Acute Serum Hormone Levels: Characterization and Prognosis after Severe Traumatic Brain Injury

Abstract

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n = 536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n = 14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

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

“…Similar to reports regarding acute serum hormone levels, 10 older subjects had higher estradiol ( p = 0.033) and testosterone ( p = 0.051) levels. E2/ T ratios were not affected by age.…”

“…Testosterone pretreatment in models of TBI, however, can increase histological damage. 12 Our clinical research supports the dual and varied temporal effects of estradiol and testosterone on CNS neuroprotection and neuroplasticity, discussed in these studies cited above, by showing that high acute serum testosterone and estradiol levels are linked with worse outcomes, 10 whereas higher chronic endogenous serum testosterone and estrogen levels over the first year postinjury are associated with better outcomes in a small population of men with severe TBI (sTBI). 13 However, to date, no studies have established cerebrospinal fluid (CSF) estradiol and testosterone profiles after TBI, their relationships to serum hormone profiles, and if or how these profiles might relate to secondary TBI and outcome.…”

“…These findings in CSF contrast with low serum testosterone and relatively normal serum estradiol overall for TBI subjects, compared to controls. 10 In bivariate analysis with the TBI cohort, those who had higher CSF E2/ T ratios had lower acute mortality rates and better GOS-6 scores. T-allele carriers for rs2470152 had significantly worse outcomes as well as lower CSF E2/T ratios, suggesting that the T allele may be a risk allele.…”

“…Previous work shows that hormone values from morning versus evening samples were not statistically different, and this finding is consistent with the concept that normal physiological hormone variation is disrupted and rapid development of hypogonadotropic hypogonadism occurs after sTBI. 10 Upon collection, each sample was centrifuged, aliquoted, and stored at -80°C until assayed. For control subjects, blood was drawn at 7:00 am, processed, and stored until assayed.…”

“…9 Although hormone use in animal models has demonstrated the neuroprotective qualities of estradiol, systemic estradiol levels early after severe injury in humans are associated with mortality and poor outcomes. 10 Androgens can also influence neuronal growth and plasticity in the CNS. Removal of testes in rats and monkeys reduces the density of synaptic contacts on CA1 neurons, an effect reversed by administering testosterone.…”