Progesterone for Traumatic Brain Injury
August 27, 2009
The National Institutes of Health recently announced an important phase III study of the
beneficial effects of progesterone on Traumatic Brain Injury (TBI). Seventeen medical
centers in fifteen states will enroll over eleven hundred patients for this important study.
These include Emory University, Henry Ford Hospital, The Medical Colleges of Virginia
and Wisconsin, New York Presbyterian Hospital, Oregon Health and Science University,
Stanford and Temple University and the Universities of Arizona, California, Cincinnati,
Kentucky, Maryland, Minnesota, Pennsylvania and Texas, and Wayne State University.
The goal of the study is to determine whether intravenous progesterone started within
four hours of a moderate to severe TBI, given over a total of ninetysix
hours is more
effective than placebo in treating victims. This will be a randomized, double blind
placebo controlled study. Outcomes will be determined through the Glasgow Outcome
(GOSE) score at six months post injury. Secondary outcome measures
include mortality, cognitive, neurological, and functional outcomes. The study is
scheduled to begin in March 2010 and last up to five years.
An initial loading dose of 0.714 mg/kg will be given followed by a continuous infusion of
0.5mg/kg over a seventytwo
hour period, and tapered over an additional twentyfour
hours. Those eligible for the study will be men and women eighteen years of age and
older. Inclusion criteria are moderate to severe TBI (Glasgow Coma Scale 412),
blunt closed head injury. Arrival to the hospital must be less than four hours after injury.
Exclusion criteria include persons who do not speak English or Spanish, other nonsurvivable
injury, bilateral dilated unresponsive pupils, severe intoxication (ETOH > 2.50
mg.%), spinal cord injury with neurological deficits, cardiopulmonary arrest, status
epilepticus on arrival, systolic blood pressure < 90 on arrival or for at least five minutes
prior to enrollment, O2 saturation < 90 on arrival or for at least five minutes prior to
enrollment, prisoner or ward of the state, pregnant female, active breast or reproductive
organ cancers, known allergy to progesterone or egg yolk, and known history of
thromboembolic events. Dr. David W. Wright of Emory University is the lead
In approving the design for the phase III study, NIH reviewed a number of prior animal
and human studies. A great deal of credit goes to Donald G. Stein, Ph.D., who observed
some years ago that female rats given experimental TBI seemed to recover better than
male rats. Animal studies suggest that progesterone exerts a significant neuroprotective
effect upon the central nervous system through protecting or rebuilding the bloodbrain
barrier, decreasing the cerebral edema, downregulating
the inflammatory cascade of
excitatory neurotoxic events and limiting cellular necrosis and apoptosis through axonal
remyelinization and enhancing synaptogenesis and dendritic aborization. The mechanism
of action in humans remains unclear, but it likely involves more than one neuroprotective
An earlier Emory University study looked at 100 adult trauma patients who had arrived
within eleven hours after injury with post resuscitation GCS scores ranging from 412
(Ann. Energ. Med. 2007 April; 49 (4): 391402).
The use of progesterone demonstrated
an improvement in outcome using the GOSE and disability rating scale scores with no ill
effects. Those with a moderate TBI who received progesterone had better outcome
scores than those who received placebo. The lead author was Dr. David W. Wright.
Dr. G. Xiao, et al., published an article titled, "Improved Outcomes From the
Administration of Progesterone for Patients with Acute Severe Traumatic Brain Injury, A
Randomized Controlled Study," in Critical Care 2008, 12: 2. The study, conducted in
Hangzhou China, randomized 159 patients in the neurotrauma center of the teaching
hospital who had a GCS of 8 or less, into a randomized, placebocontrolled
progesterone. It also used the GOSE three months and six months after injury with the
Modified Functional Independence Measure (MFIM). Those who had received
progesterone exhibited more favorable outcomes than patients who did not. The
mortality rate of the progesterone group was significantly lower at sixmonth
Intracranial pressure values at seventytwo
hours and seven days after injury were lower
in the progesterone group, but statistical significance was not found. Next of kin consent
was not required if the Institutional Review Board approved a subject’s inclusion.
Based upon earlier studies with promising results, a fifteen state, multicenter
sponsored study of progesterone in moderate and severe TBI will begin soon.
Relevance to Forensic Psychiatrists
Many forensic psychiatrists conduct brain injury evaluations in medicolegal settings. If
the NIH study finds in a largescale
model, what earlier studies found, it is likely that
more individuals with severe TBI will be surviving, and those with both severe and
moderate TBI may, with progesterone, have better outcome scores. When hours matter
and patients are incompetent to give informed consent, informed consent issues will be
Robert S. Brown, Jr., M.D.
Copyright Forensicpsychiatry.com 2009