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A serious potential complication of these ovulation promoting medications is promotion of ovarian cancer. Overall, about 1 in 70 women in the USA develop ovarian cancer in their lifetime, with widely recognized risk factors for ovarian cancer including low parity, decreased fertility and delayed childbearing. It is also known that oral contraceptive pills decrease the incidence of epithelial types of ovarian cancers, presumably as a result of inhibition of ovulation.
This epidemiological information has led to the theory that “the more a woman ovulates the greater her chance for developing ovarian cancer.” Unfortunately, there is almost no appropriate information available to either support or reject this theory. The follow up theory as it relates to fertility medications is that “fertility medication that causes the maturation and release of more than one egg per month may concurrently enhance the chances of developing ovarian cancer.” Again, no adequate information is available to either accept or reject this theory.
Concern with an association between ovulation and ovarian cancer is not new. As early as 1971 it was proposed that each ovulation results in a small area of trauma at the ovulation site that then is repaired. A disruption in the repair process may somehow result in an abnormal and uncontrolled growth of this tissue (cancer).
In 1978, it was noted that the inclusion cysts that are occasionally found in epithelial ovarian cancers resemble the inclusion cysts that result from some ovulation and repair cycles. The theory was proposed that these inclusion cysts in some way cause epithelial ovarian cancers. Since the 1970s, the thought has persisted that fertility drugs enhancing the number of ovulations (albeit generally a small increase in comparison to the total number of ovulations in a typical reproductive lifespan) may also increase the chance for an accident in the repair process that may then result in developing an ovarian cancer.
Articles published on these concerns have been widely publicized by the mass media. Unfortunately, the information collected in the published reports does not allow a firm position on the issue of a relationship between fertility drugs and ovarian cancer.
One widely publicized article from 1992 (A.S. Whittemore and colleagues) reviewed the data from 12 case control studies and suggested that the risk of developing ovarian cancer is increased in women who have used “fertility drugs.” The risk was greatest in women who had never been pregnant. On critical review of this study, it is seen that detailed information on fertility drugs was only available in 3 of the 12 studies (leaving a total number of 96 infertile women with cancer compared to a control group of only 135 infertile women) and the particular fertility drugs used by these women was not identified. Perhaps the most important criticism of this study regards the ages of the cancer patients in comparison to the dates that the cancers were diagnosed. The average age at diagnosis was 53 and the time of diagnosis was 1977-1981, meaning that if it is assumed that the women were 30-40 at the time of fertility medication treatment then the actual years of treatment were between 1954 and 1967. Clomiphene citrate was not FDA approved until 1967, menotropins until 1969 and bromocriptine until 1978, so that it appears impossible that these were the drugs referred to in the reviewed articles.
The National Institutes of Health issued a call for abstracts to study the association between ovarian cancers and fertility drugs soon after this publication, and suggested that given the relative rarity of the disease (1 in 70 in the USA) a reasonable study of relative risk would need to include 30,000 women years of exposure. This is a far greater amount of exposure than is contained in any study to date.
A second widely publicized article from 1994 (M.A. Rossing and colleagues) compared a cohort of 3800 plus women evaluated for infertility between 1974 and 1985 in Seattle and found that there were 11 ovarian cancers among these women as compared to an expected number of 4.4. The 11 cancers consisted of 5 borderline tumors, 4 invasive epithelial cancers, and 2 granulosa cell tumors. Of the 11 women developing cancer, 9 had used clomiphene citrate. Comparisons of cancer developing in infertile clomiphene users to infertile women who had not used clomiphene demonstrated no significant difference in the clomiphene group. However, when infertile women who used clomiphene for 12 or more months was compared to the control group, an increased risk was identified. Oddly, the risk for clomiphene users if 12 or more cycles was greater in gravid women than in nulligravid women, since gravity is known to be protective. Also, most cause and effect relationships have a dose dependent increase in outcome, such that the risk of cancer should be directly proportional to the amount of clomiphene used. In this study, there was a mild protective effect if up to 11 cycles of clomiphene was used and then suddenly there was an increase in the risk when 12 cycles were used. The number of cases in this study is also quite small, with only 5 cases of cancer being considered when looking at infertile women with 12 or more cycles of clomiphene use.
In 1995 an Australian group followed 10,000 plus IVF patients, about 5,000 of whom used ovulation enhancing medications and about 5,000 of whom underwent natural cycle IVF (without menotropins) or did not receive treatment. This group found that the age standardized incidence ratios for ovarian cancer was not statistically different between those who used fertility medication and those who did not. This group did identify a significant increase in risk for ovarian cancers in couples with “unexplained infertility” as compared to the infertile controls. Unfortunately, the follow-up period for this important study was only 5-10 years.
The potential association between fertility drug use and ovarian cancer is quite important. Hopefully, there will continue to be interest in this field over the next several years. Unfortunately, there is not enough information at this time to firmly express an opinion based on fact. One interesting observation of my own is that at national meetings (USA) this subject is occasionally approached by very conservative senior infertility specialists who all seemingly recount that their own extensive experience with fertility drugs does not suggest an association with ovarian cancers.
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