Opinion: Should We Consider Progesterone as a Treatment for Brain Injury?

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Progesterone has long been considered a female sex hormone primarily involved in regulating pregnancy. Recent research demonstrates that it is also a potent pleiotropic neurosteroid that can protect damaged cells in the central and peripheral nervous systems. It was recently tested in two Phase II clinical trials for traumatic brain injury, and an NIH-sponsored, nationwide, Phase III trial (ProTECT III) is currently enrolling patients. Preclinical data suggest that progesterone may also be effective in stroke and neurodegenerative disorders.

A recent PubMed search for “traumatic brain injury” (in quotes) turned up 10,667 papers going back as far as 1958. Clinical trials seeking a safe and effective treatment for TBI started over 30 years ago. More than 50 compounds have been tested, but none have identified an acute-stage treatment that can confer neuroprotection and enhance functional outcomes. Recent data from the Department of Defense (DoD) show that as many as 30% of wounded warriors seen at Walter Reed Army Hospital have TBI, prompting Congress and the DoD to advance considerable funding for TBI research.

Treatment for stroke has been almost as elusive. Over 100 clinical trials for stroke have yielded little aside from tissue plasminogen activator (tPA), which can be given only in the first 3-4 hours after stroke onset, so only about 3% of patients receive it. tPA can reduce or eliminate a blood clot but does not have any neuroprotective or anti-inflammatory effects.

There are now well over 100 papers showing that post-injury administration of progesterone (PROG) can lead to substantial and sustained improvements in cytological, morphological and functional outcomes [1-8] when given in the first few hours after an initial TBI. PROG given to both males and females can: cross the blood-brain barrier (BBB) [9]; reduce edema [10, 11]; reduce lipid peroxidation and isoprostanes, which contribute to post-injury ischemic conditions [12]; generate metabolites which reduce pro-apoptotic and increase anti-apoptotic enzymes [13]; inhibit the expression of pro-inflammatory genes and their protein products [3, 14]; and influence the expression of aquaporins implicated in the resolution of edema [15]. In cerebral ischemia, PROG can reduce the area of necrotic cell death and speed recovery of behavioral functions [16] while providing neuroprotection to  neurons in the penumbra of the injury [17, 18]. The neurosteroid and its metabolite allopregnanolone can also enhance oligodendrocyte-induced remyelination in young and aged rats with demyelinating disorders [19, 20], and produce significant sparing of cognitive, sensory and spatial learning performance in rats after bilateral medial frontal cortex (MFC) injury [17, 18]. PROG has now been shown to have beneficial effects in 22 different injury models. There are a number of recent comprehensive reviews on this topic [21-23].

The first successful clinical  trial for the treatment of TBI in more than 30 years of research was recently completed. This NINDS-sponsored, Phase IIa single-center clinical trial for PROG in the treatment of moderate to severe adult TBI[24] found that the mortality rate among patients given intravenous PROG for 3 days post-injury was less than half that of controls given standard of practice care but no hormone (13.6% versus 30.4%). Thirty-day functional outcomes for moderately injured patients in the PROG group were significantly better than those for the placebo group. It is of interest to note that an NIH-appointed Data Safety Monitoring Board found no serious adverse events attributable to PROG treatment in this trialNow a second independent, randomized double-blind study from China has examined PROG in 159 patients with severe TBI given a course of intramuscular injections for 5 days. The investigators reported very similar beneficial outcomes on morbidity and mortality at both 30 days and 6 months after injury, again without any serious adverse events caused by the treatment [25]. An NINDS-funded Phase III, 17-center, double-blind, randomized clinical trial for TBI started enrolling over 1000 patients in April 2010.

Stroke has a number of overlapping pathophysiological mechanisms with TBI, and the preclinical stroke data and recent human studies in TBI support a potential role for PROG in acute stroke. Our laboratory has recently reported significant neuroprotective effects of acute post-injury administration of PROG in an adult rat model of permanent and transient (2h) MCAO stroke [26, 27]. Our findings corroborated other studies showing PROG to be neuroprotective following global ischemia in cats [28, 29], and transient focal ischemia in rats [16, 30].

TBI and stroke are nevertheless very different diseases, and there is no guarantee that PROG treatment will work in human stroke. Before going forward to clinical application, we need to determine whether PROG treatment, combined with tPA, has positive or negative outcomes. Our own recent study suggests that PROG may upregulate the expression of endogenous tPA and extend its window of effectiveness beyond 3 hours, but this will need to be confirmed by further research [14]. As of this writing, no clinical trials using PROG or its metabolites are planned for stroke patients. 

PROG and some of its metabolites have shown beneficial effects, including enhanced remyelination and improved motor function, in animal models of neurodegenerative disorders and spinal cord injury [23, 31, 32]; Jung-Testas, 1994 #1209; Schumacher, 1996 #955}. In a diabetic neuropathy model in rats, Leonelli et al. [33] showed that treatment with PROG and its metabolites sustains nerve conduction velocity, restores skin innervation, and maintains sensitivity to thermal stimulation. Treatment with allopregnanolone in an animal model of Niemmann-Pick type C disease seems to delay the onset of symptoms (tremor, ataxia, weight loss) {Ahmad, 2005 #1556; Griffin, 2004 #1554}.  ]Another neurodegenerative condition, experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, responded to treatment with PROG or its metabolites [34]. PROG administration following trauma-hemorrhage has been reported to ameliorate the proinflammatory response and, subsequently, hepatocellular injury via direct action on immunocompetent cells [35]. 

How can PROG have so many different salutary effects on tissue repair? PROG is a naturally occurring hormone found in both males and females, although females have higher levels than males. In pregnant females, PROG levels increase more than 10-fold and remain high throughout gestation. Within one hour after parturition, PROG levels drop precipitously. In our lab, we think that PROG’s mechanisms of action help to protect the developing fetus from oxidative stress and immune-inflammatory rejection reactions while at the same time playing a critical role in neuronal-glial signaling, synaptic and dendritic activity (through its effects on GABA), and normal neuronal development. Almost four decades ago it was proposed that many of the processes of CNS repair recapitulate fetal development [36]. This is why we think PROG as a neurosteroid may also show promise in the treatment of traumatic and degenerative disorders of the brain and central nervous system.

In summary, over 25 years of pre-clinical research by our laboratory and others has defined many of the physiological mechanisms underlying PROG’s benefits. There are more than 100 pre-clinical studies from laboratories in the U.S. and abroad demonstrating the beneficial effects of PROG treatment in a number of CNS injury models [2, 37]. PROG appears to be very safe, is easy to administer and inexpensive. Given that so little else is available this hormone and its metabolites may be the first viable treatment option for the acute stage of injury.  The Phase III trial now in progress will provide the final answer

Disclosure

Dr. Donald Stein is entitled to royalty from products of BHR Pharma related to the research described in this presentation, and may receive research funding from BHR, which is developing products related to this research. In addition, the author serves as consultant to BHR and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

References

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