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Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17beta-estradiol (E2) and flutamide improve cardiac function after T-H, whether E2 and flutamide produce their salutary effect via the same or a different mechanism is unknown. We hypothesized that E2 and flutamide mediate their effects via estrogen receptor (ER)-mediated upregulation of peroxisome proliferator-activated receptor coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial function, induces mitochondrial genes by activating transcription factors such as nuclear respiratory factor 2 (NRF-2), which regulates mitochondrial proteins [i.e., mitochondrial transcription factor A (Tfam), cytochrome-c oxidase subunit IV, and beta-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for approximately 90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 microg/kg). Another group received the ER antagonist ICI-182780 (3 mg/kg) with or without flutamide. Flutamide or E2 administration after T-H restored depressed cardiac function. Moreover, E2 and flutamide normalized expression of cardiac PGC-1, NRF-2, Tfam, cytochrome-c oxidase subunit IV, and the mitochondrial DNA-encoded gene cytochrome-c oxidase subunit I and beta-ATP synthase, mitochondrial ATP, and cytochrome-c oxidase activity. However, if the ER antagonist ICI-182780 was administered with flutamide, flutamide-mediated PGC-1 upregulation was totally abolished. These results indicate that E2 and flutamide upregulate PGC-1 via the ER. Thus PGC-1 upregulation appears to be the common mechanism by which E2 and flutamide mediate their salutary effects on cardiac function after T-H.

Sex is increasingly recognized as a major factor in the outcome of patients who have trauma and sepsis. Moreover, sex steroids influence chemokine/adhesion molecule expression and neutrophil accumulation. Heat shock proteins, heat shock factor 1, and peroxisome proliferator-activated receptor γ coactivator 1 are regulated by the estrogen receptors and consequently contribute to organ protection after trauma-hemorrhage. Additionally, sex steroids regulate inflammatory cytokines, leading to increased morbidity and mortality. This article deals with trauma-hemorrhage and examines the following: 1) the evidence for sex differences; 2) the mechanisms by which sex hormones affect organ protection; 3) the tissue-specific effect of sex hormone receptors; and 4) the effect of genomic and nongenomic (i.e. membrane-initiated steroid signaling) pathways of sex hormones after trauma. The available information indicates that sex steroids modulate cardiovascular responses after trauma. Thus, alteration or modulation of the prevailing hormone milieu at the time of injury seems to be a novel therapeutic option for improving outcome after injury.

Recording of cancer diagnoses and survival estimates based on these diagnosis codes in the NHI database are generally consistent with the NCR. Studies using NHI database data must pay careful attention to eligibility and record linkage; use of both sources is recommended.

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