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Is there a role for Progesterone in the treatment of severe head injury?

Three Part Question

In the treatment of [acute head injury] does the use of [progesterone] result in a [better outcome]?

Clinical Scenario

A patient is brought into the emergency department with a severe acute head injury. You remember that there was recent trial in the hospital on the use of progesterone in head injury and wondered if it would be in the patients best interests?

Search Strategy

Medline 1966- 01/15
(Head OR exp Craniocerebral trauma AND progesterone LIMIT English and human studies.)
Pubmed 1996-01/15
"Head injury" and "progesterone"

Search Outcome

Total articles found= 78
Duplicates= 6
Excluded= 65

Relevant articles= 7

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Xiao G et Al
159 patients: progesterone (82) vs placebo (77): Inclusion Criteria: GCS<8, admitted within 8h of injury Exclusion Criteria: use of investigational drugs 30 days prior to the enrolment eg progesterone, oestrogen,patients with severe anoxic intracerebral damage or brain death, and patients whose clinical condition was unstable and pregnant patientsProspective randomised placebo controlled double blind trial. IV progesterone vs placebo.Favourable GCS outcome at 3 monthsprogesterone 47% placebo 31% (p=0.032Low number of female participants (1/3 of total) Use of the GCS outcome scale results in low detail outcome measurements Although a total of 25 placebo and 15 progesterone patients died before discharge this was not accounted in results
Unfavourable GCS outcome at 3 monthsprogesterone 53% placebo 70%% (p=0.022)
Favourable GCS outcome at 6 monthsprogesterone 58% placebo 42% (p=0.048)
Unfavourable GCS outcome at 6 monthsprogesterone 41% placebo 57% (p=0.048)
Women only, favourable GCS outcome at 6 monthsprogesterone 43% placebo 28% (p=0.044)
Mortality within 6 monthsprogesterone 18% placebo 32% (p=0.039)
Skolnick B et Al
1195 patients: progesterone (591) vs placebo (588) 16 excluded Inclusion Criteria: 16 to 70 years of age, with Glasgow Coma Scale score ≤8, presenting within 8 hours of injury. Exclusion Criteria: GCS score of 3 and bilaterally fixed and dilated pupils, a life expectancy of less than 24 hours, prolonged or in-correctable hypoxaemia (partial pressure of arterial oxygen, <60 mm Hg), hypotension (systolic blood pressure, <90 mm Hg) at the time of randomisation, spinal cord injury, pregnancy.Multinational, prospective, double-blind, parallel-group trial. IV progesterone vs placebo.Proportional-odds modelNo effect of progesterone treatment in either unadjusted or adjusted analyses (adjusted odds ratio, 0.96; 95% confidence interval [CI], 0.77 to 1.18)Low number of female patients within trial (78% male) No gender based results
Favourable GCS outcome at 6 months50.4% progesterone 50.5% placebo group
Proportion of patients in a vegetative state or who died in 6 months22.2% progesterone 22.3% placebo
Sliding dichotomy split based on baseline prognostic riskNo significant difference between progesterone and placebo outcome
Wright DN et Al
Georgia, USA
100 patients randomised: progesterone (77) vs placebo (23) Inclusion: GCS 4-12, within 11 hours of injury, Exclusion: Blood alcohol concentration greater than 250 mg/dL, penetrating brain injury, <18 years, GCS score <4 or >12, indeterminate time of injury, pregnant, history of active cancer, acute stroke or history of older stroke with residual motor deficits, acute or chronic spinal cord injury with neurologic deficits.Phase II, randomised, double-blind, placebo-controlled trial. IV progesterone vs placebo% Death within 30 days Progesterone (n=77) 13% Placebo (n=23) 30.4%Small sample. High chance of type II error. Disproportionate numbers in control and treatment group. Use of those with GCS >8 in study as not severe head injury
All other adverse effectsNo significant difference
Average coma lengthProgesterone 10.1 days [95% CI 7.7 to 12.5 days] Placebo 3.9 days [95% CI 2.5 to 5.4 days])
Mortality of those with GCS 4-8 after 30 daysProgesterone 13.2% Placebo 40% RR 0.33; 95% CI 0.13 to 0.83
