Review Article

In-Vitro Fertilization Impact on the Risk of Breast Cancer: A Review Article


Background: Due to the increasing prevalence of infertility, the number of referrals to infertility treatment centers has also increased. Nowadays, assisted reproductive technology (ART), including in vitro fertilization (IVF), is a treatment for infertility or genetic problems. Considering the possible consequences of this method among women undergoing in vitro fertilization (IVF) and kids conceived by IVF, extensive research has been conducted in this regard.

Methods: Overall, 100 articles were entered into the study, and relevant articles were searched and extracted from PubMed, Springer, and Google Scholar databases. In IVF procedure, medications such as Clomiphene citrate and gonadotropins are used to stimulate and mature follicles and thus increase ovulation.

Results: There are conflicting opinions on this issue. Some findings report a slight increase in cancer risk for hormone-sensitive cancers including breast cancer. The long-term use of IVF medications can increase estrogen hormones and cause excessive expression of genes, resulting in an increased risk of breast cancer, which is one of the most frequent cancers among women.

Conclusion: There are some risks to be aware of, which followed the hypothesis that long IVF treatment process may lead to breast cancer among IVF candidates. Furthermore, the risk of breast cancer may be increased in those women with a positive family history and related inherited genes. Therefore, women candidates for IVF should be informed of the probable implications of the reproductive therapy techniques.

