Breast Cancer Research and Treatment

, Volume 150, Issue 2, pp 405–413 | Cite as

Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies

  • Alessandra GennariEmail author
  • Mauro Costa
  • Matteo Puntoni
  • Laura Paleari
  • Andrea De Censi
  • Maria Pia Sormani
  • Nicoletta Provinciali
  • Paolo Bruzzi


The increasing practice of hormonal infertility treatments (HITs) raised concerns about their effects on breast cancer (BC) risk. Available evidence reported conflicting results. The aim of this study was to assess the potential association between HITs and BC risk. The literature was searched through November 2014. Eligible studies included cohort studies reporting BC incidence in women undergone HITs. Data were analyzed with standard meta-analytic techniques. Subgroup analyses were performed by type of intervention (IVF vs. NO IVF), follow-up duration (<10 vs. >10 years), and type of control (population vs. infertile). 20 eligible studies (207.914 women, 2347 BC) were retrieved: no increased risk was detected (SRR = 1.05, 95 % CI 0.96–1.14), with a significant heterogeneity (I 2 = 59 %, p = 0.001) among studies. In the seven studies with the in vitro fertilization (IVF) procedure, no increase in BC risk was observed (SRR = 0.96, 95 % CI 0.80–1.14); in the three NO IVF studies, an increased BC risk was identified (SRR = 1.26, 95 %CI 1.06–1.50). A borderline interaction between type of intervention (IVF vs. NO IVF) and BC risk was observed (p = 0.06). An increased risk with longer follow-up (≥10 vs. <10 years) was detected (SRR = 1.13, 95 % CI 1.02–1.26 vs. SRR = 0.95, 95 % CI 0.85–1.06). Overall, HITs are not associated with an increased BC risk. In particular, no increased risk was observed in women undergoing IVF. Conversely, an increased in BC risk cannot be ruled out with older treatment protocols based on clomiphene. The long-term administration of clomiphene outside the current indications should be discouraged because of a possible increase in BC risk.


