The Newsletter of CIRCL, the Center for Injury Research & Control at the University of Pittsburgh

Volume 10, Issue 1: Spring 2007

Evaluating the Impact of Neuroendocrine Hormones on Pathophysiology and Outcomes after Traumatic Brain Injury (TBI)

Dr. Amy Wagner's study "Evaluating the Impact of Neuroendocrine Hormones on Pathophysiology and Outcomes after Traumatic Brain Injury (TBI)" is an ongoing examination of the role of hormones and markers of pathophysiology in the brain injury recovery process. Historically, men have had a higher incidence of TBI than women. Despite the fact that about 25% of the population with TBI is women, the large majority of clinical and animal research on TBI has been with males. Research reports suggest acute neuroprotection in the presence of female hormones. However, clinical studies evaluating gender differences in TBI pathophysiology and outcome have found that functional outcome is worse for female TBI patients. Determining whether endogenous hormones play a role in acute neuroprotection and influence later functional recovery is a major focus of the study. Further, understanding the role of sex hormones on both acute injury parameters and later outcome is important to optimize interventions for both males and females in this population.

Currently, there are 50 subjects, 40 males and 10 females, enrolled in the chronic examination of serum hormone levels over the first year post injury through the study. An additional 58 subjects have had cerebral spinal fluid (CSF) collected during their first week post-injury in order to evaluate hormone and injury biomarker levels, and an additional 60 subjects have had blood samples collected the first week post injury to analyze serum hormone levels during this first week of injury. All eligible subjects also complete neuropsychological outcome assessments at 6 and 12 months post injury to assess functional and cognitive outcomes. Initial functional outcomes assessment suggests that, for people who initially survive their injuries, global outcome and disability levels appear to be better for females. Preliminary analyses also suggest that there are several disruptions in CSF injury biomarker levels over the first 6 days post injury, some of which appear to be influenced by gender. Currently, the biomarker analysis examines levels of cell injury, antioxidant reserves and protein oxidation.

Initial analysis of CSF hormone levels over the first five days after injury reveals a disruption in normal hormone levels, where CSF cortisol levels are markedly elevated in the setting of low progesterone, testosterone, and estrogen levels. In addition, gender appears to influence the time course of some CSF hormonal production. Initial analysis of serum hormone levels after TBI also reveals disruption in hormonal patterns over the first five days post injury. The relationship of serum hormones with pituitary function suggests that hypogonadotropic hypogonadism may occur early after injury in males. Ongoing work will determine the duration and severity of this phenomenon over time as well as the relationship with pituitary function and female peripheral reproductive hormone status. Preliminary analysis suggests that serum progesterone levels are associated with CSF progesterone levels. However, no other associations between CSF hormones and their respective serum values or pituitary hormone levels are currently observed. These data also suggest that CNS progesterone, a substrate for neurosteroidogenesis, is dependent, in part, on progesterone levels in the periphery, while alterations in other CNS hormone levels are primarily a result of altered local neurosteroidogenesis. This association may also have implications for systemic progesterone supplementation as a treatment for TBI.

Latent Growth Curve Analysis is used to model trends of how groups of individuals change over time. One of the key unknown aspects of this study is how hormone/biomarker levels change over time after a TBI, and also whether particular groups of people with TBI have different patterns of change. Initial analysis has suggests that subjects can be clustered based on temporal patterns of CSF hormone and biomarker accumulation, and in some cases, clustering patterns for biomarkers were linked with mortality. These findings have implications for novel ways to use biomarkers with outcome prognostication in TBI.

Recently, IRB approval was granted for 30 control subjects to participate in an additional portion of the study for the purposes of obtaining blood and CSF. Dr. Wagner and fellow researchers plan to use these samples to establish baseline, or control, values for the injury related biomarkers and hormones being evaluated. Without control values for CSF sex hormones using the contemporary ELISA techniques, it is difficult to directly compare changes and alterations to CSF levels in brain injured patients with literature based control values. These data will further validate conclusions drawn about injury biomarker, gender and hormonal patterns observed with TBI.

With established baseline values for blood and CSF samples, continued analysis of hormone and biomarker changes, both acutely and chronically after TBI, and further latent growth curve analysis, a clearer picture of the role of sex hormones on outcome in TBI is emerging.