Associate Editor: J.L. Turgeon
Estrogen and the cardiovascular system

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Abstract

Estrogen is a potent steroid with pleiotropic effects, which have yet to be fully elucidated. Estrogen has both nuclear and non-nuclear effects. The rapid response to estrogen, which involves a membrane associated estrogen receptor(ER) and is protective, involves signaling through PI3K, Akt, and ERK 1/2. The nuclear response is much slower, as the ER-estrogen complex moves to the nucleus, where it functions as a transcription factor, both activating and repressing gene expression. Several different ERs regulate the specificity of response to estrogen, and appear to have specific effects in cardiac remodeling and the response to injury. However, much remains to be understood about the selectivity of these receptors and their specific effects on gene expression. Basic studies have demonstrated that estrogen treatment prevents apoptosis and necrosis of cardiac and endothelial cells. Estrogen also attenuates pathologic cardiac hypertrophy. Estrogen may have great benefit in aging as an anti-inflammatory agent. However, clinical investigations of estrogen have had mixed results, and not shown the clear-cut benefit of more basic investigations. This can be explained in part by differences in study design: in basic studies estrogen treatment was used immediately or shortly after ovariectomy, while in some key clinical trials, estrogen was given years after menopause. Further basic research into the underlying molecular mechanisms of estrogen's actions is essential to provide a better comprehension of the many properties of this powerful hormone.

Introduction

Estrogen is a potent steroid hormone present in high levels in females from adolescence to menopause and in low levels in men. Much anecdotal evidence accumulated over many years had supported the idea that estrogen post-menopause reduced cardiovascular disease. In the 1990s several double blind, controlled trials of estrogen replacement post-menopause were conducted including the Women's Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study (HERS) (Hulley et al., 1998, Grady et al., 2002, Writing Group for the Women's Health Initiative Investigators, 2002). These studies showed an increased risk of both cancer and cardiovascular disease in those taking estrogen replacement. However scrutiny of these studies led to recognition of a possible cause of lack of estrogen efficacy based on the design of these studies, as a result of the effort to enroll women who definitely were post-menopause; 10 years had elapsed on average between menopause and the onset of estrogen replacement in these studies. This realization led to the development of the timing hypothesis (Grodstein et al., 2003, Dubey et al., 2005, Barrett-Connor, 2007). This hypothesis proposed that the prolonged delay after the onset of menopause led to significant tissue and gene expression changes, such that late estrogen replacement post-menopause was occurring in a markedly different tissue state than 10 years earlier, when estrogen production ceased.

A second issue in hormone replacement therapy (HRT) is the type and route of hormone replacement. The current review focuses on estrogen; however the combination of progesterone and estrogen has been addressed elsewhere by others (Canonico et al., 2010, Tchaikovski and Rosing, 2010). Estrogen is a potent steroid hormone with 17β-estradiol (E2) being the most active metabolite. There are two key issues in hormone replacement. First, the oral delivery of estrogen results in high hepatic levels of estrogen from first pass metabolism, which can stimulate protein synthesis and appears to be associated with increased risk of thrombosis compared to transdermal delivery, though this remains controversial (Bagot et al., 2010, Canonico et al., 2010, Tchaikovski and Rosing, 2010, Olié et al., 2011). Estrogen will, through its nuclear properties, change hepatic gene expression and can potentially effect expression of genes involved in coagulation. Estrogen replacement using a transdermal patch avoids the first pass surge in hepatic estrogen levels and may have less complications, though some controversy remains. Second, conjugated equine estrogen (CEE) is the most commonly used estrogen compound for HRT. CEE is derived from the urine of pregnant mares and includes estrogen compounds not found in humans. The composition of CEE differs significantly from the estrogens found in premenopausal women. Different estrogens differ in their binding affinities and selectivity for the estrogen receptors (ER); consequently they have different downstream effects. These differences could have a significant impact on the effects of HRT. CEE contains sodium estrone sulfate, sodium equilin sulfate, and sodium 17α-dihydroequilenin, but no 17β-estradiol, the major and most potent form of estrogen found in premenopausal women (Booth & Lucchesi, 2008). Recently estrone levels have been linked with thrombin generation, a central step in the coagulation cascade, in postmenopausal women (Bagot et al., 2010). Thus, estrones have the potential to greatly increase the risk of thrombosis, and as CEE contains a large amount of estrones, CEE would be expected to be associated with an increased risk of thrombotic events. However, the studies in this area are limited and it is premature to draw definitive conclusions.

Estrogen is a complex hormone with pleiotropic effects. Basic research is essential to understand the underlying cell and molecular mechanisms of estrogen's actions and to gain insight into the clinical effects of estrogen. This review will focus on basic cardiovascular research on estrogen, which provides the underpinning for our understanding of the clinical effects of this hormone.

