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Estrogenic hormone action in the heart: regulatory network and function

Fawzi A Babiker, Leon J De Windt, Martin van Eickels, Christian Grohe, Rainer Meyer, Pieter A Doevendans
DOI: http://dx.doi.org/10.1016/S0008-6363(01)00526-0 709-719 First published online: 15 February 2002


Cardiovascular diseases are the leading cause of death in the industrialised countries and display significant gender-based differences. Estrogen plays an important role in the pathogenesis of heart disease and is able to modulate the progression of cardiovascular disease. The focus on the beneficial influence of estrogen is gradually shifting from the vascular system to the myocardium. The presence of functional estrogen receptors in the myocardium has been demonstrated. Estrogen is important for cardiovascular baseline physiology and modulates the myocardial response under pathological conditions. Here we summarise the current knowledge of the regulatory network of estrogenic action in the myocardium and its effects on cardiovascular function.

  • Atherosclerosis
  • Coronary disease
  • Gender
  • Hormones
  • ACE, angiotensin converting enzyme
  • AF-1, trans-activation function-1
  • AF-2, trans-activation function-2
  • ANF, atrial natriuretic factor
  • Ang, angiotensin
  • CAD, coronary artery disease
  • CHD, coronary heat disease
  • cGK, cyclic GMP-dependent protein kinase
  • cGMP, cyclic guanosine monophosphate
  • DBD, DNA binding domain
  • estrogen, 17β-estradiol
  • EGF, epidermal growth factor
  • eNOS, endothelial nitric oxide synthase
  • Egr, early growth response factor
  • ERT, estrogen replacement therapy
  • ER, estrogen receptors
  • ERE, estrogen response element
  • ERK, extracellular related kinase
  • ERKO, estrogen receptor knockout mouse
  • ERRs, estrogen receptor-related receptors
  • GH, growth hormone
  • HBD, hormone binding domain
  • HDL, high density lipoprotein cholesterol
  • HRT, hormone replacement therapy
  • HSP, heat shock proteins
  • IGF-1, insulin-like growth factor
  • IGF-1R, insulin-like growth factor receptor
  • Int, initiator of transcription
  • iNOS, inducible nitric oxide synthase
  • JNK, C-jun N-terminal kinase
  • LDL, low density lipoprotein cholesterol
  • LVH, left ventricular hypertrophy
  • MAPK, mitogen activated protein kinase
  • MHC, myosin heavy chain
  • MI, myocardial infarction
  • MLC2a, myosin light chain-2a
  • NO, nitric oxide
  • NOS, nitric oxide synthase
  • NR, nuclear receptor
  • SHR, spontaneous hypertensive rat
  • SERM, selective estrogen receptor modulator
  • TAC, transverse aortic construction

Time for primary review 29 days.

1. Introduction

There are significant gender-based differences in the incidence of a wide variety of cardiovascular diseases [1,2], like left ventricular hypertrophy (LVH) or coronary artery disease (CAD) and subsequent cardiac remodeling after myocardial infarction (MI) [3,4]. Premenopausal women have a lower prevalence of LVH than their age-matched male counterparts [3]. For many years this was attributed largely to differences between men and women in body size and risk factor profiles. Careful analysis of the Framingham Heart Study data, however, has shown that left ventricular mass is significantly greater in men than in women even after indexing for body surface area [5]. The results of several recent studies demonstrating clinically relevant gender-based differences in the pathophysiology of hypertensive heart disease have raised new questions regarding the mechanisms responsible for the observed differences. The Coronary Artery Risk Development In young Adults (CARDIA) study demonstrated that the higher prevalence of LVH in men remains even after correction for a large number of risk factors and further demonstrated that these differences in left ventricular mass (or wall thickness) begin early in life. These studies suggest that gender-related intrinsic factors may modulate the response to pathophysiological factors that lead to LVH [6].

In retrospective studies, cardiovascular mortality in postmenopausal women receiving estrogen replacement therapy (ERT), with estrogen alone or in combination with progesterone, appears to be lower than in untreated women [7]. From this perspective, it appears that the hormone 17β-estradiol (estrogen) might play an important role in the prevention of heart disease by lowering low-density lipoprotein cholesterol (LDL), increasing plasma levels of high density lipoprotein cholesterol (HDL), promoting coronary vasodilatation, improving glucose metabolism and decreasing serum insulin levels. However, the effects of ERT on the risk factor profile only account for about 50% of the reduction in cardiovascular disease, indicating that there must exist additional mechanisms whereby estrogen exerts its cardioprotective action [8].

