Genetic background conditions the effect of sex steroids on the inflammatory response during endotoxic shock

Objective: The contribution of gender to the mortality and morbidity of trauma patients is controversial. In addition, a genetic contribution has been recently indicated. The influence of these two variables was studied in a murine model of endotoxemia. Design: Prospective, controlled, and randomized animal study. Setting: A university research laboratory. Subjects: Female and male mice (6-8 wks old) were injected with Escherichia coli lipopolysaccharide (15 mg/kg). Additionally, mice were gonadectomized and supplemented with 5-α-dihydrotestosterone (357 mg/day), 17-β-estradiol (23.8 μg/day), or placebo for 21 days and injected with lipopolysaccharide. Tumor necrosis factor-α was measured in plasma samples obtained after 1.5 hrs of lipopolysaccharide injection. Measurements and Main Results: Higher tumor necrosis factor-α plasma levels were observed in C57BL/6J (B6) female mice as compared with males. Because this phenotype is not sex linked, we evaluated the role of sex steroids. Castrated male B6 mice showed higher lipopolysaccharide-induced tumor necrosis factor-α plasma levels than nonoperated controls. These lipopolysaccharide-induced tumor necrosis factor-α levels were further increased after the administration of 17-β-estradiol to castrated B6 male mice as compared with nonoperated male or female mice. In addition, 17-β-estradiol-supplemented castrated mice showed a higher frequency of mortality than castrated males without hormone replacement or nonoperated mice. Analysis of castrated male mice from other strains (A/J, DBA/2J, AKR/J, BALB/cJ) supplemented with 17-β-estradiol presented the opposite effect, a reduction in lipopolysaccharide-induced tumor necrosis factor-α plasma levels. Conclusions: These results suggest that sex steroids can modulate the inflammatory response and the outcome after injury in mice. The effect of sex steroids depends on the genetic background.