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Infertility, Ovulation Induction Treatments and the Incidence of Breast Cancer—a Historical Prospective Cohort of Israeli Women

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Context

Ovulation induction drugs may be associated with increased breast cancer risk. Results so far have been inconclusive.

Objective

To evaluate the association between infertility, exposure to ovulation induction drugs and the incidence of breast cancer.

Design

Historical prospective cohort and nested case–control study.

Setting

Institutional practice

Patients

About 5,788 women attending five infertility centers in Israel between 1964 and 1984.

Intention

Abstracting of medical records and telephone interviews.

Main outcome measure

Breast cancer incidence was determined through linkage with the National Cancer Registry database. Standardized incidence ratios (SIRs) and 95% confidence intervals were computed by comparing the observed to the expected cancer rates in the general population. In addition, a nested case–control study within the cohort was performed with interviews of breast cancer cases and two matched controls.

Results

The study cohort included 120,895 women years of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.9–1.4). Risk for breast cancer was significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0–1.8). Similar results were noted when comparisons were carried out between treated and untreated women, and when multivariate models were applied.

In the nested case–control study, higher cycle index (OR = 2.2; 95% CI 1.0–4.8) and treatment with clomiphene citrate (OR=2.7; 95% CI 1.3–5.7) were associated with higher risk for breast cancer.

Conclusion

Infertility and usage of infertility drugs in general are not associated with increased risk for breast cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is elevated.

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References

  1. Mosher WD, Pratt WF (1991) Fecundity and infertility in the United States: incidence and trends. Fertil Steril 56:192–198

    PubMed  CAS  Google Scholar 

  2. Schenker JG, Laufer N, Weinstein D, Yarkoni S (1980) Quintuplet pregnancies. Eur J Obstet Gynecol Reprod Biol 10:257–268

    Article  PubMed  CAS  Google Scholar 

  3. Hack M, Brish M, Serr DM, Insler V, Salomy M, Lunenfeld B (1972) Outcome of pregnancy after induced ovulation. Follow-up of pregnancies and children born after clomiphene therapy. JAMA 220:1329–1333

    Article  PubMed  CAS  Google Scholar 

  4. Oelsner G, Menashe Y, Tur-Kaspa I, Ben-Rafael Z, Blankstein J, Serr DM, Mashiach S (1989) The role of gonadotropins in the etiology of ectopic pregnancy. Fertil Steril 52:514–516

    PubMed  CAS  Google Scholar 

  5. Bider D, Menashe Y, Oelsner G, Serr DM, Mashiach S, Ben-Rafael Z (1989) Ovarian hyperstimulation syndrome due to exogenous gonadotropin administration. Acta Obstet Gynecol Scand 68:511–514

    PubMed  CAS  Google Scholar 

  6. Schenker JG, Weinstein D (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 30:255–268

    PubMed  CAS  Google Scholar 

  7. Navot D, Relou A, Birkenfeld A, Rabinowitz R, Brzezinski A, Margalioth EJ (1988) Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynceol 159:210–215

    CAS  Google Scholar 

  8. Johannes CB, Caro JJ, Hartz SC, Marrs R (1993) Adverse effects of ovulatory stimulants: a review. Assis Reprod Rev 3:68–74

    Google Scholar 

  9. Schenker JG, Ezra Y (1994) Complications of assisted reproductive techniques. Fertil Steril 61:411–422

    PubMed  CAS  Google Scholar 

  10. Cancer in Israel, State of Israel Ministry of Health, Israel Cancer Registry, 1996

  11. Kelsey JL, Gammon MD (1991) The epidemiology of breast cancer. Cancer 41:146–165

    CAS  Google Scholar 

  12. Key TJ, Verkasaklo PK, Banke E (2001) Epidemiology of breast cancer. Lancet Oncol 2:133–140

    Article  PubMed  CAS  Google Scholar 

  13. Sutherland RL, Watts CKW, Hall RE, Ruenitz PC (1987) Mechanisms of growth inhibition by non-steroidal anti-estrogens in human breast cancer cells. J Steroid Biochem 27:891–897

