Oral contraceptive and menopausal hormone therapy use and risk of pancreatic cancer: a systematic review, meta-analysis, and dose–response analysis

Pancreatic cancer has a poor prognosis, and hormonal factors have been proposed as potential modifiers of risk. However, the association between exogenous female hormone use and pancreatic cancer remains uncertain. We conducted a comprehensive systematic review and meta-analysis to evaluate the relationship between menopausal hormone therapy (MHT), estrogen therapy (ET), estrogen–progestin therapy (EPT), and oral contraceptive pills (OCPs) use and pancreatic cancer risk. We systematically searched PubMed, Scopus, and Embase for observational studies up to July 2026. Random-effects meta-analyses of adjusted and crude effect estimates were performed to estimate pooled relative risks (RRs) for adjusted analyses and ORs for crude analyses. Linear and non-linear dose–response meta-analyses were performed. Heterogeneity was assessed using the I 2 statistic, and publication bias was evaluated using Egger’s and Begg’s tests. Study quality was assessed using the Newcastle–Ottawa Scale, and certainty of evidence was evaluated using GRADE. Twenty-seven reports were included in the review. In the adjusted analyses, neither OCPs use (20 studies; RR = 0.99, 95% CI: 0.86–1.14; 95% prediction interval (PI): 0.62–1.59; I 2 = 61.4%; very-low-certainty evidence) nor MHT use (18 studies; RR = 0.92, 95% CI: 0.79–1.06; 95% PI: 0.54–1.56; I 2 = 75.9%; very-low-certainty evidence) was significantly associated with pancreatic cancer risk. ET use was also not significantly associated with risk (6 studies; RR = 0.82, 95% CI: 0.63–1.07; 95% PI: 0.54–1.26; I 2 = 41.9%; very-low-certainty evidence). In contrast, EPT use was associated with a modest inverse association (5 studies; RR = 0.85, 95% CI: 0.78–0.93; 95% PI: 0.77–0.94; I 2 = 0%; low-certainty evidence). In secondary crude analyses, lower odds of pancreatic cancer were observed for OCP use (OR = 0.70, 95% CI: 0.61–0.81; 95% PI: 0.42–1.17) and EPT use (OR = 0.55, 95% CI: 0.34–0.91; 95% PI: 0.16–1.97); however, both analyses showed substantial heterogeneity. Dose–response analyses showed no significant association per 5-year increase in OCP use (RR = 1.07, 95% CI: 0.98–1.17; p = 0.158) or MHT use (RR = 0.84, 95% CI: 0.67–1.05; p = 0.128), and no significant non-linear associations were identified. Adjusted evidence did not show a consistent association between OCP, MHT, or ET use and pancreatic cancer risk. Although EPT use was associated with a modest inverse association, this finding was based on low-certainty observational evidence. Wide prediction intervals for OCP and MHT indicate that associations may vary across populations and settings. Further large prospective studies are warranted to clarify long-term hormonal effects on pancreatic carcinogenesis.