Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials

Lin, Chao; He, Hong; Zheng, Liping; Liu, Yinglong; Chao, Honglu; Ji, Jing; Liu, Ning

doi:10.1038/srep13442

Cited by 30 publications

(17 citation statements)

References 36 publications

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“…The potential therapeutic effects of estrogen and progesterone are beyond the scope of this Review, but they have been well studied in humans and animals. It is worth noting that, although many preclinical studies have indicated a multitude of positive benefits for progesterone treatment post‐TBI, from decreased inflammation and cerebral edema to increased functional skills in rats, a recent meta‐analysis of seven randomized clinical control trials (six of which included a representative female population) failed to demonstrate a significant mortality difference between the progesterone‐treated group and the placebo group and concluded that progesterone did not improve outcomes over placebo after TBI (Hirschberg, ; Lin et al, ). One reason for this discrepancy between preclinical and clinical outcomes probably lies in the heterogeneous nature of human TBI, which is more complex and variable than in laboratory models (Wright et al, ).…”

Section: Sex Differences In Preclinical Outcomesmentioning

confidence: 99%

Do microglia play a role in sex differences in TBI?

Caplan¹,

Cox²,

Bedi³

2016

J of Neuroscience Research

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Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality for both males and females and is, thus, a major focus of current study. Although the overall death rate of TBI for males is roughly three times higher than that for females, males have been disproportionately represented in clinical and preclinical studies. Gender differences are known to exist in many neurologic disorders, such as multiple sclerosis and stroke, and differences appear to exist in TBI. Furthermore, it is known that microglia have sexually dimorphic roles in CNS development and other neurologic conditions; however, most animal studies of microglia and TBI have focused on male subjects. Microglia are a current target of many preclinical and clinical therapeutic trials for TBI. Understanding the relationship among sex, sex hormones, and microglia is critical to truly understanding the pathophysiology of TBI. However, the evidence for sex differences in TBI centers mainly on sex hormones, and evidenced-based conclusions are often contradictory. In an attempt to review the current literature, it is apparent that sex differences likely exist, but the contradictory nature and magnitude of such differences in the existing literature does not allow definite conclusions to be drawn, except that more investigation of this issue is necessary. © 2016 Wiley Periodicals, Inc.

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Section: Sex Differences In Preclinical Outcomesmentioning

confidence: 99%

Do microglia play a role in sex differences in TBI?

Caplan¹,

Cox²,

Bedi³

2016

J of Neuroscience Research

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“…Traumatic brain injury (TBI) is a leading cause of human death and morbidity worldwide and affects as many as 2 million individuals in the United States with 70,000–90,000 new cases annually (Lenzlinger et al, ; Maas et al, ). In recent years, clinical outcome improvement has improved, yet large numbers of patients are unable to make a full recovery (Lin et al, ). Damage to the brain can be separated into two phases, the initial primary physical trauma that results from the physical displacements of the brain tissue, and the second injury, which is the brain's response to the trauma.…”

Section: Introductionmentioning

confidence: 99%

“…Despite this abundance of research suggesting that P4 is beneficial following injury and the success of a few small Phase 2 trials, when larger multicenter Phase 3 trials were conducted, no effect of P4 was found over placebo (Lin et al, ; Schumacher et al, ). Furthermore, many have suggested that while there are limitations to preclinical animal studies by current standards, the Phase 3 trials were designed and conducted well and the problem lies in the fundamental bias in the present practice of scientific inquiry (Schumacher et al, ; Schwamm, ).…”

Section: Introductionmentioning

confidence: 99%

Exogenous progesterone is neuroprotective following injury to the male zebra finch brain

