The Hypothalamic-Pituitary-Adrenal Feedback Loop
Cortisol normally suppresses its own release via negative feedback.
- Hypothalamus: CRH source (paraventricular nucleus)
- Anterior pituitary: ACTH source (corticotroph cells)
- Adrenal cortex: Cortisol source (zona fasciculata)
- 5–23 µg/dL: Normal AM cortisol (diurnal peak at 8am)
Negative feedback keeps cortisol in a tight range
Hypothalamus releases CRH, pituitary releases ACTH, adrenal makes cortisol.
Cortisol then feeds back to suppress CRH and ACTH.
Exogenous glucocorticoid mimics cortisol and shuts the axis down.
Low-Dose Dexamethasone — The Screening Test
1 mg dexamethasone at 11pm; cortisol drawn at 8am the next day.
- 1 mg PO: Standard dose (overnight, 11pm)
- <1.8 µg/dL: Normal suppression (8am cortisol cutoff)
- ~95%: Sensitivity (for Cushing's syndrome)
- Obesity, stress: False positives (depression, OCPs)
Failure to suppress signals autonomous cortisol production
Dexamethasone does not bind the assay, so a positive test is real.
Cushing's patients keep making cortisol despite the pituitary being suppressed.
A single failed low-dose test does not localize the cause yet.
High-Dose Dexamethasone — Localizing the Source
8 mg overnight distinguishes pituitary disease from ectopic or adrenal tumors.
- 8 mg PO: Standard dose (overnight, 11pm)
- >50% suppression: Pituitary response (still feedback-sensitive)
- No suppression: Ectopic/adrenal (autonomous source)
- Confirmed Cushing's: Classic use (only, after low-dose fails)
Pituitary adenomas retain partial feedback sensitivity
A pituitary corticotroph tumor still has some glucocorticoid receptors.
Ectopic tumors and adrenal tumors are almost fully autonomous.
Modern workup often pairs this with ACTH and imaging.
Comparing Pre- and Post-Dexamethasone Cortisol
Plotting all three scenarios reveals the diagnostic suppression pattern.
- ~90% drop: Normal, low-dose (strong suppression)
- ~25% drop: Pituitary, low-dose (inadequate suppression)
- ~70% drop: Pituitary, high-dose (partial suppression)
- ~15% drop: Ectopic/adrenal, high-dose (resistant to suppression)
Suppression magnitude is the key diagnostic signal
Bar height drop from baseline to post-dex tells the whole story.
Bigger drop means feedback is intact; small drop means autonomy.
Use both slider controls to explore every combination.
Interpreting the Full Suppression Pattern
Low- and high-dose results together confirm and localize Cushing's syndrome.
- Suppresses at low dose: Normal pattern (axis intact)
- Fails low, passes high: Pituitary pattern (Cushing disease)
- Fails both doses: Ectopic/adrenal pattern (autonomous source)
- ACTH + imaging: Next step (MRI pituitary / CT chest-abd)
From screening to source localization
Suppression testing separates normal physiology from true Cushing's.
High-dose results then point toward pituitary versus ectopic/adrenal source.
Always confirm with plasma ACTH and cross-sectional imaging.