Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: A randomized clinical trial with placebo group

Aminmansour, Bahram; Nikbakht, Hossein; Ghorbani, Abbas; Rezvani, Majid; Rahmani, Paiman; Torkashvand, Mostaffa; Nourian, Mohammadamin; Moradi, Mehran

Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: A randomized clinical trial with placebo group

Authors

¹ Department of Neurosurgery, Isfahan University Of Medical Sciences, Isfahan, Iran

² Department of Neurology, Al-zahra Hospital, Isfahan University Of Medical Sciences, Isfahan, Iran

Abstract

Background: Due to the heterogeneity of traumatic brain injury (TBI), many of single treatments have not been successful in prevention and cure of these kinds of injuries. The neuroprotective effect of progesterone drug on severe brain injuries has been identified, and recently, the neuroprotective effect of vitamin D has also been studied as the combination of these two drugs has shown better effects on animal samples in some studies. This study was conducted to examine the effect of vitamin D and progesterone on brain injury treatment after brain trauma.
Materials and Methods: This study was performed on patients with severe brain trauma (Glasgow Coma Scale (GCS) ≤ 8) from April to September, 2011. The patients were divided to 3 groups (placebo, progesterone, progesterone-vitamin D), each with 20 people. Upon the patients' admission, their GCS and demographic information were recorded. After 3 months, they were reassessed, and their GCS and GOS (Glasgow outcome scale) were recorded. The collected data were analyzed using SPSS 18 software (SPSS Inc., Chicago IL, USA).
Results: Before intervention, GCS mean of the placebo, progesterone, and progesterone-vitamin D groups were 6.3 ± 0.88, 6.31 ± 0.87, and 6 ± 0.88, respectively. They increased to 9.16 ± 1.11, 10.25 ± 1.34, and 11.27 ± 2.27, respectively 3 months after intervention. There was a significant difference among GCS means of the 3 groups (P-value = 0.001). GOS was classified to 2 main categories of favorable and unfavorable recovery, of which, favorable recovery in placebo, progesterone, and progesterone-vitamin D was 25%, 45%, and 60%, respectively which showed a statistical significant difference among the groups (P-value = 0.03).
Conclusion: The results showed that recovery rate in patients with severe brain trauma in the group receiving progesterone and vitamin D together was significantly higher than that of progesterone group, which was in turn higher than that of placebo group.

Keywords

References

1.	Atif F, Sayeed I, Ishrat T, Stein DG. Progesterone with Vitamin D affords better neuroprotectionagainst excitotoxicity in cultured cortical neurons than progesterone alone. Mol Med 2009;15:328-36.
2.	Margulies S, Hicks R. Combination Therapies for Traumatic Brain Injury Workshop. Rockville, MD: 2008. Participants.
3.	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. Neurol Neurosurg Psychiatry 1998;65:729-33.
4.	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;78:375-82.
5.	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.
6.	Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005;22:106-18.
7.	Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: Neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000;17:367-88.
8.	Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev 2008;57:386-97.
9.	Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 1997;31:1-11.
10.	Roof RL, Duvdevani R, Stein DG. Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor Neurol Neurosci 1992;4:425-7.
11.	Ransohoff RM, Tani M. Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci 1998;21:154-9.
12.	Eelen G, Verlinden L, van Camp M, van Hummelen P, Marchal K, de Moor B, et al. The effects of 1alpha,25- dihydroxyvitamin D3 on the expression of DNA replication genes. J Bone Miner Res 2004;19:133-46.
13.	Milos C, Iqbal S, Donald G. Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease. Neuroendocrinology 2009;30:158-72.
14.	Bergeron R, de Montigny C, Debonnel G. Pregnancy reduces brain sigma receptor function. Br J Pharmacol 1999;127:1769-76.
15.	Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, et al. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 1996;93:8072-7.
16.	Valera S, Ballivet M, Bertrand D. Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A 1992;89:9949-53.
17.	Eelen G, Verlinden L, van Camp M, van Hummelen P, Marchal K, de Moor B, et al. The effects of 1alpha,25-dihydroxyvitamin D3 on the expression of DNA replication genes. J Bone Miner Res 2004;19:133-46.
18.	Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80:1717S-20S.
19.	Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem 2003;88:695-705.
20.	Cohen-Lahav M, Douvdevani A, Chaimovitz C, Shany S. The anti-inflammatory activity of 1,25- dihydroxyvitamin D3 in macrophages. J Steroid Biochem Mol Biol 2007;103:558-62.
21.	Gibson CL, Gray LJ, Bath PM, Murphy SP. Progesterone for the treatment of experimental brain injury; a systematic review. Brain 2008;131:318-28.
22.	Singh M, Sumien N, Kyser C, Simpkins JW. Estrogens and progesterone as neuroprotectants: What animal models teach us. Front Biosci 2008;13:1083-9.
23.	Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev 2008;57:386-97.
24.	Cutler SM, Cekic M, Miller DM, Wali B, VanLandingham JW, Stein DG. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma 2007;24:1475-86.
25.	He J, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor Neurol Neurosci 2004;22:19-31.
26.	Wang Y, Chiang YH, Su TP, Hayashi T, Morales M, Hoffer BJ, et al. Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 2000;39:873-80.
27.	Almeras L, Eyles D, Benech P, Laffite D, Villard C, Patatian A, et al. Developmental vitamin D deficiency alters brain protein expression in the adult rat: Implications for neuropsychiatric disorders. Proteomics 2007;7:769-80.

Advanced Biomedical Research