The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury

Abstract

BACKGROUND Clinical research characterizing the mechanisms responsible for sex-based outcome differences after injury remains conflicting. Currently lacking is an understanding of the early sex hormone milieu of the injured patient and the effects these early hormone differences have on clinical outcomes and the innate immune response following injury. METHODS A prospective cohort study was performed over a 20-month period. Blunt injury patients requiring intensive care unit admission were enrolled. Samples were collected within 6 hours and at 24 hours after injury and were analyzed for total testosterone (TT) and estradiol concentrations. Outcomes of interest included multiple-organ failure (MOF; Marshall Multiple Organ Dysfunction Score [MODScore] > 5), nosocomial infection (NI), mortality, and serial cytokine/chemokine measurements. Multivariate logistic regression was used to determine the independent risks associated with early sex hormone measurements. RESULTS In 288 prospectively enrolled patients, 69% were male, with a median Injury Severity Score (ISS) of 16 (interquartile range 10-21). Elevated TT levels at 6 hours were associated with elevated interleukin 6 levels and cytokine/chemokine measurements (18 of 24 measured). Rising TT levels were significantly associated with more than a fivefold and twofold higher independent risk of MOF and NI, respectively (odds ratio [OR], 5.2; p = 0.02; 95% confidence interval [CI], 1.2-22.3; and OR, 2.1; p = 0.03; 95% CI, 1.02-4.2). At 24 hours, TT levels were no longer associated with poor outcome, while estradiol levels were significantly associated with nearly a fourfold higher independent risk of MOF (OR, 3.9; p = 0.04, 95% CI, 1.05-13). CONCLUSION Early elevations and increasing testosterone levels over initial 24 hours after injury are associated with an exaggerated inflammatory response and a significantly greater risk of MOF and NI. High estrogen levels at 24 hours are independently associated with an increased risk of MOF. The current analysis suggests that an early evolving testosterone to estrogen hormonal environment is associated with a significantly higher independent risk of poor outcome following traumatic injury. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level II.