Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update.

Despite decades of laboratory research and clinical trials, a safe and effective treatment for traumatic brain injury has yet to reach clinical practice. The failure is due in part to the prevalence of a reductionist philosophy and research praxis that targets a single receptor mechanism, gene, or brain locus. This approach fails to account for the fact that traumatic brain injury is a very complex disease caused by a cascade of systemic toxic events in the brain and throughout the body. Attention is now turning to pleiotropic drugs that act on multiple genomic, proteomic, and metabolic pathways to enhance morphological and functional outcomes after brain injury. Of the agents now in clinical trial, the neurosteroid progesterone appears to hold considerable promise. Many still assume that progesterone is "just a female hormone" with limited, if any, neuroprotective properties, but this view is outdated. This review will survey the evidence that progesterone has salient pleiotropic properties as a neuroprotective agent in a variety of central nervous system injury models. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.