Decreased 5α-dihydrotestosterone catabolism suppresses T lymphocyte functions in males after trauma-hemorrhage

Abstract

Trauma-hemorrhage produces profound immunosuppression in males but not in proestrus females. Prior castration or flutamide treatment of males following trauma-hemorrhage prevents immunosuppression, implicating 5α-dihydrotestosterone for the immunosuppressive effects. 5α-Dihydrotestosterone, a high-affinity androgen receptor-binding steroid, is synthesized in tissues as needed and seldom accumulates. The presence of steroidogenic enzymes in T lymphocytes suggests both synthesis and catabolism of 5α-dihydrotestosterone. We hypothesized, therefore, that the basis for high 5α-dihydrotestosterone activity in T lymphocytes of males following trauma-hemorrhage is due to decreased catabolism. Accordingly, catabolism of 5α-dihydrotestosterone was assessed in splenic T lymphocytes by examining the activity and expression of enzymes involved. Analysis showed increased synthesis and decreased catabolism of 5α-dihydrotestosterone in intact male T lymphocytes following trauma-hemorrhage. In contrast, reduced 5α-reductase activity and increased expression of 17β-hydroxysteroid dehydrogenase oxidative isomers suggest inactivation of 5α-dihydrotestosterone in precastrated males. Thus our study suggests increased synthesis and decreased catabolism of 5α-dihydrotestosterone as a reason for loss of T lymphocyte functions in intact males following trauma-hemorrhage, as evidenced by decreased release of interleukin-2 and -6.