Corresponding Author: Didik
Supriyadi Kusumo Budoyo
E-mail: kusumobudoyo95@gmail.com
INTRODUCTION
Cardiovascular disease is the leading cause of death
in both women and men in the USA, accounting for >20%. Each year, an
estimated 390,000 women experience myocardial infarction and acute coronary
syndrome that is either new or recurrent (Pagidipati &
Peterson, 2016). Based on the Global Burden of Disease and the
Institute for Health Metric and Evaluation (IHME) 2014-2019, heart disease is
the highest cause of death in Indonesia, at 14.4%. Basic Health Research
(Riskesdas) data from 2013 and 2018 also showed increased heart disease, from
0.5% in 2013 to 1.5% in 2018 (Tarmizi, 2022).
The incidence of cardiovascular disease is closely
related to gender. Pre-menopausal women have a lower incidence of hypertension,
atherosclerosis, myocardial dysfunction, ventricular hypertrophy, heart
failure, and myocardial ischemia than men of the same age. However, this
condition gradually decreases after menopause, and the risk of cardiovascular
disease will increase even higher in women than men of the same age (Du et al., 2021). Epidemiological studies show that women before
menopause can be said to be "protected" from the incidence of
cardiovascular disease compared to men. The incidence is lower in women than
men at the same age and will only be equal in men ten years later (Iorga et al., 2017).
Acute coronary syndrome (ACS) includes three clinical
conditions: STEMI (ST-segment elevation myocardial infarction) refers to
complete coronary artery thrombosis and myocardial necrosis; NSTEMI
(non-ST-segment elevation myocardial infarction) refers to partial coronary
artery thrombosis and myocardial necrosis; while UAP (unstable angina pectoris)
refers to partial coronary artery thrombosis but no myocardial necrosis. Among
patients with ACS, women have a lower incidence of STEMI and NSTEMI, but UAP is
more common than men. Analysis of the GUSTO IIb trial showed that STEMI was
significantly lower in women than men (27.2% vs 37.0%; P<0.001) (Pagidipati &
Peterson, 2016).
The pathophysiology of ACS also differs based on
gender. Plaque erosion is the most common cause of ACS in women, whereas plaque
rupture is more common in men. Plaque erosion seen on vascular imaging is
almost 1/3 of the cases in women with ACS, with no visible lesions identified
on angiography. Conversely, plaque rupture is more easily detected on
angiography. Spontaneous coronary artery dissection (SCAD), a rare cause of
ACS, can be said to occur only in women. A prospective cohort study of SCAD
patients stated that more than 90% occurred in women, 25.7% with STEMI, and
74.3% with NSTEMI (Costello & Younis,
2020).
Considering conventional risk factors, the main
difference in these events is the level of Estrogen (Pathak et al., 2017). Women are thought to be protected from
cardiovascular disease, especially ACS, due to endogenous Estrogen, which has
far-reaching effects on the circulatory system (Costello & Younis,
2020).
Theoretically
and in pre-clinical studies, estrogen replacement therapy is a logical
intervention to reduce cardiovascular events in post-menopausal women, but the
results of large-scale clinical trials such as HERS and WHI do not support
this, even suggesting an increased risk of thromboembolism. The KEEPS study,
which was conducted to overcome the design flaws of the WHI, has also received
results. Whether the results are the same as the previous two clinical trials
will be discussed in this review.
Based on the above, this review aims to understand the
cardiovasculoprotective effects of Estrogen better and answer the question of
whether Estrogen can be used as hormonal replacement therapy in postmenopausal
women in order to prevent cardiovascular events.
METHOD
The method
used was a literature review, conducted in January 2023 at the Division of
Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Dr.
Sardjito Central General Hospital/Faculty of Medicine, Public Health, and
Nursing, Gadjah Mada University, Yogyakarta, Indonesia. It is based on data
sources from offline and online references related to the topic to gather
information regarding the cardio-vascular protective effects of Estrogen, its
mechanism of action, and its possible use as hormone replacement therapy to
reduce cardiovascular events in postmenopausal women.
