International Agency for Research on Cancer (IARC) - Summaries & Evaluations

(Group 1)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p.280)

A. Evidence for carcinogenicity to humans (sufficient)

A number of studies, utilizing a variety of designs, have shown a consistent, strongly positive association between exposure to a number of oestrogenic substances and risk of endometrial cancer, with evidence of positive dose-response relationships both for strength of medication and duration of use [ref: 1]. Consistent findings have also been seen in more recent studies [ref: 2-16]. The rise and fall of incidence of endometrial cancer in several areas of the USA was compatible with trends in oestrogen use [ref: 1,15].

Of the 20 epidemiological studies of oestrogen replacement therapy and breast cancer risk [ref: 16-35], nine show a positive relation between oestrogen use and breast cancer [ref: 17-20,22-24,28,33]. The increased risks tend to be small; for example, a 50% increase was found with 20 years of menopausal oestrogen replacement therapy use [ref: 24]. All except one [ref: 33] of the positive studies involved use of population controls (eight of the nine studies with population controls gave positive results), and most showed increased risk after prolonged use or after ten or more years since initial exposure. One study showed a positive association with current oestrogen use [ref: 28].

One possible reason that studies with hospital controls gave negative results and those with population controls positive results is that oestrogen replacement therapy may be used more frequently in hospitalized women than in the general population. However, in two studies involving use of both hospital and population control groups, one giving positive [ref: 29] and the other largely negative [ref: 25] results, similar results were obtained when hospital and population controls were used to estimate the relative risk. Three of the studies with negative results [ref: 26,27,34] probably did not permit the authors to address satisfactorily the question of long-term use of oestrogen replacement therapy. The large hospital-based study that showed a positive finding used as controls subjects with a large spectrum of acute conditions unrelated to any of the known or suspected risk factors for breast cancer [ref: 33].

One cohort study of 1439 women initially treated for benign breast disease showed increased risk for women who took exogenous oestrogens after biopsy, but not for those who had taken them before biopsy. The increased risk in the former group appeared to be associated with epithelial hyperplasia or calcification in the initial lesion [ref: 35].

Overall evaluation

Oestrogen replacement therapy is carcinogenic to humans (Group 1).

For definition of the italicized terms, see Preamble Evaluation.

Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)

Subsequent evaluation: Vol. 72 (1999)


1. IARC Monographs, 21, 95-102, 147-159, 1979

2. Buring, J.E., Bain, C.J. & Ehrmann, R.L. (1986) Conjugated estrogen use and risk of endometrial cancer. Am. J. Epidemiol., 124, 434-441

3. Ewertz, M., Machado, S.G., Boice, J.D., Jr & Jensen, O.M. (1984) Endometrial cancer following treatment for breast cancer: A case-control study in Denmark. Br. J. Cancer, 50, 687-692

4. Henderson, B.E., Casagrande, J.T., Pike, M.C., Mack, T., Rosario, I. & Duke, A. (1983) The epidemiology of endometrial cancer in young women. Br. J. Cancer, 47, 749-756

5. Hulka, B.S., Fowler, W.C., Jr, Kaufman, D.G., Grimson, R.C., Greenberg, B.G., Hogue, C.J.R., Berger, G.S. & Pulliam, C.C. (1980) Estrogen and endometrial cancer: Cases and two control groups from North Carolina. Am. J. Obstet. Gynecol., 137, 92-101

6. Kelsey, J.L., LiVolsi, V.A., Holford, T.R., Fischer, D.B., Mostow, E.D., Schwartz, P.E., O'Connor, T. & White, C. (1982) A case-control study of cancer of the endometrium. Am. J. Epidemiol., 116, 333-342

7. La Vecchia, C., Franceschi, S., Gallus, G., DeCarli, A., Colombo, E., Mangioni, C. & Tognoni, G. (1982) Oestrogens and obesity as risk factors for endometrial cancer in Italy. Int. J. Epidemiol., 11, 120-126

8. La Vecchia, C., Franceschi, S., DeCarli, A., Gallus, G. & Tognoni, G. (1984) Risk factors for endometrial cancer at different ages. J. natl Cancer Inst., 73, 667-671

9. Öbrink, A., Bunne, G., Collén, J. & Tjernberg, B. (1981) Estrogen regimen of women with endometrial carcinoma. A retrospective case-control study at Radiumhemmet. Acta obstet. gynecol. scand., 60, 191-197

10. Shapiro, S., Kaufman, D.W., Slone, D., Rosenberg, L., Miettinen, O.S., Stolley, P.D., Rosenshein, N.B., Watring, W.G., Leavitt, T., Jr & Knapp, R.C. (1980) Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. New Engl. J. Med., 303, 485-489

11. Shapiro, S., Kelly, J.P., Rosenberg, L., Kaufman, D.W., Helmrich, S.P., Rosenshein, N.B., Lewis, J.L., Jr, Knapp, R.C., Stolley, P.D. & Schottenfeld, D. (1985) Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. New Engl. J. Med., 313, 969-972

12. Spengler, R.F., Clarke, E.A., Woolever, C.A., Newman, A.M. & Osborn, R.W. (1981) Exogenous estrogens and endometrial cancer: a case-control study and assessment of potential biases. Am. J. Epidemiol., 114, 497-506