The therapeutic application of estrogen in heart disease is hampered by the fact that its fundamental myocardial actions are still poorly understood [6,8,9]. Estrogens increase vasodilation and inhibit the response of blood vessels to injury [4]. Estrogen induced vasodilatation occurs 5–20 min after administration and is not dependent on changes in gene expression: this action of estrogen is referred to as ‘nongenomic’. The estrogen-induced inhibition of the response to vascular injury and the preventive effect of estrogen against atherosclerosis occur over a period of hours or days after initiation of estrogen treatment and are dependent on tissue-specific transcriptional regulation. These actions are referred to as ‘genomic’ [10]. The pleiotropic, cellular actions of estrogen mainly result from binding of the hormone to intra-cellular estrogen receptors (ERs) [11]. Despite recent advances in our understanding of the vascular effects of estrogen, the mechanisms through which estrogen modulates cardiac (patho)physiology [12] are still poorly understood. The scope of the present review, therefore, is to summarize the recent insights on the nongenomic and genomic action of estrogen in the heart.

2. Molecular mechanisms of estrogens

2.1. Estrogen receptors

The main pathway of estrogen-mediated gene transcription is through the binding of estrogen (the ligand) to the ERs [10,13,14]. Two ER isoforms have been identified to date: ERα and ERβ [15,16]. ERα contains 595 amino acids, while ERβ is shorter than ERα, containing 530 amino acids [17]. Both ERα as well as ERβ belong to the nuclear receptor (NR) gene family of transcription factors. At the molecular level, NR structure can be subdivided into six distinct functional regions, which have been designated region A through F [18]. NRs have a N-terminal domain of variable length, termed the A/B domain (Fig. 1A) and this region displays the lowest homology among NR family members. The A/B region contains a ligand independent transactivation domain (AF-1), whereas a hormone-inducible transcription activating function (AF-2) is present within the hormone binding domain (HBD) of the E region [11]. Both AF-1 and AF-2 are required for maximal ER transcriptional activity.

Adjacent to the A/B domain is the DNA binding domain (DBD) or C domain, the most conserved region among NRs. This region contains two zinc finger motifs, in which the P-box confers DNA-binding specificity to the different NRs and is critical for target gene recognition (Fig. 1B). The C domain is linked to the hinge domain or D domain. The E domain is less well characterized and displays 53% homology among NR family members. Finally, the E/F domain is involved in heat shock protein (HSP) interaction, binding with NR (ant)agonist, dimerization properties, cofactor binding, nuclear localization and transactivation function [19]. Furthermore, ERβ lacks a large portion of the F domain [20]. It is known that this region is important for the (ant)agonistic effects of certain anti-estrogens [21]. The gene for ERα has three known polymorphisms, PvuII, XbaI, and B-variant polymorphisms [22–24]. In addition, the gene for human ERα contains a polymorphism in the regulatory region of the gene. The importance of ER polymorphisms is unknown in the heart. The presence of ERs were identified in atrial and ventricular myocytes and in cardiac fibroblasts and are operational in both the male and female myocardium. Both the α and β isoform are present in the human heart [16] as well as in rodents [6].

2.2. Transcriptional aspects

ERα and ERβ are capable of forming homodimers and heterodimers to stimulate downstream target genes [25]. The two ER subtypes also have distinct physiological roles, as suggested by their structural differences in the HBD. ERα homodimers and ERα/ERβ heterodimers are preferentially formed over ERβ homodimers [25]. ERs interact in a protein DNA manner with cognate DNA sequences called hormone responsive cis elements [26]. Upon estrogen binding the ligand–receptor complex recognizes the consensus sequence AGGTCA as a homo- or heterodimer and activates transcription [27] (Fig. 1C). Estrogen receptors may also suppress the transcription of selected target genes by interacting with corepressors [10].

