European Journal of Epidemiology

, Volume 20, Issue 8, pp 699–711 | Cite as

Factors Modifying the Association Between Hormone-Replacement Therapy and Breast Cancer Risk

  • Beate Pesch
  • Yon Ko
  • Hiltrud Brauch
  • Ute Hamann
  • Volker Harth
  • Sylvia Rabstein
  • Christiane Pierl
  • Hans-Peter Fischer
  • Christian Baisch
  • Christina Justenhoven
  • Ulrich Ranft
  • Thomas Brüning


Objectives: Hormone-replacement therapy (HRT) is an established risk factor for breast cancer. HRT users are different from non-users with respect to socio-economic and other characteristics. There may be women where the HRT-related risk could be modulated by other factors.

Methods: We conducted a population-based case–control study with 688 breast cancer cases and 724 controls to characterize HRT users and to estimate odds ratios (OR) and 95% confidence intervals (CI) for HRT use and potentially risk modifying factors.

Results: In women aged 50 years and older, 58% of controls and 61% of cases ever used HRT. Among women in natural menopause, HRT use for 10 years and more years was associated with an increased breast cancer risk (OR 1.79, 95% CI, 1.12–2.87), but not among women in surgical menopause (OR 0.61, 95% CI, 0.09–4.17). In the subgroup of women with a positive family history of breast cancer, each year of HRT use increased the risk by 1.22 (95% CI, 1.02–1.47). Another subgroup comprised women with at least 10 diagnostic mammograms (OR 4.04, 95% CI, 1.10–14.81 for using HRT 10 or more years).

Conclusions: Long-term HRT use was associated with a breast cancer risk in women with natural menopause. Our findings suggest that this risk may be increased in women with a positive family history of breast cancer and in women who received frequent diagnostic mammographic screens.

Key words

Breast cancer risks Case–control study Family history of cancer Hormone-replacement therapy Mammography Risk-modifying factors 