RESULTS AND DISCUSSION
Estrogen and Estrogen Receptors
Estrogen is a fat-soluble steroid hormone that plays an
important role in the development and physiology of various organs such as the
mammary, uterus, bone, and cardiovascular systems. There are three types of
Estrogen in humans, namely estrone (E1), 17b-estradiol (E2), and estriol (E3). Among the three, E2
has the strongest biological activity (Du et al., 2021). Estradiol, also known as 17b-estradiol or Estrogen (E2), is the most abundant type
and is considered a female hormone. E2 is synthesized and secreted primarily by
the ovaries in pre-menopausal women but is also produced by fat tissue, brain,
bone, vascular endothelial, and aortic smooth muscle cells. Gonadal E2 acts
broadly as an endocrine for distant tissues. In contrast, extra-gonadal E2 acts
locally as a paracrine or intracrine in the tissue where it is synthesized (Iorga et al., 2017). Extra-gonadal E2 production plays an important role and
is the sole source of endogenous E2 in pre-pubertal, postmenopausal women and
men, acting as both endocrine and paracrine/intracrine to maintain
tissue-specific functions (Du et al., 2021), (Iorga et al., 2017).
Almost 90% of estradiol in pre-menopausal women is
produced by the ovaries; the precursor androstenedione is metabolized to
estrone and then to estradiol. The conversion is mediated by aromatase (an
enzyme from cytochrome P450); the process also occurs in extra-gonadal tissues
such as the brain, fat, muscle, bone, and mammary glands (Morselli et al., 2017). Gonadal estrogen production of ovarian follicles (see
Figure 1) is carried out by granulosa cells and theca cells under the influence
of the synergistic effects of follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). Theca cells, under the influence of LH, will utilize
LDL-cholesterol (LDL-C) as a precursor for synthesizing androstenedione and
testosterone, which will diffuse to granulosa cells through the basement
membrane. Aromatase activity in granulosa cells under FSH will convert androstenedione
to estrone and testosterone to estradiol (Du et al., 2021), (Ko & Jung, 2021). The process is known as the two-cell-two gonadotropin
theory of estrogen synthesis (Du et al., 2021).
Figure 1.
Synthesis of estradiol in the ovary (Ko &
Jung, 2021)
The cellular effects of Estrogen are mediated by two
estrogen receptors (ER): the classic nuclear estrogen receptor (nER) and the
membrane estrogen receptor (mER). There are two types of nER, ERa and ERb.
Further research found that some target cells can react
quickly to Estrogen without going through estrogen receptors. So, in addition
to the slow-acting classical nER, fast-acting membrane receptors were found,
namely G protein-coupled estrogen receptors (GPERs), which include G
protein-coupled receptor 30 (GPR30) and ER-X (Du et al., 2021).
Estrogen receptors a (ERa) are found in the uterus, testes, ovaries, prostate,
skeletal muscle, kidney, skin, and many more (Du et al., 2021). Animal studies have shown that this receptor has
cardioprotective and vasculo-protective functions. These results are consistent
with human data that decreased ERa is associated with an increased risk of atherosclerotic
plaque, especially in pre-menopausal women (Morselli et al., 2017). ERb is found in the ovaries, colon, brain tissue, kidney, and male reproductive
system (Du et al., 2021). This receptor has more metabolic effects, such as
insulin resistance and glucose intolerance, by involving the activation of
peroxisome proliferator-activated receptor g (PPARg) in adipose tissue, it does not play a vasculoprotective
role but can improve myocardial function after acute myocardial infarction (Morselli et al., 2017).
G protein-coupled receptor 30 (GPR30) is widely found in
brain tissue, adrenal medulla, renal pelvis, and ovary. It is also widely found
in the cardiovascular system, such as endothelial cells and cardiomyocytes.
Meanwhile, ER-X expression is limited during the fetal development phase and
rarely found in adulthood. GPR30 is cardioprotective (Du et al., 2021), (Morselli et al., 2017).
