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Fertility Drugs and Ovarian Cancer: What are the risks when used for Surrogacy? By: Ivor Benjamin, M.D., co-Editor-in-Chief, OncoLink
Ovulation inducing agents have been available for clinical use for approximately thirty years. Initially these medications were only used for patients who were not ovulating, in order to make them ovulate and hopefully become pregnant. However, with the advent of modern assisted reproductive technologies their use has escalated dramatically in recent years. Ovarian stimulation is now used in many infertility situations, including women who are considering egg donation and women who are thinking of gestational surrogacy. In view of this dramatic increase in the use of these agents it is understandable that women are concerned about their possible adverse effects. A major putative risk that has received much publicity recently is that these ovulation-inducing drugs may increase the risk for developing ovarian cancers. Is this risk real? Are the concerns justified?Unfortunately, at the present time, there is no definitive answer to this question, because although there are data in support of an association between fertility drugs and ovarian cancer, there are equally convincing data that suggest that there is no such an association. However, it is reassuring that since no clear consensus can be found, it is very unlikely that a dramatic increased risk of ovarian cancer exists for egg donors and gestational surrogates.
Data that suggest an association are based on retrospective studies and case reports which are not the best types of scientific studies. In fact, retrospective studies are considered to provide the lowest level of evidence in support of their hypothesis and case reports are anecdotal. There are at least 3 such studies. The one that probably first drew attention to this possible association was that by Whittemore et al in 1992, [1] which found a 3-fold increased risk of ovarian cancer in infertile women who used ovarian stimulating drugs, and a 27-fold increased risk if the women had never been pregnant before. Rossing et al [2] reported that they found an increased risk if the widely prescribed oral ovulation-inducing drug clomiphene citrate was used for more than 12 months. This article lead to several letters to the Editor regarding this subject. [3] Shushan et al, [4] however, did not find an increased risk even when this medication was used for over 12 months, but they did report a 9-fold increase of one particular indolent form of ovarian cancer (the low malignant potential or "borderline" tumor) when the injectable ovulation-inducing drug human menopausal gonadotropin (HMG) had been given.
Contrarily, there are also several studies that suggested that there is no relationship between fertility drug use and ovarian cancer. For example, Ron et al [5] studied a group of 2,632 infertility patients and found no difference in the risk of ovarian cancer between those who did and those who did not receive ovulation-inducing medications. Similarly, a paper by Venn et al [6] in 1995 reported on a prospective cohort of 10,358 women referred to an Australian In Vitro Fertilization (IVF) Program. About half of the women were given ovulation-inducing agents and the other half had natural cycle treatment. There was no statistical difference in the incidence of ovarian cancer between the two groups. There are several other publications on both sides of the issue and many additional ones are currently ongoing.
It is difficult to know how to apply to clinical practice the apparently contradictory data that have accumulated so far on this important issue. The life-time risk that a woman in the United States has of developing ovarian cancer is between 1.4 and 1.8%. If, from the aforementioned studies, one believes that there is a risk of ovarian cancer in using ovarian stimulating medications, this risk may be 2-3 times that of the general population. These estimates suggest a life-time risk of, at most, 4-5% among women who had received ovulation medications. However, one must weigh against this a widely accepted view that the attainment of pregnancy and subsequent breast feeding, (both of which suppress ovulation) may be protective against ovarian cancer. There is abundant evidence that suppression of ovulation, (for example by the use of birth control pills or pregnancy) reduces significantly the incidence of ovarian cancer.
If a risk does exist from ovulation induction, and pregnancy is protective, then ideally perhaps only women who have had children or who have used birth control pills for extended periods of time, should be used as egg donors.
Spirtas et al at the National Institute of Child Health and Human Development [7] has stated that, based on all the data available at present, there is no need to change the current clinical practice of using fertility drugs. However, they suggest that egg donors who do not benefit from pregnancy should be counseled about what is presently known regarding the situation. It is also prudent to inform patients that there may be an increased risk of ovarian malignancy with ovulation induction prior to egg donation or in preparation for gestational surrogacy. And medical providers who treat infertility patients should try to avoid the use of prolonged courses of ovulation-inducing medications.
References
1. Whittemore AS, Harris R, Itnyre J. Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. 11. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184-203.
2. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771-6.
3. Correspondence: Risk of Ovarian Cancer after Treatment for Infertility. N Engl J Med 1995;332 (19).
4. Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13-18.
5. Ron E, Lunenfeld B, Menczer J, Blumstein T, Katz L, Oelsner G, Serr D. Cancer incidence in a cohort of infertile women. Am J Epidem 1987; 125:780-90.
6. Venn A, Watson L, Lumley J, Giles G, King C, and Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilization. Lancet 1995;346:995-1000.
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