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

Abstract

Despite significant advances in the management of head trauma, there remains a lack of pharmacological treatment options for traumatic brain injury (TBI). While progesterone clinical trials have shown promise, corticosteroid trials have failed. The purpose of this study was to (1) characterize endogenous cerebrospinal fluid (CSF) progesterone and cortisol levels after TBI, (2) determine relationships between CSF and serum profiles, and (3) assess the utility of these hormones as predictors of long-term outcomes. We evaluated 130 adults with severe TBI. Serum samples (n = 538) and CSF samples (n = 746) were collected for 6 days post-injury, analyzed for cortisol and progesterone, and compared with healthy controls (n = 13). Hormone data were linked with clinical data, including Glasgow Outcome Scale (GOS) scores at 6 and 12 months. Group based trajectory (TRAJ) analysis was used to develop temporal hormone profiles delineating distinct subpopulations. Compared with controls, CSF cortisol levels were significantly and persistently elevated during the first week after TBI, and high CSF cortisol levels were associated with poor outcome. As a precursor to cortisol, progesterone mediated these effects. Serum and CSF levels for both cortisol and progesterone were strongly correlated after TBI relative to controls, possibly because of blood-brain barrier disruption. Also, differentially impaired hormone transport and metabolism mechanisms after TBI, potential de novo synthesis of steroids within the brain, and the complex interplay of cortisol and pro-inflammatory cytokines may explain these acute hormone profiles and, when taken together, may help shed light on why corticosteroid trials have previously failed and why progesterone treatment after TBI may be beneficial.

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

“…Previous studies (Santarsieri et al, 2014) show that IL-6 levels, but not other inflammatory markers (IL-10, TNFa, sICAM, and sFAS) are significantly higher in CSF compared to serum, suggesting potential for IL-6 as a neuro-specific inflammatory marker that is sensitive to outcome, even in the post-acute phase.…”

“…CSF IL-6 concentrations in clinical TBI populations are highly variable, ranging from 50-124,000 pg/mL in one study (Hillman et al, 2007), suggesting that robust statistical methods may be required to accurately characterize the inflammatory response. Previously, our group has applied group based trajectory modeling (TRAJ) analysis in order to identify temporal biomarker profiles for distinct TBI populations with similar physiological responses post-injury (Wagner et al, 2011a,b;Goyal et al, 2013;Niyonkuru et al, 2013;Santarsieri et al, 2014). Applying TRAJ to inflammatory biomarker studies may capture and characterize longitudinal inflammatory responses after TBI and identify patient and clinical characteristics and prognoses associated with these profiles consistent with a Rehabilomics approach (Wagner, 2010;Wagner and Zitelli, 2013;Wagner, 2014).…”

Early endocrine alterations reflect prolonged stress and relate to 1-year functional outcome in patients with severe brain injury

“…However, low Glasgow Outcome Scale-Extended scores were more frequent in patients with reduced gonadal and/or thyroid hormones and increased stress hormones, whereas only increased stress hormones remained independently related to a worse Glasgow Outcome Scale-Extended score at the 1-year follow-up. Santarsieri et al (38) recently measured cortisol in the cerebrospinal fluid of the TBI patients and showed persistently elevated cortisol during the first 6 days after trauma, which was associated with poorer outcomes, as measured by Glasgow Outcome Scale scores and Functional Independence Measure cognitive scores 6 months after the injury. Recently, pituitary abnormalities in 27% of patients 3-6 months after a subarachnoid haemorrhage were significantly related to lower median Glasgow Outcome Scale scores at follow-up, with more prevalent endocrine abnormalities occurring when bleeding sites were closer to the hypothalamus (39).…”

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system

“…This transient increase in plasma progesterone most likely reflected stimulation of the adrenal gland and may be neuroprotective [231]. In contrast to progesterone, levels of cortisol remained elevated in both sexes [232].…”