    Article  PubMed  CAS  Google Scholar 

  14. Gammon M, Thompson WD (1990) Infertility and breast cancer: a population-based case–control study. Am J Epidemiol 132:708–716

    PubMed  CAS  Google Scholar 

  15. Braga C, Negri E, La Vecchia C, Parazzini F, Dal Maso L, Franceschi S (1996) Fertility treatment and risk of breast cancer. Hum Reprod 11:300–303

    PubMed  CAS  Google Scholar 

  16. Ricci E, Parazzini F, Negri E, Marsico S, La Vecchia C (1999) Fertility and the risk of breast cancer. Human Reprod 14:1653–1655

    Article  CAS  Google Scholar 

  17. Burkman RT, Tang MC, Malone KE, Marchbanks PA, McDonald JA, Folger SG (2003) Infertility and the risk of breast cancer: findings from the national institute of child health and human development women’s contraceptive and reproductive experiences study. Fertil Steril 79:844–854

    Article  PubMed  Google Scholar 

  18. Cowan LD, Gordis L, Tonascia JA, Jones GS (1981) Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 114:209–217

    PubMed  CAS  Google Scholar 

  19. Coulam CB, Annegers JF, Kranz JS (1983) Chronic anovulation syndrome and associated neoplasia. Obstet Gynecol 61:403–407

    PubMed  CAS  Google Scholar 

  20. Ron E, Lunenfeld B, Menczer J, Blumstein T, Katz L, Oelsner G, Serr D (1987) Cancer incidence in a cohort of infertile women. Am J Epidemiol 125:780–790

    PubMed  CAS  Google Scholar 

  21. Brinton LA, Melton LJ, Malkasian GD Jr, Bond A, Hoover R (1989) Cancer risk after evaluation for infertility. Am J␣Epidemiol 129:712–722

    PubMed  CAS  Google Scholar 

  22. Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, Oelsner G, Freedman L, Mashiach S, Lunenfeld B (1998) Cancer incidence in a cohort of infertile women. Am J Epidemiol 147:1038–1042

    PubMed  CAS  Google Scholar 

  23. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SGL (1996) Risk of breast cancer in a cohort of infertile women. Gynecol Oncol 60:3–7

    Article  PubMed  CAS  Google Scholar 

  24. 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 71:853–859

    Article  PubMed  CAS  Google Scholar 

  25. Doyle P, Maconochie N, Beral V, Swerdlow AJ, Tan SL (2002) Cancer incidence following treatment for infertility at a clinic in the UK. Human Reprod 17:2209–2213

    Article  Google Scholar 

  26. Brzezinski A, Peretz T, Mor-Yosef S, Schenker JG (1994) Ovarian stimulation and breast cancer: is there a link? Gynecol Oncol 52:292–295

    Article  PubMed  CAS  Google Scholar 

  27. Venn A, Watson L, Lumley J, Giles G, King C, Healy D (1995) Breast and ovarian cancer incidence after infertility and in-vitro fertilization. Lancet 346:995–1000

    Article  PubMed  CAS  Google Scholar 

  28. Venn A, Watson L, Bruinsma F, Giles G, Healy D (1999) Risk of cancer after use of fertility drugs with in-vitro fertilization. Lancet 354:1586–1590

    Article  PubMed  CAS  Google Scholar 

  29. Dor J, Lerner-Geva L, Rabinovici J, Chetrit A, Levran D, Lunenfeld B, Mashiach S, Modan B (2002) Cancer incidence in a cohort of infertile women treated with in vitro fertilization. Fertil Steril 77:324–327

    Article  PubMed  Google Scholar 

  30. 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 13:23–27

    Article  PubMed  CAS  Google Scholar 

  31. Gauthier E, Paoletti X, Clavel-Chapelon F, the E3N Group (2004) Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Human Reprod 19:2216–2221

