The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 1810-1812
Copyright © 1999 by The Endocrine Society
The Efficacy of Hormonal Therapy for Reducing Coronary Artery Disease in Women
C. Noel Bairey Merz
Cedars-Sinai Research Institute, Cedars-Sinai Medical Center and
Department of Medicine, University of California School of
Medicine
Los Angeles, California 90048
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Introduction
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HALF of all coronary artery disease deaths occur in women,
claiming the lives of nearly 250,000 women in the United States each
year, far outweighing mortality due to cancer and other causes combined
(1). Notably, the bulk of this mortality is experienced by women over
the age of 75 yr, and fatal coronary artery disease rates among women
only begin to approximate those of men for women over the age of 85 yr
(1). Nevertheless, recent data demonstrate that the incidence of
nonfatal coronary artery disease has doubled among women in the last
decade, as have rates of cardiac catheterization (2), suggesting that
there is an increased awareness of coronary artery disease in women.
Further study has demonstrated that women with coronary artery disease
have a worse prognosis compared with their male counterparts (3, 4),
suggesting that sex-related differences in disease physiology,
detection, and treatment may adversely impact outcomes in women.
Importantly, 92% of coronary artery disease deaths among women
are experienced in the postmenopausal age group, where coronary artery
disease prevalence and case-fatality rates accelerate compared with
premenopausal women (5). The operative factors behind this
postmenopausal acceleration of coronary artery disease in women are
poorly understood. Adverse changes in lipoprotein profiles associated
with declining endogenous estrogen levels account for only 25–50% of
the increased postmenopausal risk (6). It has been known for some time
that both systemic and coronary arterial walls contain estrogen
receptors (7). Recent animal and human work has demonstrated that
estrogen withdrawal is associated with enhanced arterial
vasoconstriction (8), and that estrogen treatment appears to reverse
this (9, 10). Other evidence suggests that hormonal therapy may
beneficially influence thrombosis, although this data is preliminary
(11, 12).
Hormone therapy, most typically administered to women in the
setting of natural or surgical menopause, has been used for decades to
relieve peri- and menopausal symptoms associated with declining
endogenous estrogen levels. While this has evolved over time, it has
frequently included an estrogenic compound in the form of estrogen
given in relatively high oral doses, necessary because of a potent
first pass liver degradation effect. Accordingly, although hormone
therapy dosing is targeted to provide replacement, or physiological,
blood estrogen levels comparable to premenopausal levels, it must be
acknowledged that a pharmacological dose is typically given, with
direct hepatic effects that may also play role in efficacy. Also, as
the bulk of efficacy data has evaluated oral equine estrogen, the
relevance of these findings to the newer synthetic estradiol products,
particularly delivered transcutaneously via patches, is unclear.
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Efficacy of hormone therapy
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Reduction of cardiac death and myocardial infarction. Despite
relatively widespread use of hormone therapy over recent decades,
little evidence exists in the form of randomized, controlled trials
regarding the efficacy for reduction of cardiac events such as cardiac
death and myocardial infarction. The one randomized trial of unopposed
estrogen demonstrated an insignificant mortality reduction, with less
cancer and cardiac deaths and lower occurence of myocardial infarction
observed in those women randomized to estrogen and cyclical
progesterone, at a chronic care facility over a 10-yr period of time
(13). One additional historical trial randomized men with established
coronary artery disease to relatively high dose estrogen therapy
(compared with current dosing) and found a detrimental increase in
cardiac events, likely attributable to increased thrombosis associated
with the high doses of estrogen (14).
The Hormone Estrogen Replacement Study (HERS) is a recently published,
randomized trial of over 2,000 postmenopausal women with established
coronary artery disease, treate with equine estrogen with
medroxyprogesterone or placebo, and followed for 5 yr (15). The
primary outcomes, cardiac death and myocardial infarction, were,
surprisingly, not different between the intervention and placebo
groups. Indeed, the trial demonstrated both an early adverse effect of
more myocardial infarctions in the first 12 months and a late
beneficial effect of reduced cardiac death and myocardial infarction at
trial end in the hormone therapy group. There were beneficial effects
in serum lipids in the hormone therapy group compared with the placebo
group, although the magnitude was somewhat reduced compared with
previous trials, possibly due to the use of medroxyprogesterone and/or
cholesterol lowering medication (the latter as usual care) or both.
Subgroup analyses did not indicate which women were susceptible to
either the early adverse or late beneficial hormone therapy effects.
Longer term follow-up of HERS, as well as ancillary studies with stored
serum, may help resolve these outstanding issues of risk and
benefit.
Multiple new randomized hormone therapy trials, now ongoing, are
designed to explore the question of the efficacy of reducing coronary
artery disease events. The Women’s Health Initiative (WHI) is a large
NIH-sponsored study that includes a randomized trial of postmenopausal
women free of established coronary artery disease at baseline and
treated with hormone therapy for 10 years (16). Cardiac outcome data
from this study are expected to be available in 2005. Additional
NIH-sponsored studies designed to assess the impact of various
strategies of hormone therapy on coronary angiography: Women’s
Angiographic Vitamin and Estrogen (WAVE) study, and the Estrogen
Receptor Assay (ERA) Study, as well a study of the influence of hormone
levels on coronary artery disease pathophysiology and test response
(Women’s Ischemia Syndrome Evaluation (WISE), are also ongoing.
