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19 December 2000 | Volume 133 Issue 12 | Pages 933-941
Background: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard.
Objective: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease.
Design: Prospective, observational cohort study.
Setting: Nurses' Health Study, with follow-up from 1976 to 1996.
Patients: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified.
Measurements: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders.
Results: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated estrogen, the risk for coronary events was similarly reduced in those currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67]) and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0.37 to 0.92]) compared with never-users. However, the risk for stroke was statistically significantly increased among women taking 0.625 mg or more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to 1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for
Conclusions: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.
Author and Article Information
From the Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts.
Grant Support: By grants HL34594 and CA40356 from the National Institutes of Health. Dr. Grodstein is partially supported by a New Scholars award from the Ellison Medical Foundation and a FIRST award from the National Institutes of Health (AG13482).
Requests for Single Reprints: Francine Grodstein, ScD, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115.
Current Author Addresses: Drs. Grodstein, Colditz, Speizer, and Stampfer: Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115.
Dr. Manson: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215.
Dr. Willett: Department of Nutrition, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.
Author Contributions: Conception and design: F. Grodstein, J.E. Manson, G.A. Colditz, W.C. Willett, F.E. Speizer, M.J. Stampfer.
Analysis and interpretation of the data: F. Grodstein, J.E. Manson, G.A. Colditz, W.C. Willett, M.J. Stampfer.
Drafting of the article: F. Grodstein, G.A. Colditz.
Critical revision of the article for important intellectual content: F. Grodstein, J.E. Manson, W.C. Willett, F.E. Speizer, M.J. Stampfer.
Final approval of the article: F. Grodstein, J.E. Manson, J.E. Manson, G.A. Colditz, W.C. Willett, F.E. Speizer, M.J. Stampfer.
Statistical expertise: F. Grodstein, G.A. Colditz, W.C. Willett.
Obtaining of funding: J.E. Manson, W.C. Willett.
Administrative, technical, or logistic support: F. Grodstein, G.A. Colditz, W.C. Willett, F.E. Speizer.
Collection and assembly of data: F. Grodstein, J.E. Manson, G.A. Colditz, M.J. Stampfer. ARTICLE
A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease
1.25 mg/d) and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10 to 1.92]). Overall, little relation was observed between combination hormone therapy and risk for cardiovascular disease (major coronary heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]).
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 A. Wakatsuki, Y. Okatani, N. Ikenoue, K. Shinohara, K. Watanabe, and T. Fukaya Effect of Lower Dose of Oral Conjugated Equine Estrogen on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women Circulation, August 19, 2003; 108(7): 808 - 813. [Abstract] [Full Text] [PDF]
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K. Yaffe Hormone Therapy and the Brain: Deja Vu All Over Again? JAMA, May 28, 2003; 289(20): 2717 - 2719. [Full Text] [PDF]
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F. Grodstein, J. E. Manson, and M. J. Stampfer Postmenopausal Hormone Replacement Therapy Ann Intern Med, April 15, 2003; 138(8): 688 - 688. [Full Text] [PDF]
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K. B. Michels and J. E. Manson Postmenopausal Hormone Therapy: A Reversal of Fortune Circulation, April 15, 2003; 107(14): 1830 - 1833. [Full Text] [PDF]
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M. Sanada, Y. Higashi, K. Nakagawa, M. Tsuda, I. Kodama, M. Kimura, K. Chayama, and K. Ohama A Comparison of Low-Dose and Standard-Dose Oral Estrogen on Forearm Endothelial Function in Early Postmenopausal Women J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1303 - 1309. [Abstract] [Full Text] [PDF]
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 G. Filippatos and J. T. Parissis Estrogen administration in patients with chronic heart failure: not ready for prime time Eur J Heart Fail, March 1, 2003; 5(2): 113 - 116. [Full Text] [PDF]
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E Lokkegaard, A T Pedersen, B L Heitmann, Z Jovanovic, N Keiding, Y A Hundrup, E B Obel, and B Ottesen Relation between hormone replacement therapy and ischaemic heart disease in women: prospective observational study BMJ, February 22, 2003; 326(7386): 426 - 426. [Abstract] [Full Text] [PDF]
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 F. Grodstein, T. B. Clarkson, and J. E. Manson Understanding the Divergent Data on Postmenopausal Hormone Therapy N. Engl. J. Med., February 13, 2003; 348(7): 645 - 650. [Full Text] [PDF]
