In contrast to oral contraceptives, the estrogens used for replacement therapy in menopausal women are “natural” estrogens, used in physiologic quantity as opposed to synthetic estrogen (ethinyl estradiol) in therapeutic quantity. There is no thrombogenic potential associated with the physiologic doses of estrogen used for estrogen replacement therapy (ERT) (11).
The rationale for ERT in menopausal women includes diminution of vasomotor symptoms, improved psychophysiology, and prophylaxis against genitourinary atrophy, osteoporosis, and cardiovascular disease. Although the current discussion is focused on the role of postmenopausal estrogens in the prevention of cardiovascular disease, it is important to acknowledge that genitourinary atrophy and osteoporosis are other undesirable sequelae of long-term estrogen deficiency that are also more amenable to prevention than to treatment.
There are considerable epidemiologic data to support a 40%-60% reduction in the risk of cardiovascular disease in postmenopausal women who are given ERT(3,5,12,13). In the largest study, which included 48,470 nurses, the postmenopausal women using estrogen demonstrated one-half the risk of coronary heart disease seen in untreated women(13). Although this study included many young women and did not conclusively demonstrate any benefit among older women, a more recent study confirmed that the benefit of ERT persists into the eighth decade of life (9).
The Leisure World study, which involved older women (average age, 73), found a 50% reduction in the incidence of myocardial infarction and stroke among estrogen-treated women (5). A further important finding of this study was that recent use was even more important than duration of use. The Lipid Research Clinics study demonstrated a similar reduction in the risk of coronary heart disease, and Bush et al. suggested that nonlipidmediated events were as important as the alterations in lipoprotein levels (3).
The results of more than 30 published observational studies, which provide overwhelming support for a cardioprotective effect of ERT, may actually be underestimates because so many women discontinue ERT after its initiation. While it is true that no data are currently available for ERT in primary prevention trials, the available data are very encouraging.
MECHANISM OF ACTION
It has been well-established that oral estrogens positively impact the less favorable lipoprotein profile seen in postmenopausal women. The net effect of unopposed oral estrogen is an increase in high-density lipoprotein (HDL) cholesterol of 13%-16% (2). There is a similar decline in low-density lipoprotein (LDL) cholesterol, but the amount is more variable. ERT is associated with an improvement in all fractions of the lipid profile, except for an increase in triglyceride levels. This appears to be clinically significant only in women who have hypertriglyceridemia (> 300 mg·dl-1) and thus are at risk for pancreatitis.
Numerous other studies have proposed additional nonlipid-mediated cardioprotective effects of estrogens. Cynomolgus monkeys fed an atherogenic diet and given progestin-dominant oral contraceptives to lower their HDL cholesterol had less coronary plaque formation and LDL cholesterol arterial wall uptake than did the control animals (4). Further studies revealed that estrogen inhibited an induced vasoconstriction of atherosclerotic coronary arteries in the monkeys (17), and that estrogen with and without the addition of a progestin protected the monkeys against coronary atherosclerosis (16).
Four case-control studies utilizing coronary angiography found a beneficial local effect of estrogen on coronary arteries. In Sullivan's study of 1822 women with angiographically documented coronary occlusion of varying degrees, the greatest difference in survival between estrogen users and nonusers occurred in the more severely stenotic group (14).
There is growing evidence that patients with established cardiovascular disease benefit most from ERT (2,15). There are data to support decreased platelet adhesiveness (1), altered coronary vasomotor responsiveness by endothelium-derived factors(6), and favorable effects on clotting factors(11), blood pressure (8), and insulin sensitivity (12).
CONCERNS AND QUESTIONS
There is concern that the addition of a progestin to ERT in women with a uterus hormone replacement therapy (HRT) may blunt the cardioprotective effect of ERT. Definitive data about HRT are lacking, but preliminary studies suggest that the deleterious effect of progestin, particularly on lipid profiles, diminishes with longer-term therapy and is dependent on both the dose and the androgenicity of the progestin used (10). Although there is also concern regarding a possible oncogenic influence of estrogen on breast cancer, the cardiovascular benefits exceed any potential adverse effect. Extensive scrutiny of observational data has failed to demonstrate any statistically significant increase in the incidence of breast cancer in the United States associated with the use of Physiologic replacement doses of estrogen; data for combined estrogen/progestin regimens are limited. Since exercise and hormone replacement confer similar improvement in lipoprotein metabolism (7) and atherogenesis, it will be of interest to see whether these benefits are additive or synergistic.
