Abstract
Sex and gender disparities have emerged as critical determinants of COVID-19 outcomes, with males exhibiting higher hospitalization and mortality rates than females. Sex steroids such as estradiol, progesterone, and testosterone have been proposed as modulators of these differences, given their known roles in inflammation, immune function, and vascular health. However, the precise hormonal mechanisms underlying COVID-19 severity, particularly among individuals with comorbid hypertension-a major risk factor for adverse outcomes-remain unclear. In this study, we investigated circulating levels of key sex hormones and their neuroactive metabolites in 116 hypertensive COVID-19 patients enrolled through an urban academic emergency department. Our findings revealed distinct sex-based hormonal profiles and associations with disease severity. Males exhibited higher serum estradiol and testosterone levels, while progesterone levels were significantly higher in postmenopausal females. Notably, hospitalized patients showed elevated estradiol and progesterone levels compared to non-hospitalized individuals, whereas ICU-admitted patients had significantly lower concentrations of all three hormones. A unique exception was ICU-admitted postmenopausal females, who exhibited increased serum testosterone levels relative to non-ICU females. Additionally, in males, elevated 3α-diol was associated with hospitalization and ICU admission, while lower allopregnanolone and estradiol levels correlated with hypoxia in males and females, respectively. These results highlight a dynamic, sex-specific hormonal response to COVID-19 progression in hypertensive individuals, suggesting early upregulation and late depletion of protective sex steroids. Understanding these patterns may improve clinical risk stratification and inform the development of sex-targeted therapeutic interventions for COVID-19 and related inflammatory conditions.