More than a fertility struggle? Infertility’s tie to ovarian cancer risk

Ovarian cancer is a condition that starts in the reproductive glands responsible for producing eggs and hormones in people assigned female at birth. In its early stages, it often develops without noticeable symptoms, making detection difficult until the disease has already spread. Although anyone with ovaries can develop ovarian cancer, certain factors—such as age, family history, genetic mutations, and hormone therapy—can increase the risk. Reproductive health also plays a significant role, but one aspect that remains less understood is how infertility itself might influence ovarian cancer risk. While conditions like endometriosis and hormonal imbalances are known to contribute to both infertility and cancer risk, researchers are still working to determine whether infertility is an independent risk factor or simply a marker of underlying reproductive health issues.

Adding another layer of complexity, some studies suggest that fertility treatments involving ovulation-stimulating drugs could slightly increase the risk of ovarian cancer. However, the challenge in studying this relationship comes from the tendency to group infertility together with Assisted Reproductive Technologies (ART)—a set of medical procedures designed to help individuals conceive by manipulating eggs, sperm, or embryos outside the body. The most well-known form of ART is In Vitro Fertilization (IVF), in which eggs are retrieved from the ovaries, fertilized with sperm in a laboratory, and then transferred into the uterus. Because previous studies have often combined infertility and ART exposure, it has been difficult to determine whether ovarian cancer risk is linked to infertility itself, the underlying causes of infertility, or the medical interventions used to treat it.

A recent study published in Cancer Causes & Control aimed to answer this question by analyzing data from the Women’s Health Initiative (WHI) cohort study. Unlike previous studies, which often included women who had undergone ART procedures such as IVF, this study looked only at an ART-naïve population which enables researchers to isolate the effect of infertility itself. The WHI study, following almost 113,000 postmenopausal women for more than 25 years, is one of the largest and longest studies to examine infertility and ovarian cancer risk while avoiding the confounding effects of ART. At enrollment, participants were asked whether they had ever tried to become pregnant for more than a year without success. Those who answered “yes” were classified as having a history of infertility, while those who had conceived without difficulty served as the comparison group. The study then tracked ovarian cancer diagnoses over time, using medical record verification to ensure accuracy.

According to Dr. Holly Harris, an epidemiologist at the Fred Hutchinson Cancer Center and a lead author on the study, one of the major strengths of the study lay in separating infertility from ART effects. "Much of the prior work on infertility and cancer risk has focused on the use of ART, mainly IVF. This has made it hard to disentangle whether treatments for infertility or infertility itself impacts cancer risk. Using the WHI allowed us [to] examine infertility without the impacts of ART as the age of the WHI population meant that the majority of our study population had not been exposed to IVF."

Building on what we know about reproductive health and cancer risk, the study found no significant overall association between infertility and ovarian cancer risk. However, when researchers examined specific ovarian cancer subtypes, a more nuanced picture emerged. Women with a history of infertility had a 90% higher risk of developing endometrioid and clear cell ovarian cancers—two histotypes previously linked to endometriosis. Interestingly, the reported cause of infertility did not appear to influence this association, suggesting that infertility itself, rather than any single underlying condition, may be a relevant factor. In contrast, infertility was not linked to an increased risk of high-grade serous or mucinous ovarian cancers, which are the more common forms of the disease. One possible explanation for this association is undiagnosed or subclinical endometriosis, a condition known to increase the risk of these specific ovarian cancer subtypes. However, because the study did not have sufficient data to analyze infertility causes separately, this remains an open question.

Understanding the biological mechanisms behind the link between infertility and specific ovarian cancer subtypes is crucial for improving risk assessment and prevention strategies. Future research should focus on identifying which biological pathways drive the increased risk of endometrioid and clear cell ovarian cancers in women with infertility, particularly whether undiagnosed endometriosis plays a central role. As Dr. Harris noted, “This [finding] highlights the need for further understanding the underlying etiology and natural history of endometriosis so we can identify which people with endometriosis are at highest risk for ovarian cancer.” Large-scale studies incorporating genetic, hormonal, and inflammatory biomarkers may provide the key to distinguishing which women are most vulnerable and how best to intervene before cancer develops.

This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through the WHI program. Additional funding was provided by NICHD R03 HD102403 (Farland).

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Holly Harris contributed to this work.

Harris, H. R., Lind, K., Fest, S., Thomson, C. A., Saquib, N., Shadyab, A. H., Schnatz, P. F., Robles-Morales, R., Qi, L., Strickler, H. D., Roe, D. J., & Farland, L. V. 2025. Infertility and Risk of Ovarian Cancer in the Women's Health Initiative. Cancer causes & control: CCC, 10.1007/s10552-025-01962-z. Advance online publication.