Caushing syndrome

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Here is a comprehensive overview of Cushing Syndrome based on authoritative medical textbooks.

Cushing Syndrome

Definition & Terminology

Cushing syndrome refers to the clinical state caused by chronic exposure to excess glucocorticoids — from any source. Cushing disease is a specific subtype: excess cortisol driven by an ACTH-secreting pituitary corticotroph adenoma. The term "Cushing disease" should not be used interchangeably with "Cushing syndrome."

"Cushing syndrome reflects excessive tissue exposure to glucocorticoids... the most common cause is when excess cortisol is produced by the unmitigated release of ACTH from a pituitary adenoma; the term Cushing disease is reserved for this specific cause." — Goldman-Cecil Medicine

Causes (Classification)

1. Exogenous (most common overall)

Iatrogenic glucocorticoid administration (the #1 cause worldwide)

2. ACTH-Dependent (endogenous, ~80–85%)

Cause	Proportion
Cushing disease (pituitary corticotroph adenoma)	~80% of ACTH-dependent cases
Ectopic ACTH secretion (lung carcinoid, SCLC, thymic tumors)	~20% of ACTH-dependent cases

3. ACTH-Independent (~15–20%)

Adrenocortical adenoma
Adrenocortical carcinoma
Bilateral adrenal nodular hyperplasia (primary pigmented nodular adrenocortical disease, PPNAD)

"ACTH-dependent hypercortisolism accounts for 80% to 85% of endogenous Cushing syndrome. Approximately 80% of ACTH-dependent disease results from primary pituitary pathology and is known as Cushing disease." — Campbell-Walsh-Wein Urology

Pathophysiology

The hypothalamic-pituitary-adrenal (HPA) axis normally operates via negative feedback:

Hypothalamus secretes CRH → stimulates anterior pituitary
Pituitary secretes ACTH (cleaved from POMC) → stimulates adrenal zona fasciculata
Adrenal produces cortisol → feeds back to suppress CRH and ACTH
Cortisol follows a circadian rhythm (peak in morning, nadir ~11 PM)

In Cushing syndrome, this feedback loop is disrupted, producing sustained hypercortisolism without the normal diurnal variation.

Clinical Features

Classic Physical Signs

Central / Fat redistribution:

Centripetal (truncal) obesity — sparing of limbs
Moon facies — rounded face from fat deposition
Buffalo hump — dorsocervical fat pad between scapulae
Supraclavicular fat pads
Facial plethora (ruddy cheeks from increased hematocrit)

Skin:

Wide violaceous striae — >1 fingerbreadth wide, purple; distinguishable from pregnancy striae by their width and color
Easy bruising / ecchymoses — from capillary fragility and thin skin
Hyperpigmentation — particularly in ectopic ACTH syndrome (excess ACTH binds MC1R)
Hirsutism, acne, thin skin, impaired wound healing, edema

Musculoskeletal:

Proximal muscle weakness — difficulty rising from chairs, climbing stairs
Osteoporosis, vertebral fractures, back pain

Metabolic:

Glucose intolerance / diabetes mellitus
Hypokalemia and metabolic alkalosis (particularly in ectopic ACTH)
Hypercalciuria and nephrolithiasis

Reproductive:

Oligomenorrhea / amenorrhea in women
Decreased libido in both sexes
Female-pattern baldness in women

Neuropsychiatric:

Depression (common; suicidal ideation in severe cases)
Emotional lability, irritability
Psychosis
Sleep disruption

Cardiovascular:

Hypertension — from direct mineralocorticoid effects of ACTH and glucocorticoid excess
Hypercoagulability → DVT and pulmonary embolism risk

Clinical Photos

Truncal obesity with violaceous striae:

Truncal obesity and violaceous striae in Cushing syndrome

Moon facies and facial plethora:

Diagnosis

Diagnosis is a two-step process: confirm hypercortisolism, then determine the cause.

Step 1 — Confirm Cortisol Excess (Screening Tests)

Test	Details
24-hour urinary free cortisol (UFC)	Elevated in Cushing syndrome; must be ≥2× ULN to be meaningful
Late-night salivary cortisol	Exploits loss of circadian rhythm; highly sensitive
Overnight 1-mg dexamethasone suppression test (DST)	Normal: cortisol <1.8 µg/dL; failure to suppress suggests hypercortisolism
Low-dose DST (2-day, 0.5 mg q6h)	More specific; failure to suppress confirms Cushing

Step 2 — Determine the Cause

Test	Purpose
Plasma ACTH level	Suppressed (<5 pg/mL) = ACTH-independent (adrenal source); elevated/normal = ACTH-dependent
High-dose DST (8 mg overnight)	Suppression to <50% baseline suggests pituitary origin (Cushing disease); no suppression suggests ectopic or adrenal
Pituitary MRI	Detects corticotroph adenoma (often <6 mm microadenoma)
CRH stimulation test	Pituitary adenoma responds (ACTH rises ≥35%, cortisol ≥20%); ectopic source does not
Inferior petrosal sinus sampling (IPSS)	Gold standard for confirming pituitary origin; central-to-peripheral ACTH ratio >2 (basal) or >3 (post-CRH) indicates Cushing disease
CT adrenals / chest imaging	For adrenal or ectopic source localization

"The high-dose DST is used to answer the question, 'Is Cushing syndrome caused by a pituitary corticotroph adenoma (Cushing disease), or from an ectopic source?'" — Quick Compendium of Clinical Pathology

Treatment

Cushing Disease (Pituitary)

Transsphenoidal surgery (TSS) — first-line; remission in 65–90% for microadenomas
Radiotherapy — for persistent/recurrent disease or surgical failures
Bilateral adrenalectomy — definitive but risks Nelson syndrome (enlarging pituitary tumor + hyperpigmentation)
Medical therapy (second-line or bridge): ketoconazole, metyrapone, mitotane, osilodrostat, pasireotide (somatostatin analog)

Adrenal Cushing (ACTH-independent)

Unilateral adrenalectomy for adenoma/carcinoma
Bilateral adrenalectomy for bilateral disease

Ectopic ACTH Syndrome

Remove the primary tumor when possible
Medical adrenal-blocking therapy while awaiting surgery

Exogenous Cushing

Gradual tapering of glucocorticoids (the HPA axis will be suppressed and requires time to recover)

Epidemiology

Endogenous Cushing syndrome: 2–5 cases/million/year
Cushing disease specifically: 1.2–2.4/million/year
Female predominance (8–10:1 in Cushing disease)
Most pituitary tumors are microadenomas (<10 mm); 10–15% are macroadenomas

Key Sources:

Goldman-Cecil Medicine, International Edition
Campbell-Walsh-Wein Urology, 3-Volume Set
Fitzpatrick's Dermatology
Quick Compendium of Clinical Pathology, 5th ed.
Washington Manual of Medical Therapeutics

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