Cushing syndrome: the dexamethasone suppression test and ACTH
A normal morning cortisol does not rule out Cushing syndrome. Use screening tests, ACTH and dexamethasone suppression to decide whether the source is the pituitary, an ectopic tumour or the adrenal.
Use cortisol testing, ACTH and dexamethasone suppression logic to localise Cushing syndrome to a pituitary, ectopic or adrenal source.
The short version
- Screen for Cushing syndrome with a 24-hour urinary free cortisol, a late-night salivary cortisol or the 1 mg overnight dexamethasone test, after excluding glucocorticoid medicines.
- A normal morning cortisol does not exclude Cushing syndrome, because the normal daily fall in cortisol is lost.
- Low or undetectable ACTH points to the adrenal; normal or high ACTH points to the pituitary or an ectopic source.
- High-dose dexamethasone usually suppresses cortisol in a pituitary tumour but not in an ectopic one.
- Imaging comes last, after the chemistry tells you where to look.
Cushing syndrome with a normal morning cortisol
A woman has a round, red face, purple stretch marks and high blood pressure. Her 9 AM cortisol is normal, yet she has Cushing syndrome. How can a normal morning cortisol fail to rule it out?
This lesson works through the logic of Cushing syndrome: how cortisol testing, ACTH and the dexamethasone suppression test decide whether the source is the pituitary, an ectopic tumour or the adrenal.[1][2]
Cushing syndrome versus Cushing disease, and where the loop breaks
Cushing syndrome means too much cortisol, from any cause. Cushing disease is the one cause that is a pituitary tumour making ACTH.[1][2]
Normally cortisol switches ACTH off. Endogenous Cushing syndrome breaks that feedback loop in one of three places: the pituitary, a tumour elsewhere, or the adrenal itself.[2]
| Type | Where the loop breaks | ACTH |
|---|---|---|
| ACTH-dependent | Pituitary tumour (Cushing disease) or ectopic ACTH-secreting tumour | Normal or high |
| ACTH-independent | Adrenal adenoma, carcinoma or primary bilateral adrenal hyperplasia | Low or undetectable |
Steps 1 and 2: exclude medicines, then screen for Cushing syndrome
Step one is to rule out glucocorticoid medicines, which cause Cushing syndrome from outside the body.[2]
Step two is to prove there is too much cortisol. Three screening tests do this.[1][2]
- 24-hour urinary free cortisol
- Late-night salivary cortisol
- 1 mg overnight dexamethasone suppression test
The 1 mg overnight dexamethasone suppression test
In the dexamethasone suppression test, the patient takes 1 mg at bedtime. In a healthy axis, dexamethasone shuts off ACTH, so next morning cortisol falls below about 1.8 micrograms/dL.[1][2]
In Cushing syndrome, cortisol secretion largely escapes feedback, so it stays above that cutoff.[1][2]
Step 3: measure ACTH to separate adrenal from pituitary or ectopic
If ACTH is low or undetectable, the adrenal is making cortisol on its own and the pituitary has been switched off. That means an adrenal adenoma, carcinoma or primary bilateral adrenal hyperplasia.[1][3]
If ACTH is normal or high, the cause is pituitary or ectopic. Small cell lung cancer is an example of an ectopic source.[1][3]
Step 4: high-dose dexamethasone, petrosal sampling and imaging
To separate pituitary from ectopic, the high-dose dexamethasone test gives 2 mg every 6 hours for 2 days. A pituitary tumour usually keeps some sensitivity to feedback, so cortisol falls by more than half. An ectopic tumour usually ignores feedback, so cortisol does not suppress.[1][3]
- 2 mg every 6 hours = 4 doses a day
- 4 × 2 mg = 8 mg a day
- 8 mg × 2 days = 16 mg
Many centres have abandoned the high-dose test and sample the petrosal veins that drain the pituitary instead. After a stimulating injection, a central to peripheral ACTH ratio above 3 points to the pituitary.[1][3]
Imaging comes last, after the chemistry tells you where to look.[1][3]
Three patients with the same cortisol excess
| Patient | ACTH | High-dose dexamethasone | Source |
|---|---|---|---|
| One | Undetectable | Not applicable | Adrenal |
| Two | High | Cortisol usually suppresses | Pituitary |
| Three | Very high | Usually no suppression | Ectopic |
The word usually matters: the high-dose test is not perfectly separating, which is one reason many centres prefer petrosal sampling.[1][3]
Practice question
Original · USMLE styleA 38-year-old woman has gained weight over the past 8 months and has facial rounding, purple abdominal striae and hypertension. She takes no medications. Late-night salivary cortisol is increased on two samples. After 1 mg of dexamethasone at bedtime, her 8 AM serum cortisol is 9.4 micrograms/dL. Serum potassium is 4.2 mEq/L. Plasma ACTH is 92 pg/mL (reference range, 7 to 63 pg/mL). After high-dose dexamethasone (2 mg every 6 hours for 48 hours), her serum cortisol decreases by 70%.
Common questions
Can Cushing syndrome be present with a normal morning cortisol?
Yes. Healthy cortisol is lowest at midnight, but in Cushing syndrome that daily fall is lost, so the morning level can look normal. Late-night salivary cortisol, urinary free cortisol or the 1 mg dexamethasone test are used for screening.
What is the difference between Cushing syndrome and Cushing disease?
Cushing syndrome means too much cortisol from any cause. Cushing disease is the one cause that is a pituitary tumour making ACTH.
How does the dexamethasone suppression test work?
After 1 mg of dexamethasone at bedtime, a healthy axis shuts off ACTH and next-morning cortisol falls below about 1.8 micrograms/dL. In Cushing syndrome, cortisol largely escapes feedback and stays above that cutoff.
