Cervical Health Awareness Month
Ovulation Induction and Cancer Risk: A Research Review
By: Lindsay Terry Sawyer
Editor’s Note: January marks Cervical Health Awareness Month. This week, we are featuring a 2005 research review summarized by Lindsay Terry Sawyer, a medical student and former FACTS elective participant. The article by Brinton et al. explores the relationship between ovulation inducing medications and the risk for ovarian, breast, and endometrial cancers, as well as cervical, thyroid and colon cancers, melanoma and gestational trophoblastic tumors. A key finding is the lack of large clinical studies, highlighting the need for more research in the area of women’s health. FACTS members enjoy access to our research database, including a brief synopsis of more than 150 articles related to fertility awareness and restorative reproductive medicine.
Ovulation-inducing agents, such as clomiphene citrate and gonadotropins, are among one of the most rapidly growing groups of drugs in the United States.  These drugs raise both estrogen and progesterone levels, hormones notably linked to the growth and development of breast and gynecologic cancers, as well as other cancers. Therefore, it is crucial to explore the potential cancer risk associated with these medications. A 2005 study by Brinton et al., titled “Ovulation Induction and Cancer Risk,” is summarized below.  The authors set out to conduct a retrospective review of literature related to ovulation induction and cancer risk. The research focused on ovarian, breast, and endometrial cancers, but also included melanoma, cervical cancer, thyroid cancer, gestational trophoblastic tumors, and colon cancer.
‘Ovulation-inducing agents, such as clomiphene citrate and gonadotropins, raise both estrogen and progesterone levels — hormones notably linked to the growth and development of breast and gynecologic cancers, as well as other cancers.”
Brinton et al. conducted a PubMed search to identify relevant studies beginning in the 1960s, when fertility drugs were first available. Key words used in the search were: ovulation induction, fertility drugs, infertility, cancer, risk, epidemiology. Literature selected was limited to previously conducted cohort and case-control studies. Included studies were then reviewed with a focus on methodologies, results, and future implications.
Previous studies suggest a link between ovulation-inducing medications and cancer risk; however, these studies yielded conflicting results. Prior prospective studies were hampered by an inability to control for other cancer predictors, such as parity, while retrospective studies were limited by concerns of selective recall. Overall, the data remains conflicted, especially when considering each type of cancer individually.
In evaluating risk of ovarian cancer, a prior case-control study limited to a subgroup of nulligravid women reported a 27-fold increase in risk associated with ovulation-inducing medications.  A retrospective cohort study by Rossing et al. estimated that clomiphene, a common ovulation-inducing agent, was associated with a 2.3-fold increased risk.  This data was based only on nine ovarian cancers, however, and had an insignificant 95% confidence interval of 0.5 to 11.4. Rossing et al. went on to note that clomiphene use for less than 12 monthly cycles was not associated with this increased risk. The relative risk of those who participated in greater or equal to one year of clomiphene use was 11.1 with a 95% confidence interval of 1.5 to 82.3. Two more recent studies looked at exposures received during IVF treatment and neither found significant risks associated with fertility drug use and increased ovarian cancer. [4,5]
Breast cancer studies, cohort and case-control alike, also failed to identify significant associations between fertility drugs and increased cancer risk. The available data revealed contradictory findings. One case-control study found an increased risk associated with long-term use of menopausal gonadotropins, but not clomiphene.  Another retrospective cohort study found a decreased but non-significant risk of cancer associated with clomiphene use.  A third cohort study found an approximately two-fold increased risk within one year of last treatment, suggesting these drugs may promote the growth of pre-existing tumors. 
The risk for endometrial cancer was found to be significantly increased in patients with longer follow-up periods after use of ovulation-induction medications, based on two larger cohort studies. [8,9] This echoes previous research findings on Tamoxifen, a selective estrogen receptor modulator (SERM) with an established link to endometrial cancer. Given the structural similarity to clomiphene, also a SERM, the cohort studies raise concern regarding effects on the endometrium. However, a separate, multicenter U.S. cohort study found an insignificant increase in risk of endometrial cancer with clomiphene use — although risk increased among women with longer duration of use. 
“The risk for endometrial cancer was found to be significantly increased in patients with longer follow-up periods after use of ovulation-induction medications.”
Studies investigating the relationship of cervical cancer with parity and use of oral contraceptives have raised concerns regarding the effects of ovulation-inducing agents. A small Seattle study found clomiphene use to be associated with decreased risk of cervical cancer, having a relative risk of 0.4 and a 95% confidence interval of 0.2 to 0.8.  Duration of use had no apparent effect on risk in this study.