Body mass index


Confidence interval


Crude odds ratio


European Prospective Investigation into Cancer and Nutrition


Hormone-replacement therapy


Oral contraceptives


Odds ratio


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  1. 1.
    Million Women Study Collaborators2002Patterns of use of hormone replacement therapy in one million women in Britain, 1996–2000BJOG10913191330Google Scholar
  2. 2.
    Nelson, HD, Humphrey, LL, Nygren, P, Teutsch, SM, Allan, JD 2002Postmenopausal hormone replacement therapy: scientific reviewJAMA288872881CrossRefPubMedGoogle Scholar
  3. 3.
    Collaborative Group on Hormonal Factors in Breast Cancer1997Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancerLancet35010471059Google Scholar
  4. 4.
    Fernandez, E, Gallus, S, Bosetti, C, Franceschi, S, Negri, E, La Vecchia, C 2003Hormone replacement therapy and cancer risk: A systematic analysis from a network of case–control studiesInt J Cancer105408412CrossRefPubMedGoogle Scholar
  5. 5.
    Rossouw, JE, Anderson, GL, Prentice, RL,  et al. 2002Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health Initiative randomized controlled trialJAMA288321333PubMedGoogle Scholar
  6. 6.
    Beral, V 2003Breast cancer and hormone-replacement therapy in the Million Women StudyLancet362419427CrossRefPubMedGoogle Scholar
  7. 7.
    Banks, E, Barnes, I, Baker, K, Key, TJ 2002Use of hormonal therapy for menopause in nine European countriesIARC Sci Publ156301303PubMedGoogle Scholar
  8. 8.
    Greiser, E 2001Hormone replacement therapy–treatment with risk factorsDtsch Med Wochenschr126255256CrossRefPubMedGoogle Scholar
  9. 9.
    Arzneimittelkommission der deutschen Aerzteschaft. [Hormone replacement therapy]. Arzneiverordnung in der Praxis-Sonderheft 2003 [in German] 2003Google Scholar
  10. 10.
    Randal, J 2003NIH workshop tries to create consensus on HRT useJ Natl Cancer Inst95911PubMedGoogle Scholar
  11. 11.
    Holle, R, Gieseke, B, Nagl, H 2000PC-gestuetzte Datenerhebung als Beitrag zur Qualitaetssicherung in Gesundheitssurveys: Erfahrungen mit DAIMON im KORA-Survey 2000Zeitschrift fuer Gesundheitswissenschaften8165173Google Scholar
  12. 12.
    WHO. WHO Scientific Group on Research on the Menopause in the 1990’s. Geneva. Switzerland. WHO Technical Report Series 866, 1994Google Scholar
  13. 13.
    SAS2000Changes and Enhancement Through Release 8.0SAS Institute SAS/STAT SoftwareCary, NC, USAGoogle Scholar
  14. 14.
    Braendle, W, Semler, J 2000Postmenopausal hormone replacement under scrutiny. “Fatal therapy”?MMW Fortschr Med1421112Google Scholar
  15. 15.
    Ursin, G, Tseng, CC, Paganini-Hill, A,  et al. 2002Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer?J Clin Oncol20699706CrossRefPubMedGoogle Scholar
  16. 16.
    Tavani, A, Braga, C, La Vecchia, C, Negri, E, Russo, A, Franceschi, S 1997Attributable risks for breast cancer in Italy: Education, family history and reproductive and hormonal factorsInt J Cancer70159163CrossRefPubMedGoogle Scholar
  17. 17.
    Biglia, N, Cozzarella, M, Ponzone, R,  et al. 2004Personal use of HRT by postmenopausal women doctors and doctors’ wives in the north of ItalyGynecol Endocrinol18165174CrossRefPubMedGoogle Scholar
  18. 18.
    Olsson, HL, Ingvar, C, Bladstrom, A 2003Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in SwedenCancer9713871392CrossRefPubMedGoogle Scholar
  19. 19.
    Steinberg, KK, Thacker, SB, Smith, SJ,  et al. 1991A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancerJAMA26519851990CrossRefPubMedGoogle Scholar
  20. 20.
    Olsson, H, Bladstrom, A, Ingvar, C, Moller, TR 2001A population-based cohort study of HRT use and breast cancer in southern SwedenBr J Cancer85674677CrossRefPubMedGoogle Scholar
  21. 21.
    Banks, E, Beral, V, Cameron, R,  et al. 2002Comparison of various characteristics of women who do and do not attend for breast cancer screeningBreast Cancer Res4R1CrossRefPubMedGoogle Scholar
  22. 22.
    Carney, PA, Miglioretti, DL, Yankaskas, BC,  et al. 2003Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammographyAnn Intern Med138168175PubMedGoogle Scholar
  23. 23.
    Chlebowski, RT, Hendrix, SL, Langer, RD,  et al. 2003Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative Randomized TrialJAMA28932433253CrossRefPubMedGoogle Scholar
  24. 24.
    Hofseth, LJ, Raafat, AM, Osuch, JR, Pathak, DR, Slomski, CA, Haslam, SZ 1999Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breastJ Clin Endocrinol Metab8445594565CrossRefPubMedGoogle Scholar
  25. 25.
    Persson, I, Thurfjell, E, Holmberg, L 1997Effect of estrogen and estrogen–progestin replacement regimens on mammographic breast parenchymal densityJ Clin Oncol1532013207PubMedGoogle Scholar
  26. 26.
    Rutter, CM, Mandelson, MT, Laya, MB, Seger, DJ, Taplin, S 2001Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapyJAMA285171176CrossRefPubMedGoogle Scholar
  27. 27.
    Andersen, MR, Smith, R, Meischke, H, Bowen, D, Urban, N 2003Breast cancer worry and mammography use by women with and without a family history in a population-based sampleCancer Epidemiol Biomarkers Prev12314320PubMedGoogle Scholar
  28. 28.
    Lerman, C, Daly, M, Sands, C,  et al. 1993Mammography adherence and psychological distress among women at risk for breast cancerJ Natl Cancer Inst8510741080PubMedGoogle Scholar
  29. 29.
    Raafat, AM, Hofseth, LJ, Haslam, SZ 2001Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal mammary gland in a murine modelAm J Obstet Gynecol184340349CrossRefPubMedGoogle Scholar
  30. 30.
    Chen, CL, Weiss, NS, Newcomb, P, Barlow, W, White, E 2002Hormone replacement therapy in relation to breast cancerJAMA287734741CrossRefPubMedGoogle Scholar
  31. 31.
    Magnusson, C, Baron, JA, Correia, N, Bergstrom, R, Adami, HO, Persson, I 1999Breast-cancer risk following long-term oestrogen- and oestrogen–progestin-replacement therapyInt J Cancer81339344CrossRefPubMedGoogle Scholar
  32. 32.
    Schairer, C, Lubin, J, Troisi, R, Sturgeon, S, Brinton, L, Hoover, R 2000Menopausal estrogen and estrogen– progestin replacement therapy and breast cancer riskJAMA283485491CrossRefPubMedGoogle Scholar
  33. 33.
    Jensen, LB, Vestergaard, P, Hermann, AP,  et al. 2003Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: A randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention StudyJ Bone Miner Res18333342PubMedGoogle Scholar
  34. 34.
    Norman, SA, Berlin, JA, Weber, AL,  et al. 2003Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal womenCancer Causes Control14933943CrossRefPubMedGoogle Scholar
  35. 35.
    Daniel, CW, Silberstein, GB, Strickland, P 1987Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiographyCancer Res4760526057PubMedGoogle Scholar
  36. 36.
    Hunter, DJ, Manson, JE, Colditz, GA,  et al. 1997Reproducibility of oral contraceptive histories and validity of hormone composition reported in a cohort of US womenContraception56373378CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Beate Pesch
    • 1
    • 6
  • Yon Ko
    • 2
  • Hiltrud Brauch
    • 3
  • Ute Hamann
    • 4
  • Volker Harth
    • 1
  • Sylvia Rabstein
    • 1
  • Christiane Pierl
    • 1
  • Hans-Peter Fischer
    • 5
  • Christian Baisch
    • 3
    • 4
  • Christina Justenhoven
    • 3
  • Ulrich Ranft
    • 6
  • Thomas Brüning
    • 1
  1. 1.Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin (BGFA)Institut der Ruhr-Universität BochumBochumGemany
  2. 2.Johanniter-Krankenhaus und Medizinische Universitäts-Poliklinik BonnGermany
  3. 3.Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie (IKP)StuttgartGermany
  4. 4.Deutsches Krebsforschungszentrum (DKFZ)HeidelbergGermany
  5. 5.Institut für PathologieUniversitätsklinikumBonnGermany
  6. 6.Institut für Umweltmedizinische Forschung (IUF)DüsseldorfGermany

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