Endocrine · Topic 14 of 14

Cushing Syndrome & Primary Aldosteronism

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Endocrine · adrenal hormone excess

Cushing Syndrome & Primary Aldosteronism

Exclude exogenous steroids and test cortisol suppression for Cushing. Screen aldosterone and renin for aldosteronism: adrenalectomy if unilateral, spironolactone if bilateral.

01 · Cushing screenDexamethasone 1 mg: normal cortisol < 1.8 mcg/dL

02 · Aldosteronism screenARR > 20, aldosterone ≥ 10 ng/dL (immunoassay)

03 · Aldosteronism treatmentUnilateral: surgery. Bilateral: spironolactone

What causes Cushing syndrome

ACTH separates the causes

ACTH-dependent

Pituitary adenoma (Cushing disease)Ectopic ACTH: small cell lung cancerEctopic ACTH: neuroendocrine tumors

ACTH-independent

Therapeutic glucocorticoidsAdrenal adenomaAdrenal carcinoma

What you'll see

In aldosteronism, potassium is often normal; hypertension may be the only finding

Cushing syndrome

Facial rounding with plethora

Truncal obesity, buffalo hump, supraclavicular fat

Striae, thin skin, easy bruising, poor healing

Slender extremities

Muscle wasting with weakness

Hypertension, glucose intolerance, hypokalemia

Osteoporosis, renal calculi

Reduced infection resistance, psychiatric disturbance

Primary aldosteronism

Autonomous aldosterone: Na⁺ kept, K⁺ and H⁺ lost, renin suppressed

Resistant hypertension

Spontaneous or diuretic-induced hypokalemia

Atrial fibrillation without structural heart disease

Hypokalemic alkalosis: episodic weakness, paresthesias

Transient paralysis, tetany

Polyuria from hypokalemic nephropathy

Sodium normal or high, edema uncommon

Diagnose Cushing syndrome, in order

Screening tests: 24-hour urine free cortisol, late-night salivary cortisol, 1-mg overnight dexamethasone suppression

Exclude exogenous glucocorticoids

Screen with one high-accuracy test

Confirm any abnormal result with a second test

Dexamethasone test: 1 mg at 11 PM–midnight, serum cortisol at 8–9 AM

Normal suppresses to under 1.8 mcg/dL (50 nmol/L); Cushing stays higher

Cortisol excess confirmed: measure plasma ACTH

ACTH undetectable: adrenal cause

ACTH normal or high: pituitary source or ectopic ACTH

Diagnose primary aldosteronism, in order

Correct hypokalemia first: it falsely lowers aldosterone

Screen plasma aldosterone, renin and potassium together

Immunoassay positive: PRA ≤ 1 ng/mL/h, aldosterone ≥ 10 ng/dL, ARR > 20

LC-MS/MS positive: aldosterone ≥ 7.5 ng/dL, ARR > 15

Screening may proceed on antihypertensives

High-risk, negative screen: consider endocrinology to retest after drug changes

High-risk, positive on a beta-blocker or central alpha-2 agonist: consider retest

Lateralize surgical candidates: adrenal CT and adrenal vein sampling

Aldosteronism testing: where sources differ

Cutoffs depend on the assay

Merck still quotes aldosterone over 15 ng/dL with ARR over 20

Merck still stops renin-angiotensin-affecting drugs for 4–6 weeks

The 2025 guideline replaces routine washout with testing on current drugs

Endocrine Society 2025 suggests screening everyone with hypertension (conditional, low confidence); the 2025 AHA/ACC guideline targets resistant hypertension regardless of potassium (see Hypertension).

When adrenal vein sampling may be skipped

Only with all of these

Age under 35

Marked aldosterone excess

Hypokalemia

Clear unilateral adenoma over 1 cm

Renin separates the causes

Low renin with high aldosterone is primary

High renin, high aldosterone: secondary

RenovascularEdematous states

Renin and aldosterone both low

LicoriceCushing syndromeLiddle syndrome

Red flags

Severe hypercortisolism block synthesis

Hypercortisolism emergency: parenteral etomidate lowers cortisol rapidly monitor closely

Adrenal tumor surgery: remaining cortex is atrophic give cortisol

Endogenous Cushing syndrome carries venous thromboembolism risk consider LMWH

Transient paralysis or tetany from hypokalemic alkalosis

Normal potassium does not exclude primary aldosteronism

Treat Cushing syndrome

Surgeryremove the cause

Remove the causative pituitary, adrenal or ectopic tumor

Give cortisol during and after adrenal tumor surgery; bilateral adrenalectomy needs lifelong glucocorticoid replacement (see Adrenal Insufficiency)