GCS Outcome of moderate/good after 30 daysProgesterone 21.2% Placebo 26.7% RR for moderate or good recovery 0.79; 95% CI 0.29 to 2.13
Shakeri M et Al
76 Patients: progesterone (38) vs control (38) Inclusion Criteria: male patients with a diffuse axonal injury, GCS ≤8, admitted within 8h of injury, over 18y Exclusion Criteria: Female patients, male patients <18y Single blinded randomised control trial. Oral progesterone VS control.Good GOS outcome in 5 ≤ GCS ≤ 8progesterone (31.67%) vs control (18.33%) (p=0.03)Weaknesses: - No placebo for control group - Small sample size,especially after such a large mortality percentage. Increased chance of T2 errors - Only male sample - Focuses solely on diffuse axonal injuries To note: -Mean GCS score on admission = progesterone (5.74±1.4) & control (5.79±1.2) p = 0.86 -defined "good outcome" as a Glasgow outcome score of moderate disability or good recovery after 3 months.
Good GOS ourcome in GCS <5no patients in either group had favourable outcome
Mortality progesterone (44.7%) control (31.6%) (p>0.05)
Wright et al,
17,681 screened, 882 randomised. Overall 73.7% male, 15,2% Black race, 14.2% Hispanic race. 53.5% moderate GCS (GCS of 6-8.) Minutes to study treatment 218.1m (±37.2) Inclusion criteria: Severe, moderate-to-severe, or moderate TBI due to a blunt mechanism, a Glasgow Coma Scale score of 4 to 12 and treatment could be initiated within 4 hours after injury. Exclusion Criteria: A patients injury sustained was non-survivable, pregnancy, status as a prisoner or ward of the state, severe intoxication (ethanol level, >249 mg per decilitre), a known history of reproductive cancer, allergy to progesterone or a fat-emulsion vehicle, a blood-clotting disorder. myocardial infarction, ischemic stroke, pulmonary embolism, or deep-vein thrombosis. Multi-centre, phase 3, randomized, double-blind, placebo-controlled clinical trial. IV progesterone in ethanol vs placebo (ethanol alone.)Outcome at 6months (±30days) based on GOS-EThe trial was stopped due to futility after a second interim analysis. After 6months favourable outcome in placebo = 55.5% in progesterone = 51.0%. Model estimating a relative benefit of 0.95% (95% CI, 0.85-1.06, P=0.35.) Indicating fewer favourable outcomes in trial group to placebo. This was confirmed after secondary analysis of GOS-E. No significant difference in mortality between groups (hazard ratio for death, 1.19; 95% CI, 0.86 to 1.63)Strong trial with thorough methods to cross barriers such as the low sensitivity of GOS, e.g. using GOS-E. The majority of the patient population is male leading to weaknesses in any gender based results. However they did provide subgroup analysis to show trends within groups.


There is limited evidence in regards to the efficacy of progesterone in the treatment of head injury at the moment in time. The three largest papers indicate no link between progesterone and outcome. There is an obvious difficulty in both replicating animal based experiments in humans and the heterogeneity of head injury in trials, and hence further papers looking into this topic would to overcome these barriers to progress from our current stage. Progress may be made looking into Dual therapy , suggested as another stage in this research in the reviewed articles due to the complex neuro-metabolic cascade after head injury. Further research is needed with large sample sizes.

Editor Comment


Clinical Bottom Line

Currently not enough evidence supporting progesterone use in severe head injury.


  1. Xiao G et Al Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial Critical Care 2008
  2. Skolnick B et Al A Clinical Trial of Progesterone for Severe Traumatic Brain Injury The New England Journal of Medicine
  3. Wright DN et Al ProTECT: A Randomized Clinical Trial of Progesterone for Acute Traumatic Brain Injury Annals of Emergency Medicine 2007
  4. Shakeri M et Al Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma Clinical Neurology and Neurosurgery
  5. Wright, David W, et al. Very early administration of progesterone for acute traumatic brain injury. New England Journal of Medicine 2014:371.26: 2457-2466.