Is this a case of exogenous or endogenous Cushing syndrome?

Exogenous vs. Endogenous Cushing Syndrome

This is unequivocally exogenous Cushing syndrome caused by chronic, inadvertent dexamethasone ingestion from an over-the-counter "anti-allergy" pill. 1, 2

Five Specific Findings Supporting Exogenous Cushing Syndrome

1. Undetectable ACTH (<5 pg/mL): The Endocrine Society guidelines state that low or undetectable ACTH levels definitively indicate ACTH-independent Cushing syndrome, and in the context of known exogenous steroid exposure, this confirms suppression of the hypothalamic-pituitary-adrenal (HPA) axis by exogenous glucocorticoids. 1, 3

2. Suppressed 8 AM serum cortisol (3 μg/dL): Endogenous cortisol production is completely suppressed, which occurs when exogenous glucocorticoids provide negative feedback to the pituitary and hypothalamus, shutting down endogenous ACTH and cortisol secretion. 1, 4

3. Documented 2-year history of daily dexamethasone intake: The patient has been taking 5 mg dexamethasone daily (a supraphysiologic dose) disguised as an "anti-allergy" medication—this is the classic presentation of iatrogenic Cushing syndrome. 5, 6

4. Classic cushingoid features with rapid onset: The constellation of moon face, buffalo hump, purple striae >1 cm, proximal muscle weakness, easy bruising, and metabolic complications (hyperglycemia, hypertension, hypokalemia, osteopenia) developed over 2 years, consistent with exogenous glucocorticoid exposure. 5, 2

5. Absence of features suggesting endogenous disease: No abdominal masses on exam (ruling out adrenal tumor), and the combination of suppressed ACTH with suppressed cortisol excludes all forms of endogenous Cushing syndrome (which would show either elevated ACTH with elevated cortisol in ACTH-dependent disease, or suppressed ACTH with elevated cortisol in adrenal tumors). 1, 3

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Adrenal Crisis Risk with Abrupt Steroid Cessation

This patient has an extremely high risk of life-threatening adrenal crisis if dexamethasone is stopped abruptly, because 2 years of daily supraphysiologic glucocorticoid exposure has completely suppressed her HPA axis, rendering her adrenal glands atrophied and unable to produce cortisol. 5, 2

Mechanism of HPA Axis Suppression

• Chronic exogenous glucocorticoid administration suppresses hypothalamic CRH and pituitary ACTH secretion through negative feedback, leading to adrenal cortex atrophy from lack of ACTH stimulation. 1, 3

• The patient's undetectable ACTH and low cortisol levels confirm complete HPA axis suppression—her adrenal glands cannot respond to physiologic stress. 1

• Abrupt withdrawal would leave the patient without any glucocorticoid coverage during the months-long period required for HPA axis recovery, exposing her to adrenal crisis during any physiologic stress (infection, trauma, surgery). 5, 2

Clinical Consequences of Adrenal Crisis

• Adrenal crisis manifests as severe hypotension, shock, hyponatremia, hyperkalemia, hypoglycemia, and can be fatal without immediate glucocorticoid replacement. 7, 2

• The Endocrine Society explicitly warns that secondary adrenocortical unresponsiveness is "particularly dangerous in times of stress, as in trauma, surgery, or illness." 8, 7

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Steroid Equivalence and Mineralocorticoid Activity

Glucocorticoid Potency Conversions

5 mg dexamethasone daily equals:

• Prednisone: 33.3 mg daily (dexamethasone is 6.67 times more potent than prednisone) 8, 9
• Hydrocortisone: 133.3 mg daily (dexamethasone is 26.67 times more potent than hydrocortisone) 7, 9

Mineralocorticoid Activity Profile

• Dexamethasone: Negligible mineralocorticoid activity (essentially zero sodium-retaining effect) 9
• Prednisone: Minimal mineralocorticoid activity (approximately 0.8 relative to hydrocortisone) 8
• Hydrocortisone: Significant mineralocorticoid activity (1.0 reference standard—has both glucocorticoid and mineralocorticoid receptor binding) 7

Clinical Implications

• The patient's hypokalemia (K 3.3 mEq/L) likely results from dexamethasone's glucocorticoid effects on renal potassium excretion rather than mineralocorticoid activity, as dexamethasone has minimal mineralocorticoid receptor binding. 5, 9

• When tapering, switching to hydrocortisone may provide more physiologic replacement due to its mineralocorticoid activity, though this must be balanced against the need for multiple daily doses. 7

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Safe Taper Protocol from Chronic Dexamethasone

The taper must be gradual over 3-6 months to allow HPA axis recovery while preventing both Cushing syndrome complications and adrenal insufficiency. 5, 10

Proposed Taper Schedule

Phase 1: Initial Dose Reduction (Weeks 1-4)

• Switch to prednisone 30 mg daily (slightly lower than equivalent dose to begin gradual reduction)
• Rationale: Prednisone has shorter half-life than dexamethasone (12-36 hours vs. 36-54 hours), allowing more physiologic dosing and easier titration 8, 9
• Monitor for withdrawal symptoms (fatigue, arthralgias, mood changes) and cushingoid feature improvement 10

