Circulation. 1996;93:1928-1937
(Circulation. 1996;93:1928-1937.)
© 1996 American Heart Association, Inc.
Cardiovascular Effects of Estrogen and Lipid-Lowering Therapies in Postmenopausal Women
Victor Guetta, MD;
Richard O. Cannon, III, MD
From the Cardiology Branch, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, Md.
Correspondence to Richard O. Cannon III, MD, National Institutes of Health, Bldg 10, Room 7B15, 10 Center Dr MSC 1650, Bethesda, MD 20892-1650.
Key Words: atherosclerosis lipoproteins hormones women drugs
 |
Introduction
|
|---|
Despite impressions to
the contrary, cardiovascular disease
is the leading
cause of death among women in the United States,
as it is among
men.
1 However, myocardial infarction and stroke
are
uncommon in women until their sixth decade and beyond. Clinicians
have
long suspected that the delay of a decade or more in
cardiovascular
disease expression in women relative to
men is due to the protective
effects of estrogen during a woman's
reproductive years. Women
in the Nurses' Health Study who
underwent surgical menopause
by bilateral oophorectomy without estrogen
replacement had more
than twice the risk of subsequent clinically
apparent coronary
heart disease as postoperative women who
received estrogen therapy.
2 In recent years, reports from
population-based observational
studies of favorable effects of
estrogen therapy on cardiovascular
morbidity and
mortality
3 4 5 have led to enthusiasm for widespread
use of
estrogen by postmenopausal women for prevention of
cardiovascular
disease events. The guidelines for
estrogen therapy issued by
the American College of Physicians include
the statement, "Women
who have coronary heart disease or who
are at increased risk
for coronary heart disease are likely to
benefit from hormone
therapy."
6
However, any potential cardiovascular benefit of
estrogen, in addition to other benefits, such as preservation of bone
mass, must be weighed against uterine cancer risks and possible breast
cancer risks with prolonged use.7 8 Indeed, despite
widespread publicity in recent years about heart disease in
postmenopausal women and the apparent cardiovascular
virtues of estrogen, many women consider their risk of heart disease
lower than their risk of breast cancer and, importantly, fear the
consequences of breast cancer more than the consequences of heart
disease.9 Furthermore, estrogen therapy is associated with
side effects in some women, including vaginal bleeding, and is
generally not recommended for chronic use by women with a family
history of breast cancer. Thus, many postmenopausal women, including
those most likely to benefit from estrogen therapy because of
established atherosclerosis,3 10 may be
unwilling or unable to take estrogen supplementation for several
decades in the absence of menopausal symptoms. A review of the
current understanding of the cardiovascular effects of
estrogen and lipid-lowering therapies suggests that
lipid-lowering therapy might achieve cardiovascular
benefits similar to those of estrogen therapy and thus be acceptable to
women who cannot take or choose not to take prolonged estrogen
supplementation in the absence of menopausal symptoms.
 |
Lipoprotein Effects of Estrogen
|
|---|
Before menopause, plasma LDL cholesterol levels are
lower and
HDL cholesterol levels are higher in women
compared with men
of the same age. After menopause, LDL
cholesterol levels rise,
commonly exceeding those of
age-matched men, with a shift to
smaller, more dense, and
potentially more atherogenic particle
sizes, and HDL
cholesterol levels decline.
11 12 13 Orally
administered
estrogen reduces LDL cholesterol levels and
increases HDL cholesterol
levels in postmenopausal women
with normal or elevated baseline
lipid levels.
14 15 16 17 18
Transdermally administered 17ß-estradiol
has no effect on
lipoprotein levels, suggesting that the hepatic
effects of estrogen
absorbed through the gut are important for
changes in lipoprotein
levels.
17 The reduction in LDL cholesterol
levels
is probably a result of accelerated conversion of hepatic
cholesterol
to bile acids
19 and increased
expression of LDL receptors on
cell surfaces,
20 resulting
in augmented clearance of LDL from
the plasma. The increase in HDL
levels is due to increased production
of apolipoprotein A-I and
decreased hepatic lipase activity,
17 21 effects that
increase levels of HDL
2, the HDL subparticle
considered
the most active in reverse cholesterol
transport. VLDL levels
increase because of enhanced production
of apolipoprotein B
and triglycerides,
17 but
these particles may not be of atherogenic
potential.
22
Estrogen therapy has also been shown to reduce
levels of
lipoprotein(a),
23 a lipoprotein with structural features
of
LDL and plasminogen, believed to be proatherogenic and
antithrombolytic,
that increases in plasma
concentration after menopause.
24 However,
the importance
of lipoprotein(a) as an independent risk factor
for
cardiovascular events is
controversial.
