Ovulation Induction Drugs
Risk of Ovarian Cancer
Ovarian cancer is the sixth most common malignancy in women and represents 4% of all cancers in females. A woman has approximately a 1.8% risk of developing ovarian cancer in her lifetime. This can be compared to a 12% lifetime risk of developing breast cancer. A small number of ovarian cancers arise in the setting of “familial ovarian cancer syndrome”. However, most ovarian cancers occur without a significant tendency.
There are three main theories on what causes ovarian cancer:
- Repeated ovulations, disruption the ovarian surface, and leading to malignant transformation.
- Persistent stimulation of the ovary by pituitary hormones, LH and FSH, may have a direct carcinogenic effect, or may act through the increased concentration of estrogen caused by the ovarian stimulation.
- Processing of chemical carcinogens in the local ovarian environment.
It has been known for some time that pregnancy, breast feeding, use of oral contraceptives (birth control pills), and early menopause decrease the risk of developing the most common forms of ovarian cancer. Thus, it appears that any phenomenon that decreases ovarian activity may have a beneficial effect in reducing a woman’s lifetime risk of developing ovarian cancer. This has lead to the concern that the opposite situation, i.e. increased ovarian activity may increase the lifetime risk of developing ovarian cancer. One example is that several studies have indicated that women who are infertile and do not become pregnant may have an increased risk of developing ovarian cancer.
Is there a link between the use of ovulation induction drugs and ovarian cancer?
In recent years, a multitude of studies have been published, attempting to find an association between the risk of ovarian cancer and environment factors, hereditary factors, and reproductive history. However, conclusive studies are scarce for a number of reasons. All examined associations appear to be weak, and the etiology of ovarian cancer appears to be multifactorial. This requires a large number of patients to reach any firm conclusion, and, based on the small number of ovarian cancers in the general population, it is difficult to find enough cases to demonstrate that a certain factor increases the risk of developing cancer.
Ovulation induction medications fall into two groups:
- The first type of medication is clomiphene citrate (Clomid and Serophene). This medication stimulates the pituitary gland to secrete the hormones LH and FSH, which in turn stimulate the ovaries. It is not a natural compound, and is a relative of tamoxifen and DES.
- The second group of ovulation inducing medications are naturally occurring compounds that are normally found in the body. These include the human menopausal gonadotropins (Pergonal and Metrodin) and GnRH (Factrel and LutrePulse). Like clomiphene, GnRH stimulates the pituitary gland to secrete the hormones LH and FSH, which in turn stimulate the ovaries. Human menopausal gonadotropins, on the other hand, directly stimulate the ovary without going through the intermediary step of the pituitary gland.
A possible association between ovulation inducing agents and an increased risk of ovarian cancer has been suggested by the following findings:
- The theoretical possibility previously discussed, which would suggest that any medication that would increase ovarian activity could result in an increased risk of ovarian cancer.
- Isolated case reports of individual women who have taken ovulation inducing medications and were found to have developed ovarian cancer.
- Retrospective case controlled studies. These studies analyzed a group of women who are known to have already developed ovarian cancer. It was noted that more of these women had taken “fertility medications” than would have been expected when compared to a “control group” of women who had not taken these medications.
Individual case reports only demonstrate that a patient was known to have certain separate findings: In other words, that an individual person who at sometime in their life has taken a particular medication such as ovulation inducing medications was subsequently noted to have developed cancer of the ovary. The only value of these case reports is to alert medical researchers of a possible association so that proper studies can be initiated to address this question. The case reports in themselves have absolutely no value in proving any type of “cause and effect” relationship between the medication and the subsequent development of a cancer. The most well known case report of this type was when comedian Gilda Radner who had undergone Pergonal treatment and IVF, later died of ovarian cancer.
