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November 2009

Gender influences outcome of brain injury: progesterone plays a protective role.

The contributions of gender and gonadal hormones in the cascade of events following brain injury are largely unexplored. We measured cerebral edema following cerebral contusion in rats under three hormonal conditions to address this issue. Normally cycling females exhibited significantly less edema than males, and pseudopregnant females were virtually spared from post-injury edema. Subsequent studies of ovariectomized females, with or without hormone treatment, indicated that the reduction of cerebral edema was associated primarily with the presence of circulating progesterone. We conclude that progesterone has a protective effect on the brain following traumatic injury.

Brain Res. 1993 Apr 2;607(1-2):333-6

Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats.

The ability of progesterone to reduce the cerebral edema associated with traumatic brain damage first became apparent when we observed that males had significantly more edema than females after cortical contusion. In addition, edema was almost absent in pseudopregnant female rats, a condition in which progesterone levels are high relative to estrogen. Progesterone injections given after injury also reduced edema and were equally effective in both males and females. The present experiment was done to determine if the progesterone-induced reduction in edema could also prevent secondary neuronal degeneration and reduce the behavioral impairments that accompany contusion of the medial frontal cortex. Progesterone-treated rats were less impaired on a Morris water maze spatial navigation task than rats treated with the oil vehicle. Progesterone-treated rats also showed less neuronal degeneration 21 days after injury in the medial dorsal thalamic nucleus, a structure that has reciprocal connections with the contused area.

Exp Neurol. 1994 Sep;129(1):64-9

Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective.

Cerebral edema is a serious side effect of traumatic brain injury. We have previously established that progesterone injections, initiated within 1 h after cortical contusion injury, reduced edema when assessed 3 days later. To determine how rapidly progesterone can reduce edema, male and female rats were given the hormone 1 h after damage to the medial frontal cortex, and edema levels were assessed between 2 h and 7 days postinjury. Progesterone decreased edema with 6 h of the injury and continued to be effective for the duration of treatment. In addition, we assessed whether progesterone injections are effective when delays are imposed between injury and initiation of treatment. Male and female rats received progesterone after postinjury delays 6, 24, or 48 h. Progesterone was effective in reducing edema when treatment was delayed until 24 h after injury.

Exp Neurol. 1996 Apr;138(2):246-51

ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.

STUDY OBJECTIVE: Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury. METHODS: This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury. RESULTS: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.

Ann Emerg Med. 2007 Apr;49(4):391-402

Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial.

BACKGROUND: Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI. METHODS: A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score </= 8 were enrolled in the study. A prospective, randomized, placebo-controlled trial of progesterone was conducted in the Neurotrauma Center of our teaching hospital. The patients were randomized to receive either progesterone or placebo. The primary endpoint was the Glasgow Outcome Scale score 3 months after brain injury. Secondary efficacy endpoints included the modified Functional Independence Measure score and mortality. In a follow-up protocol at 6 months, the Glasgow Outcome Scale and the modified Functional Independence Measure scores were again determined. RESULTS: 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 for the two groups. After 3 months and 6 months of treatment, the dichotomized Glasgow Outcome Scale score analysis exhibited more favorable outcomes among the patients who were given progesterone compared with the control individuals (P = 0.034 and P = 0.048, respectively). The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). The mean intracranial pressure values 72 hours and 7 days after injury were lower in the progesterone group than in the placebo group, but there was no statistical significance between the two groups (P > 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found. CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug.

Crit Care. 2008;12(2):R61

Progesterone exerts neuroprotective effects after brain injury.

Progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. This review assesses recent, primarily in vivo, evidence that progesterone can play an important role in promoting and enhancing repair after traumatic brain injury and stroke. Although many of its specific actions on neuroplasticity remain to be discovered, there is growing evidence that this hormone may be a safe and effective treatment for traumatic brain injury and other neural disorders in humans.

Brain Res Rev. 2008 Mar;57(2):386-97

The membrane-associated progesterone-binding protein 25-Dx: expression, cellular localization and up-regulation after brain and spinal cord injuries.