Hormonal infertility treatments Breast cancer risk Cohort studies 



This work was supported by the Italian Ministry of Health (RF 2009-1494489) and by the Italian Association for Cancer Research (AIRC).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Eliassen AH, Hankinson SE (2008) Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies. Adv Exp Med Biol 630:148–165CrossRefPubMedGoogle Scholar
  2. 2.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Writing Group for the Women’s Health Initiative (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative. JAMA 288(3):321–333CrossRefPubMedGoogle Scholar
  3. 3.
    Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 289(24):3243–3253CrossRefPubMedGoogle Scholar
  4. 4.
    Eliassen AH, Missmer SA, Tworoger SS, Spiegelman D, Barbieri RL, Dowsett M et al (2006) Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 98(19):1406–1415CrossRefPubMedGoogle Scholar
  5. 5.
    Fortner RT, Eliassen AH, Spiegelman D, Willett WC, Barbieri RL, Hankinson SE (2013) Premenopausal endogenous steroid hormones and breast cancer risk: results from the nurses’ health study II. Breast Cancer Res Treat 15(2):R19CrossRefGoogle Scholar
  6. 6.
    Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO (2011) Malignancies among women who gave birth after in vitro fertilization. Hum Reprod 26(1):253–258CrossRefPubMedGoogle Scholar
  7. 7.
    Calderon-Margalit R, Friedlander Y, Yanetz R, Kleinhaus K, Perrin MC, Manor O et al (2009) Cancer risk after exposure to treatments for ovulation induction. Am J Epidemiol 169(3):365–375CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Sunderam S, Kissin DM, Crawford D, Anderson JE, Folger SG, Jamieson DJ et al (2006) Assisted reproductive technology surveillance—United States. Morb Mortal Wly Rep 58:1–25Google Scholar
  9. 9.
    Li LL, Zhou J, Qian XJ, Chen YD (2013) Meta-analysis on the possible association between in vitro fertilization and cancer risk. Int J Gynecol Cancer 23(1):16–24CrossRefPubMedGoogle Scholar
  10. 10.
    Sergentanis TN, Diamantaras AA, Perlepe C, Kanavidis P, Skalkidou A, Petridou ET (2014) IVF and breast cancer: a systematic review and meta-analysis. Hum Reprod Update 20:106–123CrossRefPubMedGoogle Scholar
  11. 11.
    Zreik TG, Mazloom A, Chen Y (2010) Fertility drugs and the risk of breast cancer: a meta-analysis and review. Breast Cancer Res Treat 124:13–26CrossRefPubMedGoogle Scholar
  12. 12.
    Kleinbaum DG, Kupper LL, Morgenstern H (1982) Epidemiologic research. Principles and quantitative methods. Van Nostrand Reinhold, New YorkGoogle Scholar
  13. 13.
    Stroup DF, Berlin JA, Morton SC (2000) Meta-analysis of observational studies in epidemiology. A proposal for reporting. JAMA 283:2008–2012CrossRefPubMedGoogle Scholar
  14. 14.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012CrossRefPubMedGoogle Scholar
  15. 15.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  16. 16.
    Steptoe PC, Edwards RG (1978) Birth after the reimplantation of a human embryo. Lancet 2:366CrossRefPubMedGoogle Scholar
  17. 17.
    Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG (1996) Risk of breast cancer in a cohort of infertile women. Gynecol Oncol 60:3–7CrossRefPubMedGoogle Scholar
  18. 18.
    Potashnik G, Lerner-Geva L, Genkin L, Chetrit A, Lunenfeld E, Porath A (1999) Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 71:853–859CrossRefPubMedGoogle Scholar
  19. 19.
    Venn A, Watson L, Bruinsma F, Giles G, Healy D (1999) Risk of cancer after use of fertility drugs with in vitro fertilisation. Lancet 354:1586–1590CrossRefPubMedGoogle Scholar
  20. 20.
    Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B et al (2002) Cancer incidence in a cohort of infertile women who underwent in vitro fertilization. Fertil Steril 77:324–327CrossRefPubMedGoogle Scholar
  21. 21.
    Doyle P, Maconochie N, Beral V, Swerdlow AJ, Tan SL (2002) Cancer incidence following treatment for infertility at a clinic in the UK. Hum Reprod 17:2209–2213CrossRefPubMedGoogle Scholar
  22. 22.
    Lerner-Geva L, Geva E, Lessing JB, Chetrit A, Modan B, Amit A (2003) The possible association between in vitro fertilization treatments and cancer development. Int J Gynecol Cancer 13:23–27CrossRefPubMedGoogle Scholar
  23. 23.
    Gauthier E, Paoletti X, Clavel-Chapelon F, E3N Group (2004) Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hum Reprod 19:2216–2221CrossRefPubMedGoogle Scholar
  24. 24.
