CCC 2017 Proceedings Article

Coronary artery disease after menopause and the role of

estrogen replacement therapy
Stefano Savonittoa, Delia Colombob and Francesco Pratic

J Cardiovasc Med 2018, 19 (suppl 1):e107–e111 Fertile lifespan, mortality and cardiovascular
events
Keywords: coronary artery disease, estrogen, menopause
This is a complex issue, difficult to address from the
a
Manzoni Hospital, Lecco, bClinical Pharmacology, Milan and cSan Giovanni methodological point of view, but it represents the basis
Hospital and Centro per la Lotta Contro L’Infarto – CLI Foundation, Rome, Italy
for the development of goal-directed treatment. This
Correspondence to Stefano Savonitto, Manzoni Hospital, Lecco, Italy question was addressed by transversal7 as well as longi-
E-mail: s.savonitto@asst-lecco.it
tudinal8,9 studies investigating the relation between age
at menopause and all-cause as well as cardiovascular
Received 24 July 2017 Accepted 14 November 2017
mortality. Some of these studies were specifically inves-
tigating cardiovascular health,9 whereas others were lon-
Introduction gitudinal studies on cancer.7 An important longitudinal
Cardiovascular disease (CVD) represents the first cause study on more than 12 000 women followed up for up to
of mortality among women, and in Europe, more women 20 years within a screening project of breast cancer in
than men are now dying of coronary artery disease Utrecht found that any year of delay in menopause was
(CAD).1 However, premature coronary deaths, that is associated with a 2% reduction in the risk of cardio-
before the age of 65 and even 75 years, are more common vascular mortality, a benefit that extended for at least
among men.1 This observation implies that, at younger 2 decades after menopause. In this study, the benefit was
age, women are protected against CAD, and this specific consistent also among women having undergone oopho-
protection is the most likely cause of the overall survival rectomy, whereas in others the association was consistent
advantage of women over men. No such advantage is only for naturally occurring menopause, and not for
being observed for cancer, the second more frequent surgical menopause by bilateral oophorectomy.7,10 Also,
cause of death for both sexes.2 some studies have found a significant association
between early menopause and mortality only in smokers,
The most plausible cause of this fact has been considered which may well be a confounder for cardiovascular mor-
to be the protective effect of estrogen in premenopausal tality.9 In the most recent and complete meta-analysis of
women.3 Estrogen exerts direct effects on blood vessels 32 studies that included 310 329 women, those who
as well as systemic effects that may delay the develop- experienced menopause below the age of 45 appeared
ment and progression of atherosclerosis. Its rapid vaso- to have a greater risk of coronary heart disease (CHD),
dilatory effects are mediated by direct actions on vascular CVD mortality and all-cause mortality, whereas no asso-
endothelial cells. In addition, estrogen also alters serum ciation was found with stroke risk. By contrast, an age of
lipid concentrations (reduced LDL and increased HDL 45–49 years at onset of menopause, compared with 50
cholesterol), coagulation and fibrinolytic systems, anti- years or older at onset, had no apparent association with
oxidant systems, and the production of other vasoactive adverse outcomes.11 In the LADIES ACS study,6 the
molecules, such as nitric oxide and prostaglandins, all frequency of prior myocardial infarction (MI) was identi-
of which can influence the development of vascular cal (15%) among women with menopausal age below or
disease.3 In terms of atherosclerosis, disorder data suggest above median (50 years). In patients with no history of
that estrogen has an anti-inflammatory effect on athero- MI, the mean age at ACS was 73  10 years both among
sclerotic plaques, resulting in plaque stabilization, women below median menopausal age, and among those
whereas plaque erosion, a peculiar substrate for throm- above the median.
bosis in premenopausal women, does not appear to be
inhibited by estrogen.4 Studies using intravascular ultra- The hypothetical link between a longer fertility lifespan
sound (IVUS) have shown less coronary atherosclerosis in and a lower risk of cardiovascular events after menopause
women, with respect to men, despite a heavier burden of might be found in a more favorable risk factor profile as
risk factors.5 Prospective age and sex-matched data from calculated using the Framingham risk score,12 or through
the LADIES Acute Coronary Syndrome (ACS) study a lower risk of subsequent diabetes mellitus.13 An alter-
confirm that the 10-year advantage of women with regard native hypothesis considers age at menopause as a bio-
to the amount of angiographically measurable coronary logical marker of health and aging: that is, women that are
atherosclerosis persists beyond the 8th decade of age.6 biologically destined to a longer life tend to have also a
1558-2027 ß 2018 Italian Federation of Cardiology. All rights reserved. DOI:10.2459/JCM.0000000000000596

