Ovulation Induction and Cancer: Is There a Link?

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Over the last decades, several series of cases (1,2) and numerous case reports of ovarian cancer occurring in women treated with ovulation induction drugs, have been published. In addition, few epidemiological studies (3,4) observed a possible relation between these drugs and cancer incidence. In 1987, Ron et al. (5) published a report based on follow-up of 2575 infertile women treated at the Chaim Sheba Medical Center, Tel Hashomer. An excess of endometrial but not of ovarian cancer was noted, in both the treated and untreated group. An updated follow-up of this group was published by us (6) in 1998, observing 143 cancer cases as compared to 116.1 expected cases (SIR=1.2; 95% CI 1.0-1.5). Sensitivity analysis revealed that confounding by Nulli- parity, obesity and hysterectomy was unlikely to explain the raised risk of endometrial cancer, but nulli- parity might explain the small and insignificant increased risk of ovarian cancer (SIR= 1.6 ;95%Cl 0.8-2.9). The most prominent excess risk for ovarian cancer was evident in the subgroup of women with mechanical or male-related infertility and normal ovulatory cycles (SIR=2.7; 95% CI 1.0-6.0). The risk for ovarian cancer was similar among patients treated with any ovulation-induced agent as compared to untreated patients (SIR 1.7 vs. 1.6). Patients treated with clomiphene only revealed a borderline significant excess risk of ovarian cancer (SIR 2.7; 95% CI 0.97-5.8), although the data is based on small number of cases. Similar to the findings at the Sheba medical center, in a cohort of 1197 women infertile women treated with fertility promoting drugs at the Soroka Medical Center, no increased risk in ovarian, breast, and endometrial cancer was observed (7). Currently, all available information regarding ovulation induction drug usage and cancer incidence among infertile women in Israel is gathered. The cohort consisted of 5990 infertile women who were seen in the major clinics in Israel between 1964 and 1984 and were followed for cancer development through 1995. Their mean age at entry was 28.9 years (S.D. 5.6) and their mean age at the end of follow-up was 51.2 years (S.D. 8.4).

This cohort includes more than 120,000 women-years of follow-up with mean length of follow-up per woman of 22.3 years (S.D. 6.6). Of these 5990 infertile women, in 51.7% infertility was hormonal, in 21.6% it was due to mechanical reasons, in 13% there was a male factor, and in 13.7% the etiology of the infertility could not be explained. Preliminary analysis reveals 291 observed cancer cases among this large cohort as compared to 276.7 expected cases with respect to age and country of birth (SIR 1.05; 95% CI 0.93- 1.18). Further analyses with regard to specific cancer sites and ovulation induction exposure are in process. 

Summary

From all our available information to date, no link between ovulation induction and cancer could be established. When adding assisted reproductive techniques (ART) to ovulation induction, it seems that similar conclusions might be drawn. However, the relatively short follow-up period since the introduction of ART procedures permits us only limited conclusions, until these women will reach their peak cancer incidence years. Taking into consideration the short latency periods that were observed by many authors between ovulation induction treatment and cancer diagnosis, it seems justified to recommend that, prior to ovulation induction, ovarian pathology should be excluded. Moreover, clinical examination of the breast is also warranted. In addition, one could not ignore the elevated risk of endometrial cancer, particularly among women with infertility of hormonal origin, that has been observed repeatedly. Therefore, infertile women with unopposed estrogen status should be considered high-risk group for endometrial cancer, independent of ovulation induction treatments. These women should be followed closely during and after their reproductive life.

References:

Reference List

1. Cohen, J., R. Forman, S. Harlap, E. Johannisson, B. Lunenfeld, J. de Mouzon, R. Pepperell, B. Tarlatzis, and A. Templeton. IFFS expert group report on the Whittemore study related to the risk of ovarian cancer associated with the use of infertility agents. Hum.Reprod. 8: 996-999, 1993.

2. Lunenfeld, B., J. Blankstein, S., Kotev-Emeth, E. Kokia, and A.Geier. Drugs used in ovulation induction. Safety of patient and offspring. Hum.Reprod. 1: 435-439, 1986.

3. Rossing M.A., Daling J.R., Weiss N.S., Moore D.E., Self S.J. Ovarian tumors in a cohort of infertile women. New Engl J Med 331: 771-776, 1994

4. Shushan A.,Paltiel O., Iscovich J., Elchalal U., Peretz T.,Schenker J.G. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 65: 13-18, 1996.

5. Ron, E., B. Lunenfeld, J. Menczer, T. Blumstein, L. Katz, G. Oelsner, and D. Serr. Cancer incidence in a cohort of infertile women. Am.J.Epidemiol. 125: 780-790, 1987.

6. Modan, B., E. Ron, L. Lerner-Geva, T. Blumstein, J. Menczer, J. Rabinovici, G. Oelsner, L. Freedman, S. Mashiach, and B. Lunenfeld. Cancer incidence in a cohort of infertile women Am.J.Epidemiol. 147: 1038-1042, 1998.

7. Potashnik G., Lerner-Geva L., Genkin L., Chetrit A., Lunenfeld E., Porath A. Fertility drugs and the risk of breast and ovarian cancers: results of a long-term follow-up study. Fertil Steril 71: 853-859, 1999.

Acknowledgement

We wish to acknowledge that the gathering of this valuable data would not have been possible with out the help provided by: Prof. B. Modan, Prof. S. Mashiach, Dr. J. Rabinovici from the Chaim Sheba Medical Center. Prof. G. Potashnik, Dr. E. Lunenfeld from the Soroka Medical Center. Prof. J.G. Schenker, Dr. A. Shushan from the Hadassa Medical center. Prof. Y.Beith, Dr. I. Cohen from the Sapir Medical Center. and Prof D.Ayalon from the Tel-Aviv Medical center.

This work is in partial fulfillment of the requirements for the Ph.D. degree of L. Lerner-Geva from the Sackler Faculty at Tel-Aviv University.