|Year : 2017 | Volume
| Issue : 2 | Page : 84-89
Impact of progesterone administration on outcome in patients with severe traumatic brain injury
Hassan A Aboukhabar, Amr Abouelela MD , Sherif M Shaban
Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||23-Nov-2016|
|Date of Acceptance||16-Mar-2017|
|Date of Web Publication||12-May-2017|
Department of Critical Care Medicine, Faculty of Medicine, University of Alexandria, Alexandria
Source of Support: None, Conflict of Interest: None
No medication exists to halt the progression of secondary injuries in severe traumatic brain injury (TBI), but the variety of pathological events presents opportunities to find treatments that interfere with the damage processes. The effects of progesterone on the reproductive and endocrine systems are well known, but a growing body of evidence indicates that the hormone also exerts neuroprotective effects on the central nervous system by decreasing overall cerebral edema, protecting and rebuilding the blood–brain barrier, downregulating the inflammatory cascade, and limiting cellular necrosis and apoptosis.
The aim of this study was to evaluate the effect of progesterone administration on improvement in outcomes of patients with TBI as measured by the Glasgow Outcome Scale.
Patients and methods
The present study was a prospective, randomized trial. A total of 100 patients with severe TBI were enrolled for the present study. The selected patients were categorized at random into two equal groups − the control group and the progesterone group. In the control group, patients were given conventional therapy. The progesterone group was given 1 mg/kg progesterone by intramuscular injection within 8 h of admission and then every 12 h for 5 consecutive days in addition to the conventional therapy. The neurological outcome after 30 days was evaluated using the Glasgow Outcome Scale score as well as duration of ICU stay.
In the progesterone group, 33/50 (66%) patients had favorable outcomes and 17/50 (34%) had unfavorable outcomes, whereas in the control group 23/50 (46%) patients had favorable outcomes and 27/50 (54%) had unfavorable outcomes (P=0.072). Length of ICU stay had a mean value of 10.88±7.98 days in the progesterone group versus 19.96±10.36 days in the control group (P<0.001).
No significant difference in outcome between the two groups was observed, but there was a significant decrease in ICU length of stay in the progesterone group.
Keywords: Glasgow Outcome Scale, head injuries, neuroprotective agents, progesterone, traumatic brain injury
|How to cite this article:|
Aboukhabar HA, Abouelela A, Shaban SM. Impact of progesterone administration on outcome in patients with severe traumatic brain injury. Res Opin Anesth Intensive Care 2017;4:84-9
|How to cite this URL:|
Aboukhabar HA, Abouelela A, Shaban SM. Impact of progesterone administration on outcome in patients with severe traumatic brain injury. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2017 Oct 17];4:84-9. Available from: http://www.roaic.eg.net/text.asp?2017/4/2/84/206150
This study was previously presented at European Society in Intensive Care Medicine (ESICM) as an oral presentation, Lisbon, Monday 15 October 2012; Impact of progesterone administration on outcome of patients with severe traumatic brain injury.
Intens Care Med 2012; 38 (Suppl 1).
| Introduction|| |
Severe traumatic brain injury (TBI) has been increasing with greater incidence caused by traffic or sporting accidents. TBI remains one of the leading causes of injury-related deaths and severe disability ,. It can be defined as brain injury caused by trauma with a Glasgow Coma Scale (GCS) score less than or equal to 8 after the resuscitation stage. The development of neurological changes accompanying TBI is related to a number of pathophysiological events including direct mechanical damage, intraparenchymal and subarachnoid hemorrhage, breakdown of the blood–brain barrier, excitotoxicity, ischemia, and target deprivation. Recent evidence demonstrates that both acute and delayed neuronal injuries occur after TBI as early as 10 min with extensive neuronal injury observed in the cortex at the site of injury and the underlying hippocampus. After several days, injured neurons are apparent in the lateral dorsal thalamus and cerebellum. The management of TBI currently includes preventing further neurological insults (secondary injury), managing the intracranial pressure, and surgical procedures . It is very important to search for clinically effective neuroprotective drugs to prevent secondary brain injury after TBI. Despite many neuroprotective agents showing efficacy in experimental models of TBI, none has produced significant neuronal protection when tested in clinical trials .
