Estrogen therapies, lipids, and the heart disease prevention controversy
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
One of the most highly unexpected reports in recent medical literature was the lack of benefit of estrogen-progestin replacement therapy in cardiovascular disease prevention in postmenopausal women. The ensuing negative view of hormone replacement therapy has now extended to all forms of postmenopausal hormone treatment, including estrogen alone. Is this pessimism justified? A review of the effects of estrogens and progestins on the estrogen-sensitive systems of the body can help explain why combined oral estrogen and low-dose continuous medroxyprogesterone acetate administration may not be the paradigm for all other forms of postmenopausal hormone replacement. Some of these effects include the following: progestins are anti-estrogens, as evidenced in their divergent effects on plasma lipids; not all progestins are equal in their effect on lipids and other physiologic functions; administration of any hormone by mouth is not physiologic; giving estrogen 10 to 15 years postmenopausally may be too late to prevent atherosclerosis. On the other hand, high doses of oral estrogen/progestin in the presence of high cardiovascular risk appear to promote atherosclerosis risk. Given the current evidence the common sense answer to the question of the benefit of estrogen is “it depends.” Until these and other points are formally addressed, the hypothesis that estrogen prevents heart disease remains open.
- Hulley S, Grady D, Bush T, et al., for the HERS Research Group: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998, 280:605–613. The original report of nonbenefit of combined low-dose hormone replacement therapy with an apparent excess of coronary disease in the first year. CrossRef
- Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002, 288:49–57. This follow up of the HERS cohort explored whether there was a beneficial trend in CVD after the first year of excess CHD incidence. There was none. CrossRef
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288:321–333. This is the first paper of the WHI and shows that the excess of CVD and breast cancer outweighs the benefit of reduced fractures from osteoporosis. CrossRef
- Manson J, Hsia J, Johnson K, et al., for the Womens’s Health Initiative Investigators Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003, 349:523–534. This paper presents the complete follow up of the WHI cohort taking equine estrogens/medroxyprogesterone acetate. The conclusions are the same with the excess incidence in the first year again demonstrated. The control group catches up in coronary incidence to the hormone group after 6 years of follow-up. CrossRef
- Knopp RH, Zhu X-D, Bonet B: Effects of estrogens on lipoprotein metabolism and cardiovascular disease in women. Atherosclerosis 1994, 110:S83-S91. CrossRef
- Zhu X, Bonet B, Gillenwater H, Knopp RH: Opposing effects of estrogen and progestins on LDL oxidation and vascular wall cytotoxicity: implications for atherogenesis. Proc Soc Exp Biol Med 1999, 222:214–221. This paper presents data that show that progestins have a pro-oxidant effect on LDL and cytotoxicity that is opposite to the antioxidant and cytoprotective effect of estrogen. CrossRef
- The Writing Group for the PEPI Trial Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995, 273:199–208. One of the most complete studies of the lipid effects of postmenopausal hormone replacement therapy. CrossRef
- Wahl PW, Walden CE, Knopp RH, et al. Effect of estrogen/ progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983, 308:862–867. This early paper shows that the potency of different progestins results in different lipoprotein lipid responses, more favorable in estrogendominant formulations and less favorable and with elevated LDL levels in the progestin-dominant/androgenic formulations. CrossRef
- Zhu X, Bonet B, Knopp RH: Estradiol 17beta inhibition of LDL oxidation and endothelial cell cytotoxicity is opposed by progestins to different degrees. Atherosclerosis 2000, 148:31–41. This paper shows that the pro-oxidant effects of the different progestins differ at equimolar concentrations with natural progesterone having the least effect and medroxyprogesterone acetate having the greatest pro-oxidant effect. CrossRef
- Knopp RH, Broyles FE, Cheung M, et al. Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception 2001, 63:1–11. This paper shows that a progestin can oppose the effect of estrogen on not only lipids but on clotting factors and sex hormone-binding protein. Thus, the antiestrogenic effects of the progestins are potentially generalizable to all systems of the body that are under the influence of estrogen and progestin receptors, such as the vascular wall. CrossRef
- Rosenfeld ME, Kauser K, Martin-McNulty B, et al. Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intra-plaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice. Atherosclerosis 2002, 164:251–259. This paper shows that estrogen admistration after the development of atherosclerosis does not prevent the late complications of atherosclerosis such as placque rupture and thrombosis. CrossRef
- Williams JK, Anthony MS, Honore EK, et al. Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 1995, 15:827–836. This study shows the same lack of arterial benefit of estrogen in cholesterol-fed monkeys after the atherosclerosis has been allowed to develop.
- Hodis H, Mack W, Azen S, et al., for the Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med 2003, 349:535–545. This study shows that neither estrogen nor estrogen/progestin treatment in postmenopausal women had a beneficial effect on the coronary circulation in women with coronary disease also treated with diet and a statin. This study is the human counterpart to the mouse and monkey studies that show no benefit of estrogen in the presence of developed atherosclerosis. CrossRef
- 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. This study shows a vascular benefit of postmenopausal estrogen alone in women without CHD, presumably because their vascular tree was still healthy. It remains to be seen if the WHI study finds the same result, but if it doesn’t it still won’t mean that estrogen begun in the immediate perimenopause won’t be beneficial.
- Mann JI, Vessey MP, Thorogood M, Doll SIR: Myocardial infarction in young women with special reference to oral contraceptive practice. BMJ 1975, 2:241–245. This paper was the first to show that CHD in women treated with high-dose oral contraceptive was associated with classical risk factors for CHD. In other words, high-dose hormone treatment with CVD risk factors is potentially injurious, not protective. CrossRef
- Rosenberg L, Kaufman DW, Helmrich SP, et al. Myocardial infarction and cigarette smoking in women younger than 50 years of age. JAMA 1985, 253:2965–2969. This American paper is the basis for the recommendation to not prescribe oral contraceptives for women who smoke over the age of 35 years because of the astonishing increase in CVD risk of smoking and using oral contraceptives together. CrossRef
- Knopp R, Aikawa K. Estrogen, female gender and heart disease. In Textbook of Cardiovascular Medicine, edn 2. Edited by Topol EJ, Califf RM, Isner J, et al. Philadelphia: Lippincott Williams & Wilkins; 2002:171–188.
- Wilson PW, Garrison RJ, Castelli WP: Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985, 313:1038–1043. This paper is the exception out of about 50 epidemiologic surveys, showing that high-dose postmenopausal estrogen treatment was associated with increased not decreased risk from coronary disease. The key difference between this study and all of the others may be that the women were using high doses of estrogen on the order of 2.5 mg/d equine estrogens. CrossRef
- The Coronary Drug Project Findings leading to discontinuation of the 2.5mg/dL estrogen group. Coronary Drug Project Research Group JAMA 1973, 226:652–657. High-dose estrogen can cause an excess of CVD in men as well as women! CrossRef
- Knopp R, Zhu X-D, Aikawa K: Estrogen and cardiovascular disease: controversy and common sense. In Textbook of Cardiovascular Medicine Update Series vol 3. Edited by Topol EJ. New York: Lippincott Williams & Wilkins; 2000:1–8.
- Million Women Study Collaborators: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003, 362:419–427. CrossRef
- Estrogen therapies, lipids, and the heart disease prevention controversy
Current Cardiology Reports
Volume 5, Issue 6 , pp 477-482
- Cover Date
- Print ISSN
- Online ISSN
- Current Medicine Group
- Additional Links