Little is known about the role of accessory proteins, but they may be required for optimal interaction of ER with estrogen response elements (ERE) [28]. Heat shock proteins of 72 and 90 kDa (HSP70, HSP90) are thought to be involved in functional modulation of ER [29] for instance HSP70 is able to bind 17β-estradiol [30], and HSP70 expression is stimulated by estrogens [31]. Removal of HSP70 results in decreased hormone-ER/ERE association, which is restored by addition of purified HSP70 to the complex, suggesting that HSP70 may act as a transcriptional co-activator.

Fig. 1

Schematic representation of the human estrogen receptor (ER) α and β. (A) Indicated are the different functional regions (A/B, C, D, E and F) on top and ERα and ERβ depicted as diagrams. ERβ is distinct from the α receptor in that it has a shorter A and F region. The number of amino acid residues is indicated above the diagrams, which amount to 66 and 46 kDa for the α and β ERs, respectively, although different splice isoforms have been reported for both ERα and β which can give rise to smaller protein products. (B) ERα zinc finger organization. Circled residues indicate the P-box motif for ERα. (C) P-boxes of the different members of the nuclear receptor (NR) family and the corresponding DNA sequence recognition sites. (GR) Glucocorticoid receptor, (MR) mineralocorticoid receptor, (PR) progesterone receptor, (AR) androgen receptor, (RAR) retinoic acid receptor, (RXR) retinoid X receptor, (thR) thyroid hormone receptor, (VDR) vitamin D receptor, (PPAR) peroxisome proliferator-activated receptor, (SF-1 and FTZ-F1) orphan receptors.

Recent studies suggest that some genomic actions of estrogen cannot be attributed to either ERα or ERβ. For example, estrogen continues to protect against vascular injury in ERα and ERβ double knockout mice, suggesting the presence of a third receptor [32]. Orphan receptors or estrogen receptor-related receptors (ERR) are attractive candidates to fulfil this role. ERRs are members of the NR superfamily too, but their specific ligands remain to be uncovered and not required for activation. Indeed, ERR2 and ERR3 are able to bind specifically EREs and activate reporter genes under control of multimerized EREs [33]. Of interest, ERR-1 is expressed in the heart and vessels [34]. Taken together, ERR1 may interact with ER via protein–protein interactions [35], and may fulfil partially redundant functions to cardiac ERs in the control over cardiac (dys)function and pathology.

3. Estrogen signaling in the cardiovascular system

3.1. Genomic estrogen effects

The long-term, genomic influence of estrogen on the cardiovascular system mediated via ERα or ERβ, leads to changes in gene expression. Estrogen enters target cells and binds ERs located in the cytoplasm, which undergo conformational changes and translocate to the nucleus to modulate transcription of target genes [36]. Immunofluorescent staining confirmed the colocalized intracellular distribution pattern of both the α and β ER subtypes [37]. Genomic effects have a delay which is at least in the range of minutes to hours. For instance, nitric oxide synthase (NOS) expression in the myocardium is modulated by estrogen, resulting in both increased expression of inducible (i)NOS and endothelial (e)NOS in cardiomyocytes (Fig. 2A) [37]. The pure estrogen receptor antagonist ICI 182,780 inhibited estrogen-induced NOS expression in cardiac myocytes [37] and an earlier study reported that 17β-estradiol is capable of inducing eNOS gene expression in the endothelium [38]. In addition, ER, as well as the progesterone receptor, are able to regulate the transcription of the predominant gap junction protein in the myocardium, connexin 43.

Estrogen influences the level of the L-type Ca2+ channel gene expression. In ERα knock out (ERKO) mice, L-type Ca2+ channel mRNA and protein levels are upregulated, leading to a prolonged QT interval [39] and binding of a dihydropyridine Ca2+ channel antagonist to cardiac membranes was enhanced [39]. These findings coincided with increased action potential duration and an increased L-type Ca2+ current density in isolated ventricular myocytes from these mice [39]. However in patients with the long QT syndrome, no mutations have been found in Ca2+ channels or ERs.

