By: Kelsey Hillyer, DO
Editor’s Note: Infertility is often approached as a disease to treat rather than as the symptom of a hidden problem to evaluate fully, diagnose, and then treat accordingly. Although the study summarized below was published two decades ago, its relevance is still significant, particularly with the rising rates of infertility seen globally in the last decade. The study findings highlight the importance of a thorough evaluation for every patient with infertility, not only to assist them to achieve their family planning goals, but also to prevent future complications – for some, possibly even cancer. Dr. Kelsey Hillyer summarized the article by Brinton et al [1] while on the FACTS elective in fertility awareness for medical students and residents.
Introduction
The relationship between infertility and subsequent cancer risk has drawn attention for years. This is largely due to the hormonal and physiologic factors shared between reproductive and oncologic health. Although previous studies have demonstrated increased risks for breast, ovarian, and uterine cancers among women with infertility, the role of specific causes of infertility in these associations remains unclear. The large, retrospective cohort study by Brinton et al [1] summarized below investigated whether different causes of infertility could predict future cancer risk.
“Although previous studies have demonstrated increased risks for breast, ovarian, and uterine cancers among women with infertility, the role of specific causes of infertility in these associations remains unclear.”
Methodology
The study enrolled 12,193 women who sought infertility treatment at five major U.S. reproductive endocrinology practices between 1965 and 1988. Through record linkage with cancer registries, national databases, and direct patient contact, the researchers tracked cancer incidence through 1999. Women were classified by the type of infertility, primary or secondary, and by specific causes of infertility.
Analyses included standardized incidence ratios (SIR) by comparing the number of observed cancer cases in the infertility cohort to expected rates based on age, race, and calendar year using the Surveillance Epidemiology and End Results (SEER) data. They also conducted internal analyses using Poisson regression to estimate rate ratios (RR) for cancer associated with specific types and causes of infertility.
Results
Comparisons with the general population
Across the cohort, 581 cancers were identified, exceeding the 475.5 expected based on population norms (SIR=1.23). The risk was elevated among women with primary infertility (SIR=1.43) compared to secondary infertility (1.27). Increased risks were found for ovarian cancer (SIR=1.98), uterine cancer (SIR=1.57), breast cancer (SIR=1.29), colon cancer (SIR=1.76), and melanoma (SIR=1.57).
Comparisons among women with infertility
Based on a standardized algorithm, women were categorized into six causes of infertility: endometriosis, anovulation, tubal disease/pelvic adhesions, male factor, cervical disorders, and uterine disorders.
Primary infertility showed increased risk for uterine (RR=1.54) and ovarian (RR=1.99) cancers. Specific causes of infertility were tied to distinct cancer risks:
- Endometriosis was linked with elevated risks of colon cancer (RR=2.00), ovarian cancer (1.25), thyroid cancer (3.09), and melanoma (2.06).
- Anovulation was associated with higher uterine cancer risk (1.13) and a possible increase in melanoma (1.53).
- Tubal disease showed associations with uterine cancer (1.39).
- Male factor infertility correlated with increased risks for colon (1.95) and uterine (2.31) cancers.
When the analysis focused on women with primary infertility and a specific cause, the associations became more pronounced. Endometriosis in primary infertility was associated with substantially higher risks for colon cancer (RR=2.40), ovarian cancer (2.88), thyroid cancer (4.65), and melanoma (2.32). Primary anovulatory infertility was strongly linked to uterine cancer (RR= 2.42). Primary tubal infertility increased the risk for ovarian cancer (RR=1.61). Primary infertility due to male factor was related to the highest observed risks for colon (RR=2.85) and uterine (RR=3.15) cancers.
“Endometriosis in primary infertility was associated with substantially higher risks for colon cancer (RR=2.40), ovarian cancer (2.88), thyroid cancer (4.65), and melanoma (2.32).”
