Shouldn't Adrenocorticotropic Hormone (ACTH) be suppressed in hypercortisolism?

ACTH Suppression in Hypercortisolism

In hypercortisolism, ACTH should be suppressed to undetectable or very low levels only in ACTH-independent causes such as adrenal adenomas or carcinomas, but not in ACTH-dependent causes like Cushing's disease or ectopic ACTH syndrome. 1

Types of Hypercortisolism and ACTH Patterns

ACTH-Dependent Hypercortisolism

• In Cushing's disease (pituitary source), ACTH is typically normal or elevated, with levels >1.1 pmol/l (>5 ng/l) 1
• In ectopic ACTH syndrome, ACTH levels are usually markedly elevated 1
• ACTH is not suppressed below 10 in these conditions, as the source of excess ACTH is autonomous 1

ACTH-Independent Hypercortisolism

• In adrenal adenomas, carcinomas, or bilateral adrenal hyperplasia, ACTH is typically suppressed due to negative feedback from autonomous cortisol production 1
• ACTH suppression occurs through the normal hypothalamic-pituitary-adrenal axis feedback mechanism 2
• Patients with adrenal-dependent Cushing's syndrome typically have undetectable ACTH levels 3

Diagnostic Approach

Initial Testing

• After excluding iatrogenic causes, initial testing for Cushing's syndrome should include one of the following: 24-hour urinary free cortisol, late-night salivary cortisol, or dexamethasone suppression test 1
• Measurement of morning plasma ACTH is crucial to distinguish between ACTH-dependent and ACTH-independent causes 1

Differential Diagnosis

• If ACTH is detectable (>5 ng/l or >1.1 pmol/l), this suggests ACTH-dependent Cushing's syndrome 1
• If ACTH is suppressed or undetectable, this suggests ACTH-independent (adrenal) Cushing's syndrome 1
• In adrenal-dependent hypercortisolism, high-dose dexamethasone testing will not suppress cortisol levels 3

Clinical Implications of ACTH Patterns

Surgical Planning

• Patients with suppressed ACTH who undergo adrenalectomy are at high risk for adrenal insufficiency postoperatively and require glucocorticoid replacement 1
• Preoperative identification of suppressed ACTH helps anticipate this complication and plan appropriate perioperative management 1

Post-Treatment Monitoring

• After successful treatment of adrenal-dependent Cushing's syndrome, ACTH levels should gradually increase as the hypothalamic-pituitary axis recovers 3
• Persistent suppression of ACTH after treatment may indicate residual disease or recurrence 1

Special Considerations

• Rare cases of concurrent pathologies can occur, such as ACTH-producing cells within a pheochromocytoma 4 or development of autonomous adrenal nodules after longstanding ACTH stimulation 3
• In subclinical Cushing's syndrome, ACTH suppression may be an important marker for determining surgical candidacy 2

Common Pitfalls and Caveats

• ACTH levels have a short half-life and fluctuate throughout the day, making interpretation challenging 1
• Failure to exclude exogenous glucocorticoid use before biochemical testing can lead to unnecessary testing and misleading results 1
• Patients with bilateral adrenalectomy for Cushing's disease require monitoring of ACTH levels to detect Nelson's syndrome (corticotroph tumor progression) 1
• When using adrenal-targeting medications, monitor ACTH levels as significant elevations may indicate tumor growth 1

In summary, ACTH should be suppressed only in ACTH-independent hypercortisolism, while in ACTH-dependent forms (like Cushing's disease), ACTH levels are normal or elevated despite hypercortisolism.