Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort

Fertil Steril. 2013 Dec;100(6):1660-6. doi: 10.1016/j.fertnstert.2013.08.008. Epub 2013 Sep 5.


Objective: To examine the relationship of ovulation-inducing drugs and ovarian cancer.

Design: Retrospective cohort study, with additional follow-up since initial report.

Setting: Five large reproductive endocrinology practices.

Patient(s): In a retrospective cohort of 9,825 women evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010, we examined the relationship of ovulation-inducing drugs and ovarian cancer (n = 85).

Intervention(s): None.

Main outcome measure(s): Hazard rate ratios (RR) and 95% confidence intervals (CI) for ovarian cancer.

Result(s): Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (CC) (adjusted RR 1.34, 95% CI 0.86-2.07) or gonadotropins (RR 1.00, 95% CI 0.48-2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk with one exception: women who used CC and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36-9.72 vs. RR 0.88, 95% CI 0.47-1.63).

Conclusion(s): Our overall results were reassuring and consistent with other studies. A reason for an association between CC use and ovarian cancer among persistently nulligravid women remains to be determined. Given the large and increasing number of women treated with ovulation-inducing drugs, the increased risk of ovarian cancer among the subset of women who remained nulligravid should be further monitored.

Keywords: Ovarian cancer; clomiphene citrate; gonadotropins; infertility; risk.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Causality
  • Clomiphene / administration & dosage*
  • Cohort Studies
  • Comorbidity
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Female
  • Fertility Agents, Female / administration & dosage
  • Follow-Up Studies
  • Gonadotropins / administration & dosage*
  • Humans
  • Incidence
  • Infertility, Female / epidemiology*
  • Infertility, Female / therapy*
  • Middle Aged
  • Ovarian Neoplasms / epidemiology*
  • Ovulation Induction / statistics & numerical data*
  • Retrospective Studies
  • Risk Factors
  • Treatment Outcome
  • United States / epidemiology


  • Fertility Agents, Female
  • Gonadotropins
  • Clomiphene