Estrogen increases the expression of atrial natriuretic factor (ANF), which is known to possess anti-hypertrophic effects [40] and may therefore play a role in the modulation of the hypertrophic response in postmenopausal hypertensive heart disease. Estrogen is known to alter several systemic factors that may play a role in cardiovascular physiology and disease. Estrogen affects the renin angiotensin system by inhibiting ACE activity, thus preventing the generation of Ang II while increasing plasma renin and Ang I [41,42]. Gordon et al. [43] have demonstrated that estrogen treatment induces significant and rapid angiotensinogen mRNA production, which could be due to the presence of ERE in the promoter region of the angiotensinogen gene [44]. The proximal renin promoter also contains EREs [45]. Estrogen deficiency upregulates Ang II receptor subtype 1 (AT1) expression [47]. Taken together, it is tempting to speculate that the tissue renin and angiotensinogen response to estrogen depends on tissue-specific expression of genes containing either ERE and/or SP-1 sites [46].

Fig. 2

ER activation of gene expression. (A) Depicted are estrogens entering the cell by passive diffusion and binding to intracellular ERs α and β. These receptors undergo conformational changes, form homo or heterodimers and bind to specific sites in the control regions of their target genes (estrogen responsive element) affecting the transcription of genes. (B) Mechanisms of rapid (non-genomic), estrogen-mediated activation of NO pathways. Indicated is the activation of putative plasma membrane ERs, which results in coupling of the ER with NOS by G protein αI and increasing NO production. NO activates guanylyl cyclase that stimulates cGMP formation and subsequent cGK activation. One downstream effect of cGK activation is the opening of calcium channels and relaxation effects on the cell. (C) Interaction between ER and IGF-1R signaling cascade. ERα binds to estrogen and activates IGF-1R, which in turn activates ERK1/2 MAPK. ERK1/2 stimulates the activity of ERα.

3.2. Non-genomic estrogen effects

A number of reported cellular effects of estrogen develop in such a rapid fashion, that they are unlikely to be a consequence of altered gene expression. In contrast to the genomic effects of estrogen, signal transduction pathways of non-genomic estrogenic effects on the myocardium have been much less well characterized. Some effects seem to depend on the presence of the classical ER α and β while others are ER independent (Fig. 2B). There are some indications that membrane impermeable ligand variants (estrogen coupled to BSA) have the ability to modulate L-type Ca2+ channels via a cGMP-dependent pathway [48]. Here estrogens bind to the external surface of the membrane of endometrial cells [49] or to a membrane receptor on pituitary tumour GH3/B6 cells and increases calcium release [50]. Although there is no direct evidence of a membrane ERs, data reporting on the non-genomic action of estrogen in various cell types of the vascular system [51] including cardiomyocytes [52] suggest that estrogen may act via a membrane-bound type receptor through G protein αi [51] (Fig. 2B).

An acute relaxing action of non-physiological μM concentrations of estradiol on precontracted vascular smooth muscle tissue has been demonstrated [53,54]. The relaxation was not dependent on the presence of the nuclear ERs and was accompanied by a lower Ca2+ influx into endothelium denuded arteries [53,55]. The reduced influx seems to be due to a partial block of L-type calcium channels by estrogen [54,56,57].

Comparable μM concentrations of estrogen were associated with reduction of the contractile force in the heart, e.g., in human atrial trabeculae and ventricular papillary muscles [58] as well as shortening of ventricular myocytes [59], which may be explained by an estrogen-mediated reduction in L-type Ca2+ current conductance as measured in the guinea pig [60,61], rat and human [61]. In addition, studies on whole hearts revealed that μM concentrations of estrogen produced an acute dose-dependent decrease in sinusoidal frequency in rabbit and rat heart [62]. The Ca2+ antagonistic influence develops within seconds [61] and may be induced by estrogen without ER involvement [55]. Cardiac L-type Ca2+ currents are sensitive to NO via a cGMP signaling cascade [63], suggesting one plausible mechanism through which estrogen is able to influence L-type Ca2+ current density. Indeed, estrogen causes a rapid release of NO in endothelial cells [64] as well as adenylate cyclase activation [65]. Recently Wyckoff et al. [51] showed a role for G protein αi in coupling plasma membrane receptor to eNOS.

