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No Link Found Between Fertility Drugs and Breast, Ovarian, and Uterine Cancers

'Generally reassuring' results from a large 30-year study

There is "little evidence" that the use of conventional fertility hormones used for ovarian stimulation in the treatment of infertility increases the long-term risk of breast and gynecological cancers, according to the results of a 30-year follow-up study. However, the extended use of clomiphene citrate was associated with a higher risk of breast cancer among women who had used the fertility drug for 12 cycles or more.

Gonadotrophins, more commonly used for ovarian stimulation today, were not generally associated with any increased risk, except in a subgroup of women who remained childless after treatment. Results of the study, which was funded in part by the National Institutes of Health, were presented at the annual meeting of the European Society of Human Reproduction and Embryology in Munich.

The study was a retrospective investigation involving 12,193 women treated for infertility between 1965 and 1988 at five U.S. sites. Follow-up lasted until 2010, with evaluation based on questionnaires and linkage to U.S. death and cancer registries. A total of 9,892 women were successfully followed for cancer outcomes.

Fertility drugs are known to increase levels of the principal female hormones estradiol and progesterone, both of which have been implicated in the pathogenesis of breast, ovarian, and uterine cancers. Drugs to stimulate the ovaries for ovulation induction and in vitro fertilization have included clomiphene and fertility hormones derived from human subjects — human menopausal gonadotrophins (hMG) and follicle stimulating hormone (FSH). Both hMG and FSH were not introduced into widespread use until the very early 1980s; until then clomiphene was the most commonly used agent.

Over the 30 years of follow-up, 749 breast, 119 endometrial (uterine), and 85 ovarian cancers were identified in the 9,892 subjects. The "ever use" of clomiphene — which included approximately 40% of the cohort — was not associated with any increased breast cancer risk, except when subjects had used the drug in 12 or more treatment cycles. In such cases, clomiphene use was associated with a significant hazard ratio (HR) of invasive breast cancer of 1.69 (95% confidence interval [CI], 1.16–2.45). This risk remained relatively unchanged after adjustment for causes of infertility and multiple breast cancer predictors.

Clomiphene use was not significantly associated with either endometrial (HR, 1.41; 95% CI, 0.98–2.04) or ovarian (HR, 1.34; 95% CI, 0.86–2.07) cancers, even when multiple exposure cycles were involved.

Only 10% of the cohort had been treated with gonadotrophins (hMG and FSH) — usually in combination with clomiphene — and no association with cancer risk was identified, except in those who remained childless (HR, 1.98). "Given that the majority of our women who received gonadotrophins also received clomiphene, it is likely that the increased risk among nulligravid women reflects an effect on risk of their infertility rather than that of drug usage," said Dr. Humberto Scoccia of the University of Illinois at Chicago, who presented the findings.

Dr. Scoccia added that the study's findings do not support "a strong relationship" between the use of fertility drugs (mainly clomiphene citrate) and breast, uterine, and ovarian cancers. He described the results as "generally reassuring," noting that this study had considerably more statistical power than previous efforts. However, he urged continuous monitoring because of the "relatively young age of our study population and the later peak incidence of most of these cancers."

Source: ESHRE; June 30, 2014.

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