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European Journal of Heart Failure 2003 5(2):113-116; doi:10.1016/S1388-9842(02)00255-6
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© 2002 European Society of Cardiology

Estrogen administration in patients with chronic heart failure: not ready for prime time

Gerasimos Filippatosa,* and John T. Parissisb

a Second Department of Cardiology, Heart Failure Clinic Evagelismos Hospital, Athens, Greece
b Heart Failure Clinic, Amalia Fleming Hospital Athens, Greece

* Corresponding author. 28 Doukissis Plakentias str, 11523 Athens, Greece. Tel.: +30-10-8048427; fax: +30-10-8104367 E-mail address: geros{at}compulink.gr

Key Words: Chronic heart failure • Estrogen • Clinical trials • Patient outcome • Pathophysiological mechanisms

Received October 1, 2002; Accepted October 16, 2002

Chronic heart failure (CHF) is a major clinical problem resulting in significant morbidity and mortality but its pathogenesis remains unclear. Energy starvation, abnormalities in excitation–contraction coupling, in sarcomeric function and in extracellular matrix composition, as well as cell loss by apoptosis and necrosis, may all contribute to myocardial remodeling and subsequent impairment of diastolic and systolic cardiac function [1–3]. Moreover, impaired peripheral vasorelaxation (which is known as endothelial dysfunction) as a result of over-activation of various neurohormones and proinflammatory cytokines, increased oxidative stress and abnormal metabolism of nitric oxide, is also an important pathophysiological parameter of CHF progression [4]. Although new treatments have improved the outcome of CHF, morbidity and mortality remain high. New therapeutic targets using agents with combined effects on the myocardial remodeling process and peripheral vasoconstriction are still needed [5].

Experimental and clinical data indicate that estrogen may have beneficial short- and long-term cardiovascular effects, and may be useful as a potential therapeutic agent for the treatment of cardiovascular diseases [6]. Moreover, there is some evidence that estrogen has protective effects in patients with CHF [7,8]. Currently, the specific molecular pathways involved in these effects are unknown, but anti-oxidative, anti-apoptotic and vasorelaxing effects may play a significant role [7,8]. Further clarification of the mechanisms by which estrogen acts on the cardiovascular system could provide additional rationale for the clinical use of this agent in the management of patients with CHF. The main pathway through which estrogen modulates cardiovascular pathophysiology may be via the binding of the hormone to intra-cellular estrogen receptors (ERs). Two ER (ER{alpha} and ERβ) have been identified in most cells, including atrial and ventricular myocytes, fibroblasts, vascular endothelial and smooth muscle cells, and are operational in both the male and the female cardiovascular system [9]. Recent studies suggested the presence of a third receptor and of cell specific ER-associated coregulatory proteins. It has been proposed that tissue-specific differences and differential activation of these proteins lead to cell-specific effects. Recently, alternative pathways for ER action have been reported. In these pathways specific proteins can activate signaling cascades, leading to activation of the ERs in the absence of estrogen [10,11]. Moreover, the genes for human ERs have at least three polymorphisms. Their importance in the cardiovascular system is unknown.

Estrogen plays an important role in the cardiovascular system by improving lipid profile and glucose metabolism and through modification of various circulating factors with systemic action involved in coagulation, fibrinolysis and the inflammatory process associated with atherosclerosis [12,13].

These are mainly effects of estrogen in hepatic cells. It has been suggested that the route of administration is very important for the divergent effects of hormone replacement therapy on various circulating factors [i.e. insulin like growth factor-1 (IGF-1), inflammatory markers, etc.]. The concentration of CRP increases and IGF-1 decreases after oral administration of estradiol, as a result of a first-pass liver effect, while transdermal estradiol has the opposite results. These effects have been used to explain the conflicting results of different estrogen formulations used in clinical practice.

However, estrogen also has direct effects on the heart and vasculature, such as an increase in nitric oxide (NO) production and endothelial cell growth and a decrease in smooth muscle cell and cardiomyocyte growth, vascular injury and atherosclerotic lesion formation [11–13]. In spontaneously hypertensive rats, estrogen reduces arterial collagen and stiffness. Estrogen also appears to preserve endothelium-dependent coronary artery dilatation in experimental models of ischemia-reperfusion, possibly by increasing NO production, and by reducing free radical generation into vascular wall and NO breakdown [14].

Extending the cardioprotective role of estrogen in the setting of CHF, several investigators have shown that chronic administration of this agent in animals with sustained heart failure reduced total peripheral resistance and left ventricular end-diastolic pressure [15,16]. These vasodilatory effects may be explained by the observation that chronic 17β-estradiol augments the relaxant role of basal NO in blood vessels from rats with CHF and increases expression of atrial natriuretic factor [16]. Moreover, estrogen prevents oxidative stress-induced endothelial cell apoptosis in experimental CHF [17]. In addition to the peripheral effects of estrogen in CHF, experimental data also suggest that this agent has anti-mitogenic and anti-apoptotic action in the failing heart, by attenuating hypertrophic response in pressure-overload conditions through a decrease of afterload and suppression of renin–angiotensin and endothelin system activation [18]. Moreover, it protects myocardial cell survival through a decrease in oxidative stress and a reduction in proinflammatory cytokine activity [18,19]. In contrast, estrogen deficiency up-regulates the expression of angiotensin II type 1 receptor, the receptor responsible, among other functions, for apoptosis.

