Physicians and patients are both interested in identifying factors that may increase the risk for the development of ovarian cancer. One of the leading established risk factors for ovarian cancer has been whether or not a woman has been pregnant. Women that have never delivered a baby seem to have a higher risk of ovarian cancer than women who have delivered a baby. Women with infertility were also thought to be at higher risk for ovarian cancer.  

In recent years, studies have brought up concerns regarding women treated with fertility drugs, in particular for women who had never been pregnant and for those who used the drugs long term. However, several subsequent studies were reassuring as they did not confirm a strong link between ovarian cancer and the use of fertility drugs.

The two most recent studies, showed no overall increase in the incidence of ovarian cancer after use of clomiphene citrate or gonadotropins.

It should be noted, however, that most of these studies were not able to distinguish the possible effects of fertility medications from the underlying causes of infertility, which could independently affect the risk of ovarian cancer.

In order to make a convincing argument that any factor causes an increase in the risk of cancer, scientists would like to see several things:

• The relationship makes sense - Two theories are usually used to explain how fertility drugs might affect the risk of ovarian cancer. The continual ovulation theory suggests that repeated, uninterrupted ovulation causes trauma to the surface of the ovaries, leading eventually to a cancerous change. The gonadotropin theory suggests that exposure of the ovaries to the hormones contained in fertility drugs could stimulate the development of cancer as well.
• Dose response effect – This means that if “Drug X” causes ovarian cancer, then women who take a higher dose of “Drug X” or take it for a longer period of time should develop cancer more often. Previous studies were criticized because of the absence of a dose-response effect.
• Latency effect – It may take many years for cancer to start and develop to a point where it can be diagnosed. Most women are diagnosed with ovarian cancer in their fifties and sixties. If “Drug X” causes ovarian cancer, than the longer you observe women after taking “Drug X”, the more should be found to have it.

Fertility Drugs and Ovarian Cancer Study

54, 449 Danish women with primary or secondary infertility who sought care from 1963 until 1998 were identified for a study on the effect of fertility drugs on ovarian cancer risk. Primary infertility occurs when a woman has never been pregnant before. Secondary infertility occurs when a women has difficulty conceiving after she has been pregnant at least once.

To determine the women’s status for ovarian cancer after enrollment, the subjects were linked to the Danish Cancer Registry and the Danish Registry of Pathology. The group was followed for occurrence of ovarian cancer from the first infertility evaluation until the date they left the country, death, or June 30, 2006.

Invasive ovarian cancer was found in 193 women during the follow-up. This represents the largest number of infertility associated cases of ovarian cancer ever studied. The “cases” were compared to a random sample of women in the group. This comparison group is known as a “cohort”.

Results

Women were followed up for an average of 16 years. Fertility drugs were used by 49% of the women with ovarian cancer and 50% of the comparison group. Clomid was the most commonly used drug, taken by 37% of the cases and 33% of the comparison group. The next most common drugs taken in order were human chorionic gonadotropins (31% and 33%), gonadotropins (such as Pergonal) (17% and 15%), and gonadotropin releasing hormone agonists (such as Lupron) (10% and 9%).

The age of the women at birth of first and last child didn’t significantly affect the overall risk of ovarian cancer. In contrast, women with pregnancies did have a lower risk for ovarian cancer than women without pregnancies. The risk for ovarian cancer was not affected by the specific cause of infertility. In other words, women whose infertility was due to their partner’s sperm problems and the same risk of developing ovarian cancer as women with ovulation problems or endometriosis.

The overall risk for ovarian cancer was not significantly affected by the use of any fertility drug. This result also accounts for the number of treatments recieved and years since first use. None of the five most commonly used drugs in combination affected the risk either.

Discussion

Overall, there was no association found between the use of fertility medications and the risk of ovarian cancer. The risk did not differ according to the number of cycles of use, length of follow-up, or whether a woman had previously given birth. In addition, none of the risk estimates changed after adjustments for causes of infertility and any use of oral contraceptives.

This study addressed some of the deficiencies in previous studies. The followed women for a longer period of time, they accounted for the number of treatments received and there were enough cases of cancer to make valid comparisons.

Conclusions

The risk of ovarian cancer is related to the presence of infertility but is not influenced by the use of fertility drugs either alone or in combination. This should provide some reassurance to those women who have used these drugs for treatment.