Blocksevere hypercortisolism

Metyrapone Ketoconazole Osilodrostat

Block steroid synthesis

Ketoconazole: liver toxicity, QT prolongation

Etomidateemergency

Etomidate, parenteral

Lowers cortisol rapidly

Needs careful monitoring

Supportwhile treating

Potassium

High protein intake; usual treatment of hyperglycemia and hypertension

LMWHconsider, endogenous Cushing

LMWH, weight-based prophylactic

From diagnosis to 3 months after biochemical remission, unless contraindicated

2025 Delphi consensus position; best duration after cure remains uncertain

Cortisol testing and localizing ACTH

Urine free cortisol over 120 mcg/24 h in almost all Cushing syndromeOver 4 times the upper limit is nearly diagnostic; 100–150 mcg/24 h may reflect obesity, depression or polycystic ovaries

Serum cortisol normally falls under 1.8 mcg/dL at midnightCushing syndrome loses this rhythm even when morning cortisol is normal. Collect 2–3 salivary samples. Estrogen spuriously raises serum cortisol with normal diurnal variation

Detectable ACTH: pituitary MRI and desmopressin testing localize itPetrosal-to-peripheral ACTH ratio over 3 virtually excludes ectopic secretion. Most centers have abandoned the high-dose dexamethasone test

Treat primary aldosteronism

Adrenalectomyunilateral disease

Laparoscopic adrenalectomy

Antagonistbilateral or nonsurgical

Spironolactone 12.5–25 mg daily, start Eplerenone

Mineralocorticoid receptor antagonist, usually spironolactone

Eplerenone has fewer antiandrogen effects

Monitoron an antagonist

Potassium and creatinine within 1 week of starting or changing

Renin at 2–3 months; titrate to raise renin

Saline test, cortisol co-secretion, outcomes, spironolactone start

Seated saline suppression: 2 L over 4 hoursCommonly used for intermediate probability when surgery is wanted; skip it with spontaneous hypokalemia, suppressed renin and high aldosterone

Aldosteronism with an adenoma: give a 1-mg dexamethasone testAbout 22% have mild autonomous cortisol secretion, which can cause adrenal insufficiency after adrenalectomy

After adenoma removal, potassium normalizes and BP falls in all patientsBP normalizes in 50–70%. 70% with bilateral hyperplasia remain hypertensive after adrenalectomy, so surgery is not recommended for hyperplasia

Merck starts spironolactone at 50 mg daily for hyperplasiathe 2025 guideline summary starts lower and titrates to BP, potassium and renin

After adrenalectomy for aldosteronism

Stop mineralocorticoid antagonists and potassium on postoperative day 1 stop day 1

Monitor potassium: contralateral suppression causes hyperkalemia, usually mild

Up to 5% need fludrocortisone for persistent hypoaldosteronism

One series of 69 patients: any postoperative hyperkalemia 23%, clinically meaningful 5.8%.

Primary or secondary aldosteronism?

	Primary	Secondary
Renin	Suppressed	High
Aldosterone	High	High
Serum sodium	Normal or high	Normal or low
Edema	Uncommon	Present in edematous states

Pearl

Cortisol that will not suppress, renin that stays suppressed: two adrenal excess states, two different first tests.

Sources · Merck Manual Professional — Cushing Syndrome · Nieman LK et al. The diagnosis of Cushing’s syndrome: Endocrine Society guideline. J Clin Endocrinol Metab 2008 · Adler GK et al. Primary Aldosteronism: Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2025 (abstract) · Primary aldosteronism: Interpreting the 2025 Endocrine Society clinical practice guideline update. Cleve Clin J Med 2026 · Merck Manual Professional — Primary Aldosteronism · Delphi panel consensus on thromboprophylaxis of venous thromboembolism in endogenous Cushing’s syndrome: a position statement. Eur J Endocrinol 2025 (abstract) · Korean Endocrine Society Consensus Guidelines for Primary Aldosteronism. Endocrinol Metab 2023 · UIC Drug Information Group — Overview of the 2025 Hypertension Guidelines (Dec 2025) · Fischer E et al. Prolonged zona glomerulosa insufficiency causing hyperkalemia in primary aldosteronism following adrenalectomy. Endocrine Abstracts 2012 · Follow your institution's protocols.