the Framingham cohort had
initial myocardial infarction an average 20 years later than men, and
this long delay in expression of coronary events persists today. This
observation is remarkably consistent across different patient
populations -- even in countries with different rates of death from CVD.
It is commonly
believed that there is a link between menopause and an increased
incidence of CVD, but Furman in 1968 and Tunstall-Pedoe in 1998 did not
observe a sharp increase in CVD after menopause. Instead, they found a
constant increase in CVD incidence in women during middle life. There
was an excess of CVD mortality in men in all age groups, and this gap
narrowed with age. However, this narrowing is due to a decrease in CVD
death rates in men as opposed to an increase in women (Fig 3). The
reasons for this trend are unclear, but there may be a survivor effect
in older men.
In contrast, the
data from women who undergo premature menopause -- natural and surgical
-- indicate that CVD develops prematurely in these women, supporting the
concept that menopause and CVD are linked. Autopsy studies have shown a
clear increase in coronary disease in women after oophorectomy or
premature ovarian failure. There are many possible confounding variables
in these studies, including pituitary hormone increases after surgery
and the antecedent disease processes that necessitated oophorectomy or
caused the ovarian failure. However, the fact remains that after
oophorectomy, the incidence of CVD in women is increased.
studies suggest that postmenopausal hormone replacement therapy (HRT),
including various estrogen preparations with or without progestin (most
commonly synthetic progestin), reduce CVD risk by 35% to 50%. Studies
also suggest that estrogen may slow the progression of existing coronary
artery disease in postmenopausal women and limit the proliferation of
vascular smooth muscle cells after vascular injury (ie, after
angioplasty). These studies are supported by a large number of animal
data. However, there are very few prospective, randomized controlled
trials evaluating HRT and its effects on CVD in humans.
effects of menopause and, specifically, the loss of ovarian hormones and
replacement with exogenous estrogens/progestins on CVD risk is difficult
because of confounding variables: women are aging as they go through
menopause, and the prevalence of more traditional CVD risk factors
increases as they age. We will discuss the lines of evidence from
observational studies, animals, and the few randomized, controlled
trials dealing with hormones and their effects on CVD.
A number of
biologically plausible mechanisms exist for hormone-mediated protection
from CVD. The Postmenopausal Estrogen/Progestin Intervention (PEPI)
trial examined the effect of estrogen replacement therapy (ERT) --
conjugated equine estrogen alone or in various combinations with
medroxyprogesterone acetate (MPA) or micronized progesterone -- on
cardiovascular risk factors. The PEPI trial and numerous observational
studies have shown that oral estrogen therapy is associated with a 10%
to 15% increase in high-density lipoprotein cholesterol (HDL-C) and a
similar decrease in low-density lipoprotein cholesterol (LDL-C). The
elevation in HDL-C level is due to increased production of HDL2
and apolipoprotein A-1, whereas the decrease in LDL-C is due to
increased expression of hepatic LDL receptors. Oxidation of LDL-C is
believed to be an inciting event in atherogenesis, and estradiol and/or
other estrogens may inhibit this process. Oral conjugated estrogens are
also associated with an increase in very low-density lipoprotein (VLDL),
triglycerides, and apolipoprotein B levels, as well as a decreased level
of Lp(a) lipoprotein. These are not large changes, however, and the
effects of modest alterations in these molecules on the development of
CVD are uncertain. In contrast, oral estradiol or transdermal estrogen
does not undergo "first-pass" metabolism in the liver and is not
associated with the same degree of lipoprotein alteration.
effects of estrogen on lipoproteins are responsible for only a
portion of the observed benefits with respect to CVD. There is
evidence that estrogen also has direct effects on vascular
walls. For example, estrogen treatment is associated with
decreased lipid uptake and accumulation in the vessel wall.
Estrogen administration also reduces the extent of
atherosclerotic plaques in oophorectomized cynomolgus monkeys
with diet-induced atherosclerosis. Further, in animal models and
in postmenopausal women, both short-term and long-term estrogen
administration reverses the pathologic vasoconstriction seen in
atherosclerotic arteries in response to acetylcholine. The
acetylcholine-mediated vasodilation seen in normal coronary
arteries and in atherosclerotic arteries of postmenopausal women
taking ERT is likely mediated by nitric oxide as an
endothelial-derived relaxing factor. Estrogen use is associated
with increased transcription of nitric oxide synthase and
augmentation of nitric oxide release.
