In an individual with Cushing's (Cushing's disease) disease, would you expect Adrenocorticotropic Hormone (ACTH) to be elevated?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: January 27, 2026 • View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

ACTH Levels in Cushing's Disease

Yes, in Cushing's disease, ACTH levels are elevated or inappropriately normal-to-high in the context of hypercortisolism. This is the defining biochemical feature that distinguishes ACTH-dependent from ACTH-independent causes of Cushing's syndrome. 1

Understanding ACTH in Cushing's Disease

Cushing's disease specifically refers to ACTH-dependent Cushing's syndrome caused by a pituitary corticotroph adenoma, which accounts for 75-80% of all ACTH-dependent cases. 1, 2 The pituitary tumor autonomously secretes ACTH, driving excessive cortisol production from otherwise normal adrenal glands.

Expected ACTH Values

  • Any detectable ACTH level >5 pg/mL (or >5 ng/L) in the presence of confirmed hypercortisolism indicates ACTH-dependent Cushing's syndrome with high certainty. 1, 2

  • ACTH levels >29 pg/mL have 70% sensitivity and 100% specificity for diagnosing Cushing's disease (as opposed to ectopic ACTH syndrome). 1, 2

  • Morning (08:00-09:00h) plasma ACTH measurement is the optimal timing for initial assessment, as this provides standardization and allows comparison with established reference ranges. 1

Diagnostic Algorithm Using ACTH

The ACTH level serves as the critical branch point in the diagnostic workup:

Step 1: Confirm Hypercortisolism

Before measuring ACTH, hypercortisolism must be confirmed using at least two of the following first-line tests: 2

  • 24-hour urinary free cortisol (UFC)
  • Late-night salivary cortisol (LNSC)
  • Low-dose dexamethasone suppression test (LDDST with cortisol <1.8 μg/dL being normal)

Step 2: Measure Morning ACTH

Once hypercortisolism is confirmed, obtain a morning (08:00-09:00h) plasma ACTH level: 1

If ACTH is elevated or detectable (>5 pg/mL): This indicates ACTH-dependent Cushing's syndrome, which includes:

  • Cushing's disease (pituitary adenoma) - most common
  • Ectopic ACTH syndrome (rare)
  • Ectopic CRH syndrome (very rare)

If ACTH is low or undetectable (<5 pg/mL): This indicates ACTH-independent Cushing's syndrome, caused by: 1

  • Adrenal adenoma
  • Adrenal carcinoma
  • Bilateral adrenal hyperplasia

Step 3: Localize the ACTH Source (if ACTH-dependent)

For ACTH-dependent cases, proceed with: 1

  • Pituitary MRI as the next step
  • If adenoma ≥10 mm is found, presume Cushing's disease
  • If no adenoma or lesion <6 mm is found, perform bilateral inferior petrosal sinus sampling (BIPSS) to definitively distinguish pituitary from ectopic sources

Critical Clinical Nuances

Why ACTH is "Inappropriately Normal" Rather Than Always Elevated

In Cushing's disease, ACTH levels may appear "normal" (within the reference range) but are actually inappropriately elevated for the degree of hypercortisolism present. 3, 4 In healthy individuals, elevated cortisol would suppress ACTH to undetectable levels through negative feedback. The fact that ACTH remains detectable despite high cortisol indicates loss of normal feedback inhibition—the hallmark of Cushing's disease.

Loss of Diurnal Variation

Cushing's disease disrupts the normal circadian rhythm of ACTH and cortisol secretion. 1 Normally, ACTH and cortisol peak in the early morning and reach their nadir at midnight. In Cushing's disease, this pattern is lost, with persistently elevated or irregular secretion throughout the day.

Distinguishing from Ectopic ACTH Syndrome

While both Cushing's disease and ectopic ACTH syndrome present with elevated ACTH, ectopic sources typically produce: 3, 5

  • Much higher ACTH levels (often markedly elevated)
  • More severe hypokalemia
  • More rapid onset of symptoms
  • Less responsiveness to high-dose dexamethasone suppression
  • Lack of response to CRH stimulation

Common Pitfalls to Avoid

Never interpret ACTH in isolation—it must be evaluated in the context of confirmed hypercortisolism. 1 A "normal" ACTH level in a healthy person is appropriate; the same level in someone with elevated cortisol is pathologic.

Ensure proper timing of ACTH measurement—morning samples are essential for standardization and comparison with reference ranges. 1

For cyclic Cushing's disease, ACTH and cortisol measurements must be obtained during periods of active hypercortisolism, as levels may normalize during quiescent phases. 1

Medications affecting the hypothalamic-pituitary-adrenal axis (such as exogenous steroids, CYP3A4 inducers/inhibitors) can confound interpretation and should be documented. 6

References

1
Guideline

Cushing's Syndrome Classification and Diagnosis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

2
Guideline

Diagnosing ACTH-Dependent Cushing's Syndrome

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

3
Research

Cushing's disease.

Best practice & research. Clinical endocrinology & metabolism, 2009

5
Research

Studies of ACTH secretion control in 116 cases of Cushing's syndrome.

The Journal of clinical endocrinology and metabolism, 1975

6
Guideline

Cortisol Levels and Diagnostic Guidelines

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

Related Questions

What causes a low Adrenocorticotropic Hormone (ACTH) level?
What is the pathogenesis of Cushing's syndrome?
What does an increase in Adrenocorticotropic hormone (ACTH) levels from 16 to 46 in five days signify in a patient with Cushing's disease?
What is the recommended method for estimating Adrenocorticotropic Hormone (ACTH) levels?
What is the most likely type of Cushing's syndrome in a patient with elevated Adrenocorticotropic hormone (ACTH) and cortisol levels?
What is the recommended treatment for a patient with otitis externa, particularly those with a history of allergies or skin conditions like eczema?
What does an MRI showing mild cerebral volume loss, patchy white matter changes with small lacunar infarcts, and a small focus of gliosis in the left hemipons indicate for an older patient?
What workup is needed for a patient with hyperkalemia, impaired renal function, and osteoporosis who is taking chlorthalidone (thiazide-like diuretic)?
What is the most appropriate investigation for a patient presenting with a 2-week history of bloody diarrhea, lower abdominal cramps, tenesmus, and abdominal distension with mild tenderness?
What are the first-line antibiotic recommendations for an adult patient with no significant medical history presenting with a sinus or chest bacterial infection?
Which is preferred for a patient with QT interval prolongation, ziprasidone or haloperidol?

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.

Ask Question