Do HPA-axis–regulated cortisol rhythms affect sleep maintenance?

The hypothalamic-pituitary-adrenal (HPA) axis serves as a central regulator of systemic physiology, with direct, profound implications for sleep-wake architecture.

HPA-axis regulation of adrenal steroids

• Dual steroid pathway: Pituitary adrenocorticotropic hormone (ACTH) binds to melanocortin-2 receptors (MC2R) on the adrenal cortex to initiate a Gαs-cAMP-PKA cascade, mobilizing cholesterol via steroidogenic acute regulatory (StAR) protein and CYP11A1.
• Zonal synthesis: This cascade drives cortisol synthesis in the zona fasciculata (utilizing CYP17A1, CYP21A2, and CYP11B1) and dehydroepiandrosterone sulfate (DHEA-S) in the zona reticularis (utilizing the 17,20-lyase activity of CYP17A1 and SULT2A1). While cortisol participates in strict negative feedback, DHEA-S functions without it.

Mechanistic links to sleep maintenance

• Cortical hyperarousal: Altered cortisol profiles—specifically elevated evening or nocturnal cortisol, a flattened daytime decline, and a blunted cortisol awakening response (CAR)—provoke cortical hyperarousal. This is characterized by increased high-frequency EEG beta power and heightened noradrenergic tone.
• Sleep destabilization: Cortical hyperarousal destabilizes slow-wave and non-rapid eye movement (NREM) sleep, lowering the threshold for micro-arousals and causing frequent nocturnal awakenings.
• Pathological feedback: Conversely, sleep maintenance issues like wake after sleep onset (WASO) act as physiological stressors that trigger nocturnal cortisol secretory bursts, worsening evening cortisol elevation and establishing a self-perpetuating feedback loop.

Bottom line

• The adrenal cortex produces both cortisol and DHEA-S under HPA-axis regulation, and disruptions in these diurnal rhythms fuel a bidirectional feedback loop where elevated nocturnal cortisol drives cortical hyperarousal and sleep fragmentation.