25 26 27
The favorable effects of orally administered estrogen on lipoproteins
could reduce the progression of atherosclerosis or its
acute sequelae, as suggested by secondary-prevention
cholesterol reduction trials.28 However,
analysis of baseline plasma lipid levels of postmenopausal
women in the Lipid Research Clinic Follow-up Study suggested that
the lipoprotein effects of estrogen did not fully account for the risk
reduction in cardiovascular deaths among estrogen users
relative to nonusers.3 In the Nurses' Health
Study, significant reduction in cardiovascular risk was
noted even in current estrogen users who did not report
hypercholesterolemia or other conventional risk
factors, although lipid measurements were not made in this
study.4 Furthermore, atherogenic animal models have shown
reduction in the development and extent of
atherosclerosis with estrogen administration despite
HDL and LDL cholesterol levels similar to those of
untreated animals fed the same diet.29 30 31 Thus, the
relative importance of estrogen-induced alterations in lipoprotein
levels is unresolved at present. Accordingly, other
cardiovascular properties of estrogen may also be
important in accounting for the cardioprotective effect of the
hormone.
 |
Coronary Vasomotor Effects of Estrogen
|
|---|
Over the past 15 years, tremendous interest has been generated
by
Furchgott and Zawadzki's
32 observation that the
endothelium
importantly regulates the vasomotor tone of
underlying smooth
muscle. Subsequent studies have shown the release of
vasodilating
factors such as nitric oxide from the
endothelium by both receptor-mediated
(eg,
acetylcholine, bradykinin, serotonin, thrombin,
norepinephrine)
and receptor-independent (eg, shear
stress) mechanisms.
33 34 35 Considerable evidence indicates
that nitric oxide activity
in the systemic and coronary
circulation is impaired in conditions
predisposing to
atherosclerosis, such as
hypercholesterolemia,
hypertension, smoking,
and aging.
36 37 38 39 40 41 However,
there may be sex-related
differences in the impact of these
conditions on
endothelial function. Thus,
hypercholesterolemic
men were found to have
significantly greater impairment in acetylcholine-stimulated
forearm
flow compared with reproductive-age women despite
comparable
elevation in LDL cholesterol
levels.
42 Furthermore, the age-associated
decline in
flow-mediated brachial artery dilation during reactive
hyperemia,
which activates the
endothelium to release nitric oxide by increased
shear
stress, was reported to be delayed by a decade in women
relative to
men, with a smaller decline in the magnitude of
vasodilation with aging
in postmenopausal women relative to
aging men.
43 These
findings suggest that sex hormones may protect
endothelial
function in women from conditions that
alter endothelial function
in men.
Several groups have reported that chronic or acute administration of
estrogen to estrogen-deficient animals potentiates
endothelium-dependent vasodilation of femoral and
coronary arteries.44 45 46 In contrast to
physiological replacement doses of estrogen,
supraphysiological concentrations of estrogen
may have direct smooth muscle relaxant effects on epicardial
coronary arteries from animals or humans.47 48 49 50
Reis et al51 reported that intravenous ethinyl
estradiol administered to 15 postmenopausal women during cardiac
catheterization increased basal coronary artery
blood flow and dilated epicardial coronary arteries.
Furthermore, estradiol prevented acetylcholine-induced decreases in
coronary artery diameter and blood flow in a subset of patients
who had these responses at baseline. However, the dose of estrogen used
in this study was supraphysiological and
considerably higher than achievable with conventional hormone therapy.
Furthermore, no study was performed by these investigators to ascertain
whether vascular effects of estrogen administration were
endothelium specific.
We found that 17ß-estradiol infused into the left
coronary arteries of 20 postmenopausal women, achieving
physiological concentrations in the
coronary sinus drainage, did not affect basal coronary
blood flow but enhanced acetylcholine-stimulated increases in
coronary flow.52 The enhancement of
acetylcholine-mediated vasodilation of epicardial coronary
arteries was minimal, suggesting that most of the vasodilator effect of
estradiol was at the microvascular level. The enhancement of
acetylcholine-mediated vasodilation by estradiol was most prominent
in women with the most impaired dilator responses to acetylcholine at
both the epicardial and microvascular coronary artery levels
during baseline testing. No enhancement of nitroprusside-stimulated
flow was noted after estradiol administration, indicative of selective
potentiation of endothelium-dependent vasodilation
by estradiol at physiological concentrations.
Consistent with these findings was the report of Herrington et
al,53 in which four postmenopausal women chronically
taking conjugated equine estrogen at conventional dosages had
epicardial coronary artery dilator responses to
intracoronary acetylcholine as opposed to constrictor
responses to the same concentrations of acetylcholine noted in six
untreated postmenopausal women, with similar dilator responses to
nitroglycerin in the two groups.
Collins and coworkers54 recently reported that
intracoronary 17ß-estradiol at
physiological dosage prevented
acetylcholine-induced epicardial coronary artery
constriction and potentiated acetylcholine-stimulated
coronary blood flow in nine postmenopausal women but not in
seven men of similar age and coronary artery disease extent.