In coronary arteries, an increase of intracellular cGMP may lead to phosphorylation of K-channels by means of the cGMP-dependent protein kinase (cGK) and this phosphorylation event increases the open-state probability of K-channels [66]. The hyperpolarization started 15–20 min after addition of estrogen to the organ bath. Estrogen (5–10 μM) is capable of enhancing the open probability of BKCa [67], and this effect was dependent on cGMP, and evident 30–60 min after addition of the hormone [68]. Conclusively, these studies suggest a role for estrogen in potassium channel regulation.

With respect to intracellular signalling, ER-dependent transcriptional activity has been shown to be uniquely sensitive to extracellular signal regulated protein kinase (ERK1/2), but not p38 MAPK phosphorylation [69]. These findings are of particular interest in view of the recent findings that selective ERK1/2 activation in the heart is correlated with relatively benign forms of hypertrophy in transgenic mice [70], while p38 MAPK activation is more closely associated with malignant forms of (pressure overload) hypertrophy. Furthermore, steroid hormone receptors can be activated by peptide growth factors in the absence of steroid hormone [71]. There is evidence for a level of cross-talk between ERs and insulin-like growth factor (IGF) signal transduction pathways (Fig. 2C). Indeed, IGF-1 shares important properties with estrogen in the control of cellular proliferation. IGF-1R activation stimulates MAPKK and consequently phosphorylation of ERK1/2. Activation of ERK1/2 may, in turn, lead to phosphorylation of ERα and this may provide a plausible mechanism for ligand independent activation of ERα [72]. Other peptide growth factors like epidermal growth factor (EGF) are able to mimic estradiol actions in a similar fashion [73]. Conclusively, there is evidence to suggest that the nongenomic effects of 17β-estradiol may impinge on cardiac NO metabolism, ion homeostasis and intracellular signal transduction pathways.

4. Role of estrogens on cardiac physiology

4.1. Hemodynamic influences

Significant gender differences exist in baseline cardiovascular function [74]. A number of studies have shown that healthy women have higher ejection phase indices compared to healthy age-matched men [75]. Moreover, normotensive women tend to have a greater afterload-corrected fractional shortening under the age of 55 years [76]. Experimental animal studies support this notion. Papillary muscles from female rats have higher rates of shortening than male [77]. Pines and co-workers [78] found that premenopausal women have a higher pressure–volume ratio, ejection fraction and ejection rate when compared to postmenopausal women. Hormone withdrawal leads to a significant fall in aortic peak flow velocity, mean aortic acceleration time and cardiac index [79]. Using gonadectomised rats, Schaible and Scheuer [80] demonstrated a decreased ejection fraction, fractional shortening and ventricular mass in estrogen-depleted female animals.

In addition to the globally improved cardiac function found in females under physiological conditions, gender influences vascular homeostasis. Women have a higher arterial compliance than men until the age of 50, after which arterial stiffness increases [81]. In spontaneously hypertensive (SHR) rats, low doses of estrogen reduce arterial collagen and stiffness [82]. Male rabbits exhibit reduced vascular relaxation compared to their female counterparts [83]. The effects of peripheral injection of estrogen on autonomic tone and reflex control of heart rate can be antagonized by central injection of the ER antagonist ICI 182 780 [84]. In conclusion, there is evidence to suggest that estrogens may positively modulate vascular homeostasis and myocardial function, and hemodynamic function differs in a gender-dependent fashion, with distinct profiles in pre- and postmenopausal females.

5. Role of estrogens in cardiac pathology

5.1. Hypertrophy

Limited information is available about early changes occurring in the left ventricle during pressure overload [85]. Cardiac hypertrophy occurs in response to either pressure or volume overload. In response to this hemodynamic stress, myocytes enlarge until wall stress is normalized. However, myocyte lengthening with addition of new sarcomeres in series is sometimes prevailing, leading to eccentric forms of hypertrophy, in which ventricular chamber dilation is accompanied by a proportional or even reduced increase in wall thickness. Lateral expansion of myocytes with the addition of new sarcomeres in parallel presents the typical pattern of myocyte growth after pressure overload (concentric hypertrophy), in which wall thickness increases with minor chamber enlargement [86]. Reactive compensatory hypertrophy after myocyte loss (e.g., in the non-infarcted portion of the heart following an acute MI) is characterised by different degrees of myocyte lengthening and widening [86].

