Download PDF
Semin Reprod Med 2017; 35(03): 291-297
DOI: 10.1055/s-0037-1603098
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Fertility Status and Cancer

Louise A. Brinton
1   Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
› Author Affiliations
Further Information

Publication History

Publication Date:
28 June 2017 (online)

    Permissions and Reprints

Abstract

Elevated estradiol levels associated with ovulation-stimulating drugs used to treat infertility and ovarian punctures involved with in vitro fertilization (IVF) have led to concerns regarding long-term cancer effects. Assessed risks, however, have been contradictory. This may reflect small sample sizes and short follow-up times, as well as an inability of many studies to adjust for appropriate potential confounders, such as causes of infertility and parity. While early studies of ovulation-stimulating drugs suggested large increases in large ovarian cancer risk, more recent studies have not confirmed this. However, several investigations have noted risk elevations associated with drug use or IVF among women who remain nulliparous, possibly due to resistant infertility. Studies also suggest increases in borderline ovarian tumors, although the effects of surveillance bias are unclear. Investigations have not shown large increases in breast cancer risk, although a few studies suggest possible increases in select subgroups, including nulliparous women or those with high drug dosages in the distant past. A few studies have evaluated risks of other cancers (endometrium, colorectum, thyroid, and melanoma), without definitive results. Since women exposed to fertility treatments are just beginning to enter typical cancer age ranges, further well-designed investigations are needed to fully delineate long-term effects.