This observation suggests that the immediate vascular effects of
estrogen may be receptor mediated.
 |
Systemic Vasomotor Effects of Estrogen
|
|---|
We found that 17ß-estradiol infused into the brachial
arteries
of 40 postmenopausal women achieving
physiological concentrations
in the brachial vein
enhanced acetylcholine-stimulated forearm
blood
flow.
55 The 20 women in this study with risk factors
for
atherosclerosis also had slight potentiation of
endothelium-independent
(nitroprusside) blood flow
during estradiol infusion. In contrast,
the 20 women without risk
factors, who had greater baseline
forearm blood flow responses to both
acetylcholine and nitroprusside
compared with the 20 women with risk
factors, showed selective
enhancement in
endothelium-dependent vasodilation during estradiol
infusion.
Three weeks of administration of estradiol to 33
postmenopausal
women, via a transdermal patch preparation so as not to
affect
lipoprotein plasma levels, did not change basal forearm blood
flow,
vascular resistance, or blood pressure. Furthermore, the blood
flow
responses to acetylcholine were no different from pretreatment
measurements,
possibly because of lower plasma levels of estradiol
achieved
during chronic administration compared with the acute infusion
study.
56 When plasma levels were raised by reinfusion of
estradiol while
the patch preparation was still in effect, potentiation
of acetylcholine-stimulated
flow was restored. The lack of
sustained improvement in systemic
microvascular dilator function with
plasma estrogen levels achievable
with chronic therapy may account for
the absence of a blood
pressurelowering effect in
Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial
participants
18 or in hypertensive
postmenopausal women on
estrogen therapy.
57
Larger arteries may respond differently from the microcirculation to
chronic estrogen administration. Lieberman et al58
reported that oral estradiol administration to 13 postmenopausal women
for 9 weeks enhanced flow-mediated brachial artery dilator
responses during postischemic hyperemia without
potentiation of the vasodilator response to
nitroglycerin. However, the use of an oral estrogen
preparation probably caused reduction in LDL and elevation in HDL
plasma levels, changes that could have improved
endothelial function independent of a direct effect of
estrogen on brachial artery vasomotor tone.59 60 61 62 63 64 As in our
study, no hormonal effects on blood pressure were noted.
The acute vascular effects of estrogen most likely account for the
improvement in time to 1-mm ST-segment depression and the total
duration of treadmill exercise of 11 postmenopausal women with
coronary artery disease after sublingual 17ß-estradiol
administration compared with exercise after placebo in a randomized,
double-blind study.65 Because the peak heart
ratesystolic blood pressure product was not
significantly augmented by estradiol administration, systemic
vasodilating effects of acutely administered estradiol may have
accounted for improvement in exercise in this study. Whether similar
anti-ischemic benefits can be achieved with chronic
estrogen therapy associated with lower plasma estrogen levels is
unknown.
 |
Estrogen and Nitric Oxide
|
|---|
The mechanism of the acute and chronic vascular effects of
estrogen,
which appears to be largely endothelium
dependent in postmenopausal
women at physiological
or conventional pharmacological plasma
concentrations of the hormone,
is unknown. Estrogen may block
the release of
endothelium-derived constricting
factors
66 67 or enhance the release or bioavailability of
nitric oxide from
endothelial cells, resulting in
increased cGMP in underlying
smooth muscle and
vasorelaxation.
68 69 70 Preliminary studies
indicate that
17ß-estradiol augments nitric oxide release
in human umbilical
vein endothelial cells and in porcine and
bovine aortic
endothelial cells in culture,
71 72
although another
preliminary study did not confirm this finding in
cultured bovine
aortic endothelial
cells.
73 Postmenopausal women on estrogen
therapy were
found to have higher serum levels of nitrite and
nitrate, indicators
(in part) of vascular nitric oxide release,
than at baseline or
compared with untreated controls.
74 Augmented
release of
nitric oxide by estrogen might account not only for
enhancement of
endothelium-dependent vasodilation but also for
much
of the antiatherogenic effects of estrogen by inhibition of
platelet
aggregation, platelet and inflammatory cell attachment
to the
vessel wall, and release of factors that stimulate growth and
migration
of smooth muscle cells.
75 76
 |
Antioxidant Effects of Estrogen
|
|---|
Over the past decade, evidence has accumulated indicating that
oxidative
modification of LDL greatly increases its
atherogenicity
77 78 and that antioxidants may reduce the
extent of atherosclerosis
in animals and reduce
cardiovascular events in humans.
79 80 81
Several groups have examined in vitro the antioxidant properties
of
estrogen,
82 83 84 85 86 87 88 89 90 91 92 93 94 which shares
structural similarity with
lipophilic antioxidants such as probucol
and vitamin E; all have
hydroxyphenol groups, with the hydrogen
atom of the hydroxy group and
its single electron easily donated
to lipid peroxyl free radicals, thus
terminating chain propagation
of oxidation along the fatty acids of
lipoprotein membrane phospholipids.
