Summary

Endocrine Society 2016 guideline on diagnosis and treatment of primary adrenal insufficiency (PAI), co-sponsored by the European Society of Endocrinology and AACC. Establishes the standard-dose (250 μg) corticotropin stimulation test as the diagnostic gold standard, recommends hydrocortisone or cortisone acetate as first-line glucocorticoid replacement with fludrocortisone for mineralocorticoid replacement, and details adrenal crisis prevention/management with patient education, emergency kits, and stress dosing. Excludes secondary adrenal insufficiency and critical illness-related corticosteroid insufficiency.

Key Recommendations

Test for PAI in any acutely ill patient with unexplained volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or (in children) hypoglycemia.
Confirm diagnosis with standard-dose (250 μg) IV corticotropin stimulation test measuring cortisol at 30 or 60 minutes; peak cortisol <500 nmol/L (18 μg/dL) indicates adrenal insufficiency.
If corticotropin test unavailable, use morning cortisol <140 nmol/L (5 μg/dL) plus plasma ACTH >2× upper limit of normal as presumptive evidence of PAI.
Measure plasma renin and aldosterone simultaneously to detect mineralocorticoid deficiency, and screen for 21-hydroxylase autoantibodies to establish autoimmune etiology.
In suspected adrenal crisis, give IV hydrocortisone immediately at stress dose before awaiting diagnostic test results.
Treat adults with hydrocortisone 15–25 mg/day or cortisone acetate 20–35 mg/day in 2–3 divided oral doses, largest dose on awakening; avoid dexamethasone due to Cushingoid risk.
Replace mineralocorticoid with fludrocortisone (typically 50–100 μg/day) without dietary salt restriction; titrate by clinical signs (salt craving, postural BP, edema) and electrolytes.
Consider a 6-month trial of DHEA in women with persistent low libido, low mood, or low energy despite optimized gluco-/mineralocorticoid replacement; discontinue if no benefit.
Treat children with hydrocortisone ~8 mg/m²/day in 3–4 divided doses; avoid long-acting synthetic glucocorticoids (prednisolone, dexamethasone).
In pregnancy, use hydrocortisone (not dexamethasone), increase dose in the third trimester, and give major-surgery stress dosing during active labor.
Treat adrenal crisis with 100 mg IV/IM hydrocortisone bolus (50 mg/m² in children) then 200 mg/24 h continuous infusion (or 50 mg q6h) plus fluid resuscitation with isotonic saline.
Equip every patient with a steroid emergency card, medical alert ID, and parenteral hydrocortisone injection kit; educate on sick-day dosing (double for fever >38°C, triple for >39°C).
Follow up at least annually (every 3–4 months in infants); screen for associated autoimmune disorders (thyroid, T1DM, celiac, premature ovarian insufficiency, B12 deficiency).

Thresholds & Doses

Standard corticotropin test dose: 250 μg IV (adults and children ≥2 y); 15 μg/kg infants; 125 μg children <2 y.
Diagnostic peak cortisol cutoff: <500 nmol/L (18 μg/dL) at 30 or 60 min indicates adrenal insufficiency.
Screening cortisol cutoff: morning cortisol <140 nmol/L (5 μg/dL) suggestive of PAI.
ACTH threshold: plasma ACTH >2× upper limit of reference range with low cortisol consistent with PAI; ACTH >300 ng/L (66 pmol/L) = maximal adrenal stimulus.
Hydrocortisone replacement (adults): 15–25 mg/day in 2–3 divided doses.
Cortisone acetate replacement (adults): 20–35 mg/day in 2–3 divided doses.
Prednisolone alternative: 3–5 mg/day orally once or twice daily.
Fludrocortisone starting dose: 50–100 μg/day in adults; 100 μg/day in children with confirmed aldosterone deficiency.
Infant salt supplementation: NaCl 1–2 g/day (17–34 mmol/day) divided across feedings in first 6 months.
Pediatric hydrocortisone: starting daily dose ~8 mg/m² BSA in 3–4 divided doses.
DHEA replacement (women): 25–50 mg once daily in the morning; trial for 6 months; monitor morning DHEAS to mid-normal range.
Pregnancy: increase hydrocortisone by 20–40% from ~24 weeks; major-surgery stress dosing during active labor.
Adrenal crisis (adults): hydrocortisone 100 mg IV/IM bolus, then 200 mg/24 h continuous infusion (or 50 mg q6h); rapid 1000 mL isotonic saline in first hour.
Adrenal crisis (children): hydrocortisone 50 mg/m² bolus, then 50–100 mg/m²/day divided q6h; saline 20 mL/kg bolus (up to 60 mL/kg in first hour for shock).
Sick-day rules: double oral glucocorticoid dose for fever >38°C, triple for >39°C, until recovery (usually 2–3 days).
Minor/moderate surgery: hydrocortisone 25–75 mg/24 h × 1–2 days; major surgery: 100 mg IV bolus then 200 mg/24 h.
Mineralocorticoid replacement not required if hydrocortisone dose exceeds 50 mg/24 h (40 mg hydrocortisone ≈ 100 μg fludrocortisone).
Follow-up interval: at least annually for adults/children; every 3–4 months for infants.

Citations

Recommendation 1.1–1.3 — testing indications and immediate empiric treatment in suspected crisis.
Recommendation 2.1 — 250 μg corticotropin test as gold standard with 500 nmol/L cutoff.
Recommendation 2.3–2.4 — morning cortisol/ACTH as preliminary diagnostic criteria.
Recommendation 3.2–3.4 — hydrocortisone/cortisone acetate dosing; avoid dexamethasone.
Recommendation 3.7–3.10 — fludrocortisone replacement and monitoring.
Recommendation 3.14–3.17 — pregnancy management including third-trimester dose increase and labor stress dosing.
Recommendation 3.18–3.21 — pediatric hydrocortisone 8 mg/m²/day and fludrocortisone 100 μg/day.
Recommendation 4.1–4.6 and Table 3 — adrenal crisis treatment doses and emergency preparedness.
Table 4 — measures for prevention of adrenal crisis (sick-day rules, emergency kit, education).