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Mechanism of salutary effects of finasteride on post-traumatic immune/inflammatory response: upregulation of estradiol synthesis.

Frink M, Hsieh YC, Hu S, Hsieh CH, Pape HC, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH

Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.

OBJECTIVE: The aim of this study was to evaluate whether pretreatment with finasteride, a 5alpha-reductase inhibitor, improves immune functions after trauma-hemorrhage. SUMMARY BACKGROUND DATA: A number of studies have provided evidence for a gender dimorphism in host defense after trauma. Under stress conditions, such as trauma-hemorrhage, androgenic hormones have immunosuppressive effects, leading to increased susceptibility to sepsis, morbidity, and mortality. Testosterone is converted by 5alpha-reductase to 5alpha-dihydrotestosterone (DHT), a more potent androgen. METHODS: Male C3H/HeN mice (8-10 weeks) were randomly assigned to receive finasteride or vehicle for 2 days and were then subjected to trauma-hemorrhage or sham operation. Trauma-hemorrhage was induced by a midline laparotomy and approximately 90 minutes of hemorrhagic shock (blood pressure, 35 mm Hg), followed by fluid resuscitation. Animals were killed 2 hours after resuscitation or sham procedure. Plasma levels and Kupffer cell production of cytokines (TNF-alpha, IL-6, IL-10, MCP-1, KC, and MIP-1alpha), lung neutrophil infiltration, and edema were evaluated. RESULTS: Finasteride administration prevented the increase in cytokine plasma levels, decreased DHT, and increased 17beta-estradiol plasma concentrations. In addition, neutrophil infiltration and edema formation in the lung were reduced by finasteride. The salutary effects of finasteride were abrogated after coadministration with an estrogen receptor inhibitor (ICI 182,780). Increased Kupffer cell cytokine production normally observed after trauma-hemorrhage was prevented by treatment with finasteride. CONCLUSION: These results suggest that inhibition of 5alpha-reductase leads to the conversion of testosterone to 17beta-estradiol, which produces salutary effects on the post-traumatic immune response.

Published 30 October 2007 in Ann Surg, 246(5): 836-43.
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