Over the past
20 years, we have learned that unopposed estrogen use is
associated with cancer of the endometrium. This led to the
addition of a progestin to estrogen replacement therapy (ie,
HRT) in women with an intact uterus. There are fewer
observational data in these women, but most studies have shown a
beneficial effect similar to that seen with ERT. However, animal
data have raised important questions concerning the effects of
pro-gestins, particularly synthetic progestins such as MPA, on
CVD. The addition of MPA to conjugated equine estrogen
attenuated the vasodilator effect of estrogen in atherosclerotic
coronary arteries of cynomolgus monkeys after acetylcholine
administration. Treatment with MPA also completely blocked the
estrogen-associated reduction in coronary atherosclerosis in
are not alike, however, and the PEPI trial found differences in
the effects of different preparations on CVD risk factors. Women
in PEPI were treated with conjugated equine estrogen alone or in
combination with either MPA or micronized progesterone. While
all women who received estrogen had an increase in HDL-C level
and a decrease in LDL-C, the HDL-C effect was more pronounced
with micronized progesterone than with MPA.
benefits of ERT include effects on clotting factors. Levels of
fibrinogen and plasminogen activator inhibitor 1 (PAI-1)
increase after menopause, but these increases are reversed with
estrogen use. Estrogen affects prostacyclin biosynthesis by
enhancing production of prostaglandin I2
and decreasing production of thromboxane A2. Platelet
aggregation, as well as inflammatory cell attachment to vessel
walls, is also inhibited by estrogen use. Despite these possible
benefits, clinical studies have clearly associated estrogen use
with an increase in venous thrombosis. The disparity between
these laboratory data and clinical observations is particularly
important when one considers the effects of ERT on the
postmenopausal woman with established CVD; biologic plausibility
alone is not sufficient to establish a protective effect of
estrogen replacement in CVD.
Evidence By Observation
A large number
of observational data suggest substantial cardiovascular benefit
and a decrease in mortality from all causes with unopposed
estrogen therapy in postmenopausal women. This reduction in risk
is congruent with the data from laboratory investigations in
animal models and in vitro preparations. Fewer studies have
evaluated the effects of combination estrogen-progestin
replacement therapy, but most have shown a 30% to 50% decrease
in the risk of coronary events in postmenopausal women.
Henderson et al found a 40% decrease in overall mortality in
elderly women on long-term (>15 years) hormone therapy. This
effect was predominantly seen in CVD mortality, but there was
also a trend toward decreased stroke and cancer incidence in
women treated with estrogen.
In the Lipid
Research Clinic Follow-up Study, 2,270 hyperlipidemic, white
women aged 40 to 69 years at study entry were followed for more
than 8 years. Women who received estrogen had over 60% fewer CVD
deaths than those who did not. This benefit remained after
adjustment for age, hypertension, and smoking, and it was most
pronounced in women with known CVD.
Health Study used dietary and health questionnaires to evaluate
59,337 women without CVD at the time of enrollment. In women
taking estrogen alone, the relative risk of major coronary
disease was 0.60 (95% confidence interval [CI], 0.43 to 0.83),
and in those women taking estrogen with progestin, the relative
risk was 0.39 (95% CI, 0.19 to 0.78) compared to women not
taking hormones. Because of the small number of CVD events in
the combination therapy group, the results were similar to those
in women taking estrogen alone.
observational evidence suggests a beneficial effect of estrogen,
however. A 1997 Kaiser Permanente case-control study by Sidney
et al examined postmenopausal women who were admitted for an
incident myocardial infarction. They found no difference in the
odds ratio of myocardial infarction between women who were
current or former hormone users versus women who had never used
hormones. A meta-analysis by Hemminki and McPherson in 1997 also
failed to show a protective effect of postmenopausal hormone
therapy with respect to cardiovascular events.
of retrospective, nonrandomized analyses have severe
limitations, and a great deal of skepticism exists about the
populations examined and the results observed. It has been
proposed that the benefits of hormone replacement seen in
epidemiologic studies are a result of selection bias. Women who
use HRT have a better cardiovascular risk profile than those who
do not: they are better educated, they engage in more
leisure-time physical activity, their blood pressures are lower,
and they have a better lipoprotein profile. Although the bulk of
the observational data, animal data, and vascular biology
findings support a protective effect of estrogen with respect to
CVD, important questions remain. Prospective randomized trials
can overcome many of the limitations associated with the
retrospective studies listed above and will help answer many of
the current questions concerning ERT, as well as point the way
to new areas of investigation.
published results from the Heart Estrogen-Progestin Replacement
Study (HERS) have added to the controversy regarding ERT and
cardioprotection. This was the first large-scale randomized
clinical trial to test the efficacy and safety of hormone
replacement on clinical CVD outcomes in postmenopausal women.
