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JOURNAL OF WOMEN’S HEALTH
Volume 14, Number 2, 2005
Mary Ann Liebert, Inc.
The Effect of Hormone Replacement Therapy and
EFTIHIA SBAROUNI, M.D., ZENON S. KYRIAKIDES, M.D.,
Background: Homocysteine may be an independent risk factor for coronary artery disease
(CAD), and the risk is at least as strong for women as for men. Homocysteine levels are lower
in women compared with men, and homocysteine is lower during pregnancy and higher dur-
Purpose: To investigate the effects of hormone replacement therapy (HRT), simvastatin, and
their combination on plasma homocysteine levels, we treated 16 postmenopausal, hypercho-
lesterolemic women with CAD with HRT (0.625 mg conjugated equine estrogens [CEE] com-
bined continuously with 2.5 mg medroxyprogesterone), 20 mg simvastatin, and their combi-
nation in a randomized, placebo-controlled study. Each treatment period was 8 weeks long,
with a 4-week washout interval. Plasma homocysteine levels were evaluated at the end of
each treatment period.
Results: Only HRT, alone and in combination with simvastatin, significantly reduced ho-
mocysteine levels compared with placebo (11.82
؎ 0.74 and 12.22
؎ 0.71 vs 13.58
mol/L, respectively, p Ͻ 0.05). Simvastatin had no effect (13.02
؎ 0.94 mol/L), and the com-
bination therapy was not better that monotherapy with HRT.
Conclusions: Oral HRT reduces homocysteine plasma levels, whereas simvastatin has no
effect. If confirmed by randomized, prospective studies with clinical end points, HRT may
be considered for women with mild hypercholesterolemia and high homocysteine levels.
addition, homocysteine levels decrease after es-trogen and antiandrogen administration to male
LASMA HOMOCYSTEINE MAY BE an independent (transsexual) subjects and increase after androgen
risk factor for atherosclerotic vascular dis-
administration to female (transsexual) subjects.9
ease.1,2 Homocysteine levels are lower in pre-
Lipid-lowering drugs have divergent effects on
homocysteine plasma levels. Bile acid resins,
matched men.3,4 Similarly, homocysteine levels
niacin, and fibrates seem to increase homocys-
are reduced during pregnancy4 and increased af-
teine,10–15 fish oil may decrease it,16 and statins
ter menopause,5 and estrogen replacement ther-
do not modify it.12,13,15 Statin therapy is the
apy (ERT) significantly decreases homocysteine
first-line therapy for women with hypercholes-
compared with placebo in healthy postmeno-
terolemia and coronary artery disease (CAD).17
pausal women in most6,7 but not all studies.8 In
We and others have shown previously that hor-
2nd Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece.
ESTROGEN AND SIMVASTATIN AND HOMOCYSTEINE
mone replacement therapy (HRT) decreases total
minated the study early, because of significant re-
and low-density lipoprotein (LDL) cholesterol
sults, at a prescheduled interim analysis when 16
but not to the degree achieved by a statin, and
women had completed the protocol. Of note, the
only HRT lowers lipoprotein(a) (Lp(a)).18,19 No
HRT regimen is the one used in the HERS and
previous study, however, has compared the ef-
the ERA trials. Each treatment period was 8
fect of these therapies on homocysteine plasma
weeks long, and the washout period between
levels. We examined the effect of HRT, simvas-
them was a 4-week interval. All patients contin-
tatin, and their combination compared with
ued the same diet during all treatment arms, and
placebo on homocysteine in postmenopausal wo-
their antihypertensive-antianginal medications
men with hypercholesterolemia. We focused on
remained unchanged throughout the study pe-
women with CAD, as these may benefit most
riod. Blood samples were taken at the end of each
from homocysteine reduction. Most previous
studies included healthy women only.
Fasting total plasma homocysteine levels were
evaluated with a fluoresence polarization im-munoassay (FPIA) method, the AXSYM homo-cysteine assay. The results obtained by this
MATERIALS AND METHODS
method are highly correlated with those obtainedby high-performance liquid chromatography
at least 12 months of amenorrhea, who were hy-
One-way analysis of variance (ANOVA) with
percholesterolemic, with fasting total cholesterol
repeated measures and post hoc
analysis with the
200 mg/dl and LDL cholesterol Ͼ130 mg/dl,
Tukey test was applied for comparison.
and with angiographically documented CAD,that is, at least Ͼ80% diameter stenosis of an epi-cardial vessel. Women with a contraindication toHRT—history or family history of breast or en-
dometrial cancer, previous thromboembolism, orliver disorders—were excluded from the study.