© 2018 Italian Federation of Cardiology. All rights reserved.

e108 Journal of Cardiovascular Medicine 2018, Vol 19 (suppl 1)

longer fertile life,7 whereas women with any kind of Fig. 1

evident or latent disease tend to experience menopause

at a younger age.7,10 Finally, among 695 premenopausal R = 0.069 (95% CI: −0.03 to 0.17)
women followed up in the Framingham Heart Study, a 200.00 P = 0.182
R2 = 0.005
significant association was found between an earlier age
at menopause and higher premenopausal serum choles-
terol and blood pressure,14 leading the Investigators to
150.00

Total gensini score

conclude that ‘heart disease risk determines menopausal
age rather than the reverse’.

Extent of coronary artery disease in women 100.00

with more prolonged exposure to estrogen,
either physiological or pharmacological
As previously mentioned, disorder,4 IVUS5 and angiog-
raphy6 data have shown less CAD in women as compared 50.00

with men, an advantage that persists for decades after

menopause. This advantage has been plausibly attrib-
uted to the effect of estrogen through a number of 0.00
vascular protective mechanisms.3 Direct consequences 10 20 30 40 50 60
of this vision would be that women with ‘early’ meno- Fertility life span
pause should have more extensive CAD and an
Correlation between Gensini score and fertile lifespan (years),
earlier occurrence of clinically manifest CAD, and the calculated as age at menopause minus age at menarche.
therapeutic administration of estrogen might reduce, or
delay, atherosclerosis. This evidence does not exist, and
prospective studies to investigate this issue have been
scarce so far. The LADIES ACS study was the first associated with a significantly lower risk of CHD,15 which
to specifically investigate the relation between age at prompted speculation that such therapy could be used to
menopause and the extent of CAD.6 The Investigators prevent coronary events. However, subsequent random-
enrolled 426 women and 249 men (with sampling ized trials failed to show any benefit of HRT with regard
ratio 2 : 1 of women vs. age-matched men) undergoing to coronary events (Table 1). One explanation is that in
coronary angiography due to an ACS. Enrollment was observational studies, women were younger (approxi-
stratified in four age classes from 55 to more than 85 years, mately 50 years of age) and closer to menopause (typically
with mean age 74 years (interquartile range 65–82 years). within 2 years) when they initiated HRT than were the
The extent of coronary atherosclerosis was assessed in a women included in randomized trials (mean age about 65
corelab and classified by using the Gensini score, which years, typically >10 years past menopause). This so-
considers both critical and subcritical stenoses in a hier- called timing hypothesis suggests that the effects
archical order. A specific menopause questionnaire was of HRT on atherosclerosis and CHD depend on the
administered to women during index hospital stay. The timing of the initiation of hormone therapy relative to
mean Gensini score was 60  36 in men vs. 50  32 in menopause.
women (P < 0.001), being higher in men at any age. The
Studies on the progression of atherosclerosis (carotid and
Gensini score in women showed a weak association with
coronary) seem to be, at least in part, in agreement with
age (R2 0.127; P ¼ 0.0129), but not with menopausal age
this hypothesis (Table 1). In fact, the Estrogen in the
(R2 0.063; P ¼ 0.228). As shown in Fig. 1 also no signifi-
Prevention of Atherosclerosis Trial of early HRT inter-
cant association was found between fertility lifespan (i.e.
vention in healthy postmenopausal women did show
the time in years between menarche and menopause) and
some benefit in terms of reduced progression of carotid
Gensini score.6 A recent metanalysis11 assessed the rela-
intima–media thickness,16 whereas the Women’s Estro-
tion between age at menopause and carotid atheroscle-
gen–Progestin Lipid-Lowering Hormone Atheroscler-
rosis (only two studies with these measurements): pooled
osis Regression Trial failed to show any benefit of
relative risk [95% confidence interval (CI)] for the risk of
HRT in secondary prevention with regard to coronary
carotid atherosclerosis for 3388 participants was 0.74
lesions.17
(0.63–0.87) when comparing women 50 years or older with
women younger than 50 years at onset of menopause. Similarly, the Estrogen Replacement and Atherosclerosis
trial18 and the Women’s Angiographic Vitamin and
Effect of HRT on atherosclerosis and Estrogen trial19 compared HRT and placebo in post-
cardiovascular outcomes menopausal women with regard to the angiographic
Post-hoc analyses of prospective cohort studies in progression of CAD: no effect was observed with treat-
the 1980s indicated that postmenopausal HRT was ment in both trials which, however, enrolled women with

