Estrogen: The Current Status and the Future Role in Postconditioning Protection to the Heart

Review Article

Austin J Musculoskelet Disord. 2014;1(2): 1009.

Estrogen: The Current Status and the Future Role in Postconditioning Protection to the Heart

Fawzi A Babiker*

Department of Physiology, Faculty of Medicine, Kuwait University, Kuwait

*Corresponding author: Fawzi A Babiker, Department of Physiology, Faculty of Medicine, Kuwait University, B. O. Box 24923 Safat, 13110 Kuwait

Received: September 15, 2014; Accepted: October 15, 2014; Published: October 16, 2014


Ischemic Heart Disease (IHD) is one of the leading causes of worldwide morbidity and mortality. Reperfusion was the first procedure used to rescue the ischemic heart; however, this procedure is associated with subsequent reperfusion injury. Ischemic Preconditioning (IPC) was introduced as an intervention to protect against the potential injury before the insult occurred. Yet, the application of IPC in the clinic was limited because the onset of ischemia is not predictable and neither was the amount of damage caused by the event. Thus, Ischemic Postcondtioning (IPOC) was introduced as an intervention immediately following reperfusion in order to surpass the shortcomings of preconditioning translation in the clinic. Several methods and procedures were used in postconditioning, among them are postconditioning with estrogen (17-β estradiol (E2)) and Selective E2 Receptors Modulators (SERMs). However, the role of E2 is controversial and its research was challenged by the unexpected outcomes of two large clinical trials (heart and Oestrogen/progestin Replacement Study (HERS) and Women’s Health Initiative (WHI). Controversy still exists regarding the results of the experiments using E2; however, many scientists still believe that the potentials of E2 are yet to be unraveled. The aim of this review is to highlight the use and effects of E2 in postconditioning, as well as its possible use in future clinical research.

Keywords: Oestrogen/postconditioning; Ischemic heart disease; Ischemic preconditioning; selective estrogen receptors modulators


Ischemic heart disease (IHD) is known to be the leading cause of death in industrialized countries and among the leading causes of morbidity and mortality worldwide [1]. The prognosis of IHD is always running hand in hand with the size of the infarcted area. Indeed, big infarcts are associated with poor prognosis and mortality [2,3]. The first procedure introduced to protect the heart from ischemic injury is reperfusion, which is the reintroduction of blood to the ischemic part of the heart. However, this method of intervention adds to the ischemic damage by causing reperfusion injury [4]. Nevertheless, this method was the only way out for heart protection in the clinic for a long period of time. Various developments in the protective regimen of reperfusion were introduced within the past decades. Several drugs were used as pharmacological treatments to assist reperfusion and to decrease Ischemic Reperfusion (I/R) injury [5].

After the use of reperfusion with its various methods for quite some time, Murry et al. [6] introduced a new procedure of heart protection targeting I/R injury. In this procedure they showed that the heart is likely protected from I/R damage if it is challenged with brief, repetitive, ischemia before the major potentially lethal ischemic event. This technique was later called Ischemic Preconditioning (IPC), which is a repetitive ischemia reperfusion before the major ischemic insult. The protection by the IPC was shown to occur at two different time points, later named windows of protection. One of these is a very short window of 1-3 hours immediately after the IPC intervention, during which any ischemic challenge can be tolerated. The second window starts 12-24 hours IPC and lasts for 2-3 days [7]. Unfortunately, this method of protection cannot be translated in the clinic due to the lack of determination of ischemic attack onset in a healthy population. However, this method could be applied in coronary or cardiac surgery where the ischemia is expected [8,9]. Preconditioning was intensely studied to unravel the underlying mechanisms, which might be used in the protection of the heart against I/R injury. The studies done on its triggers, downstream effectors, and pathways formed the first building blocks for the future methods of heart protection against IHD. About two decades after the discovery of preconditioning, another novel technique of protection was introduced by Vinten Johansen’s group which is repeated episodes of ischemia immediately at the beginning of reperfusion [10]. This procedure resulted in a protection similar to that obtained by IPC and was named Ischemic Postconditioning (IPOC) as it is applied after the ischemic insult [10].

