'Reassuring' Data on Fertility Drugs and Cancer Risk: Study

By Megan Brooks

July 10, 2014

NEW YORK (Reuters Health) - A 30-year follow up study finds that clomiphene and other ovulation-stimulating drugs do not raise the risk of breast and gynecologic cancers, with a few caveats.

The study did find a higher risk of breast cancer among women heavily exposed to clomiphene (12+ cycles), and of ovarian cancer among women exposed to clomiphene who never became pregnant.

"As far as the clinical implications of our study findings is concerned, it provides reassurance to patients and clinicians that use of clomiphene and gonadotropins appears safe, and reaffirms the current practice to limit the use of clomiphene to < 12 months," Dr. Humberto Scoccia from University of Illinois at Chicago, told Reuters Health by email.

Dr. Scoccia presented the results of the study June 30th at the annual meeting of the European Society for Human Reproduction and Endocrinology (ESHRE) in Munich, Germany.

Fertility drugs stimulate ovulation induction and raise estradiol and progesterone levels, but how this may influence risk of breast and gynecologic cancer remains incompletely understood, the researchers say.

"Despite the biologic plausibility, results of studies of fertility drugs and breast and gynecological cancers present a mixed picture, with some showing increases in risk, others decreases, and still others showing no substantial associations," Dr. Scoccia notes in a conference statement.

"However, most of these studies had small numbers with relatively short follow-up periods, and were unable to control for other cancer predictors - including the indications for drug usage, such as anovulation or endometriosis, which could independently affect cancer risk. Many questions remain unresolved," Dr. Scoccia points out.

The current study gets around some of these shortcomings. It was a retrospective investigation involving 12,193 women treated for infertility between 1965 and 1988 at five US sites. A total of 9,892 women were successfully followed for cancer outcomes until 2010.

Over the 30 years of follow-up, 749 breast, 119 endometrial and 85 ovarian cancers were identified.

"Ever use" of clomiphene, which included approximately 40% of the cohort, was not associated with any increased breast cancer risk, except among women who had used the drug in 12 or more treatment cycles. In these women, the hazard ratio of invasive breast cancer was 1.69. This risk remained relatively unchanged after adjustment for causes of infertility and multiple breast cancer predictors.

Clomiphene was not significantly associated with either endometrial (HR 1.41) or ovarian (HR 1.34) cancer, even with multiple exposure cycles.

Only 10% of the women had been treated with gonadotropins (hMG and FSH), usually in combination with clomiphene, and no association with cancer risk emerged, except in those who remained childless (HR 1.98).

"Given that the majority of our women who received gonadotropins 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," Dr. Scoccia said in a statement.

"Overall, our findings do not support a strong relationship between fertility drug use and breast or gynecologic cancers," the investigators conclude. "However, the association between fertility drug use and cancers should continue to be monitored due to the relatively young age of our study population and the later peak incidence of most of these cancers."

In a phone call with Reuters Health, Dr. Eric Levens of Shady Grove Fertility in Rockville, Maryland said the potential of fertility drugs to increase the risk of cancer has been "heavily studied and the data have been pretty mixed."

"This is a much larger study than has been done in the past and with longer follow up and the data are reassuring that there really is not a great risk of cancer with fertility medications, that these medications are safe and that it's probably not the fertility medications but the underlying conditions that lead to the fertility problems and the fact that women go childless."

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