Uterine cancer after use of clomiphene citrate to induce ovulation

Clomiphene citrate, a selective estrogen receptor modulator, increases estradiol levels and consequently may increase risk of cancer of the uterine corpus. The authors conducted a retrospective cohort study of 8,431 US women (145,876 woman-years) evaluated for infertility during 1965-1988. Through 1999, 39 uterine cancers were ascertained by questionnaire or cancer and death registries. Poisson regression estimated adjusted rate ratios. Study results suggest that clomiphene may increase uterine cancer risk (rate ratio (RR) = 1.79, 95% confidence interval (CI): 0.9, 3.4) and present evidence of a dose response (p(trend) = 0.07) and latency effect (p(trend) = 0.04). Uterine cancer risk increased with clomiphene dose (RR = 1.93, 95% CI: 0.9, 4.0 for > 900 mg), menstrual cycles of use (RR = 2.16, 95% CI: 0.9, 5.2 for > 6 cycles), and time elapsed since initial use (RR = 2.50, 95% CI: 0.9, 7.2 for women followed for > 20 years). Risk was more strongly associated with clomiphene among nulligravid (RR = 3.49, 95% CI: 1.3, 9.3) and obese (RR = 6.02, 95% CI: 1.2, 30.0) women, with risk substantially elevated among women who were both obese and nulligravid (RR = 12.52, 95% CI: 1.5, 108.0). Clomiphene may increase uterine cancer risk, with higher doses leading to higher risk. Long-term follow-up of infertility cohorts is necessary to clarify the association between clomiphene use and uterine cancer.