Can you explain cortisol’s normal physiology, the clinical features and treatment of Cushing syndrome and adrenal insufficiency, and how to evaluate suspected cortisol abnormalities?

Cortisol: Normal Physiology, Cushing Syndrome, Adrenal Insufficiency, and Diagnostic Evaluation

Normal Cortisol Physiology

Cortisol is secreted in a pulsatile and circadian pattern, with peak levels at 8:00–9:00 AM (140–700 nmol/L or 5.1–25.4 µg/dL in adult females) and a nadir at midnight (80–350 nmol/L or 2.9–12.7 µg/dL). 1 Healthy individuals produce 5–10 mg of cortisol per m² of body surface area daily, equivalent to 15–25 mg of oral hydrocortisone. 2

• The physiologic morning peak occurs at 8:00–9:00 AM, making this the optimal time for diagnostic testing to capture maximal secretion. 1
• Midnight cortisol represents the physiologic trough; loss of this nadir (midnight cortisol ≥50 nmol/L or ≥1.8 µg/dL) yields 100% sensitivity and 60% specificity for Cushing's syndrome. 1
• A single cortisol measurement must always be interpreted in the context of collection time, as the same numeric value can be normal in the morning but pathologically elevated at night. 1

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Cushing Syndrome: Clinical Features

Cushing syndrome results from chronic glucocorticoid excess and presents with central obesity, facial plethora, proximal muscle weakness, wide purple striae, easy bruising, and hypertension. 3

• Additional features include glucose intolerance or diabetes, osteoporosis, psychiatric disturbances (depression, anxiety), menstrual irregularities, and hirsutism in women. 3
• Loss of the normal circadian rhythm is a hallmark—patients fail to suppress cortisol at midnight. 3
• Pseudo-Cushing's states (depression, alcoholism, severe obesity, polycystic ovary syndrome) can activate the HPA axis and cause mild hypercortisolism that mimics true Cushing's syndrome. 3

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Cushing Syndrome: Diagnostic Evaluation

The Endocrine Society recommends initial screening with at least two of three tests: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), or overnight 1-mg dexamethasone suppression test (DST), obtaining 2–3 measurements of each to account for biological variability. 3

Late-Night Salivary Cortisol (LNSC)

• Collect between 23:00–00:00 (11 PM to midnight) on 2–3 separate nights. 3
• Abnormal threshold: >3.6 nmol/L (>0.1 µg/dL), with sensitivity 92–100% and specificity 93–100%. 3
• Avoid testing in night-shift workers due to disrupted circadian rhythm. 3
• Blood contamination from dental work, teeth brushing, or oral trauma within 1–2 hours can falsely elevate results. 3

24-Hour Urinary Free Cortisol (UFC)

• Values >100 µg/24 hours (1.6 µmol/24 hours) are diagnostic in symptomatic patients. 3
• Sensitivity >90%, but lowest among the three screening tests; obtain 2–3 collections due to 50% random variability. 3
• A complete 24-hour collection is essential—measure volume and total creatinine excretion to assess completeness. 3
• Renal impairment or polyuria invalidates UFC results; use LNSC instead. 3

Overnight 1-mg Dexamethasone Suppression Test (DST)

• Administer 1 mg dexamethasone at 23:00–00:00 (11 PM–midnight); measure serum cortisol at 08:00 the next morning. 3
• Abnormal: cortisol ≥1.8 µg/dL (≥50 nmol/L); cortisol >5 µg/dL (138 nmol/L) indicates overt Cushing's syndrome. 3
• Sensitivity >90%; measuring dexamethasone levels concomitantly reduces false-positive results. 3
• CYP3A4 inducers (anticonvulsants, rifampin) accelerate dexamethasone metabolism, causing false-positive results. 3
• Oral contraceptives and topical hydrocortisone elevate cortisol-binding globulin, falsely increasing total cortisol. 3

Critical Pitfalls to Avoid

• Always inquire about oral contraceptives, estrogen therapy, pregnancy, and topical hydrocortisone before pursuing extensive workup—elevated total cortisol without considering CBG status is the most important clinical pitfall. 3
• Fluticasone inhalers can suppress the HPA axis and confound DST results; use additional screening tests (LNSC, UFC) to triangulate the diagnosis. 3
• If screening tests are discordant, repeat 2–3 additional UFC collections and DST, and consider measuring dexamethasone levels concomitantly. 3

