Systemic Estrone Production and Injury-Induced Sex Hormone Steroidogenesis after Severe Traumatic Brain Injury: A Prognostic Indicator of Traumatic Brain Injury-Related Mortality

Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0-3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p