While awaiting the results of these additional trials, what data
is available to help guide current clinical practice relevant to the
question of coronary artery disease? Epidemiological data and
meta-analyses suggest that hormone therapy is associated with an
overall 50% risk reduction in cardiac events, a benefit that far
outweighs mortality associated with increases in biliary tract disease,
endometrial cancer, and breast cancer (17). However, because these data
are nonrandomized and observational, they are likely to be confounded
by population differences that may in themselves influence cardiac
outcomes. Previous study, for example, has indicated that women who
take hormone therapy are better educated and leaner than those that do
not (18), suggesting the possibility that educational status and
lifestyle habits may be the causative agent in risk reduction rather
than the hormone therapy, per se. Accordingly, although these
indirect can be used as a general guideline to clinical practice
management while awaiting randomized trial evidence, they do not
provide sufficient evidence to imply that all women will receive net
benefit from hormone therapy with regard to coronary artery disease
risk reduction.
Cardiac risk factor modification. Until recently, only
indirect epidemiological data were available regarding the role of
hormone therapy in cardiac risk factors. These data indicated that
approximately 30–50% of the observed coronary artery disease risk
reduction associated with hormone therapy in postmenopausal women was
attributable to beneficial cardiac risk factor modification, including
improvements in blood pressure, low density lipoprotein (LDL) and high
density lipoprotein (HDL) cholesterol, and fasting blood sugar (6). The
Postmenopausal Estrogen and Progesterone Intervention (PEPI) study
(19), a randomized trial of equine estrogen, with and without
progesterone, has documented these benefits of hormone therapy on
cardiac risk factors in an appropriate study design. The addition of
either medroxyprogesterone or micronized progesterone to equine
estrogen did not eradicate the beneficial risk factor effects, although
micronized progesterone, not currently marketed in the United States,
performed better in this regard than medroxyprogesterone. This study
additionally documented the beneficial impact of these hormone therapy
regimens on lowering serum fibrinogen, a promotor of thrombosis. Of
note, women randomized to hormone therapy were leaner at trial end than
the placebo group, having gained relatively less weight (19).
Additional effects of hormone therapy include beneficial effects on
coronary (10) and peripheral arterial (20) vasomotion, as well as
myocardial ischemia (21), suggesting that estrogen plays a beneficial
role in coronary artery disease pathophysiology.
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Risks of hormone therapy
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Relevant to coronary artery disease, hormone therapy is
associated with modest elevations in blood triglyceride levels,
observed in both epidemiological (6) and randomized trials (19). The
relevance of this finding is unclear. Although triglycerides are an
independent risk factor for coronary artery disease in women (unlike
men) (22), it is unknown how this effect balances with the beneficial
alterations in LDL and HDL cholesterol levels observed with hormone
therapy. Results from the above mentioned randomized trials evaluating
cardiac events will provide some of the answers to this issue.
An additional possible risk associated with hormone therapy is that of
thrombosis promotion. To date, both observational and randomized trial
data indicate that hormone therapy in postmenopausal women may promote
thrombosis (15, 23, 24), although limited data is available. Again,
follow-up of the ongoing randomized trials, as well as ancillary
analyses of this outcome from the HERS study, is needed to answer this
question.
Because women fear breast cancer much more than heart disease (25), a
concern that has recently be fostered in the popular press (26), no
discussion of hormone therapy and coronary artery disease would be
complete without mentioning what data are available regarding this
risk. Several large epidemiological studies have suggested that hormone
therapy is associated with a 10–20% increase in the risk of breast
cancer (27, 28). Accordingly, two facts need to be considered when
discussing the risk of breast cancer and hormone therapy. First,
coronary artery disease accounts for 36% of mortality experienced
among women overall compared with 6% attributable to breast cancer
(1). Even a large increase in the risk of breast cancer is unlikely to
offset the predicted risk reduction and mortality reduction associated
with the more prevalent coronary artery disease. This concept is
particularly true for elderly postmenopausal women, where breast cancer
rates fall. Second, once a woman has developed coronary artery disease,
she faces a high likelihood of dying from heart disease. Effective risk
management that reduces heart disease mortality represents a high risk
management strategy for women with established coronary artery disease
that targets the risk at hand, rather than a hypothetical future
risk.
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Conclusions
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Should women take hormone therapy to prevent or manage coronary
artery disease? Definitive answers must await the publication of
ongoing trials, as well as future studies that should carefully
evaluate the risks and benefits of differing hormone therapy dosing and
duration regimens, and efficacy among subgroups. A recent decision
analysis model based on epidemiological data suggests that hormone
therapy should increase life expectancy by over 3 yr for postmenopausal
women at high risk for coronary artery disease (29). Expert consensus
guidelines from the American College of Physicians (30) and the
American Heart Association/American College of Cardiology (31) indicate
that hormone therapy should be strongly considered in women with
coronary artery disease, although the recent HERS study indicates that,
while women with coronary artery disease currently taking hormone
therapy do not need to stop, there appears to be no short-term benefit
to initiating therapy in this group (15). While awaiting the randomized
clinical trial results, clinicians and patients should make individual
decisions based on the available evidence, which indicates that the
cardiovascular hormone therapy benefits may outweigh the risks of
therapy in appropriate patients.
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Footnotes
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a This work was supported in part by grants from
the Division of Cardiology, Department of Medicine, and the Division of
Nuclear Cardiology, Department of Nuclear Medicine, Cedars-Sinai
Medical Center; the John D. and Catherine T. MacArthur Foundation; the
National Heart, Lung and Blood Institutes, Grant no. 232HL07380,
HL47337 and contract no. N01-HV-68162.
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Introduction
Efficacy of hormone therapy