Determining Etiology

• Once hypercortisolism is confirmed, measure 9 AM plasma ACTH. 3
• Normal or elevated ACTH (>1.1 pmol/L or >5 ng/L) indicates ACTH-dependent Cushing's (pituitary or ectopic); proceed to pituitary MRI. 3
• Suppressed ACTH suggests an adrenal source; obtain adrenal CT imaging. 3

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Cushing Syndrome: Treatment

Surgical resection of the causative lesion (pituitary adenoma, adrenal tumor, or ectopic ACTH-secreting tumor) is the definitive treatment for Cushing syndrome. 3

• After successful surgery for Cushing syndrome, patients develop secondary adrenal insufficiency due to prolonged ACTH suppression and require postoperative glucocorticoid replacement. 4, 5
• Standard postoperative replacement is hydrocortisone 30 mg/day, but some patients may require higher doses (60–200 mg/day initially) if intestinal absorption is impaired or if they develop symptoms of adrenal insufficiency. 4
• Gradually taper hydrocortisone over weeks to months as the HPA axis recovers; monitor for symptoms of under-replacement (nausea, fatigue, anorexia). 4, 6
• Plasma ACTH levels and diurnal cortisol rhythm typically recover within 3 weeks postoperatively in most patients. 5

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Adrenal Insufficiency: Clinical Features

Adrenal insufficiency presents with fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, hypotension (especially orthostatic), and salt craving (in primary AI). 2, 3, 7

Primary Adrenal Insufficiency (Addison's Disease)

• Hyperpigmentation of skin creases, scars, and mucous membranes due to markedly elevated ACTH. 3
• Hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of cases). 3, 7
• Orthostatic hypotension reflects insufficient mineralocorticoid. 3
• Salt craving is a key clinical clue. 3

Secondary Adrenal Insufficiency

• Normal skin color (no hyperpigmentation) due to low ACTH. 3
• Hyponatremia without hyperkalemia (mineralocorticoid function is preserved). 3
• May have additional pituitary hormone deficiencies (hypothyroidism, hypogonadism). 3

Acute Adrenal Crisis

• Severe weakness, confusion, altered mental status, loss of consciousness, or coma. 3
• Hypotension and shock with dehydration. 3
• Severe vomiting and/or diarrhea. 3
• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—mortality is high if untreated. 3, 7

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Adrenal Insufficiency: Diagnostic Evaluation

Paired measurement of early morning (8:00 AM) serum cortisol and plasma ACTH is the first-line diagnostic test. 3, 7

Interpreting Morning Cortisol and ACTH

• Morning cortisol >14 µg/dL (>386 nmol/L) effectively rules out adrenal insufficiency. 3
• Morning cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 3, 7
• Morning cortisol <400 nmol/L (<14 µg/dL) with elevated ACTH in acute illness raises strong suspicion of primary adrenal insufficiency. 3, 7
• Morning cortisol 140–275 nmol/L (5–10 µg/dL) with low or inappropriately normal ACTH suggests secondary adrenal insufficiency. 3
• Markedly elevated ACTH (>300 pg/mL) with low cortisol confirms primary adrenal insufficiency; low or inappropriately normal ACTH with low cortisol indicates secondary adrenal insufficiency. 3

ACTH (Cosyntropin/Synacthen) Stimulation Test

The ACTH stimulation test is the gold standard for confirming adrenal insufficiency when initial results are indeterminate. 3, 7

• Protocol: Administer 0.25 mg (250 µg) cosyntropin IV or IM; measure serum cortisol at baseline, 30 minutes, and 60 minutes. 3, 7
• Interpretation: Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency; peak cortisol >550 nmol/L (>18–20 µg/dL) excludes adrenal insufficiency. 3, 7
• The high-dose (250 µg) test is preferred over the low-dose (1 µg) test due to easier administration, comparable diagnostic accuracy, and FDA approval. 3

Etiologic Workup for Primary Adrenal Insufficiency

• Measure 21-hydroxylase (anti-adrenal) autoantibodies—positive in ~85% of autoimmune Addison's disease in Western populations. 2, 3
• If autoantibodies are negative, obtain adrenal CT imaging to evaluate for hemorrhage, tumors, tuberculosis, or infiltrative disease. 2, 3
• In males with negative autoantibodies, measure very long-chain fatty acids (VLCFA) to screen for X-linked adrenoleukodystrophy. 2, 3