Keywords

infertility - ovulation-stimulating drugs - in vitro fertilization - cancer risk
 

  • References

  • 1 Cetin I, Cozzi V, Antonazzo P. Infertility as a cancer risk factor - a review. Placenta 2008; 29 (Suppl B): 169-177
    CrossrefPubMedGoogle Scholar
  • 2 Yang HP, Cook LS, Weiderpass E. , et al. Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2). Br J Cancer 2015; 112 (05) 925-933
    CrossrefPubMedGoogle Scholar
  • 3 Gottschau M, Kjaer SK, Jensen A, Munk C, Mellemkjaer L. Risk of cancer among women with polycystic ovary syndrome: a Danish cohort study. Gynecol Oncol 2015; 136 (01) 99-103
    CrossrefPubMedGoogle Scholar
  • 4 Stewart LM, Holman CD, Aboagye-Sarfo P, Finn JC, Preen DB, Hart R. In vitro fertilization, endometriosis, nulliparity and ovarian cancer risk. Gynecol Oncol 2013; 128 (02) 260-264
    CrossrefPubMedGoogle Scholar
  • 5 Rasmussen CB, Jensen A, Albieri V, Andersen KK, Kjaer SK. Is pelvic inflammatory disease a risk factor for ovarian cancer?. Cancer Epidemiol Biomarkers Prev 2017; 26 (01) 104-109
    CrossrefPubMedGoogle Scholar
  • 6 Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol 2013; 24 (Suppl. 10) x16-x21
    CrossrefPubMedGoogle Scholar
  • 7 Pearce CL, Templeman C, Rossing MA. , et al; Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 2012; 13 (04) 385-394
    CrossrefPubMedGoogle Scholar
  • 8 Brinton LA, Sahasrabuddhe VV, Scoccia B. Fertility drugs and the risk of breast and gynecologic cancers. Semin Reprod Med 2012; 30 (02) 131-145
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331 (12) 771-776
    CrossrefPubMedGoogle Scholar
  • 10 Whittemore AS, Harris R, Itnyre J. ; Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992; 136 (10) 1184-1203
    CrossrefPubMedGoogle Scholar
  • 11 Calderon-Margalit R, Friedlander Y, Yanetz R. , et al. Cancer risk after exposure to treatments for ovulation induction. Am J Epidemiol 2009; 169 (03) 365-375
    PubMedGoogle Scholar
  • 12 Silva IdosS, Wark PA, McCormack VA. , et al. Ovulation-stimulation drugs and cancer risks: a long-term follow-up of a British cohort. Br J Cancer 2009; 100 (11) 1824-1831
    CrossrefPubMedGoogle Scholar
  • 13 Orgéas CC, Sanner K, Hall P. , et al. Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study. Am J Obstet Gynecol 2009; 200 (01) 72.e1-72.e7
    CrossrefPubMedGoogle Scholar
  • 14 Trabert B, Lamb EJ, Scoccia B. , et al. Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort. Fertil Steril 2013; 100 (06) 1660-1666
    CrossrefPubMedGoogle Scholar
  • 15 Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and risk of ovarian cancer: Danish Population Based Cohort Study. BMJ 2009; 338: b249
    CrossrefPubMedGoogle Scholar
  • 16 Ness RB, Cramer DW, Goodman MT. , et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002; 155 (03) 217-224
    CrossrefPubMedGoogle Scholar
  • 17 Sanner K, Conner P, Bergfeldt K. , et al. Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden. Fertil Steril 2009; 91 (04) 1152-1158
    CrossrefPubMedGoogle Scholar
  • 18 Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996; 65 (01) 13-18
    CrossrefPubMedGoogle Scholar
  • 19 Parazzini F, Negri E, La Vecchia C. , et al. Treatment for fertility and risk of ovarian tumors of borderline malignancy. Gynecol Oncol 1998; 68 (03) 226-228
    CrossrefPubMedGoogle Scholar
  • 20 Adewole IF, Babarinsa IA, Thomas JO, Ajayi AB. Ovarian cancer associated with ovulation induction: a case report. Afr J Med Med Sci 1997; 26 (3-4): 203-204
    PubMedGoogle Scholar
  • 21 Hull ME, Kriner M, Schneider E, Maiman M. Ovarian cancer after successful ovulation induction: a case report. J Reprod Med 1996; 41 (01) 52-54
    PubMedGoogle Scholar
  • 22 Brinton LA. Breast cancer risk after use of fertility drugs: stimulating new controversy. J Natl Cancer Inst 2012; 104 (13) 962-964
    CrossrefPubMedGoogle Scholar
  • 23 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 2006; 100 (02) 201-212
    CrossrefPubMedGoogle Scholar
  • 24 Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med 2006; 166 (22) 2484-2489
    CrossrefPubMedGoogle Scholar
  • 25 Jensen A, Sharif H, Olsen JH, Kjaer SK. Risk of breast cancer and gynecologic cancers in a large population of nearly 50,000 infertile Danish women. Am J Epidemiol 2008; 168 (01) 49-57
    CrossrefPubMedGoogle Scholar
  • 26 Jensen A, Sharif H, Svare EI, Frederiksen K, Kjaer SK. Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study. Cancer Epidemiol Biomarkers Prev 2007; 16 (07) 1400-1407
    CrossrefPubMedGoogle Scholar
  • 27 Gauthier E, Paoletti X, Clavel-Chapelon F. ; E3N Group. Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hum Reprod 2004; 19 (10) 2216-2221
    CrossrefPubMedGoogle Scholar
  • 28 Kotsopoulos J, Librach CL, Lubinski J. , et al; Hereditary Breast Cancer Clinical Study Group. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study. Cancer Causes Control 2008; 19 (10) 1111-1119
    CrossrefPubMedGoogle Scholar
