ACTH-Secreting Pituitary Adenoma

ACTH-secreting pituitary adenoma is a corticotroph tumour causing ACTH-dependent hypercortisolism (Cushing disease), the most common cause of endogenous Cushing syndrome.

The annual incidence is about 1 to 2 for each million people, women are affected 3 to 8 times more often than men, and most tumours are microadenomas, often under 5 mm.

USP8 variants occur in a large share of tumours, and USP48 and BRAF variants in others. Cushing disease is rarely part of MEN1.

Pathophysiology.

Tumour corticotrophs secrete ACTH autonomously with partial resistance to glucocorticoid feedback. Sustained cortisol excess causes catabolic and metabolic complications.

ACTH from the tumour stimulates adrenal growth. Cortisol excess is cyclical in some patients, so single normal tests do not exclude it.

• Central weight gain, plethora, thin skin, easy bruising, wide violaceous striae, proximal myopathy, hypertension, diabetes, osteoporosis, depression and menstrual disturbance.
• Hirsutism, recurrent infection, venous thromboembolism and kidney stones.