Critical Pitfalls to Avoid

• Do not rely on electrolyte abnormalities alone—hyperkalemia is present in only ~50% of primary AI cases, and some patients have normal electrolytes. 3, 7
• Exogenous steroids (oral prednisolone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound cortisol testing; do not attempt diagnostic testing until steroids have been discontinued with adequate washout time. 2, 3
• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic due to assay cross-reactivity with therapeutic steroids. 3
• If the patient is clinically unstable with suspected adrenal crisis, give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour—do NOT delay for testing. 3, 7

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Adrenal Insufficiency: Treatment

Patients with adrenal insufficiency require lifelong glucocorticoid replacement therapy; those with primary AI also require mineralocorticoid replacement. 2, 3

Glucocorticoid Replacement

• Preferred regimen: Hydrocortisone 15–25 mg daily in divided doses (e.g., 10 mg at 07:00,5 mg at 12:00,2.5–5 mg at 16:00). 2, 3
• Alternative: Cortisone acetate 25–37.5 mg daily in divided doses. 2, 3
• Alternative: Prednisolone 4–5 mg daily (for select patients with marked energy fluctuations or when hydrocortisone is not tolerated). 2, 3
• Avoid dexamethasone for chronic replacement therapy. 2

Mineralocorticoid Replacement (Primary AI Only)

• Fludrocortisone 50–200 µg daily (typical range; doses up to 500 µg daily may be needed in younger adults). 2, 3
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity. 2, 3
• Unrestricted sodium salt intake is essential. 2, 3

Monitoring and Dose Adjustment

• Monitoring relies primarily on clinical assessment, not serum cortisol or ACTH measurements. 2
• Over-replacement: Weight gain, insomnia, peripheral edema. 2
• Under-replacement: Lethargy, nausea, poor appetite, weight loss, increased pigmentation. 2
• Fine-tune dosing by detailed questioning about daily energy levels, mental concentration, daytime somnolence, and timing of fatigue. 2
• Waking earlier to take the first dose of hydrocortisone and returning to sleep may relieve morning nausea and lack of appetite. 2

Drug Interactions

• CYP3A4 inducers (anticonvulsants, rifampin, barbiturates) increase hydrocortisone clearance and may require higher doses. 2, 3
• CYP3A4 inhibitors (grapefruit juice, licorice) decrease hydrocortisone clearance and may require lower doses. 2, 3

Stress Dosing

• Patients must double or triple their usual dose during illness, fever, or physical stress. 2, 3
• Minor stress: Double the usual daily dose for 1–2 days. 3
• Moderate stress: Hydrocortisone 50–75 mg daily or prednisone 20 mg daily. 3
• Major stress (surgery, severe illness): Hydrocortisone 100–150 mg daily. 3

Emergency Management of Adrenal Crisis

• Immediate treatment: 100 mg IV hydrocortisone bolus plus 0.9% saline infusion at 1 L/hour (at least 2 L total). 3, 7
• Draw blood for cortisol and ACTH before steroid administration if feasible, but do not delay treatment. 3, 7
• If diagnosis is uncertain and you still need to perform ACTH stimulation testing later, use dexamethasone 4 mg IV instead of hydrocortisone (dexamethasone does not interfere with cortisol assays). 3

Patient Education and Safety

• All patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency. 2, 3
• Carry a steroid emergency card at all times. 2
• Prescribe a hydrocortisone 100 mg IM injection kit with self-injection training. 2, 3
• Educate on warning signs of impending adrenal crisis (severe vomiting, diarrhea, inability to take oral medications, marked weakness, confusion, hypotension). 3

Special Considerations

• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 3
• Patients with primary AI should undergo annual screening for associated autoimmune conditions (thyroid function, diabetes, pernicious anemia, celiac disease). 3
• Review patients at least annually with assessment of health, well-being, weight, blood pressure, and serum electrolytes. 3
• Monitor bone mineral density every 3–5 years to assess for complications of glucocorticoid therapy. 3

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Distinguishing Adrenal Insufficiency from SIADH

Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings. 7

• Both conditions show serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium. 7
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases. 7
• The absence of hyperkalemia cannot rule out adrenal insufficiency (present in only ~50% of cases). 7
• Perform a cosyntropin stimulation test to rule out adrenal insufficiency before diagnosing SIADH. 7
• Correct diagnosis is crucial: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction and possibly vasopressin receptor antagonists. 7