Dual-hormone stress reactivity predicts downstream war-zone stress-evoked PTSD
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 (CR) and testosterone reactivity (TR) 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.
Section snippets
Participants and procedures
Participants (N = 120) were recruited for the Texas Combat PTSD Risk Project, which aimed to prospectively identify biological, cognitive, and psychosocial risk factors for war-zone psychopathology. They were from 9 Army units (4 combat service support units, 4 combat units, and 1 combat support unit) planning to deploy from Ft. Hood to Iraq between August 2007 and August 2009. To reduce the possibility of perceived coercion to participate, unit leaders did not attend recruitment sessions.
Results
Incremental main effects for all modeled variables are presented in Table 2. Controlling for all covariates, soldiers’ pre-deployment cortisol reactivity to the CO2 challenge modulated the effects of war-zone stressors on PTSD symptom emergence during deployment. As presented in Fig. 1 and Table 3, relative to soldiers who exhibited an increase in cortisol in response to the CO2 challenge (b = 0.25, se = 0.17, t = 1.48, p = 0.142, r = 0.15), soldiers showing a decrease in cortisol showed greater PTSD
Discussion
Our findings identified a specific pre-deployment dual-hormone profile of PTSD risk vulnerability among healthy first-time deployed soldiers. After controlling for relevant covariates including basal levels of cortisol and testosterone, prior trauma, and emotional stress reactivity, soldiers displaying a hormone profile of blunted cortisol and blunted testosterone reactivity to a CO2 stressor challenge showed heightened PTSD symptom emergence at high levels of war-zone stressor exposure (see
Conclusion
Despite a strong theoretical basis, the sum of prior work investigating relations between HPA markers and trauma-related psychopathology has revealed overall null effects across studies (Klaassens et al., 2012, Meewisse et al., 2007). Consistent with our approach, efforts to resolve this conflicting literature have assumed ubiquitous model misspecification is responsible, and have appropriately called for more integrative and comprehensive neuroendocrine models, including identifying moderators
Financial disclosures
The authors report no biomedical financial interests or potential conflicts of interest.
Acknowledgments
This research was funded by the U.S. Army RDECOM Acquisition Center, Natick Contracting Division, and U.S. Defense Advanced Agency under Contract No. W911QY-07-C-0002 awarded to Michael J. Telch. Views expressed in this article may not necessarily be endorsed by the U.S. Army.
References (70)
- et al.
Testosterone rapidly reduces anxiety in male house mice (Mus musculus)
Horm. Behav.
(2002) - et al.
Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat
Horm. Behav.
(1993) - et al.
Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach
Eur. J. Pharmacol.
(2008) - et al.
Evidence for sex-dependent anabolic response to androgenic steroids mediated by muscle glucocorticoid receptors in the rat
J. Steroid Biochem.
(1988) - et al.
Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder
Psychoneuroendocrinology
(2007) - et al.
Measurement of lactate-induced panic and anxiety
Psychiatry Res.
(1987) - et al.
Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis
Horm. Behav.
(1994) - et al.
Androgen regulation of adrenocorticotropin and corticosterone secretion in the male-rat following novelty and foot shock stressors
Physiol. Behav.
(1994) - et al.
Response of amygdalar norepinephrine to footshock and GABAergic drugs using in vivo microdialysis and HPLC
Brain Res.
(1999) - et al.
A single administration of testosterone reduces fear-potentiated startle in humans
Biol. Psychiatry
(2006)
Stress and emotional memory: a matter of timing
Trends Cogn. Sci. (Regul. Ed.)
A behavioural neuroscience perspective on the aetiology and treatment of anxiety disorders
Behav. Res. Ther.
Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis
J. Affect. Disord.
Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: a meta-analysis
Psychoneuroendocrinology
The combat experience log: a web-based system for the in theater assessment of war zone stress
J. Anxiety Disord.
Sex differences in anxiety and depression: role of testosterone
Front. Neuroendocrinol.
The influence of gonadal hormones on conditioned fear extinction in healthy humans
Neuroscience
Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: a systematic review and meta-analysis
Clin. Psychol. Rev.
Hypersensitivity to inhalation of carbon dioxide and panic attacks
Psychiatry Res.