Discussion
This study found that women with infertility have a 23% higher overall risk of cancer compared to the general population. The risk was especially elevated for uterine and ovarian cancers, particularly among women with primary infertility. These results are consistent with findings from other large cohort studies.
A key strength of this research was its classification of causes of infertility. Unlike past studies, women could be diagnosed with more than one cause. Only those fully evaluated were labeled as having unexplained infertility. This allowed for clearer comparisons to both the general population and within the group of patients with infertility. Another strength is that this was a large, multi-center cohort study with long-term follow-up (18.8 years), providing a large dataset for analysis.
The two causes that stood out were endometriosis and anovulation. Women with endometriosis had a higher risk of ovarian cancer, especially if they had primary infertility. They also had elevated risks of colon cancer, thyroid cancer, and melanoma. The melanoma link was unexpected, but not entirely new. Prior studies have shown similar patterns, especially in women with red hair or fair skin. However, one limitation of this study was that a large proportion of melanoma cases lacked medical verification.
Anovulatory infertility was linked to a higher risk of uterine cancer, likely due to the unopposed estrogen exposure. This supports earlier research, though only 5% of women in this study met the criteria for PCOS. Unlike some earlier reports, this study did not find a strong link between anovulation and breast cancer.
“Anovulatory infertility was linked to a higher risk of uterine cancer, likely due to the unopposed estrogen exposure.”
Women with tubal disorders do not show the protective effect against ovarian cancer seen in tubal ligation studies. Those with primary infertility and tubal disease had increased ovarian cancer risk. This supports the theory that inflammation may play a role in ovarian cancer development.
The study also looked at non-gynecologic cancers. Women with infertility, especially when associated with endometriosis, have higher rates of colon and thyroid cancers. The colon cancer risk may be documented due to closer medical surveillance. Thyroid cancer risk was not elevated overall but was more common in women with both primary infertility and endometriosis. This supports past research linking endometriosis to autoimmune and endocrine disorders. The association of infertility and non-gynecologic cancers is an area that warrants future research.
An unexpected finding was the cancer risk in women whose infertility was due to male factor issues. These women, particularly those with primary infertility, had higher rates of colon and uterine cancers. The cause for this is unclear and highlights an important area for further research.
In summary, this study shows that the root cause of infertility matters. Women with primary infertility are at the highest risk of cancer, especially when linked to endometriosis, anovulation, or tubal disorders. These results suggest infertility should be seen not just as a reproductive issue but also as a potential marker of long-term health risks. This raises the question: Should infertility history be integrated into long-term health risk assessments?
“This study shows that the root cause of infertility matters. Women with primary infertility are at the highest risk of cancer, especially when linked to endometriosis, anovulation, or tubal disorders.”
Fertility awareness plays a vital role in women’s health by encouraging a deeper understanding of the body’s natural cycles and highlighting potential signs of underlying health issues. Identifying the root cause of infertility is not only essential to those seeking to conceive, but it also opens the door to proper treatment, long-term health monitoring, and preventive care. When women are in tune with their bodies, they are better equipped to advocate for themselves. Ultimately, fertility awareness empowers women to take proactive steps in managing their health.
References
[1] Brinton, Louise A., et al. “Causes of Infertility as Predictors of Subsequent Cancer Risk.” Epidemiology , vol. 16, no. 4, July 2005, pp. 500–507, https://doi.org/10.1097/01.ede.0000164812.02181.d5
ABOUT THE AUTHOR
Dr. Kelsey Hillyer
Dr. Kelsey Hillyer is a pediatric resident and graduate of Kansas City University College of Osteopathic Medicine in Joplin, Missouri. She completed her undergraduate education at the University of Kansas in Lawrence, Kansas. She is pursuing residency in pediatrics at the University of Nebraska Medical Center. Dr. Hillyer enrolled in the FACTS elective as a fourth-year medical student to gain a better understanding of women’s health and to be a better advocate for her patients.
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