To examine the risk of breast cancer after noncontraceptive treatment with estrogen, we conducted a prospective study of 23,244 women 35 years of age or older who had had estrogen prescriptions filled in the Uppsala region of Sweden. During the follow-up period (mean, 5.7 years) breast cancer developed in 253 women. Compared with other women in the same region, the women in the estrogen cohort had an overall relative risk of breast cancer of 1.1 (95 percent confidence interval, 1.0 to 1.3). The relative risk increased with the duration of estrogen treatment (P = 0.002), reaching 1.7 after nine years (95 percent confidence interval, 1.1 to 2.7). Estradiol (used in 56 percent of the treatment periods in the cohort) was associated with a 1.8-fold increase in risk after more than six years of treatment (95 percent confidence interval, 0.7 to 4.6). No increase in risk was found after the use of conjugated estrogens (used in 22 percent of the treatment periods) or other types, mainly estriols (used in 22 percent of the treatment periods). Although the numbers of women were smaller, the risk of breast cancer was highest among the women who took estrogen and progestin in combination for extended periods. The relative risk was 4.4 (95 percent confidence interval, 0.9 to 22.4) in women who used only this combination for more than six years. Among women who had previously used estrogens alone, the relative risk after three years or more of use of the combination regimen was 2.3 (95 percent confidence interval, 0.7 to 7.8). We conclude that in this cohort, long-term perimenopausal treatment with estrogens (or at least estradiol compounds) seems to be associated with a slightly increased risk of breast cancer, which is not prevented and may even be increased by the addition of progestins.
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Department of Surgery, University Hospital, Uppsala, Sweden.
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(2000). Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod
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[Abstract][Full Text]
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(2000). Effect of Hormone Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin. JNCI J Natl Cancer Inst
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[Abstract][Full Text]
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[Abstract][Full Text]
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(1999). Relative Versus Attributable Risk of Breast Cancer from Estrogen Replacement Therapy. J. Clin. Endocrinol. Metab.
84: 1875-1881
[Full Text]
Walsh, B. W.
(1999). The Individualized Approach to Menopause Management. J. Clin. Endocrinol. Metab.
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[Full Text]
Rubin, R., Quine, L.
(1999). Women's symptoms at the menopause and their expectations of hormone replacement therapy. Journal of Research in Nursing
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[Abstract]
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(1999). Effects of Estrogen and Estrogen-Progestin on Mammographic Parenchymal Density. ANN INTERN MED
130: 262-268
[Abstract][Full Text]
Brinton, L. A., Schairer, C.
(1997). Postmenopausal Hormone-Replacement Therapy -- Time for a Reappraisal?. NEJM
336: 1821-1822
[Full Text]
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(1997). Variability of Glutathione Levels in Normal Breast Tissue and Subcutaneous Fat during the Menstrual Cycle: An in Vivo Study with Microdialysis Technique. J. Clin. Endocrinol. Metab.
82: 1382-1384
[Abstract][Full Text]
Price, E. H, Little, H. K, Grant, E. C G, Steel, C M.
(1997). Women need to be warned about dangers of hormone replacement therapy. BMJ
314: 376-376
[Full Text]
Ginsburg, E. S., Mello, N. K., Mendelson, J. H., Barbieri, R. L., Teoh, S. K., Rothman, M., Gao, X., Sholar, J. W.
(1996). Effects of Alcohol Ingestion on Estrogens in Postmenopausal Women. JAMA
276: 1747-1751
[Abstract]
Rossouw, J. E.
(1996). Estrogens for Prevention of Coronary Heart Disease: Putting the Brakes on the Bandwagon. Circulation
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[Full Text]
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276: 1404-1408
[Abstract]
Mckinney, K.
(1996). Use of hormone replacement therapy. BMJ
313: 686-686
[Full Text]
Salamone, L. M., Pressman, A. R., Seeley, D. G., Cauley, J. A.
(1996). Estrogen Replacement Therapy: A Survey of Older Women's Attitudes. Arch Intern Med
156: 1293-1297
[Abstract]
Gambrell, R. D. Jr
(1996). Hormone Replacement Therapy and Breast Cancer Risk. Arch Fam Med
5: 341-348
[Abstract]
Stanford, J. L., Weiss, N. S.
(1996). Hormone Replacement Therapy and Breast Cancer. Arch Fam Med
5: 349-350
[Abstract]
Colditz, G. A.
(1996). Postmenopausal Estrogens and Breast Cancer. Reproductive Sciences
3: 50-56
McPherson, K.
(1995). Breast cancer and hormonal supplements in postmenopausal women. BMJ
311: 699-700
[Full Text]
Stanford, J. L., Weiss, N. S., Voigt, L. F., Daling, J. R., Habel, L. A., Rossing, M. A.
(1995). Combined Estrogen and Progestin Hormone Replacement Therapy in Relation to Risk of Breast Cancer in Middle-aged Women. JAMA
274: 137-142
[Abstract]
Adami, H.-O., Persson, I.
(1995). Hormone Replacement and Breast Cancer: A Remaining Controversy?. JAMA
274: 178-179
[Abstract]
Colditz, G. A., Hankinson, S. E., Hunter, D. J., Willett, W. C., Manson, J. E., Stampfer, M. J., Hennekens, C., Rosner, B., Speizer, F. E.
(1995). The Use of Estrogens and Progestins and the Risk of Breast Cancer in Postmenopausal Women. NEJM
332: 1589-1593
[Abstract][Full Text]
Davidson, N. E.
