Sex-specific mechanisms of childhood trauma-related HPA axis dysregulation: Insights across four regulatory probes.

Blunted cortisol reactivity (BCR) to stress has been linked to trauma symptoms and early life adversity (ELA). Despite evidence for sex differences in ELA's impact on cortisol reactivity, few stress reactivity studies adequately assess sex-specificity. Further, most have measured salivary cortisol response to a single regulatory probe, limiting conclusions regarding mechanisms contributing to trauma-related HPA axis dysregulation. Using measures of cortisol binding globulin (CBG), serum adrenocorticotropic hormone (ACTH), and serum and salivary cortisol across four regulatory probes, this study assessed sex-specific mechanisms of ELA-related HPA axis dysregulation. 116 adults (55 female; 61 male) completed the Trier Social Stress Test (TSST), ACTH stimulation test, and low and high dose dexamethasone suppression tests (DST), and provided serum ACTH and cortisol, salivary cortisol, and CBG samples. For women, probes were scheduled to avoid ovulatory estrogen surges. Regressions in sex-disaggregated data examined the impact of ELA on cortisol reactivity and three candidate mechanisms of BCR. We found a negative association between salivary cortisol reactivity and ELA in females (p = .037), with no relation in males. In females, neither CBG nor adrenal sensitivity explained blunting; ELA was, however, associated with enhanced feedback inhibition (p = .033). Findings imply that the relation between ELA and adult BCR may primarily be present in females. The observed patterns were more consistent with enhanced feedback inhibition as a candidate pathway to trauma-related blunting in women than altered adrenal sensitivity or blunting explained by CBG. Future sex-disaggregated approaches may clarify persistently elusive pathways between trauma, HPA axis dysregulation, and adverse health outcomes.