1. Steptoe PC, Edwards RG (1978). Birth after the reimplantation of a human embryo. Lancet, 2(8085):366.
2. Sutcliffe AG, Ludwig M (2007). Outcome of assisted reproduction. Lancet, 370(9584):351-9.
3. Boivin J, Bunting L, Collins JA, Nygren KG (2007). International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod, 22(6):1506-12.
4. Mosher WD (1982). Infertility trends among U.S. couples: 1965-1976. Fam Plann Perspect, 14(1):22-7.
5. Klip H, Burger CW, de Kraker J, van Leeuwen FE (2001). Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod, 16(11):2451-8.
6. Gauthier E, Paoletti X, Clavel-Chapelon F (2004). Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hum Reprod, 19(10):2216-21.
7. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E (2009). Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev, 7;(4):CD002249.
8. National Collaborating Centre for Ws, Children's H (2004). National Institute for Health and Clinical Excellence: Guidance. In: Fertility: Assessment and Treatment for People with Fertility Problems. Ed(s). London (UK): RCOG Press. Copyright © 2004, National Collaborating Centre for Women’s and Children’s Health.
9. Ayhan A, Salman MC, Celik H, et al (2004). Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers. Acta Obstet Gynecol Scand, 83(12):1104-11.
10. Mneimneh AS, Boulet SL, Sunderam S, et al (2013). States Monitoring Assisted Reproductive Technology (SMART) Collaborative: data collection, linkage, dissemination, and use. J Womens Health (Larchmt), 22(7):571-7.
11. Beurskens MP, Maas JW, Evers JL (1995). [Subfertility in South Limburg: calculation of incidence and appeal for specialist care]. Ned Tijdschr Geneeskd, 139(5):235-8.
12. Wysowski DK (1993). Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril, 60(6):1096-8.
13. de Jong-van den Berg LT, Cornel MC, van den Berg PB, et al (1992). Ovulation-inducing drugs: a drug utilization and risk study in the Dutch population. Int J Risk Saf Med, 3(2):99-111.
14. Jensen A, Sharif H, Olsen JH, Kjaer SK (2008). Risk of breast cancer and gynecologic cancers in a large population of nearly 50,000 infertile Danish women. Am J Epidemiol, 168(1):49-57.
15. Anstey EH, Shoemaker ML, Barrera CM, et al (2017). Breastfeeding and Breast Cancer Risk Reduction: Implications for Black Mothers. Am J Prev Med, 53(3S1):S40-S46.
16. Palmer JR, Boggs DA, Wise LA, et al (2011). Parity and lactation in relation to estrogen receptor negative breast cancer in African American women. Cancer Epidemiol Biomarkers Prev, 20(9): 1883–1891.
17. Lundberg FE, Johansson AL, Rodriguez-Wallberg K, et al (2016). Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study. Breast Cancer Res, 18(1):36.
18. Ron E, Lunenfeld B, Menczer J, et al (1987). Cancer incidence in a cohort of infertile women. Am J Epidemiol, 125(5):780-90.
19. Modan B, Ron E, Lerner-Geva L, Blumstein T, et al (1998). Cancer incidence in a cohort of infertile women. Am J Epidemiol, 147(11):1038-42.
20. Burkman RT, Tang MT, Malone KE, et al (2003). Infertility drugs 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(4):844-51.
21. Kroener L, Dumesic D, Al-Safi Z (2017). Use of fertility medications and cancer risk: a review and update. Curr Opin Obstet Gynecol, 29(4):195-201.
22. Farhud D, Zokaei S, Keykhaei M, et al (2019). Strong Evidences of the Ovarian Carcinoma Risk in Women after IVF Treatment: A Review Article. Iran J Public Health, 48(12):2124-2132.
23. Calderon-Margalit R, Friedlander Y, Yanetz R, et al (2009). Cancer risk after exposure to treatments for ovulation induction. Am J Epidemiol, 169(3):365-75.
24. Reigstad MM, Larsen IK, Myklebust T, et al (2015). Risk of breast cancer following fertility treatment--a registry based cohort study of parous women in Norway. Int J Cancer, 136(5):1140-8.
25. Brinton L (2007). Long-term effects of ovulation-stimulating drugs on cancer risk. Reprod Biomed Online, 15(1):38-44.
26. Venn A, Watson L, Bruinsma F, et al (1999). Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet, 354(9190):1586-90.
27. Kristiansson P, Björ O, Wramsby H (2007). Tumour incidence in Swedish women who gave birth following IVF treatment. Hum Reprod, 22(2):421-6.
28. Petrangelo A, Czuzoj-Shulman N, Tu-landi T, et al (2018). Ovulation In-duction for Infertility the Risk of Breast Cancer: A Population-Based Case-Control Study [11B]. bstetrics and Gynecology, 131(1):22S.
29. Williams CL, Jones ME, Swerdlow AJ, et al (2018). Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation. BMJ, 362:k2644.
30. Katz D, Paltiel O, Peretz T, et al (2008). Beginning IVF treatments after age 30 increases the risk of breast cancer: results of a case-control study. Breast J, 14(6):517-22.
31. Pappo I, Lerner-Geva L, Halevy A, et al (2008). The possible association between IVF and breast cancer incidence. Ann Surg Oncol, 15(4):1048-55.
32. Stewart LM, Holman CD, Hart R, et al (2012). In vitro fertilization and breast cancer: is there cause for concern? Fertil Steril, 98(2):334-40.
33. Travis RC, Key TJ (2003). Oestrogen exposure and breast cancer risk. Breast Cancer Res, 5(5): 239–247.
34. Brekelmans CT (2003). Risk factors and risk reduction of breast and ovarian cancer. Curr Opin Obstet Gynecol, 15(1):63-8.