    Terry KL, Willett WC, Rich-Edwards JW, Michels KB (2006) A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med 166:2484–2489CrossRefPubMedGoogle Scholar
  25. 25.
    Jensen A, Sharif H, Svare EI, Frederiksen K, Kjaer SK (2007) Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study. Cancer Epidemiol Biomark Prev 16:1400–1407CrossRefGoogle Scholar
  26. 26.
    Pappo I, Lerner-Geva L, Halevy A, Olmer L, Friedler S, Raziel A et al (2008) The possible association between in vitro fertilization and breast cancer incidence. Ann Surg Oncol 15:1048–1055CrossRefPubMedGoogle Scholar
  27. 27.
    Van den Belt-Dusebout SAW, Mooij TM, Burger CW, Van Leeuwen FE (2008) Breast cancer risk in a nation-wide cohort of 25,152 subfertile women in the Netherlands. Fertil Steril 90:S74CrossRefGoogle Scholar
  28. 28.
    Orgéas CC, Sanner K, Hall P, Conner P, Holte J, Nilsson SJ (2009) Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study. Am J Obstet Gynecol 200(1):72.e1–72.e7CrossRefGoogle Scholar
  29. 29.
    Yli-Kuha AN, Gissler M, Klemetti R, Luoto R, Hemminki E (2012) Cancer morbidity in a cohort of 9175 Finnish women treated for infertility. Hum Reprod 27:1149–1155CrossRefPubMedGoogle Scholar
  30. 30.
    Stewart LM, Holman CD, Hart R, Bulsara MK, Preen DB, Finn JC (2012) In vitro fertilization and breast cancer: is there cause for concern? Fertil Steril 98:334–340CrossRefPubMedGoogle Scholar
  31. 31.
    Lerner-Geva L, Rabinovici J, Olmer L, Blumstein T, Mashiach S, Lunenfeld B (2012) Are infertility treatments a potential risk factor for cancer development? Perspective of 30 years of follow-up. Gynecol Endocrinol 28:809–814CrossRefPubMedGoogle Scholar
  32. 32.
    Brinton LA, Trabert B, Shalev V, Lunenfeld E, Sella T, Chodick G (2013) In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Fertil Steril 99:1189–1196CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Brinton LA, Scoccia B, Moghissi KS, Westhoff CL, Niwa S, Ruggieri D et al (2014) Long-term relationship of ovulation-stimulating drugs to breast cancer risk. Cancer Epidemiol Biomark Prev 23:584–593CrossRefGoogle Scholar
  34. 34.
    Reigstad MM, Larsen IK, Myklebust TÅ, Robsahm TE, Oldereid NB, Omland AK et al (2015) Risk of brest cancer following fertility treatment: a registry based cohort study of parous women in Norway. Int J Cancer 136:1140–1148CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Bruzzi P, Negri E, La Vecchia C, Decarli A, Palli D, Parazzini F et al (1988) Short term increase in risk of breast cancer after full term pregnancy. BMJ 297:1096–1098CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Adashi EY (1996) Ovulation induction: clomiphene citrate. In: Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive endocrinology, surgery, and technology. Lippencott-Raven, Philadelphia, pp 1182–1206Google Scholar
  37. 37.
    Hughes E, Brown J, Collins JJ, Vanderkerchove P (2010) Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev, Issue 1. Art. No.: CD000057. doi: 10.1002/14651858.CD000057.pub2
  38. 38.
    The Practice Committee of the American Society for Reproductive Medicine (2013) Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 100:341–348CrossRefGoogle Scholar
  39. 39.
    National Institute for Health and Care Excellence (2013) Fertility: assessment and treatment for people with fertility problems. Acccessed 30 Jan 2015
  40. 40.
    Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr (2000) A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 6:212–224CrossRefPubMedGoogle Scholar
  41. 41.
    Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ (1986) Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 46:392–396PubMedGoogle Scholar
  42. 42.
    le Contonnec JY, Porchet HC, Beltrami V, Khan A, Toon S, Rowland M (1994) Clinical pharmacology of recombinant human follicle-stimulating hormone. II. Single doses and steady state pharmacokinetics. Fertil Steril 61:679–686PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Alessandra Gennari
    • 1
    Email author
  • Mauro Costa
    • 2
  • Matteo Puntoni
    • 1
  • Laura Paleari
    • 1
  • Andrea De Censi
    • 1
  • Maria Pia Sormani
    • 3
  • Nicoletta Provinciali
    • 1
  • Paolo Bruzzi
    • 4
  1. 1.S.C. Oncologia MedicaE.O. Ospedali GallieraGenoaItaly
  2. 2.S.S.D. Medicina della RiproduzioneOspedale Evangelico InternazionaleGenoaItaly
  3. 3.DISSALUniversità di GenovaGenoaItaly
  4. 4.S.C. Epidemiologia ClinicaIRCCS A.O.U. San Martino - ISTGenoaItaly

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