There is also increasing clinical evidence that chronic estrogen replacement therapy in healthy postmenopausal women decreases sympathetic activity and suppresses renin and angiotensinogen release, regulating beneficially neurohormonal activation [20,21]. This observation indicates a potential anti-neurohormonal role of estrogen in human disorders with abnormal neurohormonal reactions, such as CHF. On the other hand, acute administration of estrogen decreased ischemia-reperfusion arrhythmias and reduced infarct size, preventing left ventricular remodeling [22]. Acute administration of 17β-estradiol in female rats with heart failure caused a significant increase of cardiac output, in a dose-dependent manner, as a result of decreased peripheral vascular resistance. Recent studies in humans have also shown that acute administration of estrogen in males or post-menopausal women causes peripheral vasodilation as expressed by an increase in brachial blood flow or aortic relaxation [23]. Adamopoulos et al. [24] have widened this option, by investigating the effects of acute estrogen administration, not only on the systemic circulation but also on pulmonary resistance and cardiac contractility. These investigators found that acute intravenous administration of estrogen improved cardiac contractile performance and decreased pulmonary and systemic vascular resistance. Modulation of circulating neurohormonal factors (e.g. endothelin-1, angiotensin-II), potassium channel function, intracellular Ca2+ handling, vascular NO activity and cyclic AMP release may be important pathophysiological mechanisms involved in the hemodynamic effects of acute estrogen administration [12]. Although the patient population was small and excluded female patients, the results of this study confirm the beneficial role of estrogen in CHF and indicate that these agents may represent a promising therapeutic approach as an adjunctive treatment for hemodynamically stable CHF patients.

However, when the time comes to extrapolate these results to clinical practice we should do so with caution. Many observational studies support the cardioprotective and anti-atherogenic effects of estrogen and indicate that the use of hormone replacement therapy is associated with a 40–50% reduction in the relative risk of coronary artery disease in post-menopausal women [25]. The role of estrogen in primary prevention has been supported by a number of studies demonstrating the beneficial effects of this agent on lipoprotein levels and vascular function [26,27]. In contrast, the first multicenter randomized trial [28] to test the role of estrogen was in secondary prevention, the Heart and Estrogen/Progestin Replacement (HER) Study. There was no evidence that hormone replacement therapy (HRT) reduces the risk of cardiovascular events in women with established coronary artery disease.

Moreover, many observational studies have shown that in post-menopausal women with ischemic heart disease, estrogen reduces ischemia. However, in the first randomized clinical trials the administration of estrogen after unstable angina or myocardial infarction was either not effective or increased the ischemic events [29,30].

In light of the results of these studies the American Heart Association recommended that hormone replacement therapy should not be initiated for secondary prevention.

The reason for the conflict of these results with those of the observational studies was considered to be either the patient population selection or the HRT regimen. Others have maintained that HRT is an effective preventive therapy in the early stages of atherosclerosis, rather than a cure for the late stages of the disease, and that this was the reason HRT failed in secondary prevention.

However, the results of the recently published Women's Health Initiative (WHI) study, indicates that hormone replacement therapy should not be used even for primary prevention [31]. In WHI, 16 608 post-menopausal women with an intact uterus received conjugated equine estrogens 0.625 mg/day, plus medroxyprogesterone acetate, 2.5 mg/day or placebo. The active treatment group had increased risk for coronary artery disease, stroke, pulmonary embolism and breast cancer [31].

Of course, the study had some limitations. They tested only one drug formulation and the results of the study may not apply to other dosages or to hormones administered transdermally, a route which more closely mimics endogenous hormones. It is also possible that estrogen has a prothrombotic effect in genetically susceptible subjects, an association already shown in menopausal hypertensive women on HRT [32].

The other arm of the WHI study continues, testing the hypothesis that oral estrogen without progestin will prevent coronary artery disease, in 10 739 women who have had a hysterectomy. The results are expected in 2005.

What about heart failure? Recently, a retrospective analysis of Vesnarinone Studies showed that in older women with CHF, estrogen use was associated with lower overall and cardiac mortality, this was independent of age, vesnarinone use, left ventricular ejection fraction and CHF severity [8]. This observation from a retrospective analysis of a large database of women with CHF generates a new hypothesis that needs to be tested by future clinical trials.

Our understanding of the pathophysiological role of estrogen in cardiovascular diseases, and specifically the molecular basis of ERs action, has changed dramatically over the last decade as a result of the wide use of novel molecular biology techniques in the cardiovascular field. However, several questions remain to be addressed as regards the various estrogen-dependent cellular signaling pathways, cross-talk and the molecular mechanisms of estrogen action. Thus, experimental and small clinical studies which try to answer specific questions with a well designed protocol in a well controlled environment are always very useful [24]. Moreover, these clinical studies could help us answer other questions relevant to clinical practice, concerning dose and type of estrogen, use of progestin and route of delivery.

However, as the major part of our knowledge about the effects of estrogen in CHF is derived from small experimental and clinical studies and a single large retrospective clinical trial, we think that it is time for the design of prospective randomized clinical trials clarifying the therapeutic value of acute or chronic estrogen administration in CHF patients, regardless of gender.


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