How to manage a patient with fluctuating cortisol and Adrenocorticotropic hormone (ACTH) levels?

Management of Fluctuating Cortisol and ACTH Levels

Immediate Diagnostic Priority

This patient requires an ACTH stimulation test (cosyntropin test) to definitively establish whether adrenal insufficiency is present, as the fluctuating cortisol levels with inappropriately normal-to-elevated ACTH suggest either cyclic Cushing's syndrome or intermittent adrenal insufficiency. 1

The dexamethasone suppression test (DST) showing cortisol suppression to 0.9 μg/dL with a dexamethasone level of 348 ng/mL and ACTH of 40 pg/mL argues against autonomous cortisol production, making cyclic Cushing's syndrome less likely. 2 However, the extremely low morning cortisol values (0.6 and 0.9 μg/dL) with detectable ACTH levels create diagnostic uncertainty that must be resolved.

Interpretation of Current Laboratory Findings

Pattern Analysis

• Morning cortisol of 0.6 μg/dL with ACTH 38 pg/mL: This represents profound hypocortisolism with inappropriately normal ACTH, suggesting either secondary adrenal insufficiency or a transitional state 1
• Morning cortisol of 23.5 μg/dL with ACTH 61 pg/mL: This elevated cortisol with elevated ACTH could represent stress response, cyclic hypercortisolism, or ectopic ACTH 3
• Post-DST cortisol 0.9 μg/dL with ACTH 40 pg/mL: Appropriate suppression of cortisol but persistent ACTH suggests the HPA axis can be suppressed, making autonomous cortisol secretion unlikely 1
• Normal sodium (138 mEq/L) and potassium (4.4 mEq/L): These values do not exclude adrenal insufficiency, as hyperkalemia is present in only ~50% of cases and hyponatremia may be absent 1

Critical Diagnostic Consideration

The relationship between ACTH and cortisol is inconsistent with classic primary or secondary adrenal insufficiency patterns. In primary adrenal insufficiency, ACTH should be markedly elevated (typically >100 pg/mL) with consistently low cortisol. 1 In secondary adrenal insufficiency, both ACTH and cortisol should be consistently low. 1 This patient demonstrates neither pattern consistently.

Definitive Diagnostic Testing Required

ACTH Stimulation Test Protocol

Administer 250 mcg (0.25 mg) cosyntropin intramuscularly or intravenously, with cortisol measurements at baseline and 30 minutes post-administration. 1

• Perform the test preferably in the morning, though not strictly necessary 1
• Obtain baseline serum cortisol and plasma ACTH before cosyntropin administration 1
• A peak cortisol >550 nmol/L (>20 μg/dL) is considered normal 1
• A peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1

Interpretation Framework

• If peak cortisol >550 nmol/L: Adrenal insufficiency is excluded; consider cyclic Cushing's syndrome or factitious disorder 3, 4
• If peak cortisol <500 nmol/L: Adrenal insufficiency is confirmed; proceed to determine primary vs. secondary etiology 1

Differential Diagnosis Considerations

Cyclic Cushing's Syndrome

This rare variant presents with fluctuating cortisol levels that can range from severe hypercortisolemia to symptomatic hypocortisolemia due to erratic ACTH secretion. 3 The elevated cortisol value (23.5 μg/dL) with elevated ACTH (61 pg/mL) supports this possibility, but the appropriate suppression on DST argues against it. 3

Isolated ACTH Deficiency

This condition presents with secondary adrenal insufficiency but typically shows consistently low ACTH with low cortisol, not the fluctuating pattern seen here. 5 However, early or partial ACTH deficiency could explain the inappropriately normal ACTH levels with low cortisol. 5

Intermittent HPA Axis Dysfunction

The patient may have a subnormal ACTH response with decreased ACTH secretory reserve, where baseline function appears adequate but stress responses are impaired. 6 This would explain why cortisol can be normal at times but profoundly low at others.