95 96
We found that the acute administration of 17ß-estradiol into the
brachial arteries of postmenopausal women significantly delayed the
onset and rate of copper-catalyzed oxidation of LDL isolated from
ipsilateral brachial venous blood after 20 minutes of infusion compared
with baseline samples.92 After estradiol administration
via a transdermal preparation for 3 weeks, LDL was protected from
oxidation by a degree similar to that noted in the short-term
infusion study but at estradiol plasma levels approximately one third
of that achieved during the short-term study. The plasma levels of
estradiol achieved in the brachial venous plasma in these studies were
within the physiological range (
1 nmol/L
concentration), 1000-fold lower than concentrations required to protect
LDL from oxidation when added in vitro.
When we added 1 nmol/L 17ß-estradiol directly to plasma from
postmenopausal women not on hormone therapy and let it stand for up to
48 hours, no change in copper-catalyzed oxidation of LDL was noted
compared with paired plasma samples without estradiol (seven
experiments, unpublished observations). This suggests that the
antioxidant effects of estradiol may not be a result of direct
protection of LDL from oxidant stress but rather may result from the
release of antioxidant substances from the vessel wall.
We also investigated the possibility that 17ß-estradiol at 1 mg/d
transdermal delivery for 3 weeks and vitamin E (800 IU/d for 6 weeks)
might act synergistically to protect LDL from oxidation when
administered to postmenopausal women.93 However, despite
the protection of LDL from oxidation by each agent administered
independently, there was no additive or synergistic antioxidant effect
when they were coadministered to postmenopausal women in this
study.
 |
Oxidized LDL and Vasomotor Function
|
|---|
In addition to its contribution to atherogenesis, oxidized LDL
may
impair endothelium-dependent vasomotor
function.
97 98 99 100 101 Keaney et al
94 reported that
treatment of estrogen-deficient
miniature swine with
17ß-estradiol for 16 weeks normalized
the impaired
endothelium-dependent vasodilator responsiveness
of
rings from coronary arteries compared with
estrogen-deficient
animals. The estrogen-replaced group had
time to onset of copper-catalyzed
oxidation of LDL comparable to
that of the sham-operated controls
and significantly greater than
the time to onset of oxidation
of LDL from the oophorectomized
untreated group, with a high
correlation between the time to onset of
oxidation of LDL and
the extent of vascular relaxation in response to
bradykinin
and to substance P.
However, despite an antioxidant effect of 17ß-estradiol after 3
weeks of transdermal administration (0.1 mg/d),92 we saw
no improvement in forearm endothelium-dependent
microvascular dilator responsiveness compared with pretreatment
measurements.56 This finding was consistent with
our study of the effects of antioxidant vitamins in
hypercholesterolemic subjects: Despite 71%
prolongation of the time to copper-catalyzed oxidation of their LDL
after 1 month of daily vitamins C (1 g), E (800 IU), and
ß-carotene (30 mg), we found no improvement in forearm blood
responses to endothelium-dependent or
endothelium-independent agonists compared with
pretreatment measurements.102
 |
Hemostatic Effects of Estrogen
|
|---|
The influence of estrogen on coagulation factors associated
with
acute coronary syndromes has been of concern because of
thrombotic
complications associated with estrogen use in the past, such
as
the increased risk of myocardial infarction in men randomized
to
high-dose (5 mg) conjugated equine estrogen in the Coronary
Drug
Project.
103 However, recent studies of women
taking conventional
dosages of estrogen therapy (most commonly,
conjugated equine
estrogen 0.625 mg/d) have reported favorable effects
of estrogen
on hemostatic factors implicated in acute coronary
syndromes.
In the Atherosclerosis Risk in the Community
Study
104 and the
PEPI Trial,
18 users of
estrogen (alone or in combination with
a progestin) had lower plasma
levels of fibrinogen than nonusers.
In the Framingham Offspring
Study, reproductive-age women had
lower plasma levels of
PAI-1 and higher levels of TPA compared
with men of comparable age or
postmenopausal women not taking
estrogen.
105 However,
postmenopausal women on estrogen therapy
had PAI-1 and TPA levels
similar to those of reproductive-age
women.
The mechanism of the apparently favorable hemostatic effects of
estrogen is unknown. Oxidatively modified LDL depresses
endothelial release of TPA, and both oxidatively
modified LDL and lipoprotein(a) promote synthesis of PAI-1 by increased
transcription of PAI-1 mRNA.106 107 Thus, the effect of
estrogen on TPA and PAI-1 may in part be due to antioxidant protection
of LDL and reduction in lipoprotein(a) plasma levels.
 |
Other Potential Cardiovascular Effects of
Estrogen
|
|---|
In addition to presumably favorable effects of estrogen on
lipoprotein
levels, vasomotor function, LDL oxidation, and coagulation,
other
biological properties of estrogen have been proposed to
contribute
to the hormone's cardiovascular benefit.
