IMPORTANCE OF THE FIELD: Traumatic brain injury (TBI) has yet to find a safe and 
effective acute-stage neuroprotective treatment. Experimental drugs targeting a 
single receptor mechanism, gene, or brain locus have failed.
AREAS COVERED IN THIS REVIEW: We review the latest clinical trials using 
progesterone (PROG) to treat moderate to severe TBI, and present background 
showing why this hormone and some of its metabolites should be considered as 
candidates for neuroprotective therapy. TBI is a complex disease caused by a 
cascade of systemic toxic events in the brain and throughout the body. Attention 
is now turning to combinatorial or pleiotropic drugs that act on multiple 
genomic, proteomic and metabolic pathways to enhance morphological and 
functional outcomes.
WHAT THE READER WILL GAIN: PROG has long been considered merely a female 
reproductive hormone with little role in neuroprotection after brain injury. 
This review will help readers to understand that PROG and its metabolites have 
multiple neuroprotective mechanisms, and may be among the first safe, low-cost, 
easily administered, effective treatments for a variety of CNS disorders.
TAKE HOME MESSAGE: The idea that PROG is just a female reproductive hormone is 
outdated. We propose that PROG has substantial pleiotropic properties as a 
neuroprotective agent in a variety of CNS injury models.