    Google Scholar 

  32. Brinton LA, Scoccia B, Moghissi KS, Westhoff CL, Althuis MD, Mabie JE, Lamb EJ (2004) Breast cancer risk associated with ovulation-stimulating drug. Hum Reprod 19(9):2005–2013

    Article  PubMed  CAS  Google Scholar 

  33. Fishler Y, Chetrit A, Barchana M, Modan B (2003) The completeness of the national cancer registry database. Methods and results. Completeness of the data in the year 1991 and its implications on the completeness of current data. Israel Center for Disease Control, Israel, publication # 230 [Hebrew]

  34. Rothman KJ, Boice JD Jr (1979) Epidemiologic analysis with a programmable calculator. US GPO, Washington, DC (DHEW publication no. (NIH) 79-1649)

  35. SAS/STAT Software (1996) Changes and enhancements through release 6.11. SAS Institute Inc., Cary, NC, USA

    Google Scholar 

  36. Garland M, Hunter DJ, Colditz GA, Manson JE, Stampfer MJ, Spiegelman D, Speizer F, Willett WC (1998) Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol 147:636–643

    PubMed  CAS  Google Scholar 

  37. Kelsey JL, Bernstein L (1996) Epidemiology and prevention of breast cancer. Ann Rev Public Health 17:47–67

    Article  CAS  Google Scholar 

  38. Tung KH, Wilkens LR, Wu AH, Mcduffie K, Nomura AMY, Koionel LN, Terada KY, Goodman MT (2005) Effect of anovulation factors on pre and postmenopausal ovarian cancer risk: revisiting the incessant ovulation hypothesis. Am J Epidemiol 161:321–329

    Article  PubMed  Google Scholar 

  39. Key TJ, Pike MC (1998) The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24:29–43

    Article  Google Scholar 

  40. Klip H, Burger CW, Kenemans P, van Leeuwen FE (2000) Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes and Control 11:319–344

    Article  PubMed  CAS  Google Scholar 

  41. Chavez-MacGregor M, Elias SG, Onland-Moret NC, van der Schouw YT, Van Gils CH, Monninkhof E, Grobbee DE, Peeters PH (2005) Postmenopausal breast cancer risk and cumulative number of menstrual cycles. Cancer Epidemiol Biomarkers Prev 14(4):799–804

    Article  PubMed  Google Scholar 

  42. Speroff L, Glass RH, Kase NG (1999) Induction of ovulation. In: Clinical, gynecologic, endocrinology and infertility. Lippincott Williams and Wilkins, Baltimore, Maryland, USA, pp 1097–1132

  43. Clark JH, Markaverich BM (1982) The agonist-antagonist properties of clomiphene: a review. Pharmacol Ther 15:467–519

    Article  Google Scholar 

  44. Adashi EY (1984) Clomiphene citrate: mechanism(s) and site(s) of action – a hypothesis revisited. Fertil Steril 42:331–344

    PubMed  CAS  Google Scholar 

  45. Henderson BE, Ross RK, Judd HL, Krailo MD, Pike MC (1985) Do regular ovulatory cycles increase breast cancer risk? Cancer 56:1206–1208

    Article  PubMed  CAS  Google Scholar 

  46. Milliken EL, Ameduri RK, Landis MD, Behrooz A, Abdul-Karim FW, Keri RA (2002) Ovarian hyperstimulation by LH leads to mammary gland hyperplasia and cancer predisposition in transgenic mice. Endocrinol 143:3671–3680

    Article  CAS  Google Scholar 

  47. Adlercreutz H (1998) Epidemiology of phytoestrogens. Baillieres Clin Endocrinol Metab 12:605–623

    Article  PubMed  CAS  Google Scholar 

  48. Messina MJ, Loprinzi CL (2001) Soy for breast cancer survivals: a critical review of the literature. J Nutr 131:3095S-3108S

    PubMed  CAS  Google Scholar 

  49. Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike R, Kirk M, Coward L (1996) Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev 5:785–794

