Circulating Sex Hormone Levels and Survival in Men With Esophageal Squamous Cell Carcinoma

Men with esophageal squamous cell carcinoma (ESCC) have worse survival than women, a disparity in which sex hormones may play a role. Yet, whether circulating sex hormone levels are associated with survival in ESCC remains largely unexplored.

This prospective cohort study included 402 men with ESCC who underwent curative surgery in 2013-2020, with follow-up until May 1, 2023. Associations between preoperative levels of 11 sex hormone measures and all-cause mortality were assessed using multivariable Cox regression, reporting hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for age, calendar year of surgery, education, smoking, alcohol consumption, pathologic tumor stage, postoperative complications, and chemo(radio)therapy. Sex hormone measures were analyzed both as quartiles and continuously. Continuous analyses were conducted using z-scores of ln-transformed hormone levels, with HRs interpreted per one standard deviation (SD) increase.

In the overall cohort, no clear associations were observed after adjustment. In tumor stage-stratified analyses, higher free testosterone index was associated with lower mortality in stage 0-II disease (HR per 1-SD increase, 0.78; 95% CI, 0.62-0.97), whereas higher progesterone levels were associated with higher mortality in stage III-IV disease (HR per 1-SD increase, 1.21; 95% CI, 1.01-1.44), with evidence of effect modification by tumor stage for progesterone (p for interaction = 0.011).

Preoperative sex hormone measures showed possible stage-dependent associations with survival in men with ESCC, with higher free testosterone index associated with better survival in stage 0-II disease and higher progesterone levels associated with worse survival in stage III-IV disease.