Recently, it has been shown that acute treatment with estrogen (17- β estradiol (E2)) protects the heart against I/R injury [11]. However, in vivo long-term E2 treatment before ischemia did not show any protection against I/R injury [12]. Although the cardioprotective effects of E2 Replacement Therapy (ERT) are still controversial [13,14], E2 pharmacological treatment in preconditioning was found to be feasible in different species [15,16] and in humans [17]. Some researchers, in an attempt to avoid the controversy and the discrepancy shown in the use of E2 started to use Selective Estrogen Receptors Modulators (SERMs). The phytoestrogen genistein was shown to protect the heart against IHD when applied at the beginning of reperfusion [18]. The research on E2 in postconditioning seems to be jeopardized by the decreased popularity of ERT after the negative results obtained in the two large scale epidemiological studies (Heart and E2 Replacement Study (HERS) [19] and Women Health Initiative Study (WHI) [19]. However, several investigations using E2 have shown encouraging results in animal and human studies [15,16,20,21]. Several studies in pre- and postconditioning are expected to be planned by our group and others in the near future. This will require a better understanding of the present E2 research and new areas of interest in the future of pre- and postconditioning E2 research. In this review, we aimed at determining the importance of E2 in pre- and postconditioning by considering gender differences, the effect of presence and withdrawal of E2, and long- and short-term E2 treatment on the outcome of pre- and postconditioning protection. The review of the available literature in the field of E2 in pre- and postconditioning may help illuminate the role of E2 role in these methods of protection and suggest possible translation to clinical research. The aim of the present review, therefore, is to review the recent literature on the use of E2 and its effects in protection of the heart against I/R injury and its future role in postconditioning protection to the heart.


For this review we used Google scholar search engine and PubMed and Scopus databases for searching literature relevant to our review. We used ischemia, ischemia reperfusion, preconditioning, postconditioning, pharamcological postconditioning remote postconditioning and pacing postconditioning as keywords for our search. The recent findings cited in our review manuscript were presented in the references list given at the end of the manuscript

Ischemic Heart Disease and its Associated Complications

Ischemic heart disease is a complex disorder that is associated with various systemic diseases and conditions [22]. The risk of getting this life-threatening condition increases with age, smoking, hyperlipidemia, hypertension, obesity, insulin resistance, and diabetes [22]. Generally, IHD develops as a consequence of reduction or stop of blood supply to the myocardium [4]. Atherosclerosis is reported to be the major cause of this problem of blood supply [23]. The prognosis of IHD depends mainly on the severity of the disease itself [22]. Overtime, in presence of atherosclerosis, the heart might be weakened the consequences of ischemia ending up eventually in heart failure [4]. One of the potential effects of ischemia is stunning which is a reversible post-ischemic contractile dysfunction that may negatively affect the viability of the myocytes [24]. Calcium overload and ROS were proven to be essential inducers of the myocardial stunning [25,26]. Furthermore, ischemia was documented to be a cause for arrhythmia and sudden cardiac death [27]. Elevated intracellular calcium and generation of Reactive Oxygen Species (ROS), which were induced by ischemia were recognized as crucial causes for arrhythmia. Increased cytosolic calcium has been shown to be responsible for the genesis of early and delayed after depolarization contributing to the arrhythmias [28]. Additionally, ROS were reported to be directly associated with myocardial arrhythmias events [29].