Estrogen has been shown
in animal models or cell culture to reduce
collagen and elastin
synthesis
108 109 110 111 and enhance their
degradation in arterial
tissue,
112 reduce
smooth muscle cell proliferation,
113 114 decrease
platelet aggregation,
115 116 and promote
angiogenesis.
117 Prostacyclin, a potent vasodilator and
inhibitor of platelet
aggregation, has been shown in
various studies to be potentiated
or inhibited by
estrogen.
118 119 120 121 122 123 124 Recently,
hormone therapy (estradiol
valerate and norethisterone) administered
to 28 postmenopausal women
for 6 months reduced serum angiotensin-converting
enzyme
levels by 20%, in contrast to no change in serum levels of 16
untreated
women during the same interval.
125
Estrogen has also been reported to have potentially deleterious
cardiovascular effects, including potentiation of
vascular contraction in response to norepinephrine by
augmented neuronal spillover,126 by increased
-adrenergic receptor affinity for
norepinephrine,127 and by a
cyclooxygenase-dependent
mechanism.128 However, the relevance of these properties
of estrogen determined from animal and cell culture studies to
postmenopausal women taking conventional dosages of estrogen therapy is
unknown at present.
 |
Combined Effects of Progestin and Estrogen in Postmenopausal
Women
|
|---|
The majority of observational population-based studies
reporting
reduced cardiovascular mortality in estrogen
users have not
separately analyzed
cardiovascular risk of women taking a combination
of
estrogen and a progestin compound because of the infrequent
use of
combination therapy until recent years. Over the past
decade, and
recently confirmed in the PEPI Trial, unopposed
estrogen has been found
to cause endometrial dysplasia and carcinoma,
with protection of the
uterus from these effects by the addition
of a
progestin.
7 18 Although several nonrandomized studies
have
reported that the risk of myocardial infarction was reduced
by combined
estrogen-progestin therapy at least as much as by
estrogen
alone,
129 130 131 recent animal studies indicate that
the
addition of a progestin may attenuate or negate many of
the presumably
beneficial vascular effects of estrogen.
132 133 In the
PEPI Trial, women randomized to conjugated equine estrogen
and
continuous or cyclical medroxyprogesterone acetate
had smaller
increases from baseline in HDL cholesterol
levels than women
randomized to unopposed estrogen.
18 Such
an effect on HDL levels
could compromise the cardioprotective effect of
estrogen, given
the inverse association between HDL
cholesterol levels and cardiovascular
disease
in women.
3 134 Combined
progestin/17ß-estradiol administration
to postmenopausal women
was not found to increase serum nitrite
and nitrate levels, in contrast
to increases in these largely
oxidized products of
endothelium-released nitric oxide measured
in the
same women when taking estrogen alone.
74 In the Framingham
Offspring
Study, postmenopausal women taking a combination of estrogen
and
progestin had higher levels of PAI-1 than women on unopposed
estrogen
when adjustments were made for age, risk factors, and other
covariants.
105 Thus, it is possible that the
addition of a progestin compound
to estrogen in women, although
protecting the uterus from the
harmful effects of unopposed estrogen,
might negate some of
the beneficial cardiovascular
effects of unopposed estrogen.
 |
Lipid-Lowering Therapy as an Alternative to Estrogen
Therapy
|
|---|
An understanding of the cardiovascular effects of
estrogen permits
comparison with lipid-lowering therapy as a
treatment alternative
for postmenopausal women at risk for
cardiovascular disease
who cannot or will not take
chronic hormone therapy. For example,
reduction in LDL and increases in
HDL cholesterol levels can
be achieved pharmacologically to
a comparable or greater magnitude
than changes in lipoprotein levels
achieved with estrogen therapy,
with improvement in
endothelium-dependent relaxation of
coronary
arteries in humans.
60 61 62 63 64 Egashira et
al
61 reported
that 6 months of treatment of nine
hypercholesterolemic coronary
artery
disease patients (six men, three women) with
pravastatin
decreased LDL cholesterol levels by
39% and significantly attenuated
the epicardial coronary
artery constrictor response to intracoronary
acetylcholine
and potentiated acetylcholine-stimulated coronary
blood
flow compared with baseline values. The epicardial coronary
artery
dilator responses to isosorbide dinitrate and the
coronary flow
responses to papaverine were unaltered by
treatment. Although
no placebo group was included in this study, the
findings are
consistent with an
endothelium-specific beneficial effect of
cholesterol-lowering
therapy on epicardial and
resistance coronary arteries.