LVH is associated with an increased frequency of ventricular arrhythmias in the absence of CAD [87]. The terminal phase of hypertrophy is the initiation of heart failure, a common cardiac disorder with a highly unfavourable outcome [88]. Experimental data from clinical studies and animal models suggest that estrogen may modulate cardiac hypertrophy [89]. In fact, estrogen deficiency potentiates, while estrogen replacement attenuates the development of both right and left ventricular hypertrophy in rodent models of LVH [90]. Estrogen treatment attenuates myocyte hypertrophy, as determined by cross-sectional area [91].

We have recently demonstrated that estrogen attenuates the hypertrophic response to pressure overload in mice [12]. Female, ovariectomized C57BL/6 mice were randomised to receive either a physiological dose of 17β-estradiol or placebo for 1 week before they underwent transverse aortic constriction (TAC) or a sham operation. Estrogen supplementation reduced pressure overload hypertrophy by 31 and 26% compared to placebo at 4 and 8 weeks after TAC. Estrogen-supplementation had no effect on the degree of interstitial fibrosis in the hypertrophied hearts. Western blot analysis revealed that estrogen blocked TAC-induced p38 MAPK activation, while no effect was observed on the activation of ERK1/2 and c-Jun N-terminal kinase (JNK). Interestingly, estrogen treatment led to an increased expression of ANF in animals with pressure overload [12].

5.2. Heart failure

Congestive heart failure is a major clinical problem resulting in significant morbidity and mortality [92]. Although considerable progress has been made elucidating the pathophysiological mechanisms that lead to failure, many details concerning the etiology and progression remain unknown [93]. Heart failure is in part due to ventricular dilation and inadequate wall thickening that leads to impaired cardiac performance [94]. Hypertension is associated with the development of congestive heart failure by excessive stimulation of LVH. Reports on the natural history of untreated hypertension indicate that at least 50% of subjects develop congestive heart failure [95]. The adaptive changes of the heart withstand the deleterious effects of cardiac overload only temporarily. The ensuing heart failure demonstrates insufficient adaptation of the heart to overload to maintain proper excitation-contraction coupling [96]. Changes in the content and isoforms of proteins involved in Ca2+ handling, sarcomeric function and in extracellular matrix composition may all contribute to impairment of diastolic and systolic function of the heart [97]. Hypertensive and ischaemic heart disease are by far the most common causes of heart failure and is associated with pronounced systolic dysfunction, although some patients, particularly elderly female, have diastolic dysfunction [98]. MI may lead to ventricular remodelling with compensatory dilation and hypertrophy and subsequent systolic and diastolic dysfunction resulting in failure [98]. Although studies on the effect of estrogen on the cardiovascular function in animals with heart failure are very few, chronic administration of estrogen in rats with sustained heart failure reduced total peripheral resistance and left ventricular end-diastolic pressure [99]. The systemic effects of estrogens are favourable in animal models with cardiac failure.

The epidemiological evidence of protective effects of estrogens against heart failure in man is strong. Currently the specific molecular pathways are unknown, but prevention of cardiomyocyte apoptosis may play a role [100].

5.3. Myocardial ischemia

Ischemia results in cardiac injury ranging from short-term reversible contractile dysfunction to cellular necrosis and infarct with irreversible loss of function. Intermediate is myocardial prolonged reversible contractile dysfunction [101]. A consistent male to female ratio for CHD death rates ranging from 2 to 5 in a population with very different heart disease rates and lifestyles has suggested that sex hormones have a significant influence on the vasculature [102]. Sex hormone replacement might reduce coronary mortality in postmenopausal women. This hypothesis is supported by a number of retrospective and observational studies demonstrating an inverse relationship between estrogen use and coronary event end points such as MI and death from ischemic heart disease [103–105]. Acute administration of estrogen by either the intramuscular or intracoronary route similarly prevented ischemic [106,107] and reperfusion [107] arrhythmias and reduced infarct size [107]. Importantly, estrogen also increased distal coronary perfusion during both ischemia and reperfusion [106]. ERT, which provides exogenous estrogen to postmenopausal women, increases the circulating estrogen concentration and significantly decreases the morbidity and mortality of coronary heart disease in these patients [108]. Thus estrogen appears to preserve endothelium-dependent coronary artery dilation and reduce infarct size, in experimental models of regional ischemia-reperfusion [107,109]. Estrogens appear to be cardioprotective under ischemic conditions, probably due to improved vascular function.

