Comparative efficacy of progesterone and vitamin D in improving functional outcomes after traumatic brain injury
DOI:
https://doi.org/10.25305/unj.337777Keywords:
traumatic brain injury (TBI), progesterone, vitamin D, functional outcomeAbstract
Background: Traumatic brain injury (TBI) remains a major clinical challenge in neurosurgery due to its heterogeneous pathophysiology and the limited availability of effective pharmacological interventions. Progesterone and vitamin D have demonstrated neuroprotective and anti-inflammatory properties in preclinical models; however, their translational efficacy in clinical trials remains inconclusive. Clarifying their therapeutic roles may help inform adjunctive strategies in the acute management of neurotrauma.
Objectives: To assess the neuroprotective effects of progesterone and vitamin D in enhancing functional recovery following moderate to severe TBI, and to compare the clinical efficacy of these agents based on standardized neurological outcome measures derived from randomized controlled trials (RCTs).
Methods: A systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines. Randomized controlled trials (RCTs) were identified through searches of PubMed, EMBASE, Web of Science, and the Cochrane Library, comparing progesterone and/or vitamin D with placebo in patients with traumatic brain injury (TBI). Studies reporting Glasgow Outcome Scale–Extended (GOS-E) outcomes were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using Review Manager version 5.4. Study quality and heterogeneity were assessed.
Results: Six RCTs were included: three progesterone trials (n = 1,426) and three vitamin D trials (n = 192). Progesterone showed no significant improvement in functional outcomes compared with placebo (SMD = −0.07; 95% CI: −0.32 to 0.19; p = 0.60; I² = 58%). Vitamin D demonstrated a non-significant trend toward improved outcomes (SMD = 0.37; 95% CI: −0.27 to 1.02; p = 0.26; I² = 78%). Variability in trial design, timing of intervention, and baseline vitamin D deficiency status may have influenced the observed effects.
Conclusions: Although neither agent showed standalone efficacy, their safety and complementary mechanisms suggest promise for combinatorial or biomarker-guided approaches. This meta-analysis highlights the need for early, precision-targeted, and stratified neuroprotective trials in TBI care.
References
1. Lele AV. Traumatic Brain Injury in Different Age Groups. J Clin Med. 2022 Nov 14;11(22):6739. [CrossRef] [PubMed] [PubMed Central]
2. Freire MAM, Rocha GS, Bittencourt LO, Falcao D, Lima RR, Cavalcanti JRLP. Cellular and Molecular Pathophysiology of Traumatic Brain Injury: What Have We Learned So Far? Biology (Basel). 2023 Aug 17;12(8):1139. [CrossRef] [PubMed] [PubMed Central]
3. Zhou Z, Li Y, Peng R, Shi M, Gao W, Lei P, Zhang J. Progesterone induces neuroprotection associated with immune/inflammatory modulation in experimental traumatic brain injury. Neuroreport. 2024 Apr 3;35(6):352-360. [CrossRef] [PubMed] [PubMed Central]
4. 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(2):R61. [CrossRef] [PubMed] [PubMed Central]
5. Jiang H, Yang X, Wang Y, Zhou C. Vitamin D Protects against Traumatic Brain Injury via Modulating TLR4/MyD88/NF-κB Pathway-Mediated Microglial Polarization and Neuroinflammation. Biomed Res Int. 2022 Jul 15;2022:3363036. [CrossRef] [PubMed] [PubMed Central]
6. Sharma S, Kumar A, Choudhary A, Sharma S, Khurana L, Sharma N, Kumar V, Bisht A. Neuroprotective Role of Oral Vitamin D Supplementation on Consciousness and Inflammatory Biomarkers in Determining Severity Outcome in Acute Traumatic Brain Injury Patients: A Double-Blind Randomized Clinical Trial. Clin Drug Investig. 2020 Apr;40(4):327-334. [CrossRef] [PubMed] [PubMed Central]
7. Hudak AM, Caesar RR, Frol AB, Krueger K, Harper CR, Temkin NR, Dikmen SS, Carlile M, Madden C, Diaz-Arrastia R. Functional outcome scales in traumatic brain injury: a comparison of the Glasgow Outcome Scale (Extended) and the Functional Status Examination. J Neurotrauma. 2005 Nov;22(11):1319-26. [CrossRef] [PubMed]
8. Stein DG. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29(11):1259-72. [CrossRef] [PubMed] [PubMed Central]
9. Stein DG. Is progesterone a worthy candidate as a novel therapy for traumatic brain injury? Dialogues Clin Neurosci. 2011;13(3):352-9. [CrossRef] [PubMed] [PubMed Central]
10. Rebelos E, Tentolouris N, Jude E. The Role of Vitamin D in Health and Disease: A Narrative Review on the Mechanisms Linking Vitamin D with Disease and the Effects of Supplementation. Drugs. 2023 Jun;83(8):665-685. [CrossRef] [PubMed] [PubMed Central]
11. Aminmansour B, Nikbakht H, Ghorbani A, Rezvani M, Rahmani P, Torkashvand M, Nourian M, Moradi M. 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. Adv Biomed Res. 2012;1:58. [CrossRef] [PubMed] [PubMed Central]
12. Hua F, Reiss JI, Tang H, Wang J, Fowler X, Sayeed I, Stein DG. Progesterone and low-dose vitamin D hormone treatment enhances sparing of memory following traumatic brain injury. Horm Behav. 2012 Apr;61(4):642-51. [CrossRef] [PubMed] [PubMed Central]
13. Cekic M, Cutler SM, VanLandingham JW, Stein DG. Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging. 2011 May;32(5):864-74. [CrossRef] [PubMed] [PubMed Central]
14. Gibson CL, Gray LJ, Bath PM, Murphy SP. Progesterone for the treatment of experimental brain injury; a systematic review. Brain. 2008 Feb;131(Pt 2):318-28. [CrossRef] [PubMed]
15. Abdelhak A, Foschi M, Abu-Rumeileh S, Yue JK, D'Anna L, Huss A, Oeckl P, Ludolph AC, Kuhle J, Petzold A, Manley GT, Green AJ, Otto M, Tumani H. Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol. 2022 Mar;18(3):158-172. [CrossRef] [PubMed]
16. Soltani Z, Shahrokhi N, Karamouzian S, Khaksari M, Mofid B, Nakhaee N, Reihani H. Does progesterone improve outcome in diffuse axonal injury? Brain Inj. 2017;31(1):16-23. [CrossRef] [PubMed]
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Kenzie Ongko Wijaya, Nunki Puspita Utomo, Muhammad Andika Wibisono, Endro Basuki Sadjiman
This work is licensed under a Creative Commons Attribution 4.0 International License.
Ukrainian Neurosurgical Journal abides by the CREATIVE COMMONS copyright rights and permissions for open access journals.
Authors, who are published in this Journal, agree to the following conditions:
1. The authors reserve the right to authorship of the work and pass the first publication right of this work to the Journal under the terms of Creative Commons Attribution License, which allows others to freely distribute the published research with the obligatory reference to the authors of the original work and the first publication of the work in this Journal.
2. The authors have the right to conclude separate supplement agreements that relate to non-exclusive work distribution in the form of which it has been published by the Journal (for example, to upload the work to the online storage of the Journal or publish it as part of a monograph), provided that the reference to the first publication of the work in this Journal is included.