The classical pathway of estrogen action is through a
genomic mechanism where Estrogen enters the nucleus and combines with the ER of
the nucleus to form a dimer that will regulate gene expression and a series of
further actions. While the non-genomic mechanism does not involve gene
expression, Estrogen activates estrogen receptors in the membrane that will
trigger further signal transduction (see Figure 2). Genomic mechanisms are
slow-acting, taking hours to days to take effect, while non-genomic mechanisms
are fast-acting, taking seconds to minutes to take effect (Lizcano &
Guzman, 2014), (Du et al., 2021).
Figure 2.
Genomic and non-genomic mechanisms of estrogen receptors (Du et al.,
2021)
Cardiovascular
Protective Effects of Estrogen
Estradiol
(E2) works by binding to its receptors, namely traditional receptors (ERa and ERb), which work slowly because they must activate
transcription genes in the nucleus (genomic pathway), and receptors (GPR30),
which work faster because they do not pass through activation of transcription
genes in the nucleus (non-genomic pathway). E2 binding to ERa and ERb (see Figure 3) can activate both genomic and non-genomic pathways.
E2 binds to estrogen receptor (ER) in the genomic pathway, will form
homo/hetero dimer formation, translocate to the nucleus, then bind to estrogen
receptor element (ERE) or bind to transcription factors that regulate gene
expression such as eNOS (endothelial nitric oxide synthase) a potent
vasodilator and VEGF (vascular endothelial growth factor) a pro-angiogenesis
factor. E2 binds to the ER and GPR30 with the plasma membrane in the
non-genomic pathway, activating MAPK/ERK/PI3K/cAMP, resulting in eNOS
expression. E2 also binds to ER in the mitochondrial membrane, improving
mitochondrial function by reducing the production of ROS (reactive oxygen
species) and increasing cell survival (Iorga et al., 2017).
Figure 3. Genomic and non-genomic pathways (Iorga et al., 2017)
Genomic: red arrow, non-genomic: blue arrow. Also shown is the local
biosynthesis of E2 through the conversion of T (testosterone) to E2 via the
aromatase process of the CYP P450 enzyme
The cardioprotection and atheroprotection properties of
estradiol can be seen in Figure 4. Estradiol inhibits angiotensin II (AGT II),
resulting in PI3K activation and suppression of CaN (calcineurin) activity,
resulting in an anti-hypertrophic effect. Estradiol protects cardiomyocytes by
activating PI3K, PKB, and MAPK, preventing ROS formation and inhibiting
apoptosis. Activation of sirtuin 1 (SIRT) by estradiol will inhibit AGT II from producing ROS.
Estradiol suppresses the expression of microRNA-22 (miR-22) through ERa, which increases the
transcription factor Sp1 in cardiomyocytes. Sp1 increases the expression of
cardioprotective genes, such as the gene encoding cystathionine-g-lyase (CTH), leading to
increased levels of hydrogen sulfide
(H2S) so that cardiomyocyte protection against ROS increases. Cardiovascular
protective effects also occur through GPER1 (GPR30) through PI3K dependent.
Exposure to physiological concentrations of estradiol can reduce the
pro-inflammatory activity of vascular endothelial cells by reducing the
production of IL-6, IL-8, ICAM1, and VCAM1, which play a role in leukocyte
recruitment, thus preventing the development of atherosclerosis. Estradiol also
plays a role in stimulating endothelial repair during vascular injury through
the genomic/non-genomic pathway by increasing eNOS activity, which is a
vasodilator. Estradiol also plays a role in the lipoprotein profile by
increasing the amount of HDL (high-density lipoprotein). HDL will stimulate the
production of NO (nitric oxide) through scavenger receptor B type 1 (SRB1),
which will activate eNOS, resulting in vasodilation (Morselli et al., 2017).
