What is the mechanism of nocturnal cortisol regulation?

Mechanism of Nocturnal Cortisol Regulation

Normal cortisol secretion follows a circadian rhythm with peak levels in the early morning and a nadir around midnight, with this pattern being regulated by the hypothalamic-pituitary-adrenal axis and the suprachiasmatic nucleus. 1, 2

Normal Circadian Rhythm of Cortisol

• Cortisol secretion follows a distinct circadian pattern with highest levels in the early morning hours and lowest levels around midnight 1, 2
• This rhythm is orchestrated by the central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN), which regulates the timing of various bodily processes including hormone expression 1
• In healthy individuals, cortisol levels fluctuate between a peak in the early morning and a minimal level around midnight, serving as a reliable marker of circadian clock function 2

Mechanisms Controlling Nocturnal Cortisol Levels

• The cortisol nadir at midnight is tightly entrained to sleep onset rather than to a specific clock time 1
• The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol secretion through a cascade involving:
  • Corticotropin-releasing hormone (CRH) from the hypothalamus
  • Adrenocorticotropic hormone (ACTH) from the anterior pituitary
  • Cortisol production from the adrenal cortex 1
• Midnight cortisol levels are primarily regulated by suppression of ACTH secretion during the evening and night 3
• The SCN sends inhibitory signals to the HPA axis during the evening, resulting in decreased CRH, ACTH, and consequently cortisol production at night 1

Factors Affecting Nocturnal Cortisol Regulation

• Sleep onset plays a critical role in maintaining low midnight cortisol levels, as the cortisol nadir is more closely linked to sleep initiation than to clock time 1
• Disruption of normal day/night cycles (e.g., in night-shift workers) can alter the circadian pattern of cortisol secretion 1, 4
• Night shift workers show flattened cortisol profiles with higher levels at bedtime after night shifts, when levels should normally be low 4
• Awakening during the night does not appear to stimulate cortisol secretion; a recent study found no evidence for a change in the rate of cortisol increase in the hour after waking compared to the hour before waking 5

Clinical Implications

• Loss of the normal circadian nadir of cortisol secretion at midnight is a key diagnostic feature in Cushing's syndrome 1, 2
• Late-night salivary cortisol (LNSC) testing is based on the assumption that patients with Cushing's syndrome lose this normal circadian pattern 1
• The metabolic effects of elevated cortisol are more pronounced when they occur in the evening (at the trough of the daily rhythm) than in the morning (at the peak of the rhythm) 6
• Evening cortisol elevations can contribute to alterations in glucose tolerance, insulin sensitivity, and insulin secretion 6
• Measurement of midnight ACTH levels alongside cortisol is important for proper interpretation of midnight cortisol values 3

Pathological Conditions

• In Cushing's syndrome, the normal circadian rhythm of cortisol is considerably reduced or even abolished 2
• Patients with Cushing's syndrome lose the normal circadian nadir of cortisol secretion, resulting in elevated midnight cortisol levels 1
• Psychiatric disorders, alcohol use disorder, polycystic ovary syndrome, and obesity may activate the HPA axis, potentially affecting the normal circadian pattern of cortisol secretion 1