Source of Excess Cortisol in Cushing's Disease
In Cushing's disease, the excess cortisol is coming from both adrenal glands, which are being overstimulated by excessive ACTH secreted from a pituitary adenoma. 1, 2
Understanding the Pathophysiology
The cortisol itself is produced by the adrenal cortex, but the underlying problem originates in the pituitary gland. 3, 4 Here's the cascade:
- A pituitary corticotroph adenoma secretes excessive ACTH, which is the primary pathologic lesion in Cushing's disease 2, 4
- This elevated ACTH stimulates both adrenal glands to produce excessive cortisol, resulting in bilateral adrenal hyperplasia and hypercortisolism 5, 3
- The adrenal glands themselves are structurally normal but are responding appropriately to the pathologically elevated ACTH signal 6
Key Diagnostic Distinction
This mechanism is what makes Cushing's disease ACTH-dependent, distinguishing it from other forms of Cushing's syndrome:
- ACTH levels are detectable and typically elevated (>5 ng/L, with >29 ng/L having 70% sensitivity and 100% specificity for Cushing's disease) 1, 2
- In contrast, ACTH-independent Cushing's syndrome (from adrenal adenomas or carcinomas) shows suppressed ACTH levels (<5 pg/mL) because the autonomous adrenal cortisol production suppresses pituitary ACTH secretion 7
Clinical Implications
- Cushing's disease accounts for 60-70% of endogenous Cushing's syndrome cases, making it the most common cause of pathologic hypercortisolism 8, 6
- The pituitary adenomas are typically microadenomas (≤10 mm), with 98% being microadenomas and frequently ≤2 mm in diameter, which explains why MRI may be normal in up to 37% of cases 1
- Treatment targets the pituitary adenoma (transsphenoidal surgery), not the adrenal glands, because removing the source of ACTH excess allows the adrenals to return to normal function 2, 5
Common Pitfall to Avoid
Do not confuse the anatomic source of cortisol production (adrenal glands) with the pathologic source of the disease (pituitary adenoma). 4 While the cortisol molecules are synthesized in the adrenal cortex, the disease process driving the excess cortisol originates from the pituitary's excessive ACTH secretion. This distinction is critical for proper diagnosis and treatment planning. 1, 2