13. Stavraky, K.M., Collins, J.A., Donner, A. & Wells, G.A. (1981) A comparison of estrogen use by women with endometrial cancer, gynecologic disorders, and other illnesses. Am. J. Obstet. Gynecol., 141, 547-555

14. Weiss, N.S., Farewell, V.T., Szekely, D.R., English, D.R. & Kiviat, N. (1980) Oestrogens and endometrial cancer: effect of other risk factors on the association. Maturitas, 2, 185-190

15. Marrett, L.D., Meigs, J.W. & Flannery, J.T. (1982) Trends in the incidence of cancer of the corpus uteri in Connecticut, 1964-1969, in relation to consumption of exogenous estrogens. Am. J. Epidemiol., 116, 57-67

16. Vakil, D.V., Morgan, R.W. & Halliday, M. (1983) Exogenous estrogens and development of breast and endometrial cancer. Cancer Detect. Prev., 6, 415-424

17. Hoover, R., Gray, L.A., Sr, Cole, P. & MacMahon, B. (1976) Menopausal estrogens and breast cancer. New Engl. J. Med., 295, 401-405

18. Ross, R.K., Paganini-Hill, A., Gerkins, V.R., Mack, T.M., Pfeffer, R., Arthur, M. & Henderson, B.E. (1980) A case-control study of menopausal estrogen therapy and breast cancer. J. Am. med. Assoc., 243, 1635-1639

19. Hoover, R., Glass, A., Finkle, W.D., Azevedo, D. & Milne, K. (1981) Conjugated estrogens and breast cancer risk in women. J. natl Cancer Inst., 67, 815-820

20. Hulka, B.S., Chambless, L.E., Deubner, D.C. & Wilkinson, W.E. (1982) Breast cancer and estrogen replacement therapy. Am. J. Obstet. Gynecol., 143, 638-644

21. Gambrell, R.D., Jr, Maier, R.C. & Sanders, B.I. (1983) Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet. Gynecol., 62, 435-443

22. Hiatt, R.A., Bawol, R., Friedman, G.D. & Hoover, R. (1984) Exogenous estrogen and breast cancer after bilateral oophorectomy. Cancer, 54, 139-144

23. McDonald, J.A., Weiss, N.S., Daling, J.R., Francis, A.M. & Polissar, L. (1986) Menopausal estrogen use and the risk of breast cancer. Breast Cancer Res. Treat., 7, 193-199

24. Brinton, L.A., Hoover, R. & Fraumeni, J.F., Jr (1986) Menopausal oestrogens and breast cancer risk: an expanded case-control study. Br. J. Cancer, 54, 825-832

25. Nomura, A.M.Y., Kolonel, L.N., Hirohata, T. & Lee, J. (1986) The association of replacement estrogens with breast cancer. Int. J. Cancer, 37, 49-53

26. Sartwell, P.E., Arthes, F.G. & Tonascia, J.A. (1977) Exogenous hormones, reproductive history, and breast cancer. J. natl Cancer Inst., 59, 1589-1592

27. Ravnihar, B., Seigel, D.G. & Lindtner, J. (1979) An epidemiologic study of breast cancer and benign breast neoplasias in relation to the oral contraceptive and estrogen use. Eur. J. Cancer, 15, 395-405

28. Jick, H., Walker, A.M., Watkins, R.N., D'Ewart, D.C., Hunter, J.R., Danford, A., Madsen, S., Dinan, B.J. & Rothman, K.J. (1980) Replacement estrogens and breast cancer. Am. J. Epidemiol., 112, 586-594

29. Kelsey, J.L., Fischer, D.B., Holford, T.R., LiVolsi, V.A., Mostow, E.D., Goldenberg, I.S. & White, C. (1981) Exogenous estrogens and other factors in the epidemiology of breast cancer. J. natl Cancer Inst., 67, 327-333

30. Sherman, B., Wallace, R. & Bean, J. (1983) Estrogen use and breast cancer. Interaction with body mass. Cancer, 51, 1527-1531

31. Kaufman, D.W., Miller, D.R., Rosenberg, L., Helmrich, S.P., Stolley, P., Schottenfeld, D. & Shapiro, S. (1984) Noncontraceptive estrogen use and the risk of breast cancer. J. Am. med. Assoc., 252, 63-67

32. Horwitz, R.I. & Stewart, K.R. (1984) Effect of clinical features on the association of estrogens and breast cancer. Am. J. Med., 76, 192-198

33. La Vecchia, C., Decarli, A., Parazzini, F., Gentile, A., Liberati, C. & Franceschi, S. (1986) Non-contraceptive oestrogens and the risk of breast cancer in women. Int. J. Cancer, 38, 853-858

34. Wingo, P.A., Layde, P.M., Lee, N.C., Rubin, G. & Ory, H.W. (1987) The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. J. Am. med. Assoc., 257, 209-215

35. Thomas, D.B., Persing, J.P. & Hutchison, W.B. (1982) Exogenous estrogens and other risk factors for breast cancer in women with benign breast diseases. J. natl Cancer Inst., 69, 1017-1025

Last updated: 9 February 1998

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       Toxicological Abbreviations