Estrogen as a Hormone and a Therapeutic Drug

However, a lot of controversy exists in E2 studies, significant gender differences were elucidated in basic cardiovascular functions [30]. Many experimental animal studies demonstrated presence of a better papillary muscle shortening in the female rats compared to males [31]. These notions were supported by clinical studies that showed a greater myocardial and left ventricle chamber functions in women compared to men [32]. Furthermore, a higher mass-to-volume ratio was reported in men, showing a higher myocardial mass in men compared to women [33]. These gender differences shown in heart functions are mediated by E2. However, some studies reported a lack of influence of E2 decrease or withdrawal on heart functions [34]. In contrast, a significant fall in aortic peak flow velocity, mean aortic acceleration time, ejection fraction, fractional shortening and ventricular mass was demonstrated after E2 hormone withdrawal [35]. Gender also imposes evident influences on the vascular homeostasis, demonstrated by a higher arterial compliance in women compared to men [36]. Estrogen is also known to reduce arterial collagen and stiffness resulting in a more distensible blood vessel [37]. Interestingly, impairment of endothelium-dependent vasorelaxation induced by atherosclerosis was proved to be gender dependent, with females showing a better relaxation than males [38]. However, some other hormones are involved [39,40], there is a strong evidence that suggests protective effects for E2 against cardiac hypertrophy [41]. Presence of E2 was proven to abrogate and its deficiency potentiates, the development of left ventricular hypertrophy [42]. Indeed, a rapid induction of LV hypertrophy was reported in men compared to women [43]. In a previous study we also demonstrated blockade of LVH. By a pathway involving atrial natriuretic peptide [44].

Ischemic heart disease is one of the key inducers of heart failure, therefore its control is essential in the regression of disease. Estrogen was reported to play a protective role against this serious disease [45]. Observational studies demonstrated an inverse relationship between E2 use and myocardial infarction and death from ischemic heart disease [46,47]. Administration of E2 prevented ischemic [48] and reperfusion [49] arrhythmias and reduced infarct size [50]. Importantly, E2 also increased distal coronary perfusion and other hemodynamic functions of the heart during reperfusion [50]. Use of exogenous E2 by postmenopausal women, significantly decreased myocardial infarction, heart failure and the morbidity and mortality following IHD [51]. In experimental animal models of I/R, E2 was shown to improve coronary artery dilation and spare the myocardium [50].

Mechanisms of E2 Signaling in Pre- and Postconditioning

The controversy that exists in the knowledge of E2 pathways and their protective role in the cardiovascular system dictates the importance of the E2 research. The presence of E2 throughout a long period of time (premenopause) and its absence during a considerable period (postmenopause) in females, necessitates the investigation of the effects of its presence and withdrawal on the outcome of diseases, their control, and treatment. Pre- and postconditioning, as very important methods of protection against IHD, require significant knowledge of E2 influence in order to incorporate their use in the clinic. Estrogen, in its protective role against heart disease, is believed to function by genomic and non-genomic pathways [35]. Genomic transduction pathways of E2 are mediated by the classical E2 receptors (ERs) alpha (ERα) and beta (ERβ) [35]. These pathways are usually of slow effect, requiring time ranging from minutes to hours [52]. However, non-genomic actions of E2 are mediated by membrane ERs through a G protein-coupled receptor and do not require gene transcription [53-55]. These non-genomic pathways of E2 are involved in rapid vasodilatation [56], inhibition of vessel injury [57] and reduction of I/R injury [58]. Recently a G protein-coupled receptor 30 (GPER30) was shown to bind E2 and cause protection via non-genomic signaling [59,60].

Although the mechanisms of protection of preconditioning and postconditioning are not completely understood, both seem to follow the same signaling pathways resulting in protection [20,61]. Preconditioning and postconditioning depend mainly on the instant regulation of specific elements, which activate other downstream elements or the final effectors ending in protection [62,63]. However, their individual methods and times of application are completely different occurring either before or after the insult respectively [20,61]. Up to date the most important components of the protection pathways known today include adenosine (A1) [64,65] and angiotensin II (AT1) receptors [66]; opening of Mitochondrial Potassium mito KATP channel [67,68] and sarcolemmal potassium (sarc KATP) [20] channels; activation of protein kinase C (PKC) [69,70] and PI3K-Akt [69,71,72]; prevention of the opening of the mPTP [71,73,74]; production of ROS [75,76]; and induction of NO [77,78] (Figure 1 and Table 1). However, the arrangement of these components within signaling cascades is not completely understood.

Citation: Babiker FA. Estrogen: The Current Status and the Future Role in Postconditioning Protection to the Heart. Austin J Musculoskelet Disord. 2014;1(2): 1009. ISSN:2381-8948