Ovulation inducing drugs and ovarian cancer risk results from an extended followup of a large United States infertility cohort

Our findings were generally reassuring in not confirming a link between ovulation-inducing drugs and ovarian cancer; risk was increased, however, among women who, despite having used clomiphene citrate, remained nulligravid.

Britton Trabert, Ph.D., Emmet J. Lamb, M.D., Bert Scoccia, M.D., Kamran S. Moghissi, M.D., Carolyn L. Westhoff, M.D., Shelley Niwa, Louise A. Brinton, Ph.D.

Volume 100, Issue 6, Pages 1660-1666, December 2013


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

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

Five large reproductive endocrinology practices.

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).


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

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).

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.

  • I would like to thank the authors for this very interesting research. This paper provides
    reassuring information about the safety of ovulation- inducing drugs in
    relation with the risk of epithelial ovarian cancer. The size of the cohort of
    women and the long-term follow up studies are clear proof of a worthy effort
    made to evaluate the association between CC and gonadotropins with cancer. That
    issue is particularly relevant due to the risk of borderline and invasive
    ovarian tumors after ovarian stimulation for IVF, as described in a previous
    paper ( Leeuwen, F.E. et al, 2011). IVF differs from ovulation induction in
    many topics, for example; in IVF the ovary suffers an injury from the
    needle, the amount of gonadotropins is higher than in ovulation induction, and
    the number of harvested oocytes is also high, therefore the setting is
    different, but the drugs are similar. On the other hand, in this research the
    borderline cases are not reported.
    It is also interesting that the findings of women, who remained nulligravid, maintained a high risk of ovarian cancer which led to speculation that the lack of pregnancy is a key factor in the origin of gynecological cancer.

    Congratulations to the authors once again for this valuable report.

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