How should I evaluate and manage a patient with fatigue, weakness, anorexia, nausea, weight loss, orthostatic hypotension, and salt craving who has a pituitary or hypothalamic disorder or chronic exogenous glucocorticoid exposure for possible secondary adrenal insufficiency?

Secondary Adrenal Insufficiency: Evaluation and Management

In a patient with fatigue, weakness, anorexia, nausea, weight loss, orthostatic hypotension, and salt craving who has pituitary/hypothalamic disease or chronic glucocorticoid exposure, immediately obtain early-morning (8 AM) cortisol and ACTH levels—if morning cortisol is <5 µg/dL with low/inappropriately normal ACTH, diagnose secondary adrenal insufficiency and start hydrocortisone 15-25 mg daily in divided doses (typically 10-20 mg morning, 5-10 mg early afternoon). 1, 2

Diagnostic Approach

Initial Laboratory Testing

• Draw early-morning (approximately 8 AM) serum cortisol, ACTH, and DHEAS simultaneously to establish the diagnosis 1, 2
• Check serum electrolytes looking specifically for hyponatremia (common) with normal or near-normal potassium (unlike primary adrenal insufficiency where hyperkalemia occurs) 1
• Measure TSH and free T4 since hypopituitarism often affects multiple hormone axes 3

Interpretation of Initial Results

• Morning cortisol <5 µg/dL with low or inappropriately normal ACTH confirms secondary adrenal insufficiency—no further testing needed 1, 2
• Morning cortisol >13 µg/dL effectively rules out adrenal insufficiency 4
• Morning cortisol 5-10 µg/dL (intermediate range) requires confirmatory testing with cosyntropin stimulation test 2, 4

Confirmatory Testing for Intermediate Results

• Perform cosyntropin (ACTH) stimulation test: administer 250 µg cosyntropin and measure cortisol at baseline and 60 minutes 1, 2
• Peak cortisol <500 nmol/L (approximately <18 µg/dL) confirms adrenal insufficiency 1
• Peak cortisol <16 µg/dL on either low-dose or high-dose cosyntropin test reliably predicts adrenal insufficiency 4

Important caveat: In patients with recent pituitary injury (surgery, hemorrhage, apoplexy), the cosyntropin test may be falsely normal for several weeks because the adrenal glands haven't yet atrophied—clinical judgment and repeat testing in 4-6 weeks may be necessary 4, 5

Key Distinguishing Features from Primary Adrenal Insufficiency

• Salt craving is less prominent in secondary adrenal insufficiency because aldosterone production remains intact (renin-angiotensin system is preserved) 6, 2
• Hyperkalemia does NOT occur in secondary adrenal insufficiency 1
• Hyperpigmentation is absent (low ACTH means no melanocyte stimulation) 2

Management Strategy

Daily Glucocorticoid Replacement

• Start hydrocortisone 15-25 mg daily in divided doses (preferred regimen: 10-20 mg upon waking, 5-10 mg in early afternoon) 1, 2
• Alternative: prednisone 3-5 mg daily if hydrocortisone is unavailable 2
• Do NOT use dexamethasone for maintenance therapy as it lacks mineralocorticoid activity and has too long a half-life 3
• Mineralocorticoid replacement (fludrocortisone) is NOT needed in secondary adrenal insufficiency since aldosterone production is preserved 2

Critical Timing Issue with Thyroid Hormone

If the patient also has central hypothyroidism requiring levothyroxine, you MUST start hydrocortisone several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 3, 1 Thyroid hormone increases cortisol metabolism and can unmask or worsen adrenal insufficiency.

Stress Dosing Protocol

• During minor illness (fever, gastroenteritis): double or triple the usual daily dose 1, 2
• During severe illness or before surgery: hydrocortisone 100 mg IV bolus, then 200 mg/24 hours continuous infusion until the patient can take oral medications 3
• Taper stress doses back to maintenance over 5-10 days for moderate stress, or 7-14 days after major surgery 3

Emergency Management of Adrenal Crisis

If the patient presents with hypotension, altered mental status, or shock:

• Immediately give hydrocortisone 100 mg IV bolus 3, 1
• Start aggressive IV fluid resuscitation with normal saline (at least 2 liters rapidly, then 1 liter/hour) 3, 1
• Continue hydrocortisone 200 mg/24 hours as continuous IV infusion 3
• If diagnosis is uncertain and you need to perform stimulation testing, use dexamethasone 4 mg IV instead (doesn't interfere with cortisol assays) 3

Essential Safety Measures

Patient Education and Emergency Preparedness

• Prescribe an emergency injection kit (hydrocortisone 100 mg IM) and train the patient and family on its use 1, 2
• Ensure the patient wears a medical alert bracelet stating "adrenal insufficiency" so emergency personnel know to give stress-dose steroids 3, 1
• Provide written instructions on stress dosing for illness, injury, or dental procedures 3

Perioperative Management

• Notify anesthesia and surgery teams before ANY procedure 3, 1
• For major surgery: give hydrocortisone 100 mg IV at induction, then 200 mg/24 hours continuous infusion until oral intake resumes 3
• After uncomplicated surgery: double the oral replacement dose for 48 hours, or up to one week for major procedures 3

Special Considerations for Glucocorticoid-Induced Adrenal Insufficiency

This is the most common cause of secondary adrenal insufficiency, affecting approximately 7 in 1,000 people—roughly 100 times more prevalent than intrinsic pituitary disease. 6, 2

Risk Factors

• Any glucocorticoid dose ≥5 mg prednisone daily (or equivalent) for ≥1 month can suppress the HPA axis 3
• ALL routes of administration can cause suppression: oral, inhaled, topical, intranasal, intra-articular 3, 6
• Inhaled corticosteroids cause dose-dependent HPA suppression even at commonly prescribed doses 3, 6

Recovery Timeline

• The HPA axis typically recovers 6-12 months after glucocorticoid cessation, but timing is highly variable 7
• During ongoing treatment or immediately after withdrawal, approximately 50% of patients have adrenal insufficiency 8
• Testing is often neglected: <1% of at-risk patients have documented adrenal testing 8

Testing Approach During Glucocorticoid Taper

• Wait at least 24 hours after the last glucocorticoid dose before checking morning cortisol (longer for dexamethasone due to its long half-life) 8
• If morning cortisol >13 µg/dL, the axis has recovered 4
• If cortisol remains low, continue replacement and retest in 4-8 weeks 7, 8

Long-Term Monitoring

• Annual follow-up should assess symptoms, weight, blood pressure, and serum electrolytes 1
• Screen for other autoimmune conditions: thyroid function, diabetes, vitamin B12, celiac disease (particularly relevant if primary adrenal insufficiency is in the differential) 1
• Reassess patients with persistent suggestive symptoms even if initial testing was borderline 5

Common Pitfalls to Avoid

• Never assume a normal cosyntropin test rules out secondary adrenal insufficiency in recent pituitary injury—the adrenals may not have atrophied yet 4, 5
• Never start thyroid hormone before glucocorticoid replacement in patients with combined deficiencies 3, 1
• Never withhold stress-dose steroids if uncertain—short-term glucocorticoid administration has no long-term adverse consequences, but missing adrenal crisis can be fatal 3
• Don't rely solely on symptoms to diagnose adrenal insufficiency—they are nonspecific and overlap with many other conditions 2, 8
• Remember that >70% of adrenal crises are identified during acute hospital admissions where the diagnosis is easily missed due to medication errors and omissions 3, 8