Phase 2: Moderate Reduction (Weeks 5-12)

• Reduce prednisone by 5 mg every 2 weeks: 30 mg → 25 mg → 20 mg → 15 mg
• Monitor blood pressure, glucose, potassium, and clinical symptoms 10
• Slower taper needed as dose approaches physiologic replacement (7.5 mg prednisone = physiologic cortisol production) 11

Phase 3: Approach Physiologic Dose (Weeks 13-20)

• Reduce prednisone by 2.5 mg every 2 weeks: 15 mg → 12.5 mg → 10 mg → 7.5 mg
• At this phase, HPA axis may begin recovering but remains suppressed 1
• Consider morning cortisol testing when reaching 7.5 mg to assess HPA axis recovery 1

Phase 4: Transition to Physiologic Replacement (Weeks 21-28)

• Switch to hydrocortisone 20 mg AM + 10 mg noon (mimics diurnal cortisol rhythm)
• Hydrocortisone's shorter half-life (8-12 hours) allows more physiologic replacement 7
• Continue for 4-8 weeks to allow HPA axis recovery 1

Phase 5: Final Taper and HPA Axis Assessment (Weeks 29-36+)

• Reduce hydrocortisone by 5 mg every 2 weeks: 30 mg → 25 mg → 20 mg → 15 mg → 10 mg → 5 mg
• When reaching 10-15 mg hydrocortisone daily, perform 8 AM cortisol and ACTH testing before morning dose 1
• If 8 AM cortisol >10 μg/dL, consider ACTH stimulation test to confirm HPA axis recovery 1
• If cortisol remains suppressed, continue low-dose hydrocortisone and retest in 4-8 weeks 1

Critical Monitoring Parameters

• Weekly for first month: Blood pressure, weight, glucose, potassium 10
• Every 2 weeks during taper: Clinical symptoms, electrolytes 10
• HPA axis testing: 8 AM cortisol and ACTH when approaching physiologic doses 1
• Patient education: Recognize adrenal insufficiency symptoms (severe fatigue, nausea, dizziness, hypotension) and when to seek emergency care 2

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Stress-Dose Glucocorticoid Protocol

During the taper period and until HPA axis recovery is confirmed, the patient requires stress-dose glucocorticoids for any physiologic stress to prevent adrenal crisis. 7, 2

Minor Stress (Fever >38°C, Mild Illness, Dental Procedures)

• Drug: Hydrocortisone
• Dose: Double the current daily dose for 2-3 days
• Route: Oral
• Timing: Divide into 2-3 doses (e.g., if on 20 mg daily, take 20 mg AM + 20 mg noon)
• Duration: Continue until illness resolves, then return to baseline dose 7

Moderate Stress (Gastroenteritis with Vomiting, High Fever, Minor Surgery)

• Drug: Hydrocortisone
• Dose: 50 mg every 8 hours (150 mg/day total)
• Route: Intramuscular or intravenous if unable to tolerate oral; otherwise oral
• Timing: Every 8 hours around the clock
• Duration: 24-48 hours, then taper to double maintenance dose for 2-3 days, then return to baseline 7

Major Stress (Major Surgery, Severe Infection, Trauma, Labor/Delivery)

Perioperative Protocol

• Pre-operative: Hydrocortisone 100 mg IV at induction of anesthesia
• Intra-operative: Hydrocortisone 50 mg IV every 8 hours during surgery if prolonged (>2 hours)
• Post-operative Day 1: Hydrocortisone 50 mg IV every 8 hours (150 mg/day)
• Post-operative Day 2: Hydrocortisone 25 mg IV every 8 hours (75 mg/day)
• Post-operative Day 3: Resume oral maintenance dose if tolerating oral intake 7

Severe Illness/Sepsis Protocol

• Initial: Hydrocortisone 100 mg IV bolus immediately
• Maintenance: Hydrocortisone 50 mg IV every 6 hours (200 mg/day) or continuous infusion 200 mg/24 hours
• Duration: Continue until hemodynamically stable and infection controlled
• Taper: Reduce to 50 mg every 8 hours, then 25 mg every 8 hours, then oral maintenance over 3-5 days 7

Patient Emergency Instructions

• Provide injectable hydrocortisone 100 mg (Solu-Cortef) for home emergency use if patient cannot reach medical care and develops severe illness with vomiting 7
• Medical alert bracelet: Patient should wear identification stating "adrenal insufficiency, requires stress-dose steroids" 2
• Written instructions: Provide clear written protocol for when to increase doses and when to seek emergency care 10

Critical Pitfall to Avoid

• Never allow the patient to run out of glucocorticoids—even brief interruption can precipitate adrenal crisis during the recovery period when HPA axis remains suppressed. 2, 3
• The patient must understand that stress-dosing is required for any significant physiologic stress until HPA axis recovery is confirmed by formal testing (8 AM cortisol >10 μg/dL and normal ACTH stimulation test). 1, 7