(1995). Hormone-Replacement Therapy -- Breast versus Heart versus Bone. NEJM
332: 1638-1639
[Full Text]
Cobleigh, M. A., Berris, R. F., Bush, T., Davidson, N. E., Robert, N. J., Sparano, J. A., Tormey, D. C., Wood, W. C.
(1995). Estrogen Replacement Therapy in Breast Cancer Survivors-Reply. JAMA
273: 621-621
[Abstract]
Cobleigh, M. A., Berris, R. F., Bush, T., Davidson, N. E., Robert, N. J., Sparano, J. A., Tormey, D. C., Wood, W. C., Breast Cancer Committees of the Eastern Cooperativ, , Berris, R. F., Cobleigh, M. A., Davidson, N. E., Fetting, J., Gelman, R. S., Neuberg, D. S., Gilchrist, K., Goldstein, L. J., Hopper, B. B., Hughes, L., Wood, W. C., Kiel, K. D., McCaskill-Stevens, W. J., Sledge, G. W. Jr, Richman, S., Robert, N. J., Sparano, J. A., Smith, T. J., Tormey, D. C.
(1994). Estrogen Replacement Therapy in Breast Cancer Survivors: A Time for Change. JAMA
272: 540-545
[Abstract]
Belchetz, P. E.
(1994). Hormonal Treatment of Postmenopausal Women. NEJM
330: 1062-1071
[Full Text]
Baird, D. T., Glasier, A. F.
(1993). Hormonal Contraception. NEJM
328: 1543-1549
[Full Text]
Henderson, B., Ross, R., Pike, M.
(1993). Hormonal chemoprevention of cancer in women. Science
259: 633-638
[Abstract]
Grady, D., Rubin, S. M., Petitti, D. B., Fox, C. S., Black, D., Ettinger, B., Ernster, V. L., Cummings, S. R.
(1992). Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women. ANN INTERN MED
117: 1016-1037
[Abstract]
Elstein, A. S., Holzman, G. B., Belzer, L. J., Ellis, R. D.
(1992). Hormonal Replacement Therapy: Analysis of Clinical Strategies Used by Residents. Med Decis Making
12: 265-273
[Abstract]
Henrich, J. B.
(1992). The Postmenopausal Estrogen/Breast Cancer Controversy. JAMA
268: 1900-1902
[Abstract]
Henderson, B., Ross, R., Pike, M.
(1991). Toward the primary prevention of cancer. Science
254: 1131-1138
[Abstract]
Barrett-Connor, E.
(1991). Postmenopausal Estrogen and Prevention Bias. ANN INTERN MED
115: 455-456
[Abstract]
Steinberg, K. K., Thacker, S. B., Smith, S. J., Stroup, D. F., Zack, M. M., Flanders, W. D., Berkelman, R. L.
(1991). A Meta-analysis of the Effect of Estrogen Replacement Therapy on the Risk of Breast Cancer. JAMA
265: 1985-1990
[Abstract]
Vatz, J. B., Kellie, S. E.
(1991). Estrogen Replacement Therapy and Risk of Breast Cancer. JAMA
265: 1824-1825
[Abstract]
Working Group on Management of Patients with Hyper,
(1991). National Education Programs Working Group Report on the Management of Patients with Hypertension and High Blood Cholesterol. ANN INTERN MED
114: 224-237
[Abstract]
Dupont, W. D., Page, D. L.
(1991). Menopausal Estrogen Replacement Therapy and Breast Cancer. Arch Intern Med
151: 67-72
[Abstract]
Henderson, B. E., Paganini-Hill, A., Ross, R. K.
(1991). Decreased Mortality in Users of Estrogen Replacement Therapy. Arch Intern Med
151: 75-78
[Abstract]
Colditz, G. A., Stampfer, M. J., Willett, W. C., Hennekens, C. H., Rosner, B., Speizer, F. E.
(1990). Prospective Study of Estrogen Replacement Therapy and Risk of Breast Cancer in Postmenopausal Women. JAMA
264: 2648-2653
[Abstract]
Haynes, R. B.
(1990). Loose Connections between Peer-Reviewed Clinical Journals and Clinical Practice. ANN INTERN MED
113: 724-728
[Abstract]
Cummings, S. R., Browner, W. S., Grady, D., Ettinger, B.
(1990). Should Prescription of Postmenopausal Hormone Therapy Be Based on the Results of Bone Densitometry?. ANN INTERN MED
113: 565-567
[Abstract]
Tosteson, A. N. A., Rosenthal, D. I., Melton, L. J. III, Weinstein, M. C.
(1990). Cost Effectiveness of Screening Perimenopausal White Women for Osteoporosis: Bone Densitometry and Hormone Replacement Therapy. ANN INTERN MED
113: 594-603
[Abstract]
Naessen, T., Persson, I., Adami, H.-O., Bergstrom, R., Bergkvist, L.
(1990). Hormone Replacement Therapy and the Risk for First Hip Fracture: A Prospective, Population-based Cohort Study. ANN INTERN MED
113: 95-103
[Abstract]
Melton, L. J. III, Eddy, D. M., Johnston, C. C. Jr.
(1990). Screening for Osteoporosis. ANN INTERN MED
112: 516-528
[Abstract]
(1989). BREAST-CANCER RISK WITH MENOPAUSAL ESTROGEN THERAPY. JWatch General
1989: 1-1
[Full Text]
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