What are the hormonal characteristics of chronic stress?

Hormonal Characteristics of Chronic Stress

Chronic stress is characterized by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in altered glucocorticoid secretion patterns, development of insulin resistance, and inflammatory changes that contribute to significant morbidity and mortality. 1

HPA Axis Dysregulation in Chronic Stress

• Chronic stress leads to persistent activation of the HPA axis, which differs significantly from the adaptive, beneficial response seen in acute stress 1
• In normal acute stress responses, cortisol levels rise temporarily with maintained pulsatility, helping the body adapt to short-term challenges 2
• With chronic stress, the hypothalamic activation shifts from corticotropin-releasing hormone (CRH)-dominant to arginine vasopressin (AVP)-dominant patterns 2, 3
• Persistent elevated cortisol levels occur partly due to decreased cortisol metabolism rather than continuously high ACTH levels 2

Key Hormonal Changes

Glucocorticoids (Cortisol)

• Chronic stress is associated with altered diurnal cortisol rhythms, with evidence showing flattened daily cortisol curves 4
• Evening basal cortisol levels become elevated while stress responsiveness becomes blunted (hypoactive response to new stressors) 5
• Long-term elevated cortisol exposure becomes maladaptive, contributing to metabolic syndrome, obesity, cardiovascular disease, and increased infection susceptibility 2

Catecholamines

• Increased long-term catecholamine release (epinephrine, norepinephrine) occurs during chronic stress 1
• This sustained catecholamine elevation leads to:
  • Increased carnitine acyl transferase activity, causing mitochondrial overflooding with free fatty acids 1
  • Excessive beta-oxidation and inhibition of pyruvic acid dehydrogenase 1
  • Cytosolic lactic acid accumulation 1

Metabolic Hormones

• Insulin resistance and compensatory hyperinsulinemia develop as a direct result of chronic stress 1
• These changes predispose individuals to hyperglycemia and diabetes 1
• Despite elevated blood glucose values, chronic stress is associated with impaired rather than augmented metabolic performance 1

Neuroinflammatory Changes

• Chronic stress alters the immune system's regulatory function, with glucocorticoids losing their typical anti-inflammatory effects 3
• Pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α become elevated 1
• These inflammatory changes contribute to depression and anxiety disorders commonly comorbid with chronic stress 1
• The NLRP3 inflammasome pathway becomes activated, further promoting inflammatory responses 1

Structural and Functional Brain Changes

• Chronic stress and elevated glucocorticoids are associated with:
  • Reduced volume and functionality of the hippocampus and medial prefrontal cortex 1
  • Decreased hippocampal neurogenesis 1
  • Dendritic retraction in both hippocampus and prefrontal cortex 1
• These structural changes correlate with blood glucocorticoid concentrations and contribute to cognitive impairments 1

Metabolic Remodeling

• Chronic stress induces a state of "chronic stress-mediated dysmetabolism" or metabolic remodeling 1
• Key features include:
  • Disturbed tricyclic acid cycle function due to oxalate-acetic acid shortage 1
  • Deficient macroerg phosphate generation 1
  • Tendency toward ketosis development 1
  • Accumulation of toxic fatty acid products 1
  • Increased intracellular triglyceride synthesis leading to lipotoxicity 1
  • Shift from efficient mitochondrial energy production to less efficient cytosolic anaerobic glycolysis 1

Clinical Implications

• The hormonal dysregulation of chronic stress significantly increases risk for:

  • Metabolic disorders including obesity and diabetes 1, 2
  • Cardiovascular disease 2, 3
  • Mental health disorders including depression and anxiety 1
  • Immune dysfunction and increased susceptibility to infections 2, 3
  • Cognitive decline 6, 2

• Therapeutic approaches targeting the HPA axis may include:

  • CRH antagonists for conditions associated with chronic hyperactivity of the stress system 3
  • Interventions that promote environmental enrichment, which has been shown to reduce stress-related neuroinflammation 1