35. Dumitrescu RG, Cotarla I (2005). Understanding breast cancer risk -- where do we stand in 2005? J Cell Mol Med, 9(1): 208–221.
36. Nelson HD, Zakher B, Cantor A, Fu R, et al (2012). Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med, 156(9):635-48.
37. Brinton LA, Moghissi KS, Scoccia B, et al (2005). Ovulation induction and cancer risk. Fertil Steril, 83(2):261-74.
38. Pike MC, Spicer DV, Dahmoush L, Press MF (1993). Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev, 15(1):17-35.
39. Sovino H, Sir-Petermann T, Devoto L (2002). Clomiphene citrate and ovulation induction. Reprod Biomed Online, 4(3):303-10.
40. Klip H, Burger CW, Kenemans P, van Leeuwen FE (2000). Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes Control, 11(4):319-44.
41. Lerner-Geva L, Keinan-Boker L, Blumstein T, et al (2006). Infertility, ovulation induction treatments and the incidence of breast cancer--a historical prospective cohort of Israeli women. Breast Cancer Res Treat, 100(2):201-12.
42. Bernstein L (2002). Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia, 7(1):3-15.
43. Parkin DM (2004). International variation. Oncogene, 23(38):6329-40.
44. NIH (2018). Cancer Stat Facts: Female Breast Cancer. (ed)^(eds), National Institutes of Health (NIH),
45. Stewart SL, King JB, Thompson TD, et al (2004). Cancer mortality surveillance--United States, 1990-2000. MMWR Surveill Summ, 53(3):1-108.
46. Hankinson SE, Colditz GA, Willett WC (2004). Towards an integrated model for breast cancer etiology: the lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res , 6(5): 213–218.
47. Agrawal B, Reddish MA, Krantz MJ, Longenecker BM (1995). Does pregnancy immunize against breast cancer? Cancer Res, 55(11):2257-61.
48. Pathak DR, Osuch JR, He J (2000). Breast carcinoma etiology: current knowledge and new insights into the effects of reproductive and hormonal risk factors in black and white populations. Cancer, 88:1230-8.
49. Berkey CS, Frazier AL, Gardner JD, Colditz GA (1999). Adolescence and breast carcinoma risk. Cancer, 85(11):2400-9.
50. No authors listed (1997). Breast 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 cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet, 350(9084):1047-59.
51. Kelsey JL, Gammon MD, John EM (1993). Reproductive factors and breast cancer. Epidemiol Rev, 15(1):36-47.
52. Titus-Ernstoff L, Longnecker MP, Newcomb PA, et al (1998). Menstrual factors in relation to breast cancer risk. Cancer Epidemiol Biomarkers Prev, 7(9):783-9.
53. McPherson K, Steel CM, Dixon JM (2000). ABC of breast diseases. Breast cancer-epidemiology, risk factors, and genetics. BMJ, 321(7261):624-8.
54. Rossouw JE, Anderson GL, Prentice RL, et al (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA, 288(3):321-33.
55. Surakasula A, Nagarjunapu GC, Raghavaiah KV (2014). A comparative study of pre- and post-menopausal breast cancer: Risk factors, presentation, characteristics and management. J Res Pharm Pract, 3(1):12-8.
56. Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol, 13(11):1141-51.
57. Collaborative Group on Hormonal Factors in Breast Cancer (2002). Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet, 360(9328):187-95.
58. Nindrea RD, Aryandono T, Lazuardi L, Dwiprahasto I (2019). Family History of Breast Cancer and Breast Cancer Risk between Malays Ethnicity in Malaysia and Indonesia: A Meta-Analysis. Iran J Public Health, 48(2): 198–205.
59. Mehrgou A, Akouchekian M (2016). The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran, 30:369.
60. Godet I, Gilkes DM (2017). BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther, 4(1):10.
61. Ripperger T, Gadzicki D, Meindl A, Schlegelberger B (2009). Breast cancer susceptibility: current knowledge and implications for genetic counselling. Eur J Hum Genet, 17(6):722-31.
62. Ramalhinho AC, Fonseca-Moutinho JA, Breitenfeld Granadeiro LA (2012). Positive association of polymorphisms in estrogen biosynthesis gene, CYP19A1, and metabolism, GST, in breast cancer susceptibility. DNA Cell Biol, 31(6):1100-6.
63. Ellisen LW, Haber DA (1998). Hereditary breast cancer. Annu Rev Med, 49:425-36.
64. Hulka BS, Moorman PG (2001). Breast cancer: hormones and other risk factors. Maturitas, 38(1):103-13.
65. Ghisari M, Long M, Røge DM, et al (2017). Polymorphism in xenobiotic and estrogen metabolizing genes, exposure to perfluorinated compounds and subsequent breast cancer risk: A nested case-control study in the Danish National Birth Cohort. Environ Res, 154:325-333.
66. Torresan C, Oliveira MM, Torrezan GT, et al (2008). Genetic polymorphisms in oestrogen metabolic pathway and breast cancer: a positive association with combined CYP/GST genotypes. Clin Exp Med, 8(2):65-71.
67. Dos Santos EVW, Alves LNR, Louro ID (2017). Steroid metabolism gene polymorphisms and their implications on breast and ovarian cancer prognosis. Genet Mol Res, 6;16(3).
68. Antognelli C, Del Buono C, Ludovini V, et al (2009). CYP17, GSTP1, PON1 and GLO1 gene polymorphisms as risk factors for breast cancer: an Italian case-control study. BMC Cancer, 9:115.
69. Key TJ, Verkasalo PK, Banks E (2001). Epidemiology of breast cancer. Lancet Oncol, 2(3):133-40.