The effect of deployment to a combat zone on testosterone levels and the association with the development of posttraumatic stress symptoms: a longitudinal prospective Dutch military cohort study
Psychoneuroendocrinology
Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder
Biol. Psychiatry
Suppression of cortisol levels in subordinate female marmosets: reproductive and social contributions
Horm. Behav.
Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study
Biol. Psychiatry
Glucocorticoids do not reduce subjective fear in healthy subjects exposed to social stress
Biol. Psychol.
Hair cortisol concentrations and cortisol stress reactivity predict PTSD symptom increase after trauma exposure during military deployment
Psychoneuroendocrinology
Effects of threat context and cardiac sensitivity on fear responding to a 35% CO2 challenge: a test of the context-sensitivity panic vulnerability model
J. Behav. Ther. Exp. Psychiatry
Unexpected arousal, anxiety sensitivity, and their interaction on CO₂-induced panic: further evidence for the context-sensitivity vulnerability model
J. Anxiety Disord.
Gonadal hormone regulation of the emotion circuitry in humans
Neuroscience
Stress and memory in humans: twelve years of progress?
Brain Res.
The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior
Cell
Search for antiglucocorticoid activity in rat liver in vivo
Res. Exp. Med.
Multiple Regression: Testing and Interpreting Interactions
Diagnostic and Statistical Manual of Mental Disorders (DSM-5®)
Validating the primary care posttraumatic stress disorder screen and the posttraumatic stress disorder checklist with soldiers returning from combat
J. Consult. Clin. Psychol.
Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder
Am. J. Psychiatry
Cited by (22)
Genetic influences on testosterone and PTSD
2024, Journal of Psychiatric ResearchBiomarkers in PTSD-susceptible and resistant veterans with war experience of more than ten years ago: FOCUS ON cortisol, thyroid hormones, testosterone and GABA
2022, Journal of Psychiatric ResearchCitation Excerpt :Our results are also consistent with the study by Reijnen et al. (2015) showing no difference in testosterone level between PTSD and PTSD-resistant patients. It is possible that increased testosterone levels in the resistant group contribute to PTSD resistance (Josephs, 2017), but this question obviously requires further research. In our study, no significant differences were present between the studied groups in the levels of the thyroid hormones and thyroid stimulating hormone, which casts doubt on their significance as a biomarker at least in this group of military.
Melatonin pretreatment alleviates blast-induced oxidative stress in the hypothalamic-pituitary-gonadal axis by activating the Nrf2/HO-1 signaling pathway
2021, Life SciencesCitation Excerpt :We believe that the abnormal behavior caused by explosion stress may be related to unbalanced hormone levels. It has been reported that blunted cortisol and testosterone stress reactivity increased the risk of PTSD by potentiating the pathogenic effects of war-zone stressors [32]. Our findings suggest that the hormone levels of the HPG and HPA axes may be associated with PTSD.
Genomic factors underlying sex differences in trauma-related disorders
2021, Neurobiology of StressCitation Excerpt :One hypothesis for the inconsistency between studies is the involvement of both gonadal and adrenal hormones in stress reactivity, as well as the timing of trauma. In one study of soldiers in a war-zone, Josephs and colleagues found that lower pre-deployment levels of both saliva cortisol and testosterone were associated with increased risk of developing PTSD after a traumatic stressor (Josephs et al., 2017). Another study supported the effect of an underlying biological vulnerability, demonstrating a correlation of testosterone levels before stressor exposure on the development of PTSD symptomatology (Reijnen et al., 2015).
HPA axis function and diurnal cortisol in post-traumatic stress disorder: A systematic review
2019, Neurobiology of StressCitation Excerpt :The exclusion of studies that did not measure diurnal cortisol output provides a more comparable view of HPA axis functionality in PTSD sufferers as opposed to one aspect of its functionality (Ryan et al., 2016; Schumacher et al., 2018). Given the complexity of the interactions between the physiological systems and mechanisms and their associated hormones as well as the vast unknowns in psychoneuroendocrinology research itself, the selected studies have established a foundation for HPA axis functionality in PTSD sufferers as portrayed by their diurnal cortisol profiles (Josephs et al., 2017). The findings of the included studies propose that the HPA axis is not functioning properly in the PTSD population but whether this is associated with diurnal cortisol secretion output is not consistently observed.
- 1
Current address: Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.