How does ACTH help localise Cushing syndrome?
Low or undetectable ACTH means the adrenal is acting alone. Normal or high ACTH means the cause is pituitary or ectopic, which the high-dose dexamethasone test or petrosal sampling can then separate.
Transcript
Read the full narration, by chapter633 words
0:00The case: normal 9 AM cortisol, yet Cushing syndrome
A woman has a round, red face, purple stretch marks and high blood pressure. Her nine AM cortisol is normal. Yet she has Cushing syndrome. How can a normal morning cortisol not rule it out? Today: use cortisol testing, ACTH and dexamethasone suppression to decide whether the source is the pituitary, an ectopic tumour, or the adrenal.
0:24Where the cortisol-ACTH loop breaks: pituitary, ectopic, adrenal
Cushing syndrome means too much cortisol, from any cause. Cushing disease is the one cause that is a pituitary tumour making ACTH. Normally cortisol switches ACTH off. Cushing syndrome breaks that loop in one of three places: the pituitary, a tumour elsewhere, or the adrenal itself. If the source makes ACTH, the disease is ACTH dependent. If the adrenal acts alone, it is ACTH independent.
0:56Steps 1 and 2: exclude medicines, then screen
Step one: rule out glucocorticoid medicines, which cause Cushing syndrome from outside the body. Step two: prove there is too much cortisol. Three screening tests do this. A 24-hour urinary free cortisol, a late-night salivary cortisol, and a one milligram overnight dexamethasone test.
1:19Why the late-night test works
The late-night test works because healthy cortisol is lowest at midnight, but in Cushing syndrome that daily fall is lost. That is why our patient's morning cortisol was normal.
1:31The 1 mg overnight dexamethasone test
In the dexamethasone test, the patient takes one milligram at bedtime. In a healthy axis, dexamethasone shuts off ACTH, so next morning cortisol falls below about 1.8 microg/dL. In Cushing syndrome, cortisol secretion largely escapes feedback, so it stays above that cutoff.
1:52Step 3: measure ACTH
Step three: measure ACTH. If ACTH is low or undetectable, the adrenal is making cortisol on its own, and the pituitary has been switched off. That means an adrenal adenoma, carcinoma or hyperplasia. If ACTH is normal or high, the cause is pituitary or ectopic.
2:16Step 4: high-dose dexamethasone
Step four: separate those two with a high-dose dexamethasone test, two milligrams every 6 hours for 2 days. A pituitary tumour keeps some sensitivity to feedback, so cortisol falls by more than half. An ectopic tumour, such as small cell lung cancer, ignores feedback, so cortisol does not suppress.
2:38Petrosal vein sampling and imaging
Many centres have abandoned the high-dose test and sample the petrosal veins that drain the pituitary instead. After a stimulating injection, a central to peripheral ACTH ratio above three points to the pituitary. Imaging comes last, after the chemistry tells you where to look.
2:57Three patients, same excess
Three patients, same cortisol excess. Patient one: ACTH undetectable. Adrenal. Patient two: ACTH high, and cortisol usually suppresses on high-dose dexamethasone. Pituitary. Patient three: ACTH very high, and usually no suppression. Ectopic.
3:20Practice question
Your turn. A 38-year-old woman has gained weight over eight months, with facial rounding, purple abdominal striae and hypertension. She takes no medications. Late-night salivary cortisol is raised on two samples. After one milligram of dexamethasone, her morning cortisol is 9.4 micrograms per decilitre. Potassium is 4.2. Plasma ACTH is 92 picograms per millilitre, with a reference range of seven to 63. After high-dose dexamethasone for 48 hours, her serum cortisol falls by 70%. What is the most likely source of the excess cortisol? A, adrenocortical carcinoma. B, adrenal adenoma. C, pituitary corticotroph adenoma. D, ACTH secreting small cell lung cancer. E, glucocorticoid medication. Pause here and decide.
4:25Answer and explanation
A is out: a carcinoma is autonomous, so ACTH would be low, not high. B is out: an adrenal adenoma would also make ACTH low. D is out: an ectopic tumour usually does not suppress on high-dose dexamethasone. E is out: she takes no medications, and glucocorticoid medicines would suppress ACTH, not raise it. So the answer is C. ACTH is high, and cortisol suppresses by more than half, which points to a pituitary adenoma.
5:01Recap and next lesson
Three things to keep. One: screen with urine, late-night saliva or the one milligram test. Two: low ACTH means adrenal; high or normal ACTH means pituitary or ectopic. Three: high-dose dexamethasone usually suppresses a pituitary tumour but not an ectopic one. Next, primary hyperaldosteronism.
Sources
Numbers in the text, e.g. [1], point here- Cushing Syndrome. MSD Manual Professional Version. msdmanuals.com/professional/endocrine-and-metabolic-disorders/adrenal-disorders/cushing-syndrome
- Measuring cortisol in Cushing syndrome. J Clin Endocrinol Metab 2026. pmc.ncbi.nlm.nih.gov/articles/PMC13183435/
- Pituitary corticotroph tumours and ACTH-dependent Cushing syndrome. J Clin Med 2026. pmc.ncbi.nlm.nih.gov/articles/PMC13706564/
- ACTH reference range (case report table). Ther Adv Endocrinol Metab 2026. pmc.ncbi.nlm.nih.gov/articles/PMC13346833/
The cortisol-versus-clock graph is a schematic after the MSD Manual; ACTH reference ranges vary by assay.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): woman, pituitary gland, kidney with adrenal gland, lung with tumour, urine specimen bottle, test tube, clock. Pill icon by Marcel Tisch via bioicons.com (CC0). Blood pressure monitor and CT scanner icons: Health Icons (CC0). The graphs, bars, dials, petrosal schematic, lab slip, cards and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-010.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13