What is the recommended approach to diagnose and treat adrenal insufficiency (hypocortisolism) and manage associated insomnia?

Approach to Hypocortisolism (Adrenal Insufficiency)

Immediate Clinical Assessment and Emergency Management

If a patient presents with unexplained hypotension, collapse, severe vomiting/diarrhea, or altered mental status, immediately administer 100 mg IV hydrocortisone plus 0.9% saline infusion at 1 L/hour without waiting for diagnostic test results—adrenal crisis is fatal if untreated. 1, 2, 3

Critical Red Flags Requiring Immediate Treatment

• Vasopressor-resistant hypotension or shock 1
• Unexplained collapse with gastrointestinal symptoms 1
• Patients on ≥20 mg/day prednisone for ≥3 weeks who develop hypotension 1
• Severe weakness with confusion or loss of consciousness 1

Draw blood for cortisol and ACTH before giving hydrocortisone if possible, but never delay treatment. 1, 2, 3

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Diagnostic Algorithm for Stable Patients

Step 1: Morning Cortisol and ACTH (8 AM)

Obtain paired early morning (approximately 8 AM) serum cortisol and plasma ACTH as the first-line diagnostic tests. 1, 2, 3, 4

Interpretation:

• Cortisol <5 µg/dL (<140 nmol/L) with elevated ACTH = Primary adrenal insufficiency confirmed 1, 2, 3, 4
• Cortisol <5 µg/dL with low/inappropriately normal ACTH = Secondary adrenal insufficiency confirmed 1, 3, 4
• Cortisol >13 µg/dL = Adrenal insufficiency ruled out 5
• Cortisol 5-13 µg/dL (140-360 nmol/L) = Proceed to cosyntropin stimulation test 1, 4, 6

Also obtain: basic metabolic panel (sodium, potassium, glucose) to assess for hyponatremia (present in 90% of cases) and hyperkalemia (present in only ~50% of primary AI cases). 1, 2, 3

Step 2: Cosyntropin Stimulation Test (When Morning Cortisol Indeterminate)

Protocol: 1, 2, 3, 7

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration
• Perform preferably in the morning (though not strictly required)

Interpretation:

• Peak cortisol <500 nmol/L (<18 µg/dL) = Adrenal insufficiency confirmed 1, 2, 3
• Peak cortisol >550 nmol/L (>18-20 µg/dL) = Adrenal insufficiency excluded 1, 2, 3

Important caveats:

• Do NOT perform this test in patients actively taking corticosteroids (prednisone, dexamethasone, inhaled fluticasone)—exogenous steroids suppress the HPA axis and cause false results. 1, 3
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods. 1
• If diagnostic testing is needed but treatment cannot be delayed, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 1

Step 3: Distinguish Primary vs. Secondary Adrenal Insufficiency

Primary AI characteristics: 1, 2, 3

• High ACTH with low cortisol
• Hyponatremia PLUS hyperkalemia (though hyperkalemia absent in ~50% of cases)
• Hyperpigmentation of skin creases, scars, or mucous membranes
• Salt craving
• Requires both glucocorticoid AND mineralocorticoid replacement

Secondary AI characteristics: 1, 3, 4

• Low or inappropriately normal ACTH with low cortisol
• Hyponatremia WITHOUT hyperkalemia
• Normal skin coloration (no hyperpigmentation)
• May have other pituitary hormone deficiencies
• Requires only glucocorticoid replacement

Step 4: Etiologic Workup (Once Diagnosis Confirmed)

For Primary AI: 1, 2, 3

1. Measure 21-hydroxylase autoantibodies first (autoimmunity accounts for ~85% of cases in Western populations)
2. If autoantibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, metastatic disease, tuberculosis, fungal infections, or structural abnormalities
3. In males with negative antibodies, consider assaying very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

For Secondary AI: 1, 3

• Evaluate for pituitary lesions, tumors, hemorrhage, inflammatory conditions (hypophysitis, sarcoidosis), or history of pituitary surgery/radiation
• Screen for other pituitary hormone deficiencies
• Consider medication-induced causes (opioids, high-dose glucocorticoids)

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Treatment of Confirmed Adrenal Insufficiency

Maintenance Glucocorticoid Replacement

Standard regimen (preferred): 1, 2, 3, 8, 4

• Hydrocortisone 15-25 mg daily in divided doses
• Typical schedule: 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM
• Alternative effective regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg

Alternative regimens: 1, 4

• Cortisone acetate 25-37.5 mg daily in divided doses
• Prednisone 3-5 mg daily (for select patients with marked energy fluctuations on hydrocortisone)
• Avoid dexamethasone for chronic replacement therapy 1

Monitoring and dose adjustment: 1

• Base adjustments on clinical assessment, NOT serum cortisol levels
• Signs of over-replacement: weight gain, insomnia, peripheral edema → reduce dose
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, morning symptoms → increase dose
• Consider earlier morning dosing (wake to take first dose, then return to sleep) to relieve morning nausea and fatigue 1, 9

Mineralocorticoid Replacement (Primary AI Only)

Fludrocortisone 50-200 µg daily (may require up to 500 µg daily in younger adults). 1, 2, 3, 4

Monitor adequacy by assessing: 1, 2

• Salt cravings (should resolve with adequate replacement)
• Orthostatic blood pressure (should normalize)
• Peripheral edema (indicates over-replacement)
• Plasma renin activity
• Serum sodium and potassium

Unrestricted sodium salt intake is essential. 1

Drug Interactions Affecting Dosing

Medications that INCREASE hydrocortisone requirements: 1

• CYP3A4 inducers: phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs
• Etomidate, topiramate

Medications that DECREASE hydrocortisone requirements: 1

• CYP3A4 inhibitors: grapefruit juice, liquorice
• Avoid these substances

Medications that interfere with fludrocortisone: 1

• Diuretics, acetazolamide, carbenoxolone, NSAIDs

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Stress Dosing and Emergency Preparedness

Patient Education (Mandatory for All Patients)

Every patient must: 1, 2, 3, 4

• Wear a medical alert bracelet or necklace indicating adrenal insufficiency
• Carry a steroid emergency card at all times
• Receive an emergency injectable hydrocortisone 100 mg IM kit with self-injection training
• Be educated on warning signs of impending adrenal crisis

Stress Dosing Guidelines

Minor stress (mild illness, dental procedures): 1

• Double the usual daily dose for 1-2 days

Moderate stress (fever, gastroenteritis, moderate surgery): 1

• Hydrocortisone 50-75 mg daily OR prednisone 20 mg daily
• Continue until stress resolves

Major stress (severe illness, major surgery, trauma): 1

• Hydrocortisone 100-150 mg daily (or 100 mg IV bolus followed by continuous infusion)
• Continue high-dose therapy until clinically stable, then taper

Inadequate patient education on stress dosing is a frequent contributor to recurrent adrenal crises. 1

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Special Considerations and Common Pitfalls

Adrenal Insufficiency vs. SIADH

Adrenal insufficiency must be excluded before diagnosing SIADH—both present with euvolemic hypo-osmolar hyponatremia and can be clinically indistinguishable. 1 Perform cosyntropin stimulation test in patients with hyponatremia and hypo-osmolality to rule out adrenal insufficiency. 1

Concurrent Hypothyroidism

When treating both adrenal insufficiency and hypothyroidism, start corticosteroids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1, 3

Glucocorticoid-Induced Adrenal Insufficiency

• Common in patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks 1
• Do NOT attempt diagnostic testing until corticosteroids have been discontinued with adequate washout time 1, 3
• Consider endocrine consultation for recovery and weaning protocol using hydrocortisone 1
• Test for HPA axis recovery after 3 months off steroids 1

Annual Screening (Primary AI)

Screen annually for associated autoimmune conditions: 1, 2

• Thyroid function
• Diabetes (fasting glucose, HbA1c)
• Pernicious anemia (vitamin B12)
• Celiac disease (tissue transglutaminase antibodies with total IgA if frequent diarrhea)

Monitor bone mineral density every 3-5 years to assess for glucocorticoid-related complications. 1

Insomnia Management in Adrenal Insufficiency

If insomnia develops in a patient with adrenal insufficiency on standard triple-dose hydrocortisone therapy, consider adjusting to quadruple-dose therapy with a small evening dose to better mimic the natural circadian cortisol rhythm—this has been shown to improve total sleep time, slow wave sleep, and REM sleep. 9

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Mandatory Endocrine Consultation

Refer to endocrinology for: 1

• Newly diagnosed adrenal insufficiency
• Pre-operative stress-dose planning
• Recovery protocols after prolonged steroid use
• Recurrent adrenal crises
• Persistent symptoms despite apparent adequate replacement

Confirmed adrenal insufficiency from non-iatrogenic causes requires lifelong replacement therapy—never attempt to discontinue hydrocortisone in these patients, as stopping will precipitate life-threatening adrenal crisis. 1