The neuroendocrine network imbalance in post-traumatic stress disorder: from core mechanisms to clinical translation

Post-traumatic stress disorder (PTSD) is a profound neurobiological disorder in which dysregulation of the neuroendocrine system represents a core pathophysiological feature. This Review synthesizes recent advances in PTSD neuroendocrine research to delineate a comprehensive and dynamic pathological landscape that extends beyond traditional single-axis frameworks. We first examine the central role of the hypothalamic-pituitary-adrenal (HPA) axis, highlighting the well-known paradox of enhanced central drive accompanied by low peripheral cortisol levels and discussing feedback dysregulation mediated by the glucocorticoid receptor (GR) and its co-chaperone FK506-binding protein 51 (FKBP5). Moving beyond the HPA axis, we situate it within a broader neuroendocrine network, reviewing its complex interactions with the hypothalamic-pituitary-thyroid (HPT) axis, the hypothalamic-pituitary-gonadal (HPG) axis, and the sympathetic-adrenal-medullary (SAM) system, as well as with neuropeptides including neuropeptide Y (NPY), orexin, and arginine vasopressin (AVP). This integrated view reveals PTSD as a multi-system, network-level disturbance. We then explore how these neuroendocrine alterations drive downstream molecular mechanisms-specifically neuroinflammation, a shift in the kynurenine pathway, mitochondrial dysfunction, and impaired brain-derived neurotrophic factor (BDNF) signaling-that collectively remodel stress-related brain circuits. Finally, we outline future research priorities, such as spatiotemporal dynamics and multimodal network modeling, and summarize emerging therapeutic strategies. Adopting this multidimensional network perspective is essential for advancing mechanistic understanding and guiding novel interventions.