  • 29 Siegelmann-Danieli N, Tamir A, Zohar H. , et al. Breast cancer in women with recent exposure to fertility medications is associated with poor prognostic features. Ann Surg Oncol 2003; 10 (09) 1031-1038
    CrossrefPubMedGoogle Scholar
  • 30 Katz D, Paltiel O, Peretz T. , et al. Beginning IVF treatments after age 30 increases the risk of breast cancer: results of a case-control study. Breast J 2008; 14 (06) 517-522
    CrossrefPubMedGoogle Scholar
  • 31 Sprague BL, Trentham-Dietz A, Terry MB, Nichols HB, Bersch AJ, Buist DS. Fertility drug use and mammographic breast density in a mammography screening cohort of premenopausal women. Cancer Epidemiol Biomarkers Prev 2008; 17 (11) 3128-3133
    CrossrefPubMedGoogle Scholar
  • 32 Brinton LA, Westhoff CL, Scoccia B. , et al. Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort. Hum Reprod 2013; 28 (10) 2813-2821
    CrossrefPubMedGoogle Scholar
  • 33 Venn A, Watson L, Bruinsma F, Giles G, Healy D. Risk of cancer after use of fertility drugs with in-vitro fertilisation. Lancet 1999; 354 (9190): 1586-1590
    CrossrefPubMedGoogle Scholar
  • 34 Brinton LA, Moghissi KS, Scoccia B. , et al. Effects of fertility drugs on cancers other than breast and gynecologic malignancies. Fertil Steril 2015; 104 (04) 980-988
    CrossrefPubMedGoogle Scholar
  • 35 Hannibal CG, Jensen A, Sharif H, Kjaer SK. Malignant melanoma risk after exposure to fertility drugs: results from a large Danish cohort study. Cancer Causes Control 2008; 19 (07) 759-765
    CrossrefPubMedGoogle Scholar
  • 36 Hannibal CG, Jensen A, Sharif H, Kjaer SK. Risk of thyroid cancer after exposure to fertility drugs: results from a large Danish cohort study. Hum Reprod 2008; 23 (02) 451-456
    PubMedGoogle Scholar
  • 37 Stewart LM, Holman CD, Hart R, Bulsara MK, Preen DB, Finn JC. In vitro fertilization and breast cancer: is there cause for concern?. Fertil Steril 2012; 98 (02) 334-340
    CrossrefPubMedGoogle Scholar
  • 38 van Wely M. Assisted reproduction and cancer risk: how useful are national databases?. Hum Reprod 2015; 30 (08) 1753-1754
    CrossrefPubMedGoogle Scholar
  • 39 van Leeuwen FE, Klip H, Mooij TM. , et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod 2011; 26 (12) 3456-3465
    CrossrefPubMedGoogle Scholar
  • 40 Bjørnholt SM, Kjaer SK, Nielsen TS, Jensen A. Risk for borderline ovarian tumours after exposure to fertility drugs: results of a population-based cohort study. Hum Reprod 2015; 30 (01) 222-231
    CrossrefPubMedGoogle Scholar
  • 41 Stewart LM, Holman CD, Finn JC, Preen DB, Hart R. In vitro fertilization is associated with an increased risk of borderline ovarian tumours. Gynecol Oncol 2013; 129 (02) 372-376
    CrossrefPubMedGoogle Scholar
  • 42 Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Malignancies among women who gave birth after in vitro fertilization. Hum Reprod 2011; 26 (01) 253-258
    CrossrefPubMedGoogle Scholar
  • 43 Yli-Kuha AN, Gissler M, Klemetti R, Luoto R, Hemminki E. Cancer morbidity in a cohort of 9175 Finnish women treated for infertility. Hum Reprod 2012; 27 (04) 1149-1155
    CrossrefPubMedGoogle Scholar
  • 44 Reigstad MM, Larsen IK, Myklebust TA. , et al. Cancer risk among parous women following assisted reproductive technology. Hum Reprod 2015; 30 (08) 1952-1963
    CrossrefPubMedGoogle Scholar
  • 45 Brinton LA, Trabert B, Shalev V, Lunenfeld E, Sella T, Chodick G. In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Fertil Steril 2013; 99 (05) 1189-1196
    CrossrefPubMedGoogle Scholar
  • 46 Reigstad MM, Larsen IK, Myklebust TÅ. , et al. Risk of breast cancer following fertility treatment--a registry based cohort study of parous women in Norway. Int J Cancer 2015; 136 (05) 1140-1148
    CrossrefPubMedGoogle Scholar
  • 47 van den Belt-Dusebout AW, Spaan M, Lambalk CB. , et al. Ovarian stimulation for in vitro fertilization and long-term risk of breast cancer. JAMA 2016; 316 (03) 300-312
    CrossrefPubMedGoogle Scholar
  • 48 Venn A, Hemminki E, Watson L, Bruinsma F, Healy D. Mortality in a cohort of IVF patients. Hum Reprod 2001; 16 (12) 2691-2696
    CrossrefPubMedGoogle Scholar
  • 49 Lundberg FE, Johansson AL, Rodriguez-Wallberg K. , et al. Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study. Breast Cancer Res 2016; 18 (01) 36
    CrossrefPubMedGoogle Scholar
  • 50 Spaan M, van den Belt-Dusebout AW, Burger CW, van Leeuwen FEP. ; OMEGA-project group. Risk of colorectal cancer after ovarian stimulation for in vitro fertilization. Clin Gastroenterol Hepatol 2016; 14 (05) 729-37.e5
    CrossrefPubMedGoogle Scholar
  • 51 Spaan M, van den Belt-Dusebout AW, Schaapveld M, Mooij TM, Burger CW, van Leeuwen FE. ; OMEGA-project group. Melanoma risk after ovarian stimulation for in vitro fertilization. Hum Reprod 2015; 30 (05) 1216-1228
    CrossrefPubMedGoogle Scholar
  • 52 Kristiansson P, Björ O, Wramsby H. Tumour incidence in Swedish women who gave birth following IVF treatment. Hum Reprod 2007; 22 (02) 421-426
    CrossrefPubMedGoogle Scholar
  • 53 Wysowski DK. Use of fertility drugs in the United States, 1973 through 1991. Fertil Steril 1993; 60 (06) 1096-1098
    CrossrefPubMedGoogle Scholar