More reliable information concerning the possible association between ovulation inducing medications and an increased risk of developing ovarian cancer has been suggested in two recently published retrospective case controlled studies. In December of 1992, Whittmore and colleagues published a summary of a number of case controlled studies in the literature looking for an association between several factors and an increased risk of developing ovarian cancer. When infertile women who had taken any form of “fertility drugs” were compared to women who had never taken these medications, it was found that they had a 2.7 times increased relative risk of developing ovarian cancer. In other words, women who had taken the medication had a 3 to 4% risk of developing ovarian cancer compared to a 1 to 2% risk in women who had never taken the medications. It was also noted that women who took the medications, and became pregnant, did not have an increased risk of cancer. This study has been criticized by a number of experts for many shortcomings. No attempt was made to determine: why the patients had taken the medications, the type and dose of medication that was taken, and the length of time the medication was taken. The study was also based on a small number of patients. Their conclusions were based on comparing 20 patients who had taken any form of “fertility medication” and developed ovarian cancer vs. 11 control patients who had not. Although there were many legitimate criticisms about the validity of this study, it certainly raised the possibility that the use of any type of “fertility medication” might be associated with an increased risk of developing ovarian cancer, and thus sported the theoretical concerns and the original case reports about the validity of this study, it certainly raised the possiblility that the use of any type of “fertility medication” might be associated with an increased risk of developing ovarian cancer, and thus spported the theoretical concerns and the original case reports.
More recently, a second retrospective case cohort study by Rossing, et al, has appeared in our literature supporting the possible association between an increased risk of developing ovarian cancer and the use of ovulation inducing medications. In this study, the authors randomly selected a group of women who had attended an infertility clinic in the Seattle area. They then analyzed this group, comparing a number of factors to the risk of developing ovarian cancer. They noted that women who had used clomiphene citrate (Clomid, Serophene) were 3.1 times more likely to have developed ovarian cancer than women with no history of exposure to this drug. This suggested a lifetime risk of approximately 4 to 5% among exposed women. The increased risk associated with clomiphene was most evident among those women who had used the drug for more than 12 cycles. In fact, there was no significant increased risk noted in women who had taken clomiphene for less than 12 months, or who had taken Pergonal, Metrodin or HCG.
Summary and Recommendations
Because of theoretical concerns and two recent limited case controlled studies, there appears to be a concern of a possible increased risk of developing ovarian cancer in women exposed to ovulation inducing medications. These studies suggest the risk may be greatest in exposed women who do not become pregnant, and in those women who utilized clomiphene citrate for greater than 12 months. It must be emphasized that this data is preliminary and these conclusions are tentative. At the present, uncertainty makes it difficult to balance the risks and benefits of medications that enhance fertility. To address this problem, it is useful to put into perspective the likely magnitude of the risk of ovarian cancer associated with such treatment. If ovulation induction medications induce ovarian cancer, the risk appears to be about 2 to 3 times that of the general population. Ovarian cancer is an uncommon disease. The lifetime risk of a U.S. woman is approximately 1.0 to 1.8%. These estimates suggest the lifetime risk of at most approximately 4 to 5% among women who have taken ovulation inducing medications. This figure should be compared with a 12% lifetime risk of breast cancer for the average U.S. woman.
It is our recommendation that all women who are considering the use of ovulation inducing medications should be appraised of possible adverse effects of taking these medications. In addition, it seems prudent to minimize exposure to these medications by carefully considering the reasons for their usage and not continuing the medication for any longer period of time than one can expect to obtain benefit from them. It is for this reason each couple and their physician must consider the appropriateness of the use of ovulation inducing medication, in their individual situation. Once a decision has been made to utilize a given medication, limited lengths of therapy will be decided upon, at which time you will again meet in consultation with your physician to reevaluate the appropriateness of its continued use. Typically patients will not be treated for more than 4 to 6 cycles without a follow-up consultation with the physician and a complete case review. In addition, prior to initiating ovulation inducing medications, other fertility investigations such as semen analysis and testing for tubal patency will be suggested to lessen the likelihood that other factors may be limiting the success of the ovulation therapy. Also, patients will be monitored monthly with urinary LH testing or transvaginal ultrasound to assure the maximum effect from the medication while limiting your risks and costs. We feel that the continued prudent use of these medications is warranted in well selected patients who are monitored carefully and well informed.
At present, experts are unsure whether special long-term follow-up should be recommended for women who have taken ovulation induction medications. Certainly routine yearly pelvic exams and immediate investigation of any persistent ovarian abnormalities are appropriate. In addition, all future healthcare providers should be informed of your history as additional recommendations may be forthcoming.
If you have any questions about your treatment of any information concerning the use of your medications, please make an appointment with your physician.
John W. Malo, M.D., St. Paul, MN
You can also read Fertility drugs and ovarian cancer: red alert or red herring?