Increasing evidence has demonstrated a striking sex differences in the pathophysiology and outcome after acute neurological injury. Lesser susceptibility to postischemic and post-TBI in females has been observed in experimental models. Additional evidence suggests that this sex difference extends to humans as well ,.
This significant difference between male and female outcomes raised the important question of the possible effect of female sex hormones, mainly progesterone, in improvement of the neurological status of patients with TBIs. No clear answer for this theoretical hypothesis exists so far, and this is the reason for multiple studies being conducted to investigate this hypothesis.
Progesterone − a hormone that has steroidal, neuroactive action in the central nervous system − is synthesized in the brain, spinal cord, and peripheral nerves. Its direct precursor pregnenolone is either derived from the circulation or derived from local de-novo synthesis, such as in cytochrome P450 that converts cholesterol to pregnenolone, which is furthermore converted to progesterone by 3β-hydroxysteroid dehydrogenase. Macroglial cells including astrocytes, oligodendroglial cells, and Schwann cells also have the capacity to synthesize progesterone, but the expression and activity of 3β-hydroxysteroid dehydrogenase in these cells are regulated by cellular interactions in response to a neuronal signal . Although only a few studies addressing the biological significance of progesterone synthesis in the brain have been carried out, the autocrine/paracrine actions of locally synthesized progesterone are likely to play an important role in the viability of neurons and in the formation of myelin sheaths .
Despite these potential advantages and the good safety profile of progesterone described in studies utilizing animal or human subjects, there is relatively little information available on the neuroprotective properties and neurological outcomes of progesterone in patients with TBI ,.
Studies on the effects of these hormones on the brain have focused primarily on the hypothalamus. However, growing evidence forces us to recognize that various extrahypothalamic brain regions, including the cerebral cortex and the hippocampus, are equally important targets of these hormones ,,. Progesterone is involved in numerous aspects of brain function, and elicits effects ranging from the regulation of mood and cognition to the regulation of neuronal survival . Postinjury administration of progesterone in experimental models of head injury confers significant protection against TBI-induced cerebral edema and secondary neuronal death, promoting behavioral recovery ,.
The aim of the present study was to evaluate the effect of progesterone administration on improvement of outcome in patients with TBI as measured by the GOS.
| Patients and methods|| |
The present study was a prospective, randomized, controlled, open trial. From a total of 148 patients screened for possible enrollment, 100 patients fulfilled study criteria. Patients were selected from those admitted to Alexandria University Main Hospital with severe TBI, and patients who arrived within 8 h of injury with a GCS score of less than or equal to 8 after initial resuscitation were enrolled for the present study. Exclusion criteria included life-threatening trauma such as tension pneumothorax, intra-abdominal bleeding, age less than 18 years or more than 70 years, patients who received any investigational drugs 30 days before admission (such as progesterone, estrogen, and any investigational compounds), and pregnant and lactating women.
A sample size of 100, with 50 patients with severe TBI on progesterone and 50 patients with severe TBI on conventional therapy, was required to achieve 95% power to detect a difference of LOS between the null hypothesis and the alternative hypothesis with a significance level (α) of 0.05 using a two sided, two-sample t-test.
Signed, written, informed consent was obtained from patients’ relatives, and approval of the local ethics committee was also obtained. All patients were subjected to the standard treatment protocol according to ATLS guidelines and Standard treatment for management of severe TBI based on the guidelines for the management of severe head injury of the American Association of Neurologic Surgeons .
The selected patients were categorized randomly into two groups of 50 patients each − the control group and the progesterone group. Simple randomization was performed according to sequence of admission. In the control group, patients were given the conventional therapy. In the progesterone group, patients received the conventional therapy and 1 mg/kg body weight progesterone by intramuscular injection within 8 h of admission and then every 12 h for 5 consecutive days ,.
Some side-effects were expected with the administration of progesterone. This included abdominal cramps, depression, dizziness, and headache. Less frequent side-effects included anxiety, cough, diarrhea, fatigue, and musculoskeletal pain. No effect of progesterone on the respiratory or cardiovascular systems was observed.
