Progesterone should be considered as treatment option for head trauma -- and perhaps other types of central nervous system injuries, researchers urged.
The hormone's beneficial effects on neuronal survival and functional recovery following traumatic brain injury have been sufficiently documented that its clinical use is now justified, according to Donald G. Stein, PhD, of Emory University, and his recent collaborator there, Iqbal Sayeed, PhD.
"There are now about 100 preclinical studies from laboratories in the U.S. and abroad showing the beneficial effects of progesterone treatment in a number of central nervous system injury models," Stein and Sayeed wrote in a "clinical perspective" article appearing in the January 2010 issue of the American Journal of Roentgenology.
Stein has been studying the effects of sex hormones on brain function after injury for more than 20 years, primarily in animal models. But he was also an investigator in the U.S. clinical trial, which was led by another Emory colleague, David Wright, MD.
In that study, with 100 patients, 30-day mortality following head trauma was cut to 13% with progesterone compared with 30% in a placebo group. The 159-patient Chinese trial found that six-month mortality was reduced by about 40%.
In these trials, progesterone was given by injection or infusion over several days following injury. No adverse effects attributable to the hormone treatment were reported.
Stein and Sayeed suggested that, given this safety profile and the current lack of effective treatments for severe brain injuries, that it would be appropriate to consider progesterone as a treatment option.
"More than 30 years of testing and 30 trials involving 50 compounds failed to identify an acute-stage treatment for traumatic brain injury that could confer neuroprotection and enhance functional outcomes," they asserted.
They also pointed out the high frequency of brain injuries suffered by troops in Iraq and Afghanistan.
Stroke is also largely untreatable, Stein and Sayeed argued. "Aside from tissue plasminogen activator (tPA), which can be given to only about 3% of stroke victims and only during the first three to four hours after stroke onset, nothing is available for clinical use," they wrote.
No clinical trials of progesterone in stroke are planned, they acknowledged, and stroke differs in important ways from traumatic brain injury.
Progesterone has shown promise in preclinical stroke models but studies of how it behaves in conjunction with tPA should precede clinical application, the researchers recommended.
Stein and Sayeed added that animal studies have found that progesterone may also help in acute spinal cord injury as well as chronic neurodegenerative conditions such as diabetic retinopathy, Niemann-Pick C1 syndrome, and multiple sclerosis.
The exact mechanism for progesterone's neuroprotective effects are unknown, but Stein and Sayeed offered an evolutionary hypothesis for why they might exist.
They noted that progesterone levels are highest in pregnant women and they remain high throughout gestation.
"It is our contention that progesterone's mechanisms of action have evolved primarily to protect the developing fetus against oxidative stress and immune–inflammatory rejection reactions," the researchers wrote, adding that the hormone also helps regulate neuronal development.
"Many of the processes of CNS repair recapitulate the steps taking place during development, and this is why we think that progesterone may also show promise in the treatment of traumatic and degenerative disorders of the brain and CNS."
They concluded, "Given its relatively high safety profile, its ease of administration, and its low cost and ready availability, this hormone and its metabolites should be considered as a viable treatment option -- especially because, in brain injury, so little else is currently available."
