Introduction

The incidence of oesophago-gastric cancer has an age-dependent male predominance mirroring physiological changes in sex hormonal levels. Some previous studies suggest that menopausal hormone therapy (MHT) counteracts the occurrence of these tumours, but larger studies with longer follow-up and adjustment for confounders are needed, which prompted the present study.

Aims & Methods

To investigate the hypothesis that MHT decreases the risk of developing oesophago-gastric cancer, especially oesophageal adenocarcinoma.
This population-based case-control study included women aged ≥45 years in all five Nordic countries (Denmark, Finland, Iceland, Norway, Sweden) between 1995-2020. Prospectively collected data came from national complete registries for medications, cancer, diagnoses, total populations, and death. The study included 19,518 case patients with oesophago-gastric cancer and 195,094 randomly identified control participants matched for age, country and calendar year. The participants were categorised into three equal-sized groups (tertiles) of defined daily doses (DDD) of MHT, with non-users as the reference group. MHT was also categorized as systemic or local, and oestrogen only or oestrogen combined with progesterone MHT. Oesophago-gastric cancer was divided into oesophageal or cardia adenocarcinoma, oesophageal squamous cell carcinoma, and gastric non-cardia adenocarcinoma as separate outcomes. Conditional logistic regression provided odds ratios (OR) with 95% confidence intervals (CI), adjusted for age, calendar year, country, obesity, gastroesophageal reflux disease, smoking, alcohol, Helicobacter pylori eradication, use of statins and non-steroidal anti-inflammatory drugs.

Results

​Compared to non-users of MHT, the adjusted ORs of oesophageal or cardia adenocarcinoma were 0.74 (95% CI 0.67-0.81) for low MHT-use (<158 DDDs), 0.68 (95% CI 0.61-0.75) for intermediate MHT-use (158-848 DDDs), and 0.68 (95% CI 0.61-0.75) for high MHT-use (>848 DDDs). The corresponding ORs were 0.69 (95% CI 0.62-0.77), 0.70 (95% CI 0.62-0.77), and 0.71 (95% CI 0.64-0.79) for oesophageal squamous cell carcinoma, and 0.90 (95% CI 0.84-0.96), 0.85 (95% CI 0.79-0.91), and 0.80 (95% CI 0.74-0.86) for gastric non-cardia adenocarcinoma.

Table. Odds ratios (OR) and 95% confidence intervals (CI) of oesophago-gastric cancer by tertiles of defined daily doses (DDD) of menopausal hormone therapy (MHT), MHT hormonal constitution and administration of MHT.

Conclusion

This study provides support for the hypothesis of an inverse association between MHT and risk of developing oesophago-gastric cancer, and particularly for oesophageal adenocarcinoma where the association was seemingly dose-dependent and stronger for combined oestrogen and progesterone MHT and for systemic MHT. A limitation to the study was the inability to adjust for socioeconomic factors as confounders.