© 2018 Italian Federation of Cardiology. All rights reserved.

 Coronary artery disease after menopause Savonitto et al. e109

Table 1 Studies on HRT and coronary disease

Follow-up Mean Years
StudyRef. (no.)
Endpoint Intervention (year) age (year) from MP Prior CVE Result
16
EPAT (222) Progression of E vs. placebo in healthy 2 60 Not reported Excluded Reduced progression of
carotid IMT women with ATS only in w not
LDLc > 130 mg/dl taking statins
WELL HEART17 Angiographic E vs. E þ P vs. placebo 3.3 63.5 18 At least 1 coronary No effect in both groups
(226) CDS stenosis
ERA18 (309) Angiographic E vs. E þ P vs. placebo 3.2 66 Not reported MI 45% No effect in both groups
CDS PCI 51%
19
WAVE Angiographic E vs. E þ P vs. placebo 2.8 65 Not reported MI 45% No effect in both groups
CDS
20
ELITE (643) Carotid IMT, E or E þ P vs. placebo 5 55, 64 3.5 ET excluded Reduced CIMT
Angiographic 14 LT progression only in
CDS ET. Coronary ATS no
change
HERS21 (2763) CHD death or E þ P vs. placebo 4.1 67 18 QWMI 17% No effect
MI PCI 45% Increased thrombosis
CABG 42%
WHI22 (16 608) CHD death or E þ P vs. placebo 5.2 63 Not reported 10% No effect
MI Increased MI
DANISH24 (1006) Death, HF, MI E or E þ P vs. control in 11–16 50 0.5 Excluded Reduced CV events
healthy women

ATS, aterosclerosis; CABG, coronary artery bypass grafting; CDS, change in diameter stenosis; CHD, coronary heart disease; CIMT, carotid-intimal media thickness; CV,
cardiovascular; E, estrogen; EPAT, Estrogen in the Prevention of Atherosclerosis Trial; ET, early treatment; HERS, Heart and Estrogen/progestin Replacement Study; HF,
heart failure; IMT, intima–media thickness; LDLc, low density lipoprotein c; LT, late treatment; MI, myocardial infarction; P, progestin; PCI, percutaneous coronary
intervention; QWMI, Q-wave myocardial infarction; WAVE, Women’s Angiographic Vitamin and Estrogen; WHI, Women’s Health Initiative.