    PubMed  CAS  Google Scholar 

  50. Peeters PHM, Keinan-Boker L, van der Schouw YT, Grobbee DE (2003) Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Breast Cancer Res Treat 77:171–183

    Article  PubMed  CAS  Google Scholar 

  51. This P, De La Rochefordiere A, Clough K, Fourquet A, Magdelenat H, the Breast Cancer Group of the Institute Curie (2001) Phytoestrogens after breast cancer. Endocrin Related Cancer 8:129–134

    Google Scholar 

  52. Baker VL, Jaffe RB (1996) Clinical uses of antiestrogens. Obstet Gynecol Surv 51(1):45–59

    Article  PubMed  CAS  Google Scholar 

  53. Lerner LJ, Jordan VC (1990) Development of antiestrogens and their use in breast cancer: eighth chain memorial lecture Cancer Res 50:4177–4189

    Google Scholar 

  54. Palmer JR, Hatch EE, Rosenberg CL, Hartge P, Kaufman RH, Titus-Ernstoff L, Noller KL, Herbst AL, Rao RS, Troisi R, Colton T, Hoover RN (2002) Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes and Control 13:753–758

    Google Scholar 

  55. Goldstein S, Siddhantu S, Ciaccia AV, Plouffe L Jr (2000) A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 6(3):212–224

    Article  PubMed  CAS  Google Scholar 

  56. Baumann RJ, Bush TL, Cross-Doersen DE, Cashman EA, Wright PS, Zwolshen JH, Davis GF, Matthews DP, Bender DM, Bitonti AJ (1998) Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells. Biochemical Pharmacol 55(6):841–851

    Article  CAS  Google Scholar 

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Acknowledgement

This work is in partial fulfillment of the requirements of the PhD degree for L. Lerner-Geva, Sackler Faculty of Medicine, Tel Aviv University, Israel. The study was partially supported by the Israel-US bi-national scientific foundation (Grant number 96-269).

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Authors and Affiliations

  1. Women and Children’s Health Research Unit, Sheba Medical Center, Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer, Ramat Gan, 52621, Israel

    L. Lerner-Geva, T. Blumstein, V. Boyko & L. Olmar

  2. Haifa University, School of Public Health, Haifa, Israel

    L. Keinan-Boker

  3. Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    S. Mashiach & J. Rabinovici

  4. Obstetrics and Gynecology, Soroka Medical Center, Beer Sheva, Israel

    G. Potashnik & E. Lunenfeld

  5. Obstetrics and Gynecology, Hadassah Ein Karem Medical Center, Jerusalem, Israel

    J. G. Schenker & A. Shushan

  6. Obstetrics and Gynecology, Sapir Medical Center, Kfar Saba, Israel

    A. Fishman & I. Cohen

  7. Obstetrics and Gynecology, Tel Aviv Medical Center, Tel Aviv, Israel

    I. Vagman

  8. Bar Ilan University, Ramat Gan, Israel

    B. Lunenfeld

  9. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    L. Lerner-Geva, L. Keinan-Boker, S. Mashiach, J. Rabinovici, A. Fishman & I. Cohen

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  1. L. Lerner-Geva
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  2. L. Keinan-Boker
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  3. T. Blumstein
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  4. V. Boyko
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  5. L. Olmar
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  6. S. Mashiach
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  7. J. Rabinovici
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  8. G. Potashnik
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  9. E. Lunenfeld
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  10. J. G. Schenker
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  11. A. Shushan
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  12. A. Fishman
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  13. I. Cohen
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  14. I. Vagman
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  15. B. Lunenfeld
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Correspondence to L. Lerner-Geva.

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Lerner-Geva, L., Keinan-Boker, L., Blumstein, T. et al. Infertility, Ovulation Induction Treatments and the Incidence of Breast Cancer—a Historical Prospective Cohort of Israeli Women. Breast Cancer Res Treat 100, 201–212 (2006). https://doi.org/10.1007/s10549-006-9238-4

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  • DOI: https://doi.org/10.1007/s10549-006-9238-4

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