Progesterone has neuroprotective effects in the injured and diseased spinal cord and after traumatic brain injury (TBI). In addition to intracellular progesterone receptors (PR), membrane-binding sites of progesterone may be involved in neuroprotection. A first putative membrane receptor of progesterone, distinct from the classical intracellular PR isoforms, with a single membrane-spanning domain, has been cloned from porcine liver. Homologous proteins were cloned in rats (25-Dx), mice (PGRMC1) and humans (Hpr.6). We will refer to this progesterone-binding protein as 25-Dx. The distribution and regulation of 25-Dx in the nervous system may provide some clues to its functions. In spinal cord, 25-Dx is localized in cell membranes of dorsal horn neurons and ependymal cells lining the central canal. A role of 25-Dx in mediating the protective effects of progesterone in the spinal cord is supported by the observation that its mRNA and protein are up-regulated by progesterone in dorsal horn of the injured spinal cord. In contrast, the classical intracellular PRs were down-regulated under these conditions. In brain, 25-Dx is particularly abundant in the hypothalamic area, circumventricular organs, ependymal cells of the ventricular walls, and the meninges. Interestingly, it is co-expressed with vasopressin in neurons of the paraventricular, supraoptic and retrochiasmatic nuclei. In response to TBI, 25-Dx expression is up-regulated in neurons and induced in astrocytes. The expression of 25-Dx in structures involved in cerebrospinal fluid production and osmoregulation, and its up-regulation after brain damage, point to a potentially important role of this progesterone-binding protein in the maintenance of water homeostasis after TBI. Our observations suggest that progesterone’s actions may involve different signaling mechanisms depending on the pathophysiological context, and that 25-Dx may be involved in the neuroprotective effect of progesterone in the injured brain and spinal cord.

Brain Res Rev. 2008 Mar;57(2):493-505

Progesterone: therapeutic opportunities for neuroprotection and myelin repair.

Progesterone and its metabolites promote the viability of neurons in the brain and spinal cord. Their neuroprotective effects have been documented in different lesion models, including traumatic brain injury (TBI), experimentally induced ischemia, spinal cord lesions and a genetic model of motoneuron disease. Progesterone plays an important role in developmental myelination and in myelin repair, and the aging nervous system appears to remain sensitive to some of progesterone’s beneficial effects. Thus, the hormone may promote neuroregeneration by several different actions by reducing inflammation, swelling and apoptosis, thereby increasing the survival of neurons, and by promoting the formation of new myelin sheaths. Recognition of the important pleiotropic effects of progesterone opens novel perspectives for the treatment of brain lesions and diseases of the nervous system. Over the last decade, there have been a growing number of studies showing that exogenous administration of progesterone or some of its metabolites can be successfully used to treat traumatic brain and spinal cord injury, as well as ischemic stroke. Progesterone can also be synthesized by neurons and by glial cells within the nervous system. This finding opens the way for a promising therapeutic strategy, the use of pharmacological agents, such as ligands of the translocator protein (18 kDa) (TSPO; the former peripheral benzodiazepine receptor or PBR), to locally increase the synthesis of steroids with neuroprotective and neuroregenerative properties. A concept is emerging that progesterone may exert different actions and use different signaling mechanisms in normal and injured neural tissue.

Pharmacol Ther. 2007 Oct;116(1):77-106

Does progesterone have neuroprotective properties?

In this article, we review published preclinical and epidemiologic studies that examine progesterone’s role in the central nervous system. Its effects on the reproductive and endocrine systems are well known, but a large and growing body of evidence, including a recently published pilot clinical trial, indicates that the hormone also exerts neuroprotective effects on the central nervous system. We now know that it is produced in the brain, for the brain, by neurons and glial cells in the central and peripheral nervous system of both male and female individuals. Laboratories around the world have reported that administering relatively large doses of progesterone during the first few hours to days after injury significantly limits central nervous system damage, reduces loss of neural tissue, and improves functional recovery. Although the research published to date has focused primarily on progesterone’s effects on blunt traumatic brain injury, there is evidence that the hormone affords protection from several forms of acute central nervous system injury, including penetrating brain trauma, stroke, anoxic brain injury, and spinal cord injury. Progesterone appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All are plausible mechanisms of neuroprotection.

Ann Emerg Med. 2008 Feb;51(2):164-72

Progesterone improves acute recovery after traumatic brain injury in the aged rat.

Recent evidence has demonstrated that treatment with progesterone can attenuate many of the pathophysiological events following traumatic brain injury (TBI) in young adult rats, but this effect has not been investigated in aged animals. In this study, 20-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n = 4 per group) or sham operations received 8, 16, or 32 mg/kg of progesterone or vehicle. Locomotor activity was measured at 72 h to assess behavioral recovery. Brain tissue was harvested at 24, 48, and 72 h, and Western blotting was performed for inflammatory and apoptotic factors. Edema was assessed at 48 h by measuring brain water content. Injured animals treated with 8 and 16 mg/kg progesterone showed decreased expression of COX-2, IL-6, and NFkappaB at all time points, indicating a reduction in the acute inflammatory process compared to vehicle. The 16 mg/kg group also showed reduced apoptosis at all time points as well as decreased edema and improved locomotor outcomes. Thus, in aged male rats, treatment with 16 mg/kg progesterone improves short-term motor recovery and attenuates edema, secondary inflammation, and cell death after TBI.

J Neurotrauma. 2007 Sep;24(9):1475-86