Section snippets

Aging, inflammation and fibrosis

Aging and estrogen loss are indelibly linked. Aging is associated with inflammation and increased inflammatory serum cytokines such as TNF and IL-6 (Donato et al., 2008, Chung et al., 2009). Aging is also associated with increased oxidative stress and a blunting of the protective heat shock response in males and females (Fawcett et al., 1994, Locke and Tanguay, 1996, Gutsmann-Conrad et al., 1998, Jackson and McArdle, 2011, Stice et al., 2011). In the cardiovascular system, aging is accompanied

Estrogen receptors

There are two established estrogen receptors, α and β (Fig. 1). Differences in tissue distribution in these receptors are thought to modulate tissue response to estrogen, but this remains to be proven. Post-translational modifications may be important modulators of receptor function, but studies in this area have been limited. Several differences between ERα and β have been identified in the cardiovascular system, as will be discussed. These differences are summarized in Table 1.

ERα and β are

Genomics of estrogen and the cardiovascular system

Estrogen is an important modulator of gene expression; both estrogen receptors act as transcription factors and as inhibitors of gene expression. Despite these important functions, studies of the effect of estrogen on gene expression have been surprisingly limited. In Sprague Dawley rat hearts, heat shock protein (HSP) 72 levels are increased in the female heart vs. the male. It takes 9 weeks post-ovariectomy (ovx) for the level of HSP72 in the female heart to drop to the level in male hearts (

Estrogen and the vasculature

The vasculature is the site of critical changes with aging and estrogen loss including increased atherosclerosis and abnormal function (relaxation and constriction). Endothelial cells as well as VSMCs are important targets of estrogen. Thus, changes in estrogen and aging particularly impact the vasculature (Fig. 3).

Atherosclerosis

Premenopausal women have a much lower incidence of cardiovascular disease than males. Estrogen has a very positive effect on lipoprotein profiles, lowering LDL and raising HDL. This has been estimated to contribute about 30% of the cardiovascular benefit in premenopausal women (Mendelsohn & Karas, 1999). Post-menopause women have a rapid acceleration of atherosclerosis and an increase in LDL and decrease in HDL, all accompanied by an increase in the prevalence of coronary artery disease. Vital

Gender differences in cardiac disease

Premenopause women have a much lower rate of myocardial infarction than men, but post-menopause the rate of atherosclerosis and infarction greatly increases. Although estrogen is well known to improve lipid profiles, as discussed, other factors are involved in the gender differences in cardiovascular mortality (Fig. 4). For cardiac rupture the gender differences are reversed. Female patients with myocardial infarction are more likely to have cardiac rupture, an often deadly complication (

Estrogen, the extracellular matrix and cardiac remodeling

Following injury such as myocardial infarction, the heart undergoes extensive adverse remodeling. This is also seen in the pathologic (vs. physiologic hypertrophy with exercise or pregnancy) hypertrophy associated with hypertension. Prevention or modification of this pathologic hypertrophy can have significant benefits in terms of symptom relief and potentially prolongation of survival. Estrogen has a significant and important effect on myocardial hypertrophy and remodeling, which is just

Mitochondria and estrogen receptors: signaling role?

A number of studies indicate that estrogen may affect the cardiac mitochondria directly. In addition to their presence in the nuclei and plasma membrane, ERα and ERβ also localize to the mitochondria of a number of cell types and tissues in both males and females. ERβ has been studied in a wider variety of cells, including rat primary cardiomyocytes (Yang et al., 2004, Pedram et al., 2006, Simpkins et al., 2008). The known actions of estrogen on mitochondria are predominately carried out by

Estrogen, ischemia and cardiac protection

There is a substantial literature demonstrating that estrogen can protect the heart from ischemic injury and this has been the subject of several excellent reviews (Booth and Lucchesi, 2008, Ostadol et al., 2009, Deschamps et al., 2010). Table 3 summarizes the results of many of the studies investigating whether estrogen protects against cardiac injury. Both ERα and ERβ have been shown to mediate cardiac protection against ischemia/reperfusion injury through both knockout models and the use of

Experimental models and issues

Aging and estrogen status are inexorably linked. Estrogen loss occurs with aging. Menopause has onset on average at age 54, middle age in women, who generally are expected to live into their 80s (www.socialsecurity.gov). However basic estrogen research predominantly uses adolescent models, for example 6–8 week old mice. The relevance of these models to changes that occur with aging is questionable. Even elective ovx for medical indications occurs most commonly in a middle aged population. Thus,

Summary

Estrogens are complex hormones with pleiotropic effects. E2 is the most potent estrogen found in humans. Two ERs regulate the nuclear responses to E2, leading to significant changes in gene expression. Essential non-nuclear responses to E2 include eNOS activation with increased production of NO and activation of a cardio-protective signaling cascade including Akt and MAP kinases. Late estrogen replacement, similar to recent clinical trials, increased expression of inflammatory genes and those

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgment

This study was supported by a VA Merit Award (AAK), HHMI-MIG (ARL) and T32-86350 (ARL).

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