The Hypothalamic–Pituitary–Adrenal Axis in the Regulation of Mood and Emotion

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis serves as the body's primary stress response system, coordinating hormonal cascades that influence mood and psychological well-being. This network involves the hypothalamus, pituitary gland, and adrenal cortex, releasing corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol in response to stress. While normally protective, chronic HPA axis activation in modern environments creates pathological conditions impacting mental health. HPA axis hyperactivity in mood disorders, characterized by elevated cortisol levels that negatively affect mood, cognition, and neuronal structure. This dysregulation creates a cycle where stress hormones exacerbate symptoms, triggering further activation. HPA axis dysfunction is linked to increased suicide risk independent of other psychiatric conditions. Anxiety disorders manifest as heightened stress sensitivity with exaggerated cortisol responses. Recent discoveries reveal gut microbiota influences on HPA axis activity through microbial metabolites, establishing a gut-brain-HPA connection. Sex differences significantly impact stress responses, with females exhibiting more pronounced reactions, contributing to higher prevalence of stress-related disorders in women. HPA axis dysregulation impairs prefrontal cortex functioning and hyperactivates the amygdala, resulting in poor decision-making and emotional dysregulation. Future therapeutic approaches emphasize personalized medicine incorporating biomarker testing, genetic screening, and digital health technologies for real-time stress monitoring, transforming the HPA axis into a pathway for targeted intervention.