Following their investigation of potential associations between female infertility and several types of gynecological cancer—ovarian, endometrial, cervical, and breast—study authors have found a small potential link between infertility and breast cancer, but not infertility and gynecological cancer.

Using genome-wide association study findings, particularly single nucleotide polymorphisms (SNPs), and Mendelian randomization, they worked at exploring the bidirectional causal relationship between female infertility (the exposure variable) and gynecological cancer (the outcome variable). They published their findings in a recent issue of BMC Women’s Health.¹

“By applying [Mendelian randomization], we sought to provide clarity amidst the existing uncertainties,” the authors wrote, “and contribute to the understanding of these complex relationships in women’s health research.”

They also used the false discovery rate (FDR) to adjust P values for multiple comparisons. With many genome-wide studies conducting thousand of simultaneous comparisons, the FDR method works at keeping the false-positive rate low while trying to identify maximum significant comparisons.²

Overall Findings

The investigators incorporated the inverse variance method and their primary analysis approach and 5 supplemental analysis approaches: weighted mode, MR-Egger model, weighted median model, simple mode, and robust adjusted profile score (RAPS). They identified between 18 and 20 SNPs for the forward Mendelian randomization analysis and 12 to 15 SNPs for the reverse Mendelian randomization analysis.

Forward Mendelian randomization. The authors did not find causal relationships between female infertility overall and gynecological cancer:

• Breast cancer: OR, 0.95 (95% CI, 0.83-1.09; P = .47; P-FDR = .775)
• Ovarian cancer: OR, 1.01 (95% CI, 0.84-1.24; P = .789; P-FDR = .896)
• Cervical cancer: OR, 0.80 (95% CI, 0.61-1.06; P = .118; P-FDR = .775)
• Endometrial cancer: OR, 1.07 (95% CI, 0.88-1.30; P = .490; P-FDR = .775)

Study authors looked for a potential relationship between female infertility and gynecological cancer, using single nucleotide polymorphism data from genome-wide association studies and testing the strength and credibility of their data with 5 Mendelian randomization methods. | Image Credit: © dizain-stock.adobe.com

These results were seen using weighted mode, the MR-Egger model, the weighted median model, and simple mode. Using the RAPS method, however, there was a marginal causal link seen between female infertility and cervical cancer (OR, 0.79; 95% CI, 0.71-0.89; P = .049); evidence was insufficient for a definitive link.

Cochran’s Q test did not produce significant heterogeneity between female infertility and breast, ovarian, and endometrial cancers (P > .05), but it did see heterogeneity between female infertility and cervical cancer (P > .05).

Reverse Mendelian randomization. The authors did not find causal relationships between female infertility overall and 3 of the 4 gynecological cancers:

• Ovarian cancer: OR, 1.043 (95% CI, 0.999-1.087; P = .051; P-FDR = .331)
• Cervical cancer: OR, 0.992 (95% CI, 0.956-1.028; P = 0.654; P-FDR = .836)
• Endometrial cancer: OR, 1.006 (95% CI, 0.956-1.055; P = 0.809; P-FDR = .885)

A potential marginal association was seen, however, between female infertility and breast cancer (OR, 1.054; 95% CI, 1.001-1.108; P = .043; P-FDR = .331)—after the inverse variance method determined a positive causal relationship between the 2 but adjusting for multiple testing using the FDR method did not find a significant causal relationship.

Findings for this reverse analysis were seen through use of the weighted model, MR-Egger model, weighted median model, and simple mode. Also, findings under the RAPS method supported the potential marginal association between female infertility and breast cancer (P = .044) and helped to strengthen the reliability of the inverse variance weighted method.

What Do These Findings Mean?

Results are inconsistent among the many global studies that are investigating connections between female infertility and gynecological cancer, the study authors emphasized, and their conflicting results mean there is a lack of clear evidence that could help guide decisions focused on care for these patients. The authors of the present study used bidirectional Mendelian randomization to work at overcoming these issues.

At the same time, they proffered several reasons for the potential marginal causal relationship they witnessed between breast cancer and female infertility:

• Elevated estrogen and progesterone levels may negatively affect ovarian function^3,4
• Chronic inflammation may have an adverse impact on reproductive organs^5,6
• Cancer treatments are known to impair reproductive health⁷

They also explained that their findings align with those of previous Mendelian randomization studies that, too, did not find a causal relationship between female infertility and other cancers. Core strengths of their study were the large sample size of 14,759 cases and 11,583 controls and their comprehensive evaluation by using many Mendelian randomization approaches.

“Further research, including basic experiments and randomized controlled trials, is essential to establish a more definitive understanding of this relationship,” they concluded. “Importantly, our findings highlight the need for protective interventions to preserve fertility in young women diagnosed with breast cancer.”

References

1. Li J, Zeng Y, Zhnag D, et al. Association between gynecological cancers and female infertility: insights from bidirectional Mendelian randomization analysis. BMC Womens Health. 2025;25(1):191. doi:10.1186/s12905-025-03729-9

2. False discovery rate. Columbia Mailman School of Public Health. Accessed April 24, 2025. https://www.publichealth.columbia.edu/research/population-health-methods/false-discovery-rate

3. Wan S, Sun Y, Zong J, et al. METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling. Cell Death Dis. 2023;14(6):349. doi:10.1038/s41419-023-05866-1

4. Yang S, Wang H, Li D, Li M. An estrogen-NK cells regulatory axis in endometriosis, related infertility, and miscarriage. Int J Mol Sci. 2024;25(6):3362. doi:10.3390/ijms25063362

5. Villarreal-García V, Estupiñan-Jiménez JR, Vivas-Mejía PE, et al. A vicious circle in breast cancer: the interplay between inflammation, reactive oxygen species, and microRNAs. Front Oncol. 2022;12:980694. doi:10.3389/fonc.2022.980694

6. Fabozzi G, Verdone G, Allori M, et al. Personalized nutrition in the management of female infertility: new insights on chronic low-grade inflammation. Nutrients. 2022;14(9):1918. doi:10.3390/nu140919181

7. Gentile G, Scagnoli S, Arecco L, et al. Assessing risks and knowledge gaps on the impact of systemic therapies in early breast cancer on female fertility: a systematic review of the literature. Cancer Treat Rev. 2024;128:102769. doi:10.1016/j.ctrv.2024.102769