The hypothalamic-pituitary-adrenal axis is the cascade that begins with a perceived threat and ends with cortisol entering the bloodstream. The hypothalamus releases corticotropin-releasing hormone. The pituitary responds by releasing adrenocorticotropic hormone. The adrenal cortex responds by producing cortisol. A healthy feedback loop then detects rising cortisol, signals the hypothalamus to reduce CRH production, and the system returns to baseline within 30 to 60 minutes. In chronic stress, this negative feedback loop fails. Cortisol remains elevated, the receptors that should detect it and switch off the response become desensitised, and the axis runs in a persistently activated state.
The Two Phases of Chronic Stress
HPA axis dysregulation typically progresses through recognisable phases. In the early phase, cortisol is consistently elevated. Individuals feel wired but tired, struggle to wind down in the evening, wake early, and find high-intensity activity uncomfortable. In the later phase, after months to years of chronic activation, the system begins to under-produce. Cortisol output flattens, the diurnal rhythm becomes blunted, the morning cortisol awakening response diminishes, and the individual experiences profound fatigue, difficulty getting started in the morning, and reduced resilience to any additional physical or psychological demand.
The Downstream Systems Affected
- Immune function: chronic cortisol elevation suppresses cellular immunity and shifts the immune response toward a pro-inflammatory Th2 pattern
- Thyroid function: CRH and cortisol both inhibit TSH release and impair T4 to T3 conversion
- Reproductive hormones: cortisol directly suppresses GnRH release, reducing testosterone and oestrogen production
- Digestive function: sustained activation of the sympathetic system and inhibition of the parasympathetic reduces gastric acid, motility, and digestive enzyme production
- Sleep: cortisol and CRH activate the arousal system and directly impair sleep architecture, particularly slow-wave sleep
Sources
- Tsigos, C., & Chrousos, G.P. (2002). Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research, 53(4), 865-871.
- Fries, E., et al. (2005). A new view on hypocortisolism. Psychoneuroendocrinology, 30(10), 1010-1016.
- Herman, J.P., et al. (2016). Regulation of the hypothalamic-pituitary-adrenocortical stress response. Comprehensive Physiology, 6(2), 603-621.