Figure 4. Mechanisms of cardioprotection and
atheroprotection of estradiol (Morselli et al., 2017)
PI3K: phosphoinositide 3 kinase; PKB: protein
kinase B; MAPK: mitogen-activated protein kinase; IL-6/8: interleukine-6/8;
VCAM1: vascular cell adhesion molecule 1; ICAM1: intercellular adhesion
molecule 1
A summary of the mechanism of Estrogen's
protective effect on cardiovascular disease through suppression of fibrosis,
stimulation of angiogenesis and vasodilation, improving mitochondrial function,
and reducing oxidative stress can be illustrated in Figure 5.
Figure 5. Summary of the
mechanism of Estrogen's protective effect (Iorga et al., 2017)
FAO: fatty acid oxidation; MMP2: matrix
metalloproteinase 2
Menopause
and Cardiovascular Disease
Women are more protected against
cardiovascular events than men. Overall, the differences in risk factors and
outcomes of cardiovascular events between men and women lie in sex hormones and
their receptors (Davezac et al., 2021). Clinically, the Framingham Heart Study first
demonstrated the clinical presentation pattern of women in the 1980s, showing
that women generally have more angina as the clinical presentation of ischemic
heart disease and less often with acute myocardial infarction clinical
presentation than men. In ACS, women more often present with unstable
angina/NSTEMI than STEMI (Keteepe-Arachi &
Sharma, 2017). Pathophysiology also shows differences in the mechanism
of ACS. In women, mechanisms other than plaque rupture and thrombus formation
are more common causes (see Figure 6), namely plaque erosion, coronary
vasospasm, spontaneous coronary artery dissection, and stress-related
cardiomyopathy (Takotsubo cardiomyopathy). Prospect studies showed that women
have smaller coronary lumens, fewer plaque ruptures, and less necrotic plaque,
with less calcium content than men. Women are likelier to have plaque erosion
without obvious plaque rupture (Pagidipati &
Peterson, 2016).
Figure 6. Differences in ACS pathophysiology based on gender (Pagidipati &
Peterson, 2016)
Women are more likely to have coronary vasospasm, spontaneous coronary
artery dissection, and stress-related
cardiomyopathy.
Menopause is characterized by the permanent end of a
woman's menstrual cycle, which occurs around the age of 49-52 years. Along with
the depletion of ovarian follicles, the ovaries stop producing Estrogen so that
estradiol (E2) levels, which normally range from 60-200 pg/ml, decrease to 20
pg/ml (Davezac et al., 2021) (Ko & Jung, 2021). Levels of 17b-estradiol (E2), the main Estrogen in
circulation, decrease abruptly from the onset of menopause. As a result of this
sudden decline, women lose their cardiovascular protective effect, and the risk
of cardiovascular events is comparable to that of men (see Figure 7). The
cardiovascular incidence of postmenopausal women is 4.3 times higher than that
of pre-menopausal women (Davezac et al., 2021).
Figure 7. Evolution of sex hormone levels on coronary
heart disease in women and men (Davezac et al., 2021)
Decreased
estrogen levels in postmenopausal women are associated with an increased risk
of cardiovascular events (Davezac et
al., 2021). This is supported by research conducted (by Pathak et
al., 2017), who reported that estrogen levels in older
women with coronary heart disease decreased significantly compared to older
women without coronary heart disease, with the more severe the coronary
lesions, the lower the estrogen levels. Estrogen levels are also associated
with lipid profiles and fibrinolysis status (Pathak et
al., 2017).
Estrogen
Replacement Therapy
Pre-menopausal women have a lower risk of cardiovascular disease than men
of the same age, but the incidence increases after menopause. As explained
above, Estrogen has beneficial effects on the cardiovascular system. These
beneficial effects and the lower incidence of cardiovascular disease in pre-menopausal
women led to the hypothesis that Estrogen is cardioprotective, which underlies
its use as hormonal replacement therapy (HRT) to reduce the incidence of
cardiovascular disease (Murphy &
Steenbergen, 2014).
Postmenopausal women show several features of
metabolic syndrome as estrogen levels decline, such as dyslipidemia
(hypertriglyceridemia, increased LDL and decreased HDL), insulin resistance,
hypertension, increased central fat and decreased lean body mass as well as
hypercoagulation and pro-inflammatory conditions (Modena, 2016).
