The most important cause of morbidity and mortality in the developed nations is cardiovascualr diseases. The data which has always been commonly perceived that women were realtively immune to cardiovascular diseases due to the circulating estrogens and progesterones, and subsequent prevention of post menopausal cardiovascualr diseases by HRt is now being gradually challenged by reports from various trials. In retrospective studies, cardiovascular mortality in postmenopausal women receiving estrogen replacement therapy (ERT), with estrogen alone or in combination with progesterone (HRT), is apparantly lower than in women not on HRT.
Estrogen has been traditionally considered of import in maintenance of cardiovascular physiology. This was thought to be due to 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. Estrogen and Prevention of cardiovascular morbidity – a misconception? It is a commonly thought that hat coronary heart disease (CHD) is much less common in women than in men possibly due to the protective action of estrogen.
However in a report from the US National Center for Health Statistics (NCHS , 2003), the death rates from CHD were actually found to be higher in women than in men. In another report from NCHS (2004) the age-adjusted prevalence of all cardiovascular disease in women was 10. 9% compared with 12. 5% in men; CHD 4. 9% in women compared with 8. 3% in men; hypertensive heart disease 21. 9% in both men and women, and stroke 2. 4% in women compared with 2. 8% in men. Physiologic role of estrogen
Fawsi etal (2002) note that Taskin and colleague have found increases in ejection fraction, improved diastolic function, and reduced left ventricular end-diastolic and end-systolic volumes by echocardiography. Simliarly other studies show significant reductions in left ventricular mass in women treated for more than 10 years with HRT. Fawsi etal have also reported increased glucose oxidation and enhanced recovery of mechanical function in an ischemia–reperfusion models. In the myocardium, endothelial cells and vascular smooth muscle cells (VSMC) possess estrogen receptors (ER).
Thus these may be site of action of estrogen in HRT (Tolbert, 2001) ER has also been detected in cardiac myocytes and coronary arteries. An intersesting situatoin has been that ER were detected more frequently in the coronary arteries of premenopausal women free of atherosclerosis than in those with atherosclerotic disease. This may be because the atherosc`lerotic process leads to plaque formation and the clotting process detroys the intima, leading to reduced receptor concentration, with the cosequent poor response of estrogen in post menopausal women who already have atheroscelrosis (Tolbert, 2001).
This may be basis of the observations in the HERS trial, and WHI ( Women Health Initiative) trial, where it was reported that postmenopausal HRT has either no role in reduction of cardiovascualr morbidity or it may actually increase the prevalance of mortality (Bhavna, 2007, Schnatz, 2006). HERS (Heart Estrogen-Progestin Replacement Study )was the first large-scale, randomized clinical trial to test the efficacy and safety of hormone replacement on clinical cardiovascular disease outcomes in postmenopausal women.
The result of this study was that there was no significant difference between groups for the primary outcome, nonfatal myocardial infarction or coronary heart disease, death, or for several secondary cardiovascular end points (Bhavna 2007). It appears that these trials did not take in to account this factor and whether the patients included in the trial were women with preexistant cardiac disease or not, since understandably the estrogen will have a much lesser role in women of the former category. Estrogen probably acts through 2 mechanisms – genomic and nongenomic mechanisms.
acting on ER receptos, estrogen causes increased nitric oxide synthesis, which causes vasodilation of the coronary vessels ( Fawsi, 2002). Estrogen induced vasodilatation occurs 5–20 min after administration, thus it acts independent of genetic effects and is thus referred to as ‘nongenomic’. Vascular injury as for example after atherosclerosis, leads to neointima formation which can lead to stenosis. Eestrogen limits the proliferation of vascular smooth muscle cells after vascular injury, thus inhibiting the neointimal response.
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’. Estrogen prevents ischemic and reperfusion arrhythmias reduces infarct size, while increasing distal coronary perfusion during both ischemia and reperfusio.
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. Estrogens appear to be cardioprotective under ischemic conditions, probably due to improved vascular function. Estrogen adminstration also leads to reductions in total cholesterol and LDL-C and increases in HDL-C and triglycerides (Fawsi, 2002, Tolbert, 2006) Conclusion
The mechanisms responsible for the cardiac effects of estrogen are not fully understood, but evidence suggests the role 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 ER.. 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.
The WHI, the largest study still to date, provided significant information on the role of HRT and dietary intervention in middle-aged and elderly women. This study had major strengths and also major weaknesses. It became apparent from this and other similar studies that HRT may initially increase the risk of CHD events, but may have a salutary effect later on.
Referances
1. Fawzi A Babikera, Leon J De Windta, Martin van Eickelsb, Christian Grohec, Rainer Meyerc and Pieter A Doevendansa.Estrogenic hormone action in the heart: regulatory network and function. Cardiovascular Research 2002 53(3):709-719 2. Schnatz, Peter F. Hormonal Therapy: Does It Increase or Decrease Cardiovascular Risk? Volume 61(10), October 2006, pp 673-681 3. Mohandas, Bhavna; Mehta, Jawahar L. Lessons from hormone replacement therapy trials for primary prevention of cardiovascular disease. Volume 22(5), September 2007, p 434–442 4. Todd Tolbert and Suzanne Oparil. Cardiovascular Effects of Estrogen. AJH 2001; 14:186S–193S