6. Hormone replacement therapy and human studies

Evidence from multiple observational studies suggested a marked reduction in the risk of CHD associated with postmenopausal estrogen use in primary prevention. A similar effect was observed when estrogens where opposed with progestins. Recently published studies suggested 30 and 34% reduction in the risk among users of unopposed and opposed therapy, respectively, compared to non-users [110]. Current and recent use of hormone replacement therapy (HRT) was associated with an overall 28% reduction in the risk of first MI when compared with non-users [111]. In the Nurses health study there was still a strong inverse association between current HRT and the risk of CAD after controlling for many risk factors [111]. The risk of major coronary disease was substantially decreased among current users of estrogen and progestin, as well as among current users of estrogen alone [104]. Still some null finding is present in the literature, Hulley et al. [112] found during 4.1 years, that treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease (HERS: Heart and Estrogen/Progestin Replacement Study). Also The CARS (Coumadin Aspirin Reinfarction Study) showed unexpected results. In this study the incidence of unstable angina was markedly increased [113]. Contradiction of these findings with the observational studies could be because of the CAD risk profile and the duration of ERT, which is supposed to be preventive rather than curative.

Other compounds in clinical use can activate estrogen receptors. Tamoxifen a non-steroidal triphenylene derivative used in treatment of breast cancer, acts as an estrogen agonist in some tissues (e.g., the uterus) but as estrogen antagonist in other tissues (e.g., the breast). Tamoxifen has also estrogen like effects on the cardiovascular system [114]. It does produce a significant reduction in the levels of low-density lipoprotein (LDL) cholesterol and fibrinogen [115]. Randomised, placebo-controlled clinical trials showed a rapid and sustained reduction in LDL cholesterol levels by approximately 12% accompanied by 15% increase in high density lipoprotein-2 cholesterol. Raloxifene reduced serum triglycerides and serum fibrinogen levels by 7 and 10%, respectively [116]. Toremifene, droloxifene, idoxifene, TAT-59, and GW5638, are known to have similar action to tamoxifen while Ly353381 showed a clear similarity to raloxifene. ICI 182,780 demonstrates a pure antiestrogenic profile on all genes and in all tissues studied to date, and could be a superior antitumour agent [117].

Many phytoestrogens with mixed estrogen agonist and antagonist properties have been identified [118]. Soy consumption significantly decreased total cholesterol, LDL Cholesterol, and triglyceride levels. The cardiovascular benefits of soy phytoestrogens appear to be equal for males and females [119]. All heart studies thus far focused on vascular effects and not on a possible influence of estrogen on left ventricular mass.

7. Conclusions

Cardiac hypertrophy, MI and heart failure are important clinical problems in the industrialised countries. Although several methods of control and treatment have improved our clinical care, new therapeutic targets are still needed. Clinical data indicates that estrogen may have beneficial short and long-term cardiovascular effects; thus, it is important to consider the role of estrogen as a therapeutic agent for the treatment of cardiovascular diseases. The mechanisms that mediate the rapid effects of estrogen are not fully understood, but current data suggest involvement of enhanced NO release, effects on calcium handling and regulation of potassium currents. The long-term effects of estrogen are due to changes in cardiomyocyte gene expression, mediated by ERα and ERβ. The identity and effects of these target genes remain to be uncovered. Direct myocardial effects of physiological estrogen levels on cardiac structure and function appear to be of great value. Still a large number of questions remains to be addressed such as the various estrogen-dependent pathways, cross-talk and phenotypical consequences. Selective estrogen receptor modulators (SERMs) should be studied and classified according to their effects on the cardiovascular system and some of them could be selected to be used as alternatives for HRT. These SERMs could be more appropriate tools for the future treatment of selected heart diseases.


The authors were supported by grants from The Netherlands Heart Foundation (NHS 99-114), the Interuniversitary Cardiology Institute Netherlands (to P.A.D.), the Deutsche Forschungsgemeinschaft and BONFOR 0-708 (to C.G.). L.J.D.W. is supported by a Bekales Foundation Award in Cardiology and The Netherlands Foundation for Scientific Research (NWO 902-16-275).


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