AIM AND INTRODUCTION: Diabetes and prediabetes pose significant global public health challenges. Sex steroids, particularly testosterone and estradiol, play crucial roles in various metabolic processes. This study investigates the relationship between sex hormone levels and long-term mortality in adults with prediabetes and diabetes, as well as those without glucose intolerance. MATERIAL AND METHODS: This retrospective cohort study utilized data from the NHANES 2013-2016, including adults aged 50-79 across prediabetic, diabetic, and non-diabetic groups. Serum testosterone, estradiol, and their ratios (T/E) were analyzed. The primary outcomes were all-cause mortality and CVD mortality tracked until December 2019. Cox regression models estimated the associations between hormone levels and mortality risks. RESULTS: The study included 3,665 participants (male: 2,140
female: 1,775). In males with prediabetes, higher estradiol (adjusted hazard ratio [aHR] = 0.17, 95% confidence interval [CI]: 0.07-0.43) or testosterone (aHR = 0.39, 95% CI: 0.31-0.50) was significantly associated with lower risk of all-cause mortality. Higher estradiol (aHR = 0.12, 95% CI: 0.04-0.32) or testosterone (aHR = 0.36, 95% CI: 0.27-0.48) was significantly associated with lower CVD mortality risk. In females with diabetes, there was a significant association between higher estradiol levels (aHR = 0.22, 95% CI: 0.06-0.83) or T/E ratio (aHR = 0.18, 95% CI: 0.04-0.73) with a reduced all-cause mortality risk. CONCLUSIONS: This study identifies some novel associations between estradiol, testosterone, and their ratios with long-term mortality in men and women across different glycemic statuses. These findings suggest a potential protective role of sex hormones in individuals with altered glucose metabolism, with gender difference, warranting further investigation.