Based on a pool of 13 case-control studies in various countries, thyroid cancer was found to be associated with a 60% increased risk in patients exposed to ovulation-inducing medications. However, the 95% confidence interval for this data was insignificant at 0.9 to 2.9. 
Due to the increased risk of multiple pregnancies with ovulation-inducing drugs there is increased risk of gestational trophoblastic disease, and gestational trophoblastic tumors. 
Studies have not identified any notable conclusions regarding an association between melanoma or colon cancer and fertility drug use.
The research synthesized by Brinton et al. presents important information for women’s health and family planning. Should the results of future studies support findings that ovulation-inducing drugs are linked to increased cancer risk, family planning decisions may be altered. If these studies instead reveal no increased risk of cancer when using these medications, women and physicians can be more confident in their use. Considering ovulation-inducing drugs increase levels of estrogen and progesterone in the patient, it remains a logical hypothesis that these drugs may increase the risk of hormone-driven cancers. Further research is critical to investigate these nuanced relationships. It is also important to know that these medications are safe for patients and do not put them at unnecessary risk. If additional studies consistently show medications inducing ovulation significantly increase cancer risk, fertility awareness-based methods (FABMs) may become more widespread. Use of FABMs to chart a woman’s cycle can provide valuable information to aid in the diagnosis of underlying causes of infertility that may warrant more targeted treatment. Furthermore, women tracking their cycles with an FABM can more easily identify their fertile window and ovulation leading to improved pregnancy outcomes.
“If additional studies consistently show medications inducing ovulation significantly increase cancer risk, fertility awareness-based methods (FABMs) may become more widespread.”
The authors highlighted the need for further research and pointed out the lack of clinical trials. Current research lacks appropriate comparison groups, is based on small numbers, and is subject to short follow-up periods.  Further studies would benefit from a comparison of cancer rates between infertile women with or without treatment using ovulation-inducing drugs, in addition to adjusting for parity. In multiple studies, nulligravid women tended to have a higher cancer risk, but identification of the effects of ovulation-inducing drugs or the underlying cause of infertility as the causal factor remain unclear. Future studies should also investigate the use of ovulation-inducing drugs in women also exposed to other hormones, including oral contraceptives or menopausal hormone replacement therapy. Lastly, the authors noted that fertility medications were first introduced to market in the early 1960s. At the time of the study in 2005, women exposed to these medications were just reaching the age when hormone-related cancers are common.  Therefore, additional follow-up would be beneficial to evaluate the effects of these medications in more women.
 Brinton, Louise A., et al. “Ovulation Induction and Cancer Risk.” Fertility and Sterility, vol. 83, no. 2, 1 Feb. 2005, pp. 261–274.,https://doi.org/10.1016/j.fertnstert.2004.09.016.
 Whittemore AS, Harris R, Itnyre J, the Collaborative Ovarian Cancer Group. 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.
 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.
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 Klip H, Burger CW, van Leeuwen FE, the OMEGA Project Group. Risk of hormone-related cancers after ovarian stimulation for in-vitro fertilisation in a cohort of 25,152 women. In: Klip H, ed. Long-term health effects of subfertility treatment. Enschede, The Netherlands: PrintPartners Ipskamp BV, 2002:55– 82.
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 Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, et al. Cancer incidence in a cohort of infertile women. Am J Epidemiol 1998;147:1038–42.
 Althuis MD, Moghissi KS, Westhoff CL, Scoccia B, Lamb EJ, Lubin JH, et al. Clomiphene citrate for ovulation induction and endometrial cancer risk. Am J Epidemiol (in press).
 Rossing MA, Daling JR, Weiss BS, Moore DE, Self SG. In situ and invasive cervical carcinoma in a cohort of infertile women. Fertil Steril 1996;65:19 –22.
 La Vecchia C, Ron E, Franceschi S, Dal Maso L, Mark SD, Chatenoud L, et al. A pooled analysis of case-control studies of thyroid cancer. III, Oral contraceptives, menopausal replacement therapy and other female hormones. Cancer Causes Control 1999;10:157– 66.
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ABOUT THE AUTHOR
Lindsay Terry Sawyer
Lindsay Terry Sawyer is a fourth-year medical student at Oklahoma State University College of Osteopathic Medicine in Tulsa, Oklahoma. She completed her undergraduate education at Oklahoma State University in Stillwater, OK. She plans to do her residency in Obstetrics and Gynecology and is particularly interested in improving women’s health literacy.