Treasure et al62 treated 23 coronary artery
disease patients (13 men, 10 women) whose total cholesterol
levels ranged from 160 to 300 mg/dL with lovastatin or
placebo in addition to diet for 4.5 months in a randomized,
double-blind study. In the lovastatin group, LDL
cholesterol was reduced by 26% and HDL
cholesterol increased by 11% compared with baseline
values. Significant reduction in the epicardial coronary artery
constrictor response to intracoronary acetylcholine
compared with baseline values was observed in the
lovastatin group but not in the placebo group. The
epicardial coronary artery dilator responses to
nitroglycerin were unaltered by therapy. Anderson et
al63 treated 49 coronary artery disease patients
(37 men and 12 women) whose total cholesterol levels ranged
from 180 to 280 mg/dL with lovastatin and cholestyramine,
lovastatin and probucol, or placebo in addition to diet for
1 year. Lovastatin and cholestyramine produced a 38%
reduction in LDL and a nonsignificant change in HDL levels;
lovastatin and probucol resulted in a 41% reduction in LDL
and 21% reduction in HDL levels compared with baseline values. There
was significant attenuation of the epicardial coronary artery
vasoconstrictor response to intracoronary acetylcholine in
the lovastatin-probucol group (possibly enhanced by the
antioxidant effects of probucol on LDL) and a trend toward improvement
in this response in the lovastatin-cholestyramine
response. There was no change in the vasoconstrictor response to
acetylcholine in the placebo group. Although the coronary
artery responses of men and women who received lipid-lowering
therapy in these studies were not analyzed separately for sex
differences, given the relatively small population sizes in each study,
it seems unlikely that all vascular benefit was manifest in men but not
in women.
 |
Systemic Vasomotor Effects of Lipid-Lowering
Therapy
|
|---|
Goode and Heagerty
64 isolated small (<330-µm ID)
arteries
from subcutaneous biopsies performed in 18
hypercholesterolemic
patients (11 men, 7 women;
average age, 51 years) and demonstrated
impaired dilator responses to
acetylcholine and, to a lesser
degree, nitroprusside compared with
responses in small arteries
from 16 sex-matched control subjects of
similar age with normal
cholesterol levels. Ten of these
patients (sex not reported)
underwent repeat biopsies

10 months
after lipid-lowering therapy,
which reduced LDL levels by 56%.
Significant improvement in
vasodilator responses to acetylcholine and
nitroprusside were
observed in these patients compared with their
baseline values.
Of note, systolic and diastolic
blood pressures in these 10
patients were significantly lower on
treatment compared with
pretreatment values.
Thus, lipid-lowering therapy may improve systemic vasomotor
function as well as coronary vasomotor function. To the extent
that such improvement indicates augmented nitric oxide bioavailability,
other endothelial properties may also benefit, such as
reduced platelet aggregation, inflammatory cell adhesion, and
smooth muscle cell migration.75 76 77
 |
Antioxidant Effects of Cholesterol Reduction
Therapy
|
|---|
Reduction in cholesterol levels may reduce the
susceptibility
of LDL to oxidation. Thus, Kleinveld et
al
135 reported that
18 weeks of pravastatin or
simvastatin administered to 23
hypercholesterolemic
patients (15 men, 8 women)
decreased LDL cholesterol levels
by 36% and significantly
reduced the rate and extent of copper-catalyzed
LDL oxidation. LDL
particles after therapy were changed in composition
to contain less
lipid relative to protein, possibly rendering
the particle less
susceptible to oxidation.
136 Properties of
HMG-CoA
reductase inhibitors other than reduction in LDL levels
and
changes in particle composition may also be of antioxidant
importance.
In this regard, Giroux et al
137 reported that
simvastatin
diminished superoxide anion formation and LDL
oxidation by human
macrophages in tissue culture. Protection of
LDL from oxidation
could increase nitric oxide bioavailability and
improve endothelium-dependent
vasomotor,
anti-inflammatory, and anticoagulant properties of
the
endothelium.
75 76 77 78 98 99 100 101
 |
Lipid-Lowering Therapy and Thrombosis
|
|---|
Several lipid-lowering agents may potentiate
fibrinolysis independent
of alterations in plasma
lipoproteins. Thus, Fujii's group
138 139 showed that
gemfibrozil and niacin decrease PAI-1 synthesis
in hepatoma cell
cultures both in the basal state and after
stimulation of the cell
lines with mitogens such as transforming
growth
factor-ß
1. The reduction in PAI-1 secretion appeared
disproportionate
to the reduction in PAI-1 mRNA, suggesting
posttranscriptional
as well as transcriptional inhibitory
effects of these agents.
This group also reported that niacin
administered to rats for
3 weeks significantly reduced
dexamethasone-stimulated PAI-1
plasma levels. Although
the effects of gemfibrozil and niacin
on plasma PAI-1 levels have not
been reported in humans, the
HMG-CoA reductase inhibitor
pravastatin reduced PAI-1 plasma
levels in
hypercholesterolemic subjects.
