Oral Contraceptives and Endometrial Cancer: Examining a Potential Dose-Response Protective Effect

As the incidence of endometrial cancer (EMC) continues to rise globally—particularly in high-income countries—researchers are continuing the urgent search for modifiable risk factors. Hormonal influences on the endometrium have long been suspected to play a role in cancer pathogenesis, and a growing body of evidence has pointed to oral contraceptives (OCs) as a potential protective agent.

A 2025 systematic review and meta-analysis published in Acta Obstetricia et Gynecologica Scandinavica provides a timely and expansive update on the relationship between OC use and endometrial cancer risk.

A Robust Inverse Association
The analysis pooled data from 56 studies, including over 9,000 diagnosed cases of endometrial cancer. The overarching finding is consistent with previous literature: use of oral contraceptives is associated with significantly reduced odds of developing EMC. This effect appears to be both time-dependent and more pronounced among users of combined oral contraceptives (COCs).

• Any OC use correlated with a 39% reduction in EMC odds (OR = 0.61; 95% CI: 0.46–0.80)
• COC use correlated with a 54% reduction (OR = 0.46; 95% CI: 0.37–0.59)
• A clear dose-response trend emerged based on duration:
• <5 years: OR = 0.66
• ≥5 years: OR = 0.39
• ≥10 years: OR = 0.31

These findings reinforce a dose-response relationship in which longer duration of use confers greater protection.

Limitations of the Evidence Base
Despite its robust sample size and consistent findings, this meta-analysis is constrained by the quality of the included studies. Most were case–control in design, with frequent underreporting of key participant variables such as age and BMI, and few studies distinguished between ever/never OC users or specific OC types. In addition, studies didn’t consistently differentiate between Type I and Type II endometrial cancer, despite their distinct clinical profiles.

Mechanistic Considerations and Clinical Relevance
The biological rationale for this association is grounded in hormone modulation. COCs suppress cyclical exposure to endogenous estrogens and progestogens, which influence endometrial proliferation.

This hormonal downregulation likely reduces opportunities for DNA damage and clonal expansion within the endometrial lining, providing a plausible mechanism for long-term cancer risk reduction.

These findings are particularly relevant in patient populations with elevated EMC risk, such as those with obesity, polycystic ovary syndrome, or a history of anovulation.

While contraception should not be prescribed solely for cancer prevention, these data may support a more nuanced risk-benefit discussion, especially in long-term users or those considering discontinuation.

Reference

1. Harajka A, Hercsik T, das Virgens IPA, et al. Association of oral contraceptives and risk of endometrial cancer: A systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2025;104(4):591-603. doi:10.1111/aogs.15043