70. Preston-Martin S, Pike MC, Ross RK, et al (1990). Increased cell division as a cause of human cancer. Cancer Res, 50(23):7415-21.
71. Miller WL, Auchus RJ (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev, 32(1):81-151.
72. Koos RD (2011). Minireview: Putting physiology back into estrogens' mechanism of action. Endocrinology, 152(12):4481-8.
73. Liehr JG (2000). Is estradiol a genotoxic mutagenic carcinogen? Endocr Rev, 21(1):40-54.
74. McGuire WL (1973). Estrogen receptors in human breast cancer. J Clin Invest, 52(1): 73–77.
75. Bulzomi P, Bolli A, Galluzzo P, et al (2010). Naringenin and 17beta-estradiol coadministration prevents hormone-induced human cancer cell growth. IUBMB Life, 62(1):51-60.
76. Sreeja S, Kumar TRS, Lakshmi BS, Sreeja S (2012). Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation. J Nutr Biochem, 23(7):725-32.
77. Henderson BE, Ross RK, Judd HL, et al (1985). Do regular ovulatory cycles increase breast cancer risk? Cancer, 56(5):1206-8.
78. La Vecchia C, Decarli A, di Pietro S, et al (1985). Menstrual cycle patterns and the risk of breast disease. Eur J Cancer Clin Oncol, 21(4):417-22.
79. Lerner-Geva L, Geva E, Lessing JB, et al (2003). The possible association between in vitro fertilization treatments and cancer development. Int J Gynecol Cancer, 13(1):23-7.
80. Hughes E, Brown J, Collins JJ, Vanderkerchove P (2010). Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev, 2010(1):CD000057.
81. Hughes E, Collins J, Vandekerckhove P (1996). WITHDRAWN: Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev, 22;(1):CD000056.
82. Ghazeeri G, Kutteh WH, Bryer-Ash M, et al (2003). Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril, 79(3):562-6`.
83. Guzick DS, Sullivan MW, Adamson GD, et al (1998). Efficacy of treatment for unexplained infertility. Fertil Steril, 70(2):207-13.
84. Fritz MA, Holmes RT, Keenan EJ (1991). Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women. Am J Obstet Gynecol, 165(1):177-85.
85. Practice Committee of the American Society for Reproductive Medicine (2006). Use of clomiphene citrate in women. Fertil Steril, 86:S187-93.
86. Kerin JF, Liu JH, Phillipou G, Yen SS (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab, 61(2):265-8.
87. Homburg R (2008). Oral agents for ovulation induction--clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb), 11(1):17-22.
88. Homburg R (2005). Clomiphene citrate--end of an era? A mini-review. Hum Reprod, 20(8):2043-51.
89. Orgéas CC, Sanner K, Hall P, et al (2009). Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study. Am J Obstet Gynecol, 200(1):72.e1-7.
90. Petrangelo A, Abenhaim H, Czuzoj-Shulman N, et al (2018). Ovulation-Stimulating Fertility Treatments and the Long-Term Risk of Breast Cancer: a Case-Control Study Using the Clinical Practice Research Datalink. Journal of obstetrics and gynaecology Canada: JOGC, 40(6):849.
91. Parhar IS (2002). Gonadotropin-Releasing Hormone: Molecules and Receptors. 1st edn. Elsevier Science pp. 344.
92. Cole L (2014). Human Chorionic Gonadotropin (hCG). 2nd edn. Elsevier, pp. 446.
93. Huirne JA, Lambalk CB (2001). Gonadotropin-releasing-hormone-receptor antagonists. Lancet, 358(9295):1793-803.
94. Adonakis G, Deshpande N, Yates RW, Fleming R (1998). Luteinizing hormone increases estradiol secretion but has no effect on progesterone concentrations in the late follicular phase of in vitro fertilization cycles in women treated with gonadotropin-releasing hormone agonist and follicle-stimulating hormone. Fertil Steril, 69(3):450-3.
95. Schüler-Toprak S, Treeck O, Ortmann O (2017). Human Chorionic Gonadotropin and Breast Cancer. Int J Mol Sci, 18(7): 1587.
96. Kölbl AC, Schlenk K, Behrendt N, Andergassen U (2018). The importance of hCG in human endometrial adenocarcinoma and breast cancer. Int J Biol Markers, 33(1):33-39.
97. Fournier T, Guibourdenche J, Evain-Brion D (2015). Review: hCGs: different sources of production, different glycoforms and functions. Placenta, 1:S60-5.
98. Pond-Tor S, Rhodes RG, Dahlberg PE, et al (2002). Enhancement of radiosensitivity of the MCF-7 breast cancer cell line with human chorionic gonadotropin. Breast Cancer Res Treat, 72(1):45-51.
99. Kardana A, Taylor ME, Southall PJ, et al (1988). Urinary gonadotrophin peptide--isolation and purification, and its immunohistochemical distribution in normal and neoplastic tissues. Br J Cancer, 58(3):281-6.
100. Castro A, Buschbaum P, Nadji M, et al (1980). Immunochemical demonstration of human chorionic gonadotrophin (hCG) in tissue of breast carcinoma. Acta Endocrinol (Copenh), 94(4):511-6.
101. Taheripanah R, Balash F, Anbiaee R, et al (2018). Breast Cancer and Ovulation Induction Treatments. Clin Breast Cancer, 18(5):395-399.
IssueVol 50 No 3 (2021) QRcode
SectionReview Article(s)
Breast cancer In vitro fertilization (IVF) Clomiphene citrate Gonadotropins Infertility Personalized medicine

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
FARHUD D, ZOKAEI S, KEYKHAEI M, HEDAYATI M, ZARIF YEGANEH M. In-Vitro Fertilization Impact on the Risk of Breast Cancer: A Review Article. Iran J Public Health. 2021;50(3):438-447.