Published 5 February 2009, doi:10.1136/bmj.a3075
Cite this as: BMJ 2009;338:a3075

Editorials

Fertility drugs and ovarian cancer

Current evidence shows no increased risk

During the past two decades, considerable debate has centred around whether the use of fertility drugs increases a woman’s risk of developing ovarian cancer. Most ovarian cancers are assumed to arise from the layer of epithelial cells surrounding the ovary, and it has been suggested that the repeated cycle of damage and repair that occurs with ovulation may lead to DNA damage and potentially cancer—the so called "incessant ovulation" hypothesis.¹ By stimulating hyperovulation, fertility drugs might therefore increase the risk of cancer. A second hypothesis posits that increasing exposure to gonadotrophins increases the risk of ovarian cancer,² and because gonadotrophins are used to treat infertility, such treatment might, theoretically, put patients at risk. In the linked study (doi:10.1136/bmj.b249), Jensen and colleagues use data from a large cohort study of infertile women to assess the effects of fertility drugs on the risk of ovarian cancer.³

Anxiety was initially fuelled by two studies suggesting that women who had taken fertility drugs had an increased risk of developing ovarian cancer.^{4 5} However, these studies included only 20 and 11 women with ovarian cancer who had used fertility drugs. Subsequent studies have generally reported no association,⁶ but concerns remain, particularly for women who undergo 12 or more cycles of treatment or who never succeed in becoming pregnant. For example, a Cochrane review on the use of clomifene citrate for unexplained subfertility mentions that use for more than 12 cycles has been associated with increased risk of ovarian cancer.⁷ Cochrane reviews are, rightly, highly respected and widely accessible to clinicians and patients, yet the body of the review suggests the statement about ovarian cancer risk is based solely on the results of the early studies.^{4 5} So should women seeking treatment for infertility be worried that fertility drugs might increase their risk of ovarian cancer?

More than 10 cohort studies and a similar number of case-control studies have attempted to answer this question. Most have been limited by small sample sizes—only three studies have included more than 25 women with ovarian cancer who have used fertility drugs.^{8 9 10} Furthermore, infertility itself is a risk factor for ovarian cancer,⁹ but many studies have been unable to separate the potential effects of the use of fertility drugs on the risk of ovarian cancer from the effects of the underlying infertility; others could not control for potentially important confounding factors such as parity and use of oral contraceptives.

Jensen and colleagues’ study included 54 362 women with infertility problems referred to Danish fertility clinics from 1963 to 1998.³ It found that use of four groups of fertility drugs (gonadotrophins, clomifenes, human chorionic gonadotrophin, and gonadotrophin releasing hormone) was not associated with an overall increase in the risk of ovarian cancer. They also found no suggestion that risk was increased in women who had undergone 10 or more cycles of treatment or in those who remained nulliparous. Although the authors did see a significantly increased risk of the most common serous subtype of ovarian cancer in women who had used clomifene, this was just one of 20 separate comparisons in their subgroup analyses and was probably a chance association.

This study is important because it included 156 women with ovarian cancer, more than three times as many as any previous cohort study, and it compared infertile women who had used fertility drugs with infertile women who had not used fertility drugs. Although information on parity and use of oral contraceptives was unavailable for many women, analyses in the subgroup of women with this information suggested that adjusting for these variables would have had little effect on the results. However, although the study was much larger than previous investigations, it still could not exclude the possibility of a small increase in the risk of ovarian cancer in users of fertility drugs—the rate ratio for use of any fertility drug was 1.03, but the upper bound of the 95% confidence interval was 1.47.³ Larger numbers of women will need to be studied to answer this question, and these will come with further follow-up of the cohort as they enter the age range where ovarian cancer is most common.

These data are reassuring and provide further evidence that fertility drugs do not increase a woman’s risk of ovarian cancer to any great extent, although small increases in risk cannot be ruled out. Given the increasing numbers of women seeking fertility treatment,¹¹ this is important information for clinicians and their patients, and in a world where women increasingly turn to the internet for health information, clinicians should take time to discuss this matter so that women are properly informed. Some women who take fertility drugs will inevitably develop ovarian cancer by chance alone, but current evidence suggests that women who use these drugs do not have an increased risk of developing ovarian cancer.

Cite this as: BMJ 2009;338:a3075

¹ Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, QLD 4029, Australia

Research, doi:10.1136/bmj.b249

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Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Fathalla MF. Incessant ovulation—a factor in ovarian neoplasia? Lancet 1971;2:163.[CrossRef][Web of Science][Medline]
2. Cramer DW, Welch WR. Determinants of ovarian cancer risk II: inferences regarding pathogenesis. J Natl Cancer Inst 1983;71:717-21.[Web of Science][Medline]
3. Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and subsequent risk for ovarian cancer: Danish population based cohort study. BMJ 2009;338:b249.[Abstract/Free Full Text]
4. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184-203.[Abstract/Free Full Text]
5. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771-6.[Abstract/Free Full Text]
6. Brinton LA, Moghissi KS, Scoccia B, Westhoff CL, Lamb EJ. Ovulation induction and cancer risk. Fertil Steril 2005;83:261-74.[CrossRef][Web of Science][Medline]
7. Hughes E, Brown J, Collins J, Vanderkerckhove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2000;(1):CD000057.
8. Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, et al. Ovarian cancer risk after the use of ovulation-stimulating drugs. Obstet Gynecol 2004;103:1194-203.[CrossRef][Web of Science][Medline]
9. Mosgaard BJ, Lidegaard O, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: a case-control study. Fertil Steril 1997;67:1005-12.[CrossRef][Web of Science][Medline]
10. Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;155:217-24.[Abstract/Free Full Text]
11. Human Fertilisation and Embryology Authority. Facts and figures 2006—fertility problems and treatment 2008., www.hfea.gov.uk/docs/2008-10-08_Facts_and_Figures_2006_-_fertility_problems_and_treatment.pdf.

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Relevant Article

Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study

Allan Jensen, Heidi Sharif, Kirsten Frederiksen, and Susanne Krüger Kjær
BMJ 2009 338: b249. [Abstract] [Full Text] [PDF]

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