It was in 1992 when Dan Rather presented a segment on the CBS evening news about a paper that discussed the possibility of fertility drugs causing ovarian cancer (Whittemore et al. Am J Epidemiol 1992;136:184-203). The anxiety this created amongst my patients at that time was significant. A closer analysis of the data showed there to be a lot of shortcomings in the analysis (outdated infertility treatments, no information on duration or type of infertility, cases not controlled for confounding factors such as birth control pill use or family history of ovarian cancer). Subsequently, there were several studies that actually showed that fertility drugs may reduce the incidence of ovarian cancer!
Just this week there was a furor created by a paper published in the journal Human Reproduction by a Dutch group of researchers (van Leeuwen et al. Hum Reprod Advanced Access Published October 26,2011). They followed 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995. The control group was 6006 subfertile women not treated with IVF. These women were followed up for almost 15 years. They found 61 cancers (30 invasive and 31 borderline) in the IVF group and 16 in the non-IVF group (controls, 12 invasive and 4 borderline). There was no statistically significant increase in “invasive” ovarian cancer, which is deadly. There, however, was a significant increase in patients developing “borderline” ovarian cancer. These are tumors that generally are not lethal and are treated with surgery alone (no chemotherapy). In the IVF group, the incidence of ovarian cancer did not increase with a greater number of IVF cycles or ampules of fertility drugs (gonadotropins). Thus there was no "dose-response" relationship between fertility drug usage and ovarian cancer. Also, the incidence of borderline tumors (46%) is unusually high. The strengths of the study are the large size of the study group and the prolonged duration of the follow up. The weakness is the relatively small size of the control group. The overall chance of developing ovarian cancer (0.71% in IVF-treated versus 0.45% in non treated women) at age 55 remains low.
This is contrary to an earlier paper published another Dutch group that analyzed an even larger group of women (but for a shorter period of time) and found no increase in the incidence of ovarian cancer. So what does one make of all of this?
It is a well-established fact that there is an increased risk of ovarian cancer among infertile women who remain childless despite long periods of unprotected intercourse. The question often asked is whether the risk is increased with the use of ovulation-inducing drugs.
Repeated ovulation has been postulated as a potential biologic promoter of ovarian cancer. With ovulation, there is trauma to the ovarian lining (epithelium) and over a period of time, this repeated minor trauma results in the cells becoming cancerous (Fathalla’s incessant ovulation hypothesis). Support for this theory is based on the observation that ovarian cancer is reduced in women with children, those that breast fed, and in women on birth control pills – all conditions in which ovulation is suppressed.
Another theory is that persistent exposure of the ovary to fertility drugs (gonadotropins) especially those associated with resultant high estrogen levels may induce cancer.
Mahdavi et al. (Fertil Steril 2006; 85:819-826) published a critical review of the literature on this issue. They analyzed a variety of studies (cohort, case-control and descriptive) with various comparisons (fertility drugs vs. no infertility, fertility drugs vs. no use) and different drugs (clomiphene citrate, hMG). They concluded that the data (especially invasive epithelial carcinoma and non-epithelial neoplasia) regarding the risk associated with fertility drugs was reassuring, but not definitive. The association between fertility drug use and borderline tumors was not consistent among the available studies to date.
I do not think we need to panic and stop using ovulation induction medications based on this study. The overall risk for ovarian cancer even in the study candidates was low. It is actually reassuring that there was no increase in invasive ovarian cancer in patients with a history of using fertility drugs. Van Leeuwen et al. suggest that even larger prospective cohort studies of IVF-treated wome, with prolonged follow-up and a larger control group are needed to confirm or refute their findings.
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