Why do cortisol levels increase at midnight?

Why Cortisol Levels Decrease at Midnight

Cortisol levels do not increase at midnight but rather reach their nadir (lowest point) at midnight as part of the normal circadian rhythm of cortisol secretion. 1

Normal Cortisol Circadian Rhythm

• Cortisol is secreted in a pulsatile (ultradian) and circadian fashion, with peak levels in the morning and reaching its lowest point (nadir) at midnight 1
• The normal reference range for plasma cortisol is 140–700 nmol/L at 0900 hours, but only 80–350 nmol/L at midnight, demonstrating this natural decline 1
• This circadian pattern is controlled by the hypothalamic-pituitary-adrenal (HPA) axis, with corticotropin-releasing hormone (CRH) from the hypothalamus stimulating adrenocorticotropic hormone (ACTH) from the anterior pituitary, which then stimulates cortisol release from the adrenal cortex 1

Physiological Basis of Cortisol's Circadian Pattern

• The circadian rhythm of cortisol is tightly entrained to sleep-wake cycles, with the nadir occurring around midnight during normal sleep patterns 1, 2
• Individuals with normal adrenal function produce between 5-10 mg of cortisol per m² of body surface area per day, equivalent to an oral replacement dose of 15-25 mg per day 1
• The diurnal cortisol pattern (higher in morning, lower at night) is an essential biomarker of proper HPA axis function 3

Clinical Significance of Midnight Cortisol Levels

• Loss of the normal midnight cortisol nadir is a key diagnostic feature in Cushing's syndrome, where cortisol remains elevated throughout the day 1, 2
• Late-night salivary cortisol measurement is a reliable screening test for Cushing's syndrome, with elevated midnight levels suggesting pathological hypercortisolism 2
• In the 2-day Low-Dose Dexamethasone Suppression Test (LDDST), the ability to suppress cortisol below 50 nmol/L (1.8 μg/dL) indicates normal HPA axis function 4

Factors That Can Disrupt Normal Cortisol Rhythm

• Sleep deprivation can significantly alter cortisol patterns, with even partial sleep loss delaying the recovery of the HPA axis from morning stimulation 5
• After partial or total sleep deprivation, cortisol levels may be 37-45% higher in the evening of the following day 5
• Night shift workers and others with disrupted day/night cycles may have abnormal cortisol circadian patterns, making tests like late-night salivary cortisol less reliable 1
• Medications affecting CYP3A4 (the key enzyme for cortisol metabolism) can alter cortisol clearance and affect its circadian pattern 1

Clinical Applications

• Understanding the normal midnight nadir of cortisol is essential for diagnosing conditions like Cushing's syndrome, where this pattern is lost 1, 2
• Flatter diurnal cortisol slopes (smaller difference between morning and evening levels) are associated with poorer health outcomes, particularly related to immune function and inflammation (r=0.288) 3
• In patients with kidney disease, especially those with GFR lower than 29 ml/min, the assessment of cortisol patterns may be unreliable due to altered cortisol clearance 6

Understanding that cortisol naturally decreases at midnight rather than increases is fundamental to interpreting endocrine test results and diagnosing disorders of the HPA axis.