MEMORANDUM

TO: Reproductive Health Patients

FROM: Sherif G. Awadalla, M.D.

Michael D. Scheiber, M.D., M.P.H.

RE: Risk of ovarian cancer in individuals utilizing ovulation inducing drugs

DATE: January, 2003

Dear Patient:

From time-to-time we update our information regarding recent topics of interest. In the last 5 years there has been a lot of interest in the risk of ovarian cancer related to the use of ovulation inducing agents. The following is a summary of 9 articles which are pertinent to the issue.

In 1987, Ron, et al published an article in the American Journal of Epidemiology regarding the risk of ovarian cancer related to the use of ovulation inducing agents, commonly known as fertility drugs. In this particular study, which was very well done, no risk was associated with the use of ovulation inducing agents.

In 1992, Whittmore, et al published an article in the American Journal of Epidemiology examining the association of ovarian cancer with the use of ovulation inducing agents. The study itself did not contain any new information but was a reanalysis of twelve previously published studies in the United States. The studies were published between 1956 and 1986. There are many problems with this study, including the fact that many patients were enrolled during a period of time when fertility drugs were not widely utilized. There is also no clear definition of what a fertility drug is. However, the study did show that there is a slightly increased risk of developing ovarian cancer in individuals who had used fertility drugs compared to controls. The risk was focused primarily in the group who failed to conceive regardless of treatment.

In 1994, Franceschi, et al published an article in Human Reproduction regarding this same issue. Individuals who had used fertility drugs were found to be at no increased risk for the development of ovarian cancers.

In 1994, Rossing, et al published an article in the New England Journal of Medicine regarding ovarian tumors in patients with infertility. The article looked at all fertility drug use. However, the authors concluded that only clomiphene citrate (or Clomid) may be associated with an increased risk in individuals who take the medication for greater than twelve months.

In October 1996, a critical review of published data regarding the proposed association of ovulation induction and increased risk of ovarian cancer appeared in Fertility and Sterility. The authors of this review, who did a computerized search for all articles and case reports regarding this issue, concluded that an association between ovulation inducing agents and ovarian cancer does not necessarily indicate a cause and effect relationship. The study showed that infertility alone is an independent risk factor for the development of ovarian cancer. It also indicated that women who never conceived are probably a high risk category regardless of the use of fertility agents. According to the authors of this article from the UCLA School of Medicine, the apparent association between fertility drug use and ovarian cancer may arise because these women are the most likely to have used ovulation inducing agents as part of their infertility treatment.

In Fall of 1996, a large Australian study reported data at the annual meeting of American Fertility Society. The study analyzed 5,564 infertile women undergoing ovulation induction with Clomiphene or Pergonal. They were compared with approximately 5,000 demographically identical infertile women who were not treated. The study showed no increase in any gynecological cancer in this population when compared to the control population. The key author, Dr. David Healy, is internationally respected. This was the largest study to date addressing the issue of cancer risks associated with fertility agents.

In June of 1997, Mosgaard et al reported in Fertility and Sterility a large retrospective study examining all Danish women who were diagnosed with ovarian cancer from1989 to1994. Six hundred and eight-four women were alive and able to complete the questionnaire. They were compared with1,721 matched control women without ovarian cancer. As expected, women who have never given birth had twice the risk of ovarian cancer as women who had given birth. Also, as expected, this study documented that women with infertility who had never given birth and who had never taken ovulation inducing medications were at an increased risk compared to non-infertile women who had never given birth. This risk was estimated to be three times higher than normal. This is consistent with previous information showing that women with infertility were at risk for ovarian cancer. The study also found that treatment with fertility drugs did not increase the incidence of ovarian cancer when compared to infertile individuals who received no drug therapy.

In the November1999 issue of Lancet, Vann et al reported a study from Australia. they studied nearly 30,000 women referred for IVF. They found that the incidence of breast and ovarian cancer was not increased over that expected in the general population. They found no association between the number of IVF cycles and the incidence of uterine or ovarian cancer. They did find that unexplained infertility was a risk factor for ovarian cancer, irrespective of drug use. This data search has confirmed that infertility is a risk factor for ovarian cancer in and of itself. This risk is not due to drug therapy.

In October of 1999, at the American Society for Reproductive Medicine meeting in Toronto, Ontario, Croughan-Minihane, et al reported on 51,957 patients seeking care from three California infertility clinics. In the study population, they found only one-half of the number of expected cases of ovarian cancer. They found that fertility drug use was not associated with an increase risk of ovarian cancer. Fifty percent of the tumors in infertility patients were found to be " and were not highly malignant at all.

In February of 2002, Dr Ness of the Univ of Pittsburgh and colleagues published an article in the Am. J. Epidemiology. 155(3):217-24,2002. They analyzed data from 8 studies including 13,000 women. Their analysis showed that use of fertility drugs did not increase the risk of ovarian cancer. They noted that women who never became pregnant were twice as likely to develop ovarian cancer. They suggest that infertility alone, not the use of ovulation drugs increases the risk of ovarian cancer.

In summary, a significant quantity of data suggests that infertility, in and of itself, is associated with a higher risk of ovarian cancer. This risk factor is unrelated to the use of any ovulation inducing medications. It is also important to know that ovarian cancer is the sixth most common malignancy in women. It represents approximately 4% of all female cancers. Many factors protect against the risk of ovarian cancer. Birth control pill use is protective. Pregnancy and delivery are also protective. It is hoped that through the use of ovulation inducing agents, many pregnancies will occur which will offset the risk of ovarian cancer. For women who do not conceive, future use of birth control pills may also offer a protective effect.

Based on the above information, an absolutely definitive conclusion cannot be reached. However, it seems that the slight increased risk of ovarian cancer in infertile women is probably associated with the state of infertility itself and not the use of ovulation inducing agents. Those tumors that may be associated with fertility drugs tend not to be malignant or aggressive. Many studies demonstrate no association between fertility agents and ovarian cancer. This is the current state of knowledge relative to this topic. If you have any additional questions please let us know and we will be glad to address them individually. In the meantime, we think that the use of ovulation inducing agents in the proper situation for the proper duration of time remains an accepted clinical practice.