Although HRT is a logical intervention given
its many advantages based on pre-clinical studies, evidence based on clinical
trials does not support the use of estrogen therapy for the prevention of
cardiovascular disease (Manrique-Acevedo
et al., 2020). Several observational studies have reported
that postmenopausal women receiving HRT have lower cardiovascular events and
cardiac mortality than those without HRT. However, prospective clinical trials
with many participants have shown different results. The Heart and
Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative
(WHI) reported no reduction in cardiovascular events in postmenopausal women
with HRT. These studies suggest that HRT is associated with an increased risk
of stroke, thromboembolism, and deep vein thrombosis (dos Santos et
al., 2014). Although WHI and HERS reported that HRT
showed improved lipid profiles and reduced type 2 DM, it did not improve
cardiovascular outcomes (Murphy &
Steenbergen, 2014).
Several
hypotheses have been proposed to explain the WHI and HERS results as to why
Estrogen does not protect postmenopausal women against cardiovascular events.
One popular hypothesis is the "timing hypothesis," which states that
the average age at HRT is around 63 years. The participants of the study were
postmenopausal women who had already experienced estrogen deficiency several
years before receiving HRT, giving rise to the suggestion that perhaps the
administration of Estrogen immediately after menopause would be more
beneficial. A re-analysis of the WHI data on this issue found that HRT
administered immediately after menopause showed no beneficial effect on
cardiovascular events and stroke (Murphy &
Steenbergen, 2014).
The second
explanation is age-related changes that result in a decreased protective effect
of estrogen administration. Estrogen improves cardiovascular outcomes by
activating eNOS. Tetrahydrobiopterin (BH4) is a co-factor of eNOS; a decrease
in BH4 due to age will cause NOS uncoupling, resulting in decreased NO
production and increased ROS. Giving Estrogen to activate NOS without BH4 will
be more detrimental than cardioprotective (Murphy &
Steenbergen, 2014).
The third
explanation is that in postmenopausal women, there is an increase in
27-hydroxycholesterol, which will bind to estrogen receptors and is
antagonistic to the increase in estrogen-activated eNOS. Therefore,
re-administering estrogen post-menopause will be antagonistic. The fourth
explanation relates to age-related estrogen receptor levels/activity/proportion
changes. The ER can undergo post-translational modifications that alter its
activity, acetylation that affects transcriptional activity, or methylation
associated with decreased ER levels. Thus, ER levels, activity, and composition
change with age (Murphy &
Steenbergen, 2014).
A Cochrane
meta-analysis of 22 studies of postmenopausal women found an increased risk of
coronary heart disease and stroke associated with combined HRT. The American
College of Obstetricians and Gynecologists and the North American Menopause
Society have started to reduce the routine use of estrogen hormonal therapy in
postmenopausal women. The timing of HRT administration is still a matter of
debate. Administration early in menopause may still have beneficial effects.
Transdermal administration is still under promising research regarding less
risk (Manrique-Acevedo
et al., 2020).
The use of
estradiol as a cardiovascular protective therapy is controversial, as is the
use of oral contraceptives containing estradiol, which is associated with an
increased risk of venous thrombosis and consequent myocardial infarction,
stroke, and peripheral arterial disease. The WHI study showed that the estrogen
component of HRT is associated with the risk of venous thrombosis. Canonico et
al. reported the same. These studies suggest that estradiol is pro-thrombotic,
although it is still controversial and not fully understood, by increasing
pro-coagulant factors (factors VII, X, XII, and XIII) and decreasing
anti-coagulant factors (protein S and anti-thrombin). Rosendaal et al. reported
that estradiol supplementation as oral contraceptives or HRT increases the risk
of thrombosis, especially in women with coagulation disorders. Progestins as
oral contraceptives or HRT with third-generation progestogen content
(desogestrel, gestodene) are associated with a higher risk of thrombosis
compared to second-generation progestogen content such as levonorgestrel (Iorga et al.,
2017).