a mean age of 65 years, and about half had had a prior although subgroup analysis in the unopposed estrogen
MI. In the ELITE study,20 643 healthy women were part of the study of women having undergone hysterec-
randomly assigned, in a 1 : 1 ratio, to receive oral 17b- tomy did reveal a potential reduction in CHD in women
estradiol (and progesterone vaginal gel in the case of aged 50–59 years [hazard ratio, 0.59 (CI: 0.38–0.90)] but
intact uteri) or matching placebo within strata of early not in women aged 60–69 or 70–79 years, a finding that
postmenopause (<6 years since menopause) and late warrants confirmation in future studies.
postmenopause (10 years since menopause). The
A study more suitable to prove the timing hypothesis was
median age at enrollment was 55 years in the early-
the Danish Osteoporosis Prevention Study,23 which
postmenopause stratum, and 64 years in the late-
involved a cohort of women who were, on average,
postmenopause stratum, and the median time since
50 years of age and 7 months past menopause when they
menopause was 3.5 years in the early-postmenopause
were randomly assigned to receive estradiol alone or in
stratum and 14 years in the late-postmenopause stratum.
combination with sequential norethisterone acetate. This
HRT significantly reduced the rate of progression of
study showed a significantly lower risk of CHD (a com-
carotid-intimal media thickness (primary endpoint) in
posite of death, admission to hospital for heart failure and
the early treatment group, whereas no such effect was
MI) at 10 years of follow-up among women who received
observed in the late treatment group (P ¼ 0.03 for inter-
treatment than among women who received no treatment
action between strata). However, no effect at all was
(hazard ratio 0.48, 95% CI: 0.26–0.87; P ¼ 0.015). In this
observed in both groups with regard to coronary com-
study, no excess risk of any cancer, breast cancer, stroke
puted tomography data (secondary endpoint).
and venous thrombus embolism was observed in the
HRT group. However, as expected from the young
In terms of CAD events, no benefit from HRT was
women’s age at enrollment, the number of events was
observed in the Heart and Estrogen/progestin Replace-
relatively small to draw any definite conclusion.
ment Study (Table 1), again as secondary prevention in
women with average age of 67 who had had prior Q wave
MI, percutaneous coronary intervention or coronary Current recommendations for HRT
artery bypass grafting.21 The primary endpoint in the As briefly discussed in the present review, experimental
Women’s Health Initiative was the rate of CHD (defined evidence of a protective effect of estrogen with regard to
as CHD death and total MI rate). Combined estrogen and coronary atherosclerosis and cardiac events is scarce.24
progestin therapy showed a trend toward an increased Angiographic studies neither show a relation between
risk for CHD after 5 years of follow-up, which persisted menopausal age and coronary atherosclerosis, nor an
through 8.6 years [hazard ratio, 1.22 (CI: 0.99–1.50)].22 effect of HRT on CAD progression. Most studies on
For the overall enrolled population, there was no reduc- HRT have included women who were too old and after
tion in the risk for CHD with estrogen alone after nearly too many years of menopause, whereas the better
8 years of follow-up [hazard ratio, 0.95 (CI: 0.78–1.15)], designed study23 was too small to be conclusive. Among

© 2018 Italian Federation of Cardiology. All rights reserved.

e110 Journal of Cardiovascular Medicine 2018, Vol 19 (suppl 1)

the issues not discussed here are the type (of estrogen and physicians when deciding for type and duration of HRT
progestin) and duration of HRT. Some expert commit- in early postmenopausal women to improve quality of
tees and scientific societies, such as the US Preventive life, sexual function and other menopause-related com-
Services Task Force,25 the Canadian Task Force on plaints, such as joint and muscle pains, mood changes and
Preventive Healthcare and the American Academy of sleep disturbances.
Family Physicians, have taken a strong position against
the postmenopausal use of HRT (either estrogen alone in
women without uteri, or combined estrogen and proges-
Acknowledgements
Conflicts of interest
tin in women with uteri) for the prevention of chronic
There are no conflicts of interest.
conditions. Other societies have discouraged the use of
HRT for the sole aim of preventing CAD events, though
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© 2018 Italian Federation of Cardiology. All rights reserved.