Management Algorithm Based on Cosyntropin Test Results

If Adrenal Insufficiency is Confirmed (Peak Cortisol <500 nmol/L)

Initiate glucocorticoid replacement therapy immediately with hydrocortisone 15-25 mg daily in divided doses (10-15 mg upon waking, 5-10 mg in early afternoon). 7, 1

• Determine primary vs. secondary: Measure 21-hydroxylase autoantibodies to identify autoimmune primary adrenal insufficiency 1
• If autoantibodies negative: Obtain CT imaging of adrenals to evaluate for structural causes 1
• If imaging normal and ACTH remains low-normal: Diagnose secondary adrenal insufficiency; obtain pituitary MRI to evaluate for hypophysitis or other pituitary pathology 7
• Mineralocorticoid replacement: Only needed if primary adrenal insufficiency is confirmed; add fludrocortisone 0.05-0.2 mg daily 1

If Adrenal Insufficiency is Excluded (Peak Cortisol >550 nmol/L)

Pursue evaluation for cyclic Cushing's syndrome with serial measurements of 24-hour urinary free cortisol and late-night salivary cortisol during symptomatic periods. 2, 4

• Measure midnight ACTH levels in addition to midnight cortisol, as midnight ACTH-associated cortisol elevations may not correlate with true hypercortisolism 4
• If hypercortisolism is confirmed with non-suppressed ACTH, obtain pituitary MRI to evaluate for ACTH-secreting adenoma 2
• Consider inferior petrosal sinus sampling if imaging is negative but biochemical evidence supports ACTH-dependent Cushing's 2

Critical Safety Measures

Patient Education Requirements

• All patients with confirmed adrenal insufficiency require education on stress dosing: Double maintenance dose during illness, injury, or significant stress 7, 1
• Medical alert bracelet: Essential to trigger stress-dose corticosteroids by emergency medical services 7, 1
• Emergency injection kit: Consider prescribing hydrocortisone 100 mg IM for self-administration during adrenal crisis 1

Perioperative Planning

• Endocrine consultation required before any surgery or procedure for stress-dose planning 7
• Stress-dose protocol: Hydrocortisone 100 mg IV at induction, followed by 50 mg IV every 6-8 hours, tapering over 2-3 days postoperatively 7

Important Pitfalls to Avoid

Do Not Delay Treatment in Crisis

If the patient develops hypotension, altered mental status, or other signs of adrenal crisis, administer hydrocortisone 100 mg IV immediately without waiting for diagnostic test results. 1 Mortality is high if adrenal crisis is untreated. 1

Do Not Rely on Electrolytes Alone

The absence of hyperkalemia and presence of normal sodium do not exclude adrenal insufficiency. 1 Between 10-20% of patients have normal electrolytes at presentation. 1

Do Not Start Thyroid Hormone Before Corticosteroids

If concurrent hypothyroidism is identified, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 7, 1

Recognize Exogenous Steroid Interference

The dexamethasone used in the DST can suppress the HPA axis and confound subsequent testing. 1 Allow adequate washout time (at least 5 half-lives, approximately 2-3 days for dexamethasone) before performing the cosyntropin test. 8

Follow-Up Monitoring

If Adrenal Insufficiency is Confirmed

• Reassess adequacy of replacement: Monitor for symptoms of over-replacement (weight gain, hypertension, hyperglycemia) or under-replacement (fatigue, hypotension, weight loss) 1
• Annual evaluation: Check morning cortisol while on therapy (should be low due to suppression), electrolytes, and clinical status 1
• Repeat ACTH stimulation testing: Not routinely needed once diagnosis is established and patient is stable on replacement 1

If Cyclic Cushing's is Suspected

• Serial biochemical monitoring: Repeat 24-hour urinary free cortisol and late-night salivary cortisol every 2-4 weeks to capture cyclical elevations 4
• Document correlation: Record symptoms during high and low cortisol phases to establish clinical significance 3