Highlight
Recent large-scale evidence from five Nordic countries reveals that menopausal hormone therapy (MHT) use is associated with up to a 30% lower risk of developing esophageal and gastric cancers compared to nonusers. The risk reduction is strongest with combined estrogen-progestin therapies and systemic hormone formulations. These findings support estrogen’s protective role in upper gastrointestinal (GI) carcinogenesis.
Study Background
Upper gastrointestinal cancers, including esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), and gastric adenocarcinoma (GAC), continue to represent significant global health burdens due to poor prognosis and increasing incidence rates, particularly for EAC. A notable male predominance in these cancers has prompted investigation into sex hormone influence on tumorigenesis. Estrogen levels fall sharply after menopause, potentially increasing cancer risk in aging women. Previous studies on menopausal hormone therapy and GI cancer risk have yielded inconsistent and limited data.
Study Design
This comprehensive case-control study utilized the Nordic Gastroesophageal Tumor Study (NordGETS) database, integrating national prescription, cancer, and population registries from Denmark, Finland, Iceland, Norway, and Sweden over 1994-2020. The study included 19,518 women aged 45 or older diagnosed with EAC, ESCC, or GAC and 195,094 matched controls (1:10 ratio) by age, calendar year, and country.
MHT exposure was categorized by defined daily doses (DDD) into low (848 DDDs) groups and stratified into systemic or local (vaginal) and by hormone type: estrogen-only versus combined estrogen-progesterone therapy. The primary outcomes were adjusted odds ratios (aORs) for the three cancer types, controlling for confounders including age, obesity, smoking, alcohol use, gastroesophageal reflux disease, Helicobacter pylori eradication, and use of statins or NSAIDs. Socioeconomic factors were not adjusted.
Key Findings
Women using any form of MHT demonstrated statistically significant reductions in risk across all upper GI cancers studied:
- Esophageal Adenocarcinoma (EAC): aORs were 0.74 (low-dose), 0.68 (intermediate-dose), and 0.68 (high-dose), indicating about a 26–32% risk reduction. Dose-dependent protective effects were observed.
- Esophageal Squamous Cell Carcinoma (ESCC): similar inverse associations with aORs approximately 0.69–0.71 across doses.
- Gastric Adenocarcinoma (GAC): risk progressively decreased with higher MHT doses, from 0.90 (low) to 0.80 (high dose), showing a protective effect though less pronounced than for esophageal cancers.
Stratification by hormone formulation revealed combined estrogen-progestin and systemic MHT showed the strongest protective effects. For EAC, systemic MHT users had an aOR of 0.67, whereas local vaginal therapies had a slightly attenuated effect (aOR 0.72). Similarly, combined estrogen-progesterone therapy provided more substantial risk reductions than estrogen-only regimens across EAC, ESCC, and GAC.
The results suggest estrogenic signaling pathways modulate tumor development in the upper GI tract, potentially via effects on epithelial integrity and nitric oxide-mediated smooth muscle regulation.
Expert Commentary
These results provide one of the largest and most rigorous supports to date for the inverse relationship between menopausal hormone therapy and upper GI cancer risk. Dr. Victoria Wocalewski from Karolinska Institutet emphasized that the study’s robustness lies in its extensive sample size, adjustment for important confounders, and detailed analysis of hormone formulations and doses.
Biologically, estrogen may protect by enhancing epithelial tight junctions, reducing chronic mucosal inflammation, and modulating nitric oxide synthesis affecting smooth muscle function and mucosal blood flow. Such mechanisms align with epidemiologic observations of lower upper GI cancer incidence in premenopausal women and after hormone therapy use.
Limitations include lack of socioeconomic status adjustment, potential residual confounding, and inability to establish causality inherent to observational designs. Future prospective and mechanistic studies are needed to confirm these findings and guide personalized prevention strategies incorporating hormonal status.
Conclusion
This large population-based Nordic study robustly demonstrates that menopausal hormone therapy is associated with a significant reduction in the risk of esophageal and gastric cancers. The effect is particularly strong with combined estrogen-progesterone systemic formulations, underscoring the potential protective role of estrogenic signaling in upper GI carcinogenesis. These insights advance our understanding of sex hormone influence on GI cancer biology and may inform tailored prevention strategies for postmenopausal women at risk of these malignancies.
Clinicians should consider these findings within the broader context of MHT’s risk-benefit profile, and researchers are encouraged to further investigate underlying biological mechanisms and translate these epidemiological associations into clinical practice.
References
- Wocalewski V. Menopausal hormone therapy and esophago-gastric cancer risk: A Nordic population-based study. United European Gastroenterology (UEG) Week 2025.
- Camargo MC, et al. Sex Hormones and Esophageal Adenocarcinoma: A Systematic Review. Cancer Epidemiol Biomarkers Prev. 2012.
- Reynolds P, et al. Hormone Replacement Therapy and Risk of Esophageal and Gastric Cancer. Am J Epidemiol. 2007.
- James PD, et al. The Role of Estrogen in Gastrointestinal Tumorigenesis: Insights From Clinical and Experimental Studies. Front Endocrinol (Lausanne). 2021.
