Summary

Endocrine Society 2015 guideline (co-sponsored by European Society of Endocrinology) on the treatment of Cushing’s syndrome. Surgical resection of the causal lesion is first-line for all etiologies (transsphenoidal adenomectomy for Cushing’s disease, unilateral adrenalectomy for benign adrenal disease, resection with nodal dissection for ectopic ACTH). Second-line options — repeat TSS, radiotherapy/radiosurgery, steroidogenesis inhibitors, pituitary-directed agents, glucocorticoid receptor antagonists, and bilateral adrenalectomy — are individualized. Emphasizes aggressive treatment of comorbidities (CV risk, osteoporosis, VTE prophylaxis, infection risk) and lifelong recurrence surveillance.

Key Recommendations

Treat only patients with established overt Cushing’s syndrome; do not initiate cortisol-lowering therapy for borderline HPA-axis abnormalities without clinical signs.
Surgical resection of the causal lesion is first-line for all etiologies: TSS for Cushing’s disease, unilateral adrenalectomy for benign adrenal disease, and ectopic tumor resection with node dissection.
Refer all patients with ACTH-dependent CS and no clear pituitary lesion (>6 mm) to an experienced center for inferior petrosal sinus sampling to distinguish pituitary from ectopic source.
Provide perioperative VTE prophylaxis and offer influenza, herpes zoster, and pneumococcal vaccinations because of elevated thrombosis and infection risk.
After TSS, measure serum sodium repeatedly during postoperative days 5–14 and assess free T4 and prolactin within 1–2 weeks to detect hypopituitarism.
Replace glucocorticoid in postoperative hypocortisolemic patients with hydrocortisone 10–12 mg/m²/day in divided doses, with sick-day rules and a medical alert tag.
Reassess HPA axis recovery with morning cortisol, ACTH stimulation, or insulin tolerance testing and discontinue glucocorticoid once response normalizes.
For persistent or recurrent CD, choose among repeat TSS (especially if incomplete resection or visible lesion), RT/radiosurgery, medical therapy, or bilateral adrenalectomy via shared decision-making.
Use steroidogenesis inhibitors (ketoconazole, metyrapone, mitotane, etomidate) as second-line for CD, primary therapy for occult/metastatic ectopic ACTH, and adjunct in adrenocortical carcinoma.
Use mifepristone for patients with hypercortisolism-related diabetes or glucose intolerance who are not surgical candidates or have persistent disease; titrate clinically since cortisol cannot guide dosing.
After bilateral adrenalectomy for CD or presumed ectopic source, monitor for Nelson’s syndrome with annual ACTH and pituitary MRI.
Treat life-threatening hypercortisolism (sepsis, PE, CV complications, acute psychosis) urgently within 24–72 hours, often with combination steroidogenesis inhibitors or etomidate; consider bilateral adrenalectomy if medical control fails.
Lifelong follow-up for recurrence and comorbidities (HTN, DM, dyslipidemia, osteoporosis, psychiatric disease) in all patients except those resected for a low-density (<10 HU) adrenal adenoma.

Thresholds & Doses

Postoperative serum cortisol <1.8 µg/dL (50 nmol/L) — indicates likely remission/hypocortisolism after TSS or adrenal adenoma resection
Hydrocortisone replacement: 10–12 mg/m²/day in 2–3 divided doses, first dose on waking
Off-medication serum cortisol or UFC every 6–12 months — to assess RT/radiosurgery effect
Sodium monitoring days 5–14 post-TSS; FT4 and prolactin within 1–2 weeks post-TSS
Ketoconazole: 400–1600 mg/day divided every 6–8 h
Metyrapone: 500 mg/day up to 6 g/day divided every 6–8 h
Mitotane: start 250 mg, range 500 mg/day to 8 g/day (CD effective dose ~2.7 g/day; plasma target ~8.5 mg/L)
Etomidate: loading bolus 3–5 mg, then continuous infusion 0.03–0.10 mg/kg/h (≈2.5–3.0 mg/h); titrate to serum cortisol 10–20 µg/dL (280–560 nmol/L); cortisol checked every 4–6 h
Cabergoline: 1–7 mg/week
Pasireotide: 600–900 µg SC twice daily
Mifepristone: 300–1200 mg/day; start at 300 mg/d and titrate by clinical response
Adrenal adenoma CT density <10 Hounsfield units — exempt from lifelong recurrence testing
Pituitary microadenoma defined as <1 cm; visible on MRI in ~60% of adults and ~55% of children with CD
IPSS side-to-side ACTH gradient >1.4 correctly lateralizes in only 56–69% of adults
Hemihypophysectomy based on IPSS lateralization cures only ~50% (no better than chance)
After bilateral adrenalectomy: ~21% develop Nelson’s syndrome; corticotroph progression on MRI in ~50%
HPA axis recovery: ~6–12 months after ACTH-producing tumor resection; ~18 months after unilateral adrenalectomy
Ketoconazole idiosyncratic hepatic injury risk ~1 in 15,000; transaminase elevation in 10–15% of patients (FDA black box warning 2013)
Pasireotide-induced hyperglycemia in 73% of treated patients

Citations

Recommendation 1.1–1.3 — Treatment goals; only treat established overt CS
Recommendation 2.4–2.6 — VTE risk evaluation, perioperative prophylaxis, vaccination
Recommendation 3.1a–3.1c — First-line surgical approach by etiology
Recommendation 3.1ci–3.1cii — Post-TSS sodium, FT4, prolactin monitoring
Recommendation 4.3–4.4 — Late-night salivary/serum cortisol for remission and recurrence screening
Recommendation 5.1–5.2 — Glucocorticoid replacement and HPA axis recovery testing
Recommendation 6.4–6.4c — Steroidogenesis inhibitors, pituitary-directed therapy, mifepristone indications
Table 1 — Medical treatment of CS: agents, doses, adverse effects
Recommendation 7.1, 7.3 — Lifelong comorbidity surveillance; exemption for adrenal adenoma <10 HU
Recommendation 8.1 — Urgent (24–72 h) treatment of life-threatening hypercortisolism