We treated 16 women, 66 Ϯ 4 years of age
All patients had a normal mammogram and a
(range 59–72). Thirteen of these had already un-
normal cervical smear within the last year, as well
dergone revascularization procedures; 7 had per-
as normal liver and thyroid function tests. All pa-
cutaneous transluminal coronary angioplasty, 5
tients were clinically stable, and those with my-
had coronary artery bypass grafting, and 1 had
ocardial infarction (MI) or unstable angina within
both. The remaining 3 patients were on medical
the last 3 months were excluded from the study.
therapy. All treatments were well tolerated. Nine
Other exclusion criteria were uncontrolled hy-
patients reported mastalgia while on HRT, but
pertension, previous stroke, and need for antico-
only 1 of the 15 women who had an intact uterus
agulation therapy. Patients with conditions asso-
suffered vaginal bleeding, immediately after ces-
ciated with high homocysteine levels, such as
renal failure, hypothyroidism, systemic lupus
Results are expressed as mean Ϯ SE. Baseline
erythematosus (SLE), and various drug therapies,
values of lipids and homocysteine are shown in
such as theophylline, methotrexate, and L-dopa,
Table 1, and the effects of the four treatments are
were also excluded from the study. The study
shown in Table 2. Only therapies including HRT
protocol was approved by the Ethics Committee
significantly decreased homocysteine plasma lev-
els compared with placebo. The combination of
This was a randomized, placebo-controlled,
HRT and the statin was not better than HRT
crossover study. All patients were randomly as-
alone; simvastatin had no effect on homocysteine.
signed to placebo, HRT (conjugated equine es-
The changes induced by each treatment com-
trogens [CEE] 0.625 mg daily combined continu-
pared with baseline values are 1%, 5%, 14%, and
ously with medroxyprogesterone acetate [MPA]
11%, respectively, for placebo, simvastatin, HRT,
2.5 mg daily), simvastatin (20 mg daily), and the
and the combination therapy. HRT uniquely de-
combination of HRT and simvastatin in all 24 pos-
creased homocysteine as well as Lp(a). However,
sible orders (Latin square). We had to enroll 24
total and LDL cholesterol were significantly
patients according to the study design, but we ter-
lower on simvastatin compared with HRT.18
SBAROUNI ET AL.
higher methionine transamination induced by es-trogen are possible mechanisms.28 High levels of
homocysteine promote endothelial cell injury by
producing reactive oxygen species,29 and estra-
diol prevents endothelial damage by increasing
the intracellular content of glutathione in vitro
Various epidemiological studies have identi-
fied a continuous positive association betweenblood homocysteine levels and the risk of vascu-
aValues are expressed as mean Ϯ SD for lipids and mea-
lar disease,31,32 and this risk is at least as strong
sured in milligrams per deciliter. Homocysteine values
in women as in men.33,34 This association exists
are expressed as mean Ϯ SE and measured in
across a broad range of usual homocysteine lev-els; even a 1
mol/L-prolonged lower level of
blood homocysteine is associated with a 10%lower risk of vascular disease.32 At present, the
We have observed a significant decrease in upper limit of the reference range for homocys-
homocysteine plasma levels on oral HRT, either
teine is Ͻ15
mol/. It seems, however, that car-
alone or in combination with simvastatin—13%
diovascular risk increases even at lower homo-
and 10%, respectively. Previous studies on the cysteine concentrations for both stable coronaryrelation between HRT and homocysteine also
patients and acute coronary syndrome patients,35
found a decrease in homocysteine levels in wo-
and some authors propose that the desirable
men receiving HRT. Some studies showed treat-
homocysteine concentration should be Ͻ10
ment effects similar to the effect we found, be-
tween 9% and 13%;21–23 other studies observed a
Estrogen exert favorable effects on various bi-
7% reduction obtained by HRT.6,7 The addition
ological parameters (lipids, fibrinolysis, endothe-
of a progestin does not seem to have an unfa-
lium, oxidative stress). This, however, has not
vorable effect on homocysteine metabolism.23,24
been translated to improvement in clinical out-
The effect of transdermal estrogen on homocys-
comes, possibly due to proinflammatory and
teine levels is controversial.25,26 Simvastatin ther-
procoagulant the effects. Both Women’s Health
apy had no effect in our study, and this is in
Initiative (WHI), in primary prevention, and mul-
agreement with three previous reports that eval-
tiple randomized, placebo-controlled, secondary
uated atorvastatin 10 mg and simvastatin 20 mg,
prevention trials have shown no overall benefit
respectively.12,13,15 It is, however, possible that
higher doses of a statin may be effective in low-ering plasma concentrations of homocysteine.
Such an effect has been reported with 80 mg of
simvastatin.27 No other study has examined theeffect of the combination therapy on homocys-
Statins are first-line therapy in patients with
teine metabolism, and our results suggest that the
CAD and hypercholesterolemia. In addition, their
addition of a statin to HRT has no effect.
pleiotropic effects, other than lipid lowering, ren-
The mechanisms involved in homocysteine re-
der them an effective therapy even in patients
duction by estrogen are unknown, but increased
with normal cholesterol levels. Current indica-
methionine synthase activity in the kidney and
tions for HRT are hot flushes and osteoporosis.37
TABLE 2. EFFECT OF HRT AND SIMVASTATIN ON HOMOCYSTEINE LEVELS (
aResults are expressed as mean Ϯ SE.
Ͻ 0.05 vs. placebo.
ESTROGEN AND SIMVASTATIN AND HOMOCYSTEINE
Increased plasma homocysteine levels seem to in-
lipid lowering agents. A comparison between ator-
crease the risk of cardiovascular disease, but it re-
vastatin and fenofibrate in patients with mixed hy-
mains unclear if lowering homocysteine levels
perlipidemia. Atherosclerosis 2001;154:421.
will reduce this risk.38 If this is confirmed by ran-
14. Dierkes J, Westphal S, Kunstmann S, et al. Vitamin
supplementation can markedly reduce the homocys-
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points, women with mild hypercholesterolemia
and high homocysteine plasma levels may be
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