Progesterone Treatment for Brain Injury: An Update

Milos Cekic; Donald G. Stein

Disclosures

Future Neurology. 2010;5(1):37-46. 

In This Article

Abstract and Background

Abstract

Traumatic brain injury is a significant clinical problem for which there is still no effective treatment. Recent laboratory and clinical data demonstrate a potentially beneficial role for neurosteroids, such as progesterone and allopregnanolone, in the treatment of traumatic brain injury, ischemic stroke and some neurodegenerative disorders. Unlike single-target agents, progesterone affects many of the molecular and physiological processes in the cascade of secondary damage after a traumatic brain injury. This article updates a 2006 Future Neurology review of the research on progesterone and its metabolites in the treatment of traumatic brain injury, and presents new evidence that vitamin D deficiency can reduce progesterone neuroprotection, while combining progesterone with vitamin D produces better functional outcomes after TBI compared with eithertreatment alone.

Background

When our review of the role of progesterone (PROG) in brain injury was published in Future Neurology in 2006, there was no clinically available treatment for traumatic brain injury (TBI).[1] This is still the case today. TBI is a major clinical concern in the USA and worldwide, and has been receiving increased public attention (and more funding) partly owing to the large number of concussive blast injuries suffered in the conflicts in Iraq and Afghanistan. US government sources indicate that, from 2003 to 2007, as many as 43,779 surviving combat casualties have been diagnosed with varying degrees of brain injury caused by explosive devices.[101] Taken together with more than 1.5 million annual cases of TBI occurring in the USA alone (including 300,000 annual sports-related injuries in children and young adults),[102] it is evident that brain injury continues to represent a substantial clinical and social problem.

Despite these grim data, there are grounds for optimism. Two independent Phase II clinical trials have now reported that PROG can be administered with a delay of up to 6 h or more after injury and still show beneficial results. The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) trial was a randomized, double-blind, placebo-controlled trial with 100 patients suffering from moderate-to-severe brain injury (Glasgow Coma Scale [GSC] scores of 4-12).[2] The patients treated with PROG were started on an intravenous (iv.) drip of 0.71 mg/kg at 14ml/h for the first hour, reduced to 0.50 mg/kg at 10 ml/h for the next 11 h. Five additional 10-h infusions at 10 ml/h were administered for the remainder of the 3 days of treatment. No serious adverse events were noted, and patients with severe injuries receiving 3 days of iv. PROG starting within 6-8 h after injury demonstrated a more than 50% reduction in mortality at 30 days compared with controls. The group with moderate injuries also showed significant 'encouraging signs of improvement' on their Disability Rating Scale (DRS) outcomes at 30 days compared with patients receiving placebo. The researchers concluded that PROG was beneficial for patients with both severe and moderate injuries, although the results were somewhat confounded in the severely injured by the fact that many in the group administered PROG survived who would not have otherwise survived without the treatment.

The ProTECT trial results were supported by another single-center trial of 159 severely brain-injured subjects (GCS score ≤ 8)[3] that tracked patient outcomes for a longer period. The 82 subjects in the PROG group were treated for 5 days with intramuscular injections of PROG (1.0 mg/kg intramuscularly every 12 h for a total of 5 days) started within 8 h of injury and demonstrated significantly better survival as well as functional outcomes at both 3 and 6 months compared with the 77 patients given placebo. A dichotomized analysis demonstrated that at the 3-month follow-up, 47% of the PROG-treated patients showed better functional outcomes on the GCS compared with 31% of the placebo group. At the 6-month follow-up the results were similar, with favorable outcomes in 58% of the PROG group compared with 42% of the placebo group. The PROG group had 18% mortality at 6 months, while the placebo group had 32% mortality at 6 months. It is important to emphasize that in both clinical trials PROG not only reduced mortality, but also significantly improved functional outcomes. Although these reports need to be confirmed in larger multicenter trials, these two trials are the first pharmacological intervention for TBI to show a substantial benefit in human patients.[4]

Based on these promising findings, the NIH is funding a national Phase III multicenter trial to test PROG in over 1000 moderately to severely brain-injured patients. This trial, termed ProTECT III, is designed to determine the efficacy of administering iv. PROG (initiated within 4 h of injury and administered for 72 h, followed by an additional 24-h taper) versus placebo for treating victims of moderate-to-severe acute TBI (GCS score of 12-4). The trial will track mortality, number of adverse and serious adverse events, DRS, and cognitive, neurological and functional outcomes.

Since the publication of the successful Phase II trials in 2007-2008,[2,3] there has been more interest in determining the extent to which PROG and some of its metabolites can enhance neuroprotection after different kinds of CNS injury. From just a few studies beginning in the 1990s, there are now over 100 published preclinical studies from 25 different laboratories, using four different species in 22 different injury models, demonstrating that PROG and its metabolites may be highly neuroprotective. Many of these studies have been published within the last few years.

Here we summarize recent findings illuminating some of the neuroprotective mechanisms of PROG and some of its metabolites. Further details can be found in extensive reviews by Brinton et al.,[5] Schumacher et al.,[6] Singh et al.,[7] Stein and Hurn[8] and Stein.[9] The earlier literature on PROG focused mainly on the phenomenological markers of CNS repair so that, for example, if administered after a TBI, the hormone was shown to reduce cerebral edema, re-establish the compromised BBB, improve vascular tone, downregulate the expression of inflammatory factors, reduce excitotoxic damage and prevent post-traumatic seizures.[5,6,7,8,9,10] As these positive studies began to accumulate, attention turned to the question of how PROG was exerting its effects at the molecular level (whether this occurred through the classical PROG receptor or through other pathways).

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