The study population included 2,763 women with established
coronary artery disease randomized to combination HRT
(continuous conjugated equine estrogen and MPA) or placebo who
were then observed for an average of 4 years. Overall, there was
no significant difference between groups for the primary
outcome, nonfatal myocardial infarction or coronary heart
disease death, or for several secondary cardiovascular end
points. There was a statistically significant time trend, with
more coronary heart disease events in the treatment group than
in the placebo group in year 1 and fewer in years 3 and beyond.
There was an increase in the incidence of thromboembolic events
(deep venous thrombosis and pulmonary emboli) in the treatment
group; relative hazard was 2.89 (95% CI, 1.50 to 5.58). There
was also an increase in gallbladder disease in the treatment
group, with a relative hazard of 1.38 (95% CI, 1.00 to 1.92).
results do not support instituting HRT in women with established
coronary heart disease for the sole purpose of avoiding
secondary events. In HERS, the question of benefit (and risk)
from estrogen alone or from combined hormone replacement in
primary prevention was not addressed, nor was the mechanism of
the apparently biphasic effect (early detriment, later benefit)
of combined hormone replacement in women with atherosclerotic
disease elucidated. Answers to the first questions will come
from the Women's Health Initiative (WHI), a randomized trial of
estrogen and combined HRT for primary prevention, which includes
10 times as many treated women as HERS and a longer period (9
years) of treatment, and will be completed in 2005. The
remaining question can be answered only by further research in
both human subjects and animal models.
or without the addition of a progestin, is associated with a
number of systemic and local effects in addition to those seen
in CVD. Substantial data have come from observational studies
and small clinical trials on the effects of estrogen replacement
in postmenopausal women and cognition. The prospective trials
are small, and data from the observational studies are
conflicting. However, as with estrogen for CVD, there is
biologic plausibility and preliminary evidence for a favorable
effect by estrogen on cognition and dementia. Estrogen also
reduces the morbidity of osteoporosis by reducing fractures, and
it improves the symptoms associated with menopause.
benefits are associated with estrogen use, there are also
adverse effects. As mentioned above, data from the HERS trial,
the Nurses' Health Study, and other studies have clearly shown
an increased incidence of venous thromboembolic events
associated with ERT. There is also an increase in endometrial
cancer with unopposed estrogen therapy, and though this risk is
attenuated with the addition of a progestin, the long-term
consequences of estrogen and progesterone on endometrial
hyperplasia are uncertain. Breast cancer, however, is perhaps
the most well-known -- and controversial -- potential adverse
effect of ERT. In the Nurses' Health Study, despite an overall
reduction in mortality, there was a 43% increase in the risk of
breast cancer mortality in women taking hormones for more than
10 years. The Iowa Women's Health Study also found a
nonsignificant trend toward increased mortality in
postmenopausal women taking hormones. While these findings are
not universal, most analyses have found an increased risk of
breast cancer in women taking HRT, and this risk increases
proportionally with the length of time on hormones. In the
observational data so far, this risk has been offset by the
overall benefit in total mortality (most of which is due to a
decrease in CVD). The question of the risk-benefit ratio of HRT
is currently being addressed in the WHI, in which three primary
end points are CVD, osteoporosis, and breast cancer.
number of data from vascular biology, animal models,
observational studies, and randomized trials still leave the
clinician with ambiguity about the effects of estrogen with or
without a progestin for CVD. We know from HERS that there is an
early risk in HRT for postmenopausal women with known CVD, and
helpful data will likely come from the WHI. However, in the
interim, we can neither ignore the epidemiologic data nor should
we generalize the results from HERS to all women. Further
clarification is needed on the effects of micronized
progesterone versus MPA and their influence on CVD.
support an individualized approach to HRT in postmenopausal
women. There are subgroups in which estrogen currently offers
more risk than benefit. However, for the majority of women, we
must explain the risks and benefits as we currently understand
them. The decision on whether or not to proceed with HRT should
ultimately be left with the patient, with guidance and
counseling from her physician.
with a low HDL-C and no history of CVD.
with other CVD risk factors, but without documented CVD.
with menopausal symptoms.
- Women at
high risk for osteoporosis and fractures.
Replacement Therapy Contraindicated
with known CVD who are not currently receiving HRT.
with history of breast cancer or with a family history of
breast cancer in a first-degree relative.
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