Dual-hormone stress reactivity predicts downstream war-zone stress-evoked PTSD

Highlights

• We tested the singular and interactive effects of cortisol (C_R) and testosterone (T_R) reactivity as moderators of PTSD emergence in theater.

• Blunted cortisol and testosterone stress reactivity at pre-deployment prospectively predicted PTSD symptom emergence in the war-zone.

• This hormonal reactivity profile appears to confer increased risk for PTSD by potentiating the pathogenic effects of war-zone stressors.

• Findings underscore the utility of assessing both HPA and HPG stress reactivity and may inform early detection of at risk soldiers for PTSD.

Abstract

Background

The crucial role of the hypothalamic-pituitary-adrenal axis (HPA) in stress-related homeostasis suggests dysregulated HPA involvement in the pathogenesis of post-traumatic stress disorder (PTSD), yet most studies examining linkages between HPA axis measures and PTSD have yielded null findings. One untested explanation for this inconsistency is a failure to account for simultaneous adrenal and gonadal influence. Here we tested the singular and interactive effects of cortisol (C_R) and testosterone (T_R) reactivity as moderators of war-zone stress evoked PTSD emergence in the war-zone.

Methods

U.S. soldiers (N = 120) scheduled for deployment to Iraq completed pre-deployment measures of C_R and T_R stress reactivity to a CO₂ inhalation challenge. Once deployed, monthly assessments of exposure to traumatic war-zone stressors and PTSD symptoms were collected via a web-based assessment system.

Results

Cortisol hypo-reactivity potentiated the pathogenic impact of war-zone stressors only in soldiers for whom the CO₂ challenge did not elevate testosterone, suggesting that the dual hormone stress reactivity profile of blunted cortisol and testosterone may confer increased risk for PTSD emergence by potentiating the pathogenic effects of war-zone stressors.

Conclusions

Findings underscore the utility of assessing both HPA and HPG stress reactivity when assessing PTSD vulnerability and may help inform efforts for enhanced soldier screening and inoculation to war-zone stressors.

Introduction

The HPA axis’ central role in the maintenance of stress-related homeostasis (see Charmandari et al., 2005) implies HPA dysregulation should be involved in the pathogenesis of stress-related disorders, including PTSD. Seminal studies supported this view in demonstrating strong associations between hypo-corticolism and PTSD (McFarlane et al., 1997, Resnick et al., 1995, Yehuda et al., 1995). Subsequent studies have replicated these findings (De Kloet et al., 2007, Rohleder et al., 2004, Steudte-Schmiedgen et al., 2015), but many studies have not. In fact, existing meta-analyses summarizing three decades of research have shown mixed, and overall null findings for HPA dysregulation in PTSD etiology (Klaassens et al., 2012, Meewisse et al., 2007).

One potential explanation for the mixed findings across studies is a failure to account for gonadal influence on HPA-axis function. Testosterone and other androgens exhibit potent anti-glucocorticoid effects (Agarwal et al., 1979, Danhaive and Rousseau, 1988, Sasson and Mayer, 2013), mediated by androgen-sensitive afferents to structures central to HPA-modulated stress regulation, including the medial pre-optic area, central and medial amygdala, and bed nuclei of the stria terminalis (Viau et al., 1999, Viau and Meaney, 1996). Further, testosterone has direct anxiolytic effects (Hermans et al., 2006), likely due to inhibitory activation of gamma-amino-butyric-acid (GABA) receptors (Bitran et al., 1993).

PTSD is generally regarded as a disorder of dysregulated threat reactivity. In line with this view, the peritraumatic period is marked by elevated cortisol and stress-evoked cortisol hyper-reactivity, followed by a temporally-graded reduction in HPA-axis activity, culminating in cortisol hypo-reactivity (Meewisse et al., 2007, Resnick et al., 1995, Rubinow et al., 2005, Valtysdóttir et al., 2001, Weems and Carrion, 2007, Yehuda et al., 2007). By inhibiting trauma-evoked HPA-axis hyper-reactivity during the peri-traumatic period (Handa et al., 1994b), testosterone might short-circuit the transition to blunted HPA-axis stress-reactivity in the post-trauma period. Moreover, testosterone's anti-glucocorticoid effects may protect against structural damage in the hippocampus (Gouras et al., 2000), producing long-term protection against the stress-evoked glucocorticoid-mediated neural degeneration thought to characterize PTSD (Kitayama et al., 2005, Sapolsky et al., 1990). Thus, evidence for androgen modulation of HPA-axis hyper-reactivity suggests that peritraumatic elevations in testosterone might protect against the subsequent emergence of PTSD.

Capitalizing on the established reputation of CO₂ inhalation as a laboratory stressor (Harrington et al., 1996, Perna et al., 1995, Schmidt and Zvolensky, 2007, Telch et al., 2011, Telch et al., 2010), we examined whether differences in hormonal reactivity to a single 35% CO₂/65% O₂ inhalation stress challenge accounts for variability in war-zone stress-evoked PTSD symptoms. Prior to their first-ever military deployment, U.S. soldiers bound for Iraq (N = 120) provided salivary hormone samples immediately prior to, and 30 min after CO₂ inhalation. Then, during their 16-month deployment, soldiers completed monthly web-based assessments of war-zone stressors and PTSD symptoms. This prospective design allowed us to examine the singular and joint effects of pre-deployment basal cortisol (C) and testosterone (T) and CO₂ challenge-evoked cortisol reactivity (C_R) and testosterone reactivity (T_R) as moderators of traumatic war-zone stressor effects on the subsequent emergence of PTSD symptoms in theater. The strength of PTSD predictors should be proportional to the degree to which they tap threat reactivity. Therefore, hormonal stress reactivity indices may exert a more potent influence in the pathogenesis of PTSD, relative to basal concentrations.