While there are insufficient data regarding cardiovascular risk with combined estrogen-progestin therapy in postmenopausal women, considerable observational data support a 50% reduction in cardiovascular disease risk in women receiving ERT. This overwhelming cardiovascular benefit, especially among women with established coronary heart disease, exceeds any putative risk associated with estrogen use. ERT, like exercise, is associated with improvements in lipoprotein metabolism and coronary risk, as well as favorable effects on blood pressure, clotting factors, diabetes, and osteoporosis.
1. Bar, J., R. Tepper, J. Fuchs, et al. The effect of estrogen replacement therapy on platelet aggregation and adenosine triphosphate in postmenopausal women. Obstet. Gynecol.
2. Barrett-Connor, E. Estrogen and estrogen-progestogen replacement: therapy and cardiovascular diseases. Am. J. Med.
95(Suppl. 5A):40S-43S, 1993.
3. Bush, T. L., E. Barrett-Connor, L. D. Cowan, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics' Program Follow-up Study.Circulation
4. Clarkson, T. B., C. A. Shively, T. M. Morgan, et al. Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys.Obstet. Gynecol.
5. Henderson, B. E., A. Paganini-Hill, and R. K. Ross. Decreased mortality in users of estrogen replacement therapy. Arch. Intern. Med.
6. Herrington, D. M., G. A. Braden, J. K. Williams, and T. M. Morgan. Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy. Am. J. Cardiol.
7. Lindheim, S. R., M. Notelovitz, E. B. Feldman, et al. The independent effects of exercise and estrogen on lipids and lipoproteins in postmenopausal women. Obstet. Gynecol.
8. Luotola, H. Blood pressure and hemodynamics in postmenopausal women during estradiol-17b substitution. Ann. Clin. Res.
15(Suppl. 38):9-12, 1983.
9. Manolio, T. A., C. D. Furberg, L. Shemanski, et al., for The CHS Collaborative Research Group. Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women.Circulation
88(5 Part 1):2163-2171, 1993.
10. Nabulsi, A. A., A. R. Folsom, A. White, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N. Engl. J. Med.
11. Saleh, A. A., L. G. Dorey, M. P. Dombrowski, et al. Thrombosis and hormone replacement therapy in menopausal women. Am. J. Obstet. Gynecol.
12. Stampfer, M. J. and G. A. Colditz. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev. Med.
13. Stampfer, M. J., G. A. Colditz, W. C. Willett, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from The Nurses' Health Study. N. Engl. J. Med.
14. Sullivan, J. M., R. Vanderzwaag, J. P. Hughes, et al. Estrogen replacement and coronary artery disease: effects on survival in postmenopausal women. Arch. Intern. Med.
15. Utian, W. H., K. R. Epstein, M. A. Freedman, G. I. Gorodeski, and N. K. Wenger. Established cardiovascular disease: does HRT offer benefits? Menopause Manag.
11:10-16, 21,32, 1993.
16. Wagner, J. D., T. B. Clarkson, T. W. St. Clair, D. C. Schwenke, and M. R. Adams. Estrogen replacement therapy (ERT) and coronary artery (CA) atherogenesis in surgically postmenopausal cynomolgus monkeys(Abstract). Circulation
80(Part II)-331, 1989.
17. Williams, J. K., M. R. Adams, and H. S. Klopfenstein. Estrogen modulates responses of atherosclerotic coronary arteries.Circulation
Exercise and Cardiovascular Disease Risk in Women: Interaction with Selected Endocrine Factors
This mongraph is based on the proceedings of an ACSM Roundtable entitled“Exercise and Cardiovascular Disease Risk in Women: Interaction with Selected Endocrine Factors,” held June 21-22, 1994, in Indianapolis, Indiana.
The Exercise and Cardiovascular Disease Risk in Women: Interaction with Selected Endocrine Factors Roundtable was funded through a grant from Wyeth-Ayerst Laboratories.