Study question: Do fertility drugs influence the subsequent risk of endometrial cancer in a manner that is independent of other risk predictors, such as parity?
Summary answer: In this follow-up of a large cohort of women evaluated for infertility and for whom information was captured on fertility drugs, indications for usage and other risk factors that might influence cancer risk, we found no evidence for a substantial relationship between fertility drug use and endometrial cancer risk.
What is already known: Although the hormonal etiology of endometrial cancer has been well established, it remains unclear whether the use of fertility drugs has an influence on risk. Results regarding the effects of fertility drugs on endometrial cancer risk have been inconsistent, although several studies have shown some evidence for possible increases in risk. The relationship is of particular interest given that clomiphene, a commonly prescribed drug, is a selective estrogen receptor modulator, with chemical properties similar to tamoxifen, another drug linked to an increase in endometrial cancer risk.
Study design, size, duration: In a retrospective cohort of 12 193 women evaluated for infertility between 1965 and 1988 at five US sites, follow-up was pursued through 2010 via both passive as well as active (questionnaire) means.
Participants, setting, methods: Among the 9832 subjects for whom follow-up was allowed and achieved, 259 346 at-risk person-years (i.e. prior to hysterectomy) were accrued, and 118 invasive endometrial cancers identified. Cox regression determined hazard ratios (HRs) and 95% confidence intervals (CIs) for fertility treatments adjusted for endometrial cancer risk factors and causes of infertility.
Main results and the role of chance: Although we observed slight increases in endometrial cancer risk associated with clomiphene (HR = 1.39, 95% CI: 0.96-2.01) and the less commonly prescribed gonadotrophins (1.34, 0.76-2.37), there were no convincing relationships of risk with either cycles of use or cumulative exposures for either drug. A statistically significant risk associated with the use of clomiphene among women who began use at younger ages (<30) (1.93, 1.24-3.00) may have reflected indications for drug usage rather than the effect of the drug itself. Women who received clomiphene followed by gonadotrophins were at a non-significantly elevated risk (1.77, 0.98-3.19).
Limitations, reasons for caution: Like most studies of endometrial cancer, we were limited by sample sizes, particularly for evaluating subgroup associations. We were also unable to follow all women and were not able to obtain complete risk factor information (including hysterectomy status) for the entire cohort.
Wider implications of the findings: Although we found no support for a relationship between fertility drugs and endometrial cancer risk, the association should continue to be monitored given that our study population was still young and had not yet reached the age of peak endometrial cancer incidence.
Study funding/competing interest(s): This project was supported in part by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. None of the authors has any conflicting interests to declare.
Keywords: clomiphene citrate; endometrial cancer; gonadotrophins; infertility; risk.