140 The
intracellular
mechanism of PAI-1 inhibition by these pharmacologically
diverse
agents, and whether or not endothelial
synthesis of PAI-1 is
affected by these agents, are unknown. Niacin
lowers plasma
levels of lipoprotein(a) in
hypercholesterolemic subjects,
141
which may secondarily reduce PAI-1 levels by decreased transcription
of
PAI-1 mRNA.
107
 |
Cholesterol Reduction Therapy and Prevention of
Cardiovascular Events
|
|---|
As recently reviewed by Rich-Edwards et al,
142 the
majority
of prospective observational studies have reported a positive
association
between coronary heart disease and total plasma
cholesterol
levels and an inverse association between
coronary heart disease
and HDL cholesterol levels
in women. The benefit of cholesterol
reduction for
prevention of atherosclerosis
progression
143 144 145 146 or reduction in
cardiovascular events
147 148 149 150 151 in patients
with coronary artery disease has been evaluated
in a few trials
that included women, albeit small numbers in
most of these trials. Kane
et al
145 analyzed the coronary angiograms
of
72 patients (41 women) with heterozygous familial
hypercholesterolemia
randomized to diet plus
cholesterol reduction therapy versus
diet alone, with
baseline angiograms compared with angiograms
performed 26 months later.
The 22 women randomized to pharmacological
treatment had lipoprotein
changes comparable to those of men
(38% reduction in LDL
cholesterol in both groups; 27% increase
in HDL
cholesterol in women, 29% increase in men). Treatment
resulted
in significant regression of coronary
atherosclerosis in these
women compared with control
women, comparable to the effect
of treatment in men.
In the Canadian Coronary Atherosclerosis
Intervention Trial, 62 women (6 of whom were on hormone therapy) who
had serum cholesterol levels between 220 and 300 mg/dL and
angiographic evidence of coronary artery
atherosclerosis were randomized to
lovastatin (titrated to reduce LDL cholesterol
to
130 mg/dL) versus placebo in a double-blind
trial.146 Lovastatin reduced LDL
cholesterol levels by 32%. Two years later, follow-up
coronary angiography was performed in 54 of these women: The 25
lovastatin-treated women had significantly less
progression of preexisting stenoses and less development of new
lesions compared with the 29 placebo-treated women. The benefit of
therapy for coronary atherosclerosis was
similar to that measured in the 245 men who also underwent
follow-up coronary angiography.
Atherosclerotic plaque regression and stabilization by reduction in
atheroma lipid content may account for the significant
reduction in coronary events reported in secondary prevention
trials.152 In the Scandinavian Simvastatin
Survival Study, 4444 patients with coronary artery disease
(3617 men, 827 women) who had serum cholesterol levels
between 212 and 309 mg/dL were randomized to simvastatin
versus placebo in addition to diet and conventional antianginal
therapy.151 After a median of 5.4 years of treatment, the
simvastatin group had a 35% reduction in LDL and 8%
increase in HDL cholesterol levels compared with
pretreatment values and a 30% reduction in total mortality, primarily
due to fewer fatal ischemic cardiac events, compared with the
placebo group. Of the 827 women in the study, 25 in the placebo group
and 27 in the simvastatin group died,
representing an overall 50% lower mortality rate than
placebo-treated men. However, women randomized to
simvastatin had significantly fewer major coronary
events (coronary death, nonfatal myocardial infarction,
resuscitation from cardiac arrest) than women in the control group (59
versus 91), with risk reduction (0.65 [95% CI, 0.47 to 0.91])
comparable to that observed in men in this study (0.66 [95% CI, 0.58
to 0.76]).
 |
Conclusions
|
|---|
Estrogen therapy has been associated with reduced
cardiovascular
risk, with multiple biologically
plausible mechanisms demonstrated
in postmenopausal women to account
for this benefit. Although
several studies in progress, including the
Women's Health Initiative,
may ultimately prove that estrogen therapy
both prolongs the
duration and improves the quality of life of
postmenopausal
women as a group, many women at risk for
cardiovascular disease
and concerned about their health
may still be unwilling to take
estrogen compounds for decades because
of side effects and cancer
concerns. Furthermore, the addition of a
progestin compound
to estrogen for women with a uterus may compromise
to some degree
the cardiovascular benefit of estrogen.
The available data suggest
that pharmacological alteration of
lipoprotein levels in hypercholesterolemic
women
may achieve many if not most of the cardiovascular
effects
reported with estrogen administration. Lipid-lowering
therapy
should also be considered for mildly
hypercholesterolemic or
even
normocholesterolemic postmenopausal women with
atherosclerosis,
consistent with National
Cholesterol Education Program II guidelines
for lowering
LDL cholesterol to <100 mg/dL.