The neurological outcome after 30 days was evaluated using the GOS, which contains five levels of outcome: dead, vegetative state, severe disability, moderate disability, and good recovery. For statistical analysis, GOS scores were dichotomized into favorable or unfavorable outcomes. Patients in the upper two GOS outcome groups (good recovery or moderate disability) were considered to have favorable outcomes, and patients in the other groups (severe disability, vegetative state, or death) were considered to have unfavorable outcomes. A secondary parameter was also recorded − duration of ICU stay.
| Results|| |
The baseline characteristics of patients in the two studied groups are presented in [Table 1]. There were 33 (66%) males and 17 (34%) females in the control group versus 39 (78%) males and 11 (22%) females in the progesterone group, with no significant statistical difference regarding sex (P=0.181). The age range of patients was 18–65 years with a mean of 27.76±15.22 years in the control group versus 20–61 years with a mean of 26.72±18.43 years in the progesterone group, with no significant statistical difference between the two groups (P=0.588). In addition, the GCS score on admission was not significantly different between the two studied groups, as it ranged from 3 to 8 in both groups with a mean of 5.86±1.37 in the control group versus a mean of 6.14±1.47 in the progesterone group (P=0.208).
|Table 1 Comparison between the two studied groups according to baseline characteristics|
Click here to view
[Figure 1] shows the evolution of the GCS of patients in the two groups over time − from the time of presentation until 1 month later. After 1 week since the initial trauma, patients in both groups showed improvement compared with baseline with a mean GCS score in the control group of 8.19±1.01 and in the progesterone group of 9.33±1.22 with no statistically significant difference (P=0.015), whereas the results of the GCS after 2 weeks showed significant improvement in the progesterone group compared with the control group with a mean GCS score of 9.62±1.34 in the control group and 12.23±1.88 in the progesterone group (P<0.001). After 3 weeks, the GCS score was still better in the progesterone group but with less statistical difference, 11±0.99 in the control group versus 12.56±1.34 in the progesterone group (P=0.004). The last follow-up after 30 days showed a GCS score of 11.8±1.27 in the control group versus 12.47±1.04 in the progesterone with no significant statistical difference between the two groups (P=0.016).
|Figure 1 Comparison between the two studied groups according to the Glasgow Coma Scale (GCS)|
Click here to view
[Table 2] shows the comparison between the outcome using the GOS Score. In the progesterone group, 33/50 (66%) patients had favorable outcomes and 17/50 (34%) had unfavorable outcomes, whereas in the control group 23/50 (46%) patients had favorable outcomes and 27/50 (54%) had unfavorable outcomes, with no significant statistical difference between the two groups (P=0.072).
|Table 2 Comparison between the two studied groups according to the Glasgow Outcome Scale|
Click here to view
[Table 3] shows the length of ICU stay in days, which was significantly lower in the progesterone group with a mean value of 10.88±7.98 compared with 19.96±10.36 in the control (P<0.001).
No complications or side effects related to progesterone administration were reported during the study.
| Discussion|| |
The present study failed to detect any significant difference in outcome with the use of progesterone, although a generalized, better trend was observed; however, it was not statistically significant. The only significant benefit was the reduction in ICU length of stay in the progesterone group with a mean value of 10.88±7.98 compared with 19.96±10.36 in the control group (P<0.001)
The sex hormone progesterone has been shown to improve outcomes in animal models of a number of neurological diseases including TBI, ischemia, spinal cord injury, peripheral nerve injury, demyelinating disease, neuromuscular disorders, and seizures. Evidence suggests that it exerts its neuroprotective effects through several pathways involved in reducing edema, improving neuronal survival, and modulating inflammation and apoptosis .
One of the initial important trials carried out on humans was the PROTECT phase II trial by Wright et al. , which was published in 2007. The study was initiated as a pilot study on 100 patients with various degrees of head injury including moderate and severe affection to assess the safety and potential benefit of administering progesterone to patients with acute TBI. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality compared with controls, and this conclusion constituted one of the earliest evidence of possible beneficial effects of progesterone in head injuries .