The Kronos
Early Estrogen Prevention Study (KEEPS) was initiated because the WHI results
surprisingly did not support the observational study hypothesis that estrogen
replacement therapy can reduce cardiovascular events. The WHI design was
criticized for not being clinically practical, as most of the WHI participants,
despite an average age of 63 years and 12 years of menopause, did not
experience postmenopausal symptoms such as hot flashes and, therefore, did not
seek treatment for these symptoms. The WHI included many participants who were at
risk of cardiovascular events. KEEPS was designed to address this weakness by
recruiting women within three years of menopause and excluding participants
with known clinical or subclinical atherosclerosis. In a randomized,
double-masked, placebo-controlled trial, 72,8 participants were given oral
conjugated equine Estrogen (oCEE; 0.45 mg/day) or transdermal
17-estradiol (tE2; 50 mg/day), both with progesterone (200 mg/day for
12 days/month), or placebo pills and patches for four years (V M Miller et
al., 2021).
The primary
outcome of KEEPS was the change in carotid intima-medial thickness (CIMT)
measured by B-mode ultrasound. There was no significant change in CIMT in all
three groups (oCEE, tE2, and placebo). The secondary outcome is coronary artery
calcification (CAC); there was also no significant difference (Virginia M
Miller et al., 2019), (V M Miller et
al., 2021). There were no venous thrombotic events but
one myocardial infarction event in the tE2 (transdermal estrogen
administration) group. However, the event occurred before the start of
treatment (Virginia M
Miller et al., 2019). There were no major adverse cardiovascular
events or cognitive impairment events, and there were no differences in the
incidence of breast cancer among the three treatment groups (V M Miller et
al., 2021). A summary of the KEEPS study results can be
seen in Figure 8.
Figure 8. Summary of KEEPS study results (V M Miller et al., 2021)
KEEPS did not show a significant
reduction in the progression of atherosclerosis measured by CIMT and CAC in
participants with hormonal replacement therapy compared to placebo. However,
there were improvements in metabolic factors in the hormonal replacement
therapy group. In general, the KEEPS data assure the effectiveness and safety
of oCEE (0.45 mg/day) or tE2 (50 mg/day) dosing, both accompanied by oral
progesterone (200 mg/day for 12 days/month) for women considering using
hormonal replacement therapy to reduce postmenopausal symptoms with the
additional outcomes of improving sexual function and maintaining bone mass
density (V M Miller et al., 2021).
CONCLUSION
Epidemiologic
studies have shown that pre-menopausal women are more protected against
cardiovascular disease than men. A comparison of women and men for the same
cardiovascular event rate showed that women aged ten years later than men. This
protective effect is related to sexual hormone (Estrogen) levels; the incidence
and severity of cardiovascular disease increases in postmenopausal women, and
the incidence of coronary heart disease also increases in women with
oophorectomy compared to women with ovarian intake. Cardiovascular protective
effects in reproductive women are believed to be related to estrogen levels and
estrogen receptor expression. The mechanism of Estrogen's cardioprotective
effect is through increased angiogenesis and vasodilation, as well as reducing
ROS, oxidative stress, and fibrosis.
Although HRT is a logical intervention given
its many advantages based on pre-clinical studies, evidence based on clinical
trials does not support the use of estrogen therapy for the prevention of
cardiovascular disease. HERS and WHI showed no reduction in cardiovascular
events in postmenopausal women with hormonal replacement therapy, even
suggesting an increased risk of stroke, thromboembolism, and deep vein
thrombosis. One of the analyses of these events is the timing hypothesis, so
the KEEPS study was initiated, which participated in women within three years
of menopause onset. The KEEPS study stated no significant reduction in
atherosclerosis progression between the hormonal replacement therapy group and
placebo. HERS, WHI, and KEEPS showed metabolic improvement in the hormonal
replacement therapy group. However, KEEPS differed from HERS and WHI, which
stated that there was an increased risk of thromboembolism, KEEPS stated that
hormonal replacement therapy was safe, there was no risk of major cardiovascular
events, and beneficial effects such as improving symptoms related to
postmenopausal symptoms, maintaining bone density, and improving sexual
function.
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