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W. W. Parmley In the statin era, how important are intense lifestyle changes? J. Am. Coll. Cardiol., January 15, 2003; 41(2): 273 - 274. [Full Text] [PDF]
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F. Grodstein and J. E. Manson Relationship Between Hormone Replacement Therapy, Socioeconomic Status, and Coronary Heart Disease JAMA, January 1, 2003; 289(1): 44 - 44. [Full Text] [PDF]
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N. Radford, T. Church, F. E. Speizer, B. E. Pearson Murphy, S. R. Davis, H. G. Burger, W. H. Goodson III, H. R. Franke, I. Lev, A. Lahad, et al. Risks of Postmenopausal Hormone Replacement JAMA, December 11, 2002; 288(22): 2819 - 2824. [Full Text] [PDF]
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T. B. Clarkson, M. S. Anthony, T. S. Mikkola, and R. W. St Clair Comparison of Tibolone and Conjugated Equine Estrogens Effects on Carotid Artery Atherosclerosis of Postmenopausal Monkeys Stroke, November 1, 2002; 33(11): 2700 - 2703. [Abstract] [Full Text] [PDF]
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M. J. Evans, H. A. Harris, C. P. Miller, S. K. Karathanasis, and S. J. Adelman Estrogen Receptors {alpha} and {beta} Have Similar Activities in Multiple Endothelial Cell Pathways Endocrinology, October 1, 2002; 143(10): 3785 - 3795. [Abstract] [Full Text] [PDF]
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 K. L. Moreau, A. J. Donato, D. R. Seals, F. A. Dinenno, S. D. Blackett, G. L. Hoetzer, C. A. Desouza, and H. Tanaka Arterial intima-media thickness: site-specific associations with HRT and habitual exercise Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1409 - H1417. [Abstract] [Full Text] [PDF]
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L. Molero, M. Garcia-Duran, J. Diaz-Recasens, L. Rico, S. Casado, and A. Lopez-Farre Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: Regulation by estrogen Cardiovasc Res, October 1, 2002; 56(1): 43 - 51. [Abstract] [Full Text] [PDF]
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R. N. Lemaitre, S. R. Heckbert, B. M. Psaty, N. L. Smith, R. C. Kaplan, and W. T. Longstreth Jr Hormone Replacement Therapy and Associated Risk of Stroke in Postmenopausal Women Arch Intern Med, September 23, 2002; 162(17): 1954 - 1960. [Abstract] [Full Text] [PDF]
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 R. N. Butler, M. Fossel, S. M. Harman, C. B. Heward, S. J. Olshansky, T. T. Perls, D. J. Rothman, S. M. Rothman, H. R. Warner, M. D. West, et al. Is There an Antiaging Medicine? J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2002; 57(9): B333 - 338. [Abstract] [Full Text] [PDF]
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K. K. Koh Effects of estrogen on the vascular wall: vasomotor function and inflammation Cardiovasc Res, September 1, 2002; 55(4): 714 - 726. [Full Text] [PDF]
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H. D. Nelson, L. L. Humphrey, P. Nygren, S. M. Teutsch, and J. D. Allan Postmenopausal Hormone Replacement Therapy: Scientific Review JAMA, August 21, 2002; 288(7): 872 - 881. [Abstract] [Full Text] [PDF]
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L. L. Humphrey, B. K.S. Chan, and H. C. Sox Postmenopausal Hormone Replacement Therapy and the Primary Prevention of Cardiovascular Disease Ann Intern Med, August 20, 2002; 137(4): 273 - 284. [Abstract] [Full Text] [PDF]
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W. L. Isley Growth Hormone Therapy for Adults: Not Ready for Prime Time? Ann Intern Med, August 6, 2002; 137(3): 190 - 196. [Abstract] [Full Text] [PDF]
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 A. Day Lessons from the Women's Health Initiative: primary prevention and gender health Can. Med. Assoc. J., August 1, 2002; 167(4): 361 - 362. [Full Text] [PDF]
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Writing Group for the Women's Health Initiative In Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial JAMA, July 17, 2002; 288(3): 321 - 333. [Abstract] [Full Text] [PDF]
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D. Grady A 60-Year-Old Woman Trying to Discontinue Hormone Replacement Therapy JAMA, April 24, 2002; 287(16): 2130 - 2137. [Full Text] [PDF]
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E. Barrett-Connor, D. Grady, A. Sashegyi, P. W. Anderson, D. A. Cox, K. Hoszowski, P. Rautaharju, K. D. Harper, and for the MORE Investigators Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women: Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation) Randomized Trial JAMA, February 20, 2002; 287(7): 847 - 857. [Abstract] [Full Text] [PDF]
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T. S Mikkola and T. B Clarkson Estrogen replacement therapy, atherosclerosis, and vascular function Cardiovasc Res, February 15, 2002; 53(3): 605 - 619. [Abstract] [Full Text] [PDF]
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