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Coronary artery disease (CAD) and stroke are the primary causes of death in women after the age of 60. A 50-year-old woman has about 50% lifetime probability of developing and about 30% probability of dying from heart disease (1). Stroke remains a leading cause of disability and death in women and recent data suggest that one in six women in western countries will die of stroke (2). It is important to remember that in all categories cardiovascular disease in women carries a worse prognosis as compared to men, especially in diabetics. Thus, in contrast with common beliefs that women are "immune" to cardiovascular diseases, it stands to reason that preventive measures to reduce the risk for cardiovascular diseases should be implemented in women as they are in men.
The incidence of CAD and stroke rises after the menopause. This process goes in parallel with metabolic changes that add up to create an unfavorable risk factor profile for cardiovascular disease (3). This menopause metabolic syndrome, which includes weight gain and changes in lipids, insulin resistance and endothelial function, as well as increased levels of homocysteine, Lp (a) and several coagulation factors, may in part be attributable to estrogen deficiency, and may be reversible following hormone replacement therapy (HRT). Estrogen treatment leads to lowering of LDL cholesterol and elevation of HDL cholesterol, a decrease in insulin resistance, homocysteine and Lp(a), and improvement in endothelial function (through both the vasodilatory and vasoconstrictory mediators). One should mention that adverse metabolic changes might occur too, such as an increase in triglycerides, in C- reactive protein and in procoagulatory factors.
A complex balance between vasodilatory and vasoconstrictory factors and mediators maintains vascular function (4-5). Vasodilation is largely mediated by acetyl-choline and vasoconstriction is mediated by endothelin. The aging process includes derangement of vascular function. This becomes evident in the early 40's in men, but in women it occurs only after the menopause, pointing at the important vascular role of estrogen. Apart from estrogen's effects on nitric oxide synthase, prostacyclins and endothelin, it also has calcium channel blocking and ACE inhibiting properties. Since estrogen promotes vascular relaxation and negates vascular contraction, the net result is decreased vascular resistance and increased blood flow and tissue perfusion. Also, menopause is associated with a relative hypertrophy of heart walls and septum, while estrogen replacement reverses those anatomic alterations (6). The above findings are also in line with the anti-ischemic effect of estrogen reported in several studies (7).
The carotid intima-media thickness, evaluated by B-mode ultrasonography, is considered a good marker also for coronary atherosclerosis. Many studies which have investigated stroke risk or myocardial infarction risk, used this parameter. Several large surveys demonstrated that menopause is associated with thickened carotid artery walls, whereas hormone replacement was associated with thinner intima-media (8-9). These data point at a protective effect of hormones possibly through retardation of atheroma formation.
So far we were discussing secondary end points and the development of atheroma. But is HRT doing something to established atheromas? The ERA (Estrogen Replacement and Atherosclerosis) Study looked into this issue by performing repeated coronary angiograms prior to initiation of HRT and after 3.5-year follow-up (10). The conclusion of the study was that the progression of coronary atherosclerosis over this period was the same for hormone users and nonusers. Another recent important study looked at the effect of oral hormone therapy on progression of carotid atherosclerosis in healthy women with established intima-media thickening(>1 mm) at baseline (11). At the end of 48 weeks of follow-up, changes in wall thickness were similar for women using hormones and a control group of nonusers of hormones. In contrast with the results of that study, another study showed that the progression of subclinical carotid atherosclerosis during 2-year follow-up was significantly slower in estradiol users than in the placebo group (12). It seems therefore that hormone replacement may retard the development of atherosclerotic plaques when endothelium is still intact, but once a woman has established arterial atherosclerosis treatment with estrogen probably has a minor or no effect on its progression. A set of studies in monkeys came out with results that support this concept (13).
For practical reasons what really matters is of course whether or not HRT reduces the risk for cardiovascular diseases. There have been many studies on this issue, the majority of which showed a beneficial effect of HRT, namely a decreased risk for CAD in hormone users (14). It is important to note that almost all the studies were observational. The largest published series on primary prevention is the Nurses' Health Study in the United States, in which 70000 PMW have participated (15). The relative risk for a major coronary event over a 20-year follow-up period was 0.54 for users of estrogen. The results regarding HRT and the risk for stroke were problematic since unlike the case with CAD, women using standard or high dose conjugated estrogen had a significantly increased risk for stroke, whereas those on low dose estrogen actually were protected from stroke. The Cancer Prevention Study II addressed cardiovascular mortality in healthy postmenopausal women (16). The cohort was huge - around 290000 participants - and the follow-up period was 12 years. There were 12% ever users of hormones and 22% past users. During follow-up about 31000 women died. Hormone use was associated with a 34% reduction in the risk for CAD, and 19% reduction in stroke risk. A recent publication from the Nurses' Health Study puts cardioprotection by HRT in a different perspective (17). The article analyzed the trends in the incidence of CAD in the USA from 1980 to 1994. The study suggested that the 31% decline in incidence of CAD during this period is the result of improvement of dietary habits, less smoking, and in third place - increase in postmenopausal hormone use.
