Normal Physiologic Glucocorticoid Production in Humans
The normal daily production of cortisol in humans is approximately 5-7 mg/m² or about 10 mg (27.3 μmol) per day, which is significantly lower than previously believed. 1
Cortisol Production Physiology
Cortisol is the dominant glucocorticoid in humans, produced in the zona fasciculata of the adrenal cortex. Its production follows several important patterns:
- Release is pulsatile and follows a circadian rhythm
- Normal reference ranges vary throughout the day:
- 140-700 nmol/L at 0900 hours
- 80-350 nmol/L at midnight 2
Regulation and Distribution
- Controlled by adrenocorticotropic hormone (ACTH) from the anterior pituitary
- ACTH is controlled by corticotropin-releasing hormone (CRH) from the hypothalamus
- In plasma, cortisol is highly protein-bound:
- 60-80% bound to cortisol-binding globulin
- 15-35% bound to albumin
- Only about 5% exists as the free active fraction 2
Historical Context and Updated Measurements
Previous estimates of daily cortisol production were higher, but more recent research using advanced measurement techniques has revised this downward:
- Traditional estimates suggested up to 20 mg of cortisol released daily 2
- Modern studies using stable isotope dilution/mass spectrometry have determined the actual production rate to be lower:
- 27.3 ± 7.5 μmol/day (9.9 ± 2.7 mg/day)
- Or 15.7 μmol/day·m² (5.7 mg/m²·day) 1
This revised understanding has important clinical implications, particularly for glucocorticoid replacement therapy in patients with adrenal insufficiency.
Stress Response and Increased Production
During periods of physiological stress (such as major surgery), cortisol production increases significantly:
- A five-fold increase in secretion (to approximately 100 mg of cortisol per day) is common during major surgery
- Plasma cortisol typically returns to baseline within 24-48 hours after uncomplicated procedures 2
- During protracted critical illness, reduced metabolism and clearance contribute to hypercortisolemia 2
Clinical Implications
The revised understanding of normal cortisol production has important implications for replacement therapy:
- Current standard replacement doses (12-15 mg/m²/day) may be excessive compared to normal physiologic production 1
- Excessive replacement may contribute to growth retardation and Cushingoid features in treated patients 1
- Morning serum cortisol levels can help determine which patients should undergo dynamic assessment of adrenal function, with values ≥348 nmol/L providing 100% specificity for normal adrenal function 3
Circadian Variation
A previously unreported circadian variation in cortisol production rate has been observed, with cortisol concentration correlating with production rate during each sample period in normal volunteers. This indicates that cortisol secretion, rather than metabolism, is primarily responsible for changes in plasma cortisol levels 1.
Understanding the normal physiologic production of glucocorticoids is essential for appropriate replacement therapy in patients with adrenal insufficiency and for evaluating potential side effects of exogenous glucocorticoid administration.