153
Comparison of the effects of estrogen and lipid-lowering therapies
in postmenopausal women, including those not considered
hypercholesterolemic, would be of considerable
interest to women at risk for or with established
atherosclerosis faced with the prospect of decades of
therapy to delay the progression and expression of
cardiovascular disease.
 |
Selected Abbreviations and Acronyms
|
|---|
| HMG-CoA |
= |
3-hydroxy-3-methylglutaryl coenzyme A |
| PAI-1 |
= |
plasminogen activator inhibitor-1 |
| TPA |
= |
tissue-type plasminogen activator |
|
 |
Acknowledgments
|
|---|
We greatly appreciate the secretarial assistance of Toni Julia
in
the typing of the manuscript.
Received September 6, 1995;
revision received December 4, 1995;
accepted December 10, 1995.
 |
References
|
|---|
-
National Center for Health Statistics.
Vital Statistics of the United States, 1989, Vol II: Mortality,
Part A. Washington, DC: Government Printing Office; 1993. DHHS
Publication (PHS) 93-1101.
-
Colditz GA, Willett WC, Stampfer MJ, Rosner B,
Speizer FE, Hennekens CH. Menopause and the risk of
coronary heart disease in women. N Engl
J Med. 1987;316:1105-1110. [Abstract]
-
Bush TL, Barrett-Connor E, Cowan LD, Criqui MH,
Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM.
Cardiovascular mortality and noncontraceptive use of
estrogen in women: results from the Lipid Research Clinics Program
Follow-up Study. Circulation. 1987;75:1102-1109. [Abstract/Free Full Text]
-
Stampfer MJ, Colditz GA, Willett WC, Manson JE,
Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen
therapy and cardiovascular disease: ten-year
follow-up from the Nurses' Health Study. N
Engl J Med. 1991;325:756-762. [Abstract]
-
Stampfer MJ, Colditz GA. Estrogen replacement
and coronary heart disease: a quantitative assessment of the
epidemiologic evidence. Prev Med. 1991;20:47-63. [Medline]
[Order article via Infotrieve]
-
American College of Physicians. Guidelines for
counseling postmenopausal women about preventive hormone therapy.
Ann Intern Med. 1992;117:1038-1041.
-
Belchetz PE. Hormonal treatment of
postmenopausal women. N Engl J Med. 1994;330:1062-1071. [Free Full Text]
-
Colditz GA, Hankinson SE, Hunter DJ, Willett WC,
Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The
use of estrogens and progestins and the risk of breast cancer in
postmenopausal women. N Engl J Med. 1995;332:1589-1593. [Abstract/Free Full Text]
-
Pilote L, Hlatky MA. Attitudes of women
toward hormone replacement therapy and prevention of heart
disease. Am Heart J. 1995;129:1237-1238.[Medline]
[Order article via Infotrieve]
-
Sullivan JM, VanderZwaag R, Hughes JP, Kroetz
FW, Ramanathan KB, Mirvis DM. Estrogen replacement and
coronary artery disease: effect on survival in postmenopausal
women. Arch Intern Med. 1990;150:2557-2562. [Abstract]
-
Stevenson JC, Crook D, Godsland IF. Influence
of age and menopause on serum lipids and lipoproteins in healthy
women. Atherosclerosis. 1993;98:83-90. [Medline]
[Order article via Infotrieve]
-
Campos H, McNarara SR, Wilson PWF, Ordovas JM,
Schaefer EJ. Differences in low density lipoprotein subfractions
and apolipoproteins in premenopausal and postmenopausal women.
J Clin Endocrinol Metab. 1988;67:30-35. [Abstract]
-
Brown SA, Hutchinson R, Morrisett JD, Boerwinkle E,
Davis CE, Gotto AM, Patsch W. Plasma lipid, lipoprotein
cholesterol, and apoprotein distributions in selected US
communities: the Atherosclerosis Risk in Communities
(ARIC) study. Arterioscler Thromb. 1993;13:1139-1158. [Abstract/Free Full Text]
-
Tikkanen MJ, Nikkila EA, Vartianen E. Natural
oestrogen as an effective treatment for type-II
hyperlipoproteinemia in postmenopausal
women. Lancet. 1978;2:490-491. [Medline]
[Order article via Infotrieve]
-
Granfone A, Campos H, McNamara JR, Schaefer MM,
Lamon-Fava S, Ordovas JM, Schaefer EJ. Effects of estrogen
replacement on plasma lipoproteins and apolipoproteins in
postmenopausal, dyslipidemic women.
Metabolism. 1992;41:1193-1198. [Medline]
[Order article via Infotrieve]
-
Lobo RA. Effects of hormonal replacement
on lipids and lipoproteins in postmenopausal women.
J Clin Endocrinol Metab. 1991;73:925-930. [Medline]
[Order article via Infotrieve]
-
Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar
V, Sacks FM. Effects of postmenopausal estrogen replacement on
the concentrations and metabolism of plasma
lipoproteins. N Engl J Med. 1991;325:1196-1204. [Abstract]
-
The Writing Group for the PEPI Trial. Effects of
estrogen or estrogen/progestin regimens on heart disease risk factors
in postmenopausal women: the Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial. JAMA. 1995;273:199-208. [Abstract]