But in this era of evidence-based medicine we expect to have definitive answers on prevention by HRT only when properly designed, double-blind, placebo-controlled studies release their data. One such investigation was the Heart and Estrogen/Progestin Replacement Study (HERS) (18). The study enrolled 2763 PMW younger than 80 years of age (mean 67 years) who had documented CAD. Women were randomly allocated into hormone (Premarin 0.625 mg plus MPA 2.5 mg daily) or placebo treatment for a 5-year follow-up. The results of the study came out a surprise: no overall difference between HRT and placebo groups in cardiac and total mortality, and in the incidence of MI and stroke, despite a decrease in LDL-cholesterol and an increase in HDL-cholesterol in the hormone users. In addition, the HRT group suffered more venous thromboembolic. These data from the HERS study have opened a debate over the issue whether or not long-term hormone replacement - as a prophylactic treatment for heart disease - is really advisable. The debate became even stronger following the premature termination of the continuous combined arm of the Women's Health Initiative (WHI) (19). This primary prevention trial in 16000 PMW did not demonstrate any cardiovascular benefit for hormone users after 5 years of follow-up, and in fact there were more events among users. The expected higher risk for breast cancer was apparent as in previous studies. The HERS and WHI results seem to cast a huge shadow on the issue of HRT and cardioprevention, causing unnecessary panic in the public, mostly because of misinformation. Both studies recruited women in their mid-60's, thus the data should not be extrapolated to early menopause. Both studies used Prempro, a specific CEE-MPA combination, therefore we should be careful prior to generalizing the data to all hormonal preparations.
So where do we stand in year 2002? How do we summarize the clinical and epidemiological data?
The cardiovascular effects of female sex steroids have many faces and are very complex. Different disease situations, different target organs and different therapeutic regimens may exhibit different effects of estrogens and progestines. Furthermore, the interpretation of population studies may be problematic by itself, in view of so many confounders and biases involved as well as methodological flaws that are discovered only post-hoc. It seems therefore, that in such a complicated situation making definite conclusions and guidelines is almost an impossible task. My suggestion to clinicians is to try and follow the main stream of clinical data, looking at the general picture rather than the small details, and try to individualize therapy in order to maximize the benefits and minimize the adverse reactions and risks.
While the well-proven efficacy of HRT in reducing menopausal symptoms has never been challenged, and osteoprotection still being a main consideration for HRT, we should stick to those indications. Prescribing hormones for prevention of CAD or stroke is strongly unadvisable.
References
1) Grady D, Rubin SM, Petiti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-1037.
2) Bonita R, Epidemiology of stroke. Lancet 1992;339:342-344.
3) Spencer CP, Godsland IF, Stevenson JC. Is there a menopausal metabolic syndrome? Gynecological Endocrinology. 1997;11:341-355.
4) Mendelsohn ME, Karas RH. Mechanisms of disease: the protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801-1811.
5) Austin CE. Chronic and acute effects of oestrogens on vascular contractility. J Hypert 2000;18:1365-1378.
6) Pines A, Fisman EZ, Levo Y, et al. Menopause-induced changes in left ventricular wall thickness. Am J Cardiol 1993;72:240-241.
7) Rosano GMC, Sarrel PM, Poole-Wilson PA, et al. Beneficial effect of oestrogen on exercise-induced myocardial ischemia in women with coronary artery disease. Lancet 1993;342:133-136.
8) Dobs AS, Nieto FJ, Szklo M, et al. Risk factors for popliteal and carotid wall thickness in the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 1999;150:1055-1067.
9) Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis. The Tromso study. J Clin Epidemiol 2000;53:525-530.
10) Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med 2000;343:522-529.
11) Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. Arterioscler Thromb Vasc Biol 2001;21:262-268.
12) Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939-953.
13) Mikkola TS, Clarckson TB. Estrogen replacement therapy, atherosclerosis and vascular function. Cardiovasc Res 2002;53:605-619.
14) Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55-72.
15) Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-941.
16) Rodriguez C, Calle EE, Patel AV, et al. Effect of body mass on the association between estrogen replacement therapy and mortality among elderly US women. Am J Epidemiol 2001;153:145-152.
17) Hu FB, Stampfer MJ, Manson JE, et al. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. N Engl J Med 2000;343:530-537.
18) Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary artery disease in post menopausal women. JAMA 1998;280:605-613.
19) Writing Group for the Women's Health Initiative Investigators. Risks and benefits from the women's Health Initiative in healthy postmenopausal women. JAMA, 2002;288:321-333.
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