In 2008, further evidence came from China when Xiao et al.  studied a total of 159 patients who arrived within 8 h of injury with a GCS score of less than or equal to 8 in a prospective, randomized, placebo-controlled trial of progesterone in a Neurotrauma Center of a teaching hospital. The patients were randomized to receive either progesterone or placebo. The primary endpoint was the GOS score 3 months after brain injury. Of the 159 patients randomized, 82 received progesterone and 77 received placebo. The demographic characteristics, the mechanism of injury, and the time of treatment were compared between the two groups. After 3 and 6 months of treatment, the dichotomized GOS score analysis exhibited more favorable outcomes among patients who were given progesterone compared with control individuals (P=0.034 and 0.048, respectively). Instances of complications and adverse events associated with the administration of progesterone were not found .
Although the number of patients was not very high in both studies, it opens a new window to create more solid evidence toward a real hope for improving the outcome in TBIs. In the present study, we relied more on the study design of Xiao et al.  as it was focused mainly on severe head injuries excluding moderate cases. We believe that severe cases really deserve more attention and help, but we agreed for a shorter term of follow-up of 30 days because of logistic difficulties for a longer follow-up. The results of the present study showed the same trend toward better outcome in the progesterone group as seen in the other two studies; however, the results were not statistically different, which may be related to the shorter follow-up duration of our study.
The shorter stay in ICU in the progesterone group may be explained by the better neurological state as expressed by the higher GCS score in those patients, which allowed the treating team to discharge them from the ICU earlier. An important point to be considered is that not all patients discharged from the ICU were shifted to regular wards, as some of them were transferred to intermediate care units where they still needed more nursing care with more suction and tracheostomy care. Only patients with GCS scores higher than 10 were eligible for direct transfer to a regular ward. However, patients discharged from ICU in all conditions were patients with hemodynamic stability not necessitating vasopressors and were weaned off mechanical ventilation, although some of them had required tracheostomy for airway maintenance.
Wright et al.  published in December 2014 a huge, very important Experimental Clinical Treatment (PROTECT III) trial, which was a phase-3, randomized, double-blind, placebo-controlled, clinical trial, designed to determine the efficacy of early intravenous administration of progesterone versus placebo for treating patients with acute nonpenetrating TBIs caused by a blunt mechanism. The results were testing compared with previous evidence in favor of the possible beneficial effect of progesterone. The study was conducted on 882 patients at 49 trauma centers in the USA − favorable outcomes occurred in 51.0% of patients assigned to progesterone and in 55.5% of those assigned to placebo (P=0.35). There was no significant difference in mortality between the progesterone group and the placebo group. Analyzing the results of this study is very important, as it contained certain strong points such as a large number of patients enrolled and the overall design of the study. However, we should also consider many significant points of difference between this study and previous studies with positive results. The first point is the total number included patients with moderate head injuries, not only focusing on the severe head injuries. The second point is using different doses and routes of administration of progesterone (it was given at a dose of 0.05 mg of progesterone/kg of body weight/ml of infusate). The study treatment was initiated within 4 h after injury and consisted of a 1-h loading dose, 71 h of maintenance infusion, and a 24-h infusion taper. The study drug was infused continuously through a dedicated intravenous catheter at a dose of 14.3 ml/h for 1 h and then at 10 ml/h for 71 h; the dose was then tapered by 2.5 ml/h every 8 h, and the total treatment duration was of 96 h. This dose effect might be really different from the intramuscular doses given twice per day, which was applied in previous studies. The third important point of difference is the outcome parameter measured, the extended GOS that has eight different categories compared with five in the regular GOS used in the other studies, which may render the overall analysis of the results a bit confusing .
Many reasons for the disappointing record of translating promising agents from the laboratory to the clinic have been postulated, including limited preclinical development work, poor drug penetration into the brain, delayed initiation of treatment, heterogeneity of injuries, variability in routine patient care across sites, and insensitive outcome measures .
Another trial in December 2014 was published by Skolnick et al.  − a multinational placebo-controlled trial including 1195 patients with severe TBI who were randomly assigned to receive progesterone or placebo. Dosing began within 8 h after injury and was continued for 120 h. The primary efficacy end point was the GOS score at 6 months after the injury. Again the results were disappointing; the proportion of patients with a favorable outcome on the GOS (good recovery or moderate disability) was 50.4% with progesterone as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between the progesterone group and the placebo group .