Blackshear

Giessner

Hayden

et al. 2017

J of Neuroscience Research

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The use of progesterone following brain injury has a controversial history. On one hand, some lab-based models have showed progesterone as being neuroprotective, but on the other, clinical trials have showed quite the opposite. One of many complaints that arose from this discrepancy was the lack of a diverse pool of animal models and paradigms employed during the preclinical phase. However, over the past decade, the zebra finch has emerged as an optimal organism for the study of steroid-mediated neuroprotection. Following an injury, steroid hormones and receptors are upregulated, serving to decrease neuroinflammation and overall damage to the brain. As compared to other vertebrate models, zebra finches can upregulate expression of both estrogens and androgens at a faster and more robust response, suggesting that vertebrates differ in their neuroprotective mechanisms and timing following injury. Therefore, to expand the types organisms studied in pre-clinical trials, we chose to use zebra finches. While the majority of work in the zebra finch brain has focused on estrogens and androgens, we sought to clarify the role of progesterone following injury. Adult male zebra finches were given daily injections of progesterone following a penetrating injury and then were assessed for the size of injury and expression of various genes associated with neuroinflammation and cell survival. Treatment with progesterone decreased the injury size in zebra finches over controls and increased expression of various genes associated with cell survival and neuroinflammation. These data suggest that progesterone does mediate neuroprotection, most likely through the alteration of neuroinflammatory and cell survival pathways.

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“…Approximately 2,400 patients between 15 and 70 years received a progesterone or placebo therapy after an acute TBI. Disappointingly, they showed no significant differences in the favorable outcome or mortality rate (Lin et al, ; Ma et al, ; Wang et al, ). Therefore, the question arises how these differences in the effect or the deficiency of action of progesterone in various types and regions of the nervous system can be explained.…”

Section: Progesterone and Prsmentioning

confidence: 99%

Progesterone Effects in the Nervous System

Theis

Theiß

2019

The Anatomical Record

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The sex hormone progesterone is mainly known as a key factor in establishing and maintaining pregnancy. In addition, progesterone has been shown to induce morphological changes in the central and peripheral nervous system by increasing dendrito-, spino-, and synaptogenesis in Purkinje cells (Wessel et al.: Cell Mol Life Sci (2014a) 1723-1740 and increasing axonal outgrowth in dorsal root ganglia (Olbrich et al.: Endocrinology (2013) 3784-3795). These effects mediated mainly by the classical progesterone receptors (PRs) A and B seem to be limited to young neurons. It may be assumed that microRNAs (miRNAs), which are potent regulators of nervous system maturation and degeneration, are also involved in the regulation of progesterone-mediated neuronal plasticity by altering the expression patterns of the corresponding PR A/B receptors (Theis and Theiss: Neural Regen Res (2015) 547-549, Pieczora et al.: Cerebellum (2017) 376-387). This review critically discusses current data on the neuroprotective effect of progesterone and its corresponding receptors in the nervous system, with possible regulatory processes by miRNAs. Preclinical studies on stroke and traumatic brain injury revealed neuroprotective and neuroregenerative effects of progesterone in the treatment of severe neurological diseases in animal models, but have so far failed in humans. In this context, the identification of specific miRNAs that regulate the expression of progesterone and PR could help to exploit the neuroprotective potential of progesterone for the treatment of various neurological disorders. The human nervous system is a highly complex tissue composed of neurons and glial cells with a limited ability to regenerate after lesion or degeneration. In particular, the loss of neurons, for example, due to aging processes, stroke, or traumatic brain injury (TBI), is mostly irreversible. The function of the degenerating neurons can be partially compensated by neighboring neurons, but astroglial-fibrotic scar formation minimizes neuronal regeneration .Progesterone, a sexual hormone, is mainly known for its key role in the female reproductive circuit and the maintenance of pregnancy. In this context, the fact that progesterone is also expressed in the male organism is often neglected (Schumacher et al., 2014). Besides this, Abbreviations: BBB = blood brain barrier; CNS = central nervous system; DRG = dorsal root ganglia; GABA = Gamma-amino butyric acid; miRNA = microRNA; NMDAR = N-Methyl-D-aspartate receptor; PC = Purkinje cells; PGRMC1 = progesterone receptor membrane component 1; PNS = peripheral nervous system; PR = progesterone receptor; SCI = spinal cord injury; TBI = traumatic brain injury

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Efficacy of progesterone for moderate to severe traumatic brain injury: a meta-analysis of randomized clinical trials

Cited by 30 publications

References 36 publications

Do microglia play a role in sex differences in TBI?

Do microglia play a role in sex differences in TBI?

Exogenous progesterone is neuroprotective following injury to the male zebra finch brain

Progesterone Effects in the Nervous System

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