Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

Abstract

Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality ( p = 0.019) and better GOS-6 scores ( p = 0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone ( p £ 0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores ( p £ 0.05, all comparisons), and those with > 1 risk SNP variant had a higher risk for poor outcome, compared with those with £ 1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI.

Cerebrospinal Fluid Cortisol and Progesterone Profiles and Outcomes Prognostication after Severe Traumatic Brain Injury

“…Similar elevations and effects on outcome have been reported in a variety of neurological conditions, including septic shock, bacterial meningitis, post-traumatic stress disorder, Alzheimer disease, depression, and multiple sclerosis. [47][48][49][50][51][52] This study further extends previous work 33,34 by systematically attempting to elucidate the origins and implications behind endogenous hormone profiles after TBI. This goal was accomplished by identifying temporal CSF hormone profiles, investigating correlations between serum and CSF hormone levels, and examining injury-specific relationships between CSF progesterone and cortisol levels.…”

“…While high serum estradiol levels are associated with poor outcome after severe TBI and other populations with significant trauma, 33 higher CSF estradiol/ testosterone ratios are linked to better outcomes and support the neuroprotection hypothesis for estradiol. 34 So while it is possible that supplemental progesterone may be metabolized to cortisol and augment both peripheral and CNS glucocorticoid levels, it is also possible that progesterone supplementation may instead offset any potential negative effects of augmented CNS cortisol with its pleiotropic neuroprotective effects in the CNS and conversion to other hormones with neuroprotective qualities. In fact, it has been recently suggested that progesterone secretion in astrocytes can protect them from corticosterone-induced damage in rats.…”

“…33 Interestingly, estradiol and testosterone levels in the periphery were not well correlated with CSF levels. 34 Acute CSF progesterone and cortisol profiles have not been reported in the context of TBI, and their ability to discriminate outcomes has not been evaluated. Thus, the purpose of this study was to evaluate CSF progesterone and CSF cortisol profiles over the first week after severe TBI, determine relationships between these CSF profiles and concurrent serum profiles, and evaluate the sensitivity of these profiles in discriminating outcomes.…”

A New Rabbit Model of Pediatric Traumatic Brain Injury

“…69 Studies show that factors including mitochondrial polymorphisms, 70 aromatase genetic variation 71 and glucose variability 72 may impact 1376 ZHANG ET AL.…”

Insight into Traumatic Brain Injury from Intimate Partner Violence: A Grounded Theory Study

“…SNP results from a substitution, deletion, or insertion of a base in the genetic code. [42][43][44][45][46] The two most studied types of epigenetic changes that influence recovery from TBI (often in animal models) involves methylation, when a molecule of DNA is capped by a methyl group that prevents transcription (essentially turning the gene "off").…”