The long history of failed TBI trials, including the present trial and the last two studies published in 2014, is probably due to several factors including the variability of the brain injury and the fact that multiple direct and indirect injury mechanisms are at work simultaneously, especially regarding secondary brain injuries, confounding pre-existing conditions, and characteristics of individual patients. In addition, there may also be insensitivity of the available outcome measures.
In addition, current approaches to the characterization of TBI are mainly unidimensional (based on GCS scores) and do not permit appropriately targeted therapy. Multidimensional approaches are needed for better characterization of TBI to facilitate individualized treatment .
The final conclusion of the present study is that there was a trend for better outcome in patients with severe head injuries in the progesterone group but it was not enough to create a statistically significant difference. A statistically significant difference was noticed regarding ICU length of stay, which was significantly shorter in the group assigned to receive progesterone. No reported side-effects related to the administration of progesterone were observed.
The main limitations of the present study are the relatively limited number of patients, the lack of blinding during administration of progesterone, and the short follow-up duration of 1 month.
Success in translating studies on neuroprotective agents from bench to bedside may require new paradigms including innovative clinical trial methods (e.g. adaptive designs and profiling of patients who have a response in early-phase clinical trials) to identify effective drug doses and timing. The use of targeted outcomes on the basis of the mechanism of injury is needed to reduce the heterogeneity encountered in the present available studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Roberts I, Schierhout G, Alderson P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. J Neurol Neurosurg Psychiatry 1998; 65:729–733.
Muzelaar JP, Mararon A, Young HF. Improving the outcome of severe head injury with oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase trial. J Neurosury 1993; 78:375–382.
Palmer S, Bader MK, Qureshi A. The impact on outcomes in a community hospital setting of using the AANS traumatic brain injury guidelines. American Association of Neurologic Surgeons. J Trauma 2001; 50:657–664.
Saatman KE, Duhaime AC, Bullock R, Maas Al, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008; 25:719–738.
Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone play a protective role. Brain Res 1993; 607:333–336.
Roof RL, Zhang Q, Glasier MM. Gender-specific impairment on Morris water maze task after entorhinal cortex lesion. Behav Brain Res 1993; 57:41–51.
Djebaili M, Guo Q, Pettus EH. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005; 22:106–118.
Roof RL, Duvdevani R, Braswell L. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol 1994; 129:64–69.
Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 1997; 31:1–11.
Ransohoff RM, Tani M. Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci 1998; 21:154–159.
Cervantes M, Gonzalez-Vidal MD. Neuroprotective effects of progesterone on damage elicited by acute global cerebral ischemia in neurons of the caudate nucleus. Arch Med Res 2002; 33:6–14.
Asbury ET, Fritts ME, Horton JE. Progesterone facilitates the acquisition of avoidance learning and protects against subcortical neuronal death following prefrontal cortex ablation in the rat. Behav Brain Res 1998; 97:99–106.
Shear DA, Galani R, Hoffman SW. Progesterone protects against necrotic damage and behavioral abnormalities caused by traumatic brain injury. Exp Neurol 2002; 178:59–67.
Pettus EH, Wright DW, Stein DG. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 2005; 1049:112–119.
Chen J, Chopp M, Li Y. Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. Neurol Sci 1999; 171:24–30.
Wright DW, Kellermann AL, Hertzberg VS, Hertzberg VS, Clark PL, Frankel M et al.
ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007; 49:391–402.
Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008; 12:R61.
Deutsch ER, Espinoza TR, Atif F, Woodall E, Kaylor J, Wright DW. Progesterone’s role in neuroprotection, a review of the evidence. Brain Res 2013; 1530:82–105.
Wright D, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M et al.
Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014; 371:2457–2466.
Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB et al.
Clinical trials in head injury. J Neurotrauma 2002; 19:503–557.
Skolnick B, Maas A, Narayan R, van Der Hop RG, MacAllister T, Ward JD et al.
A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014; 371:2467–2476.
Manley GT, M aas AI. Traumatic brain injury: an international knowledge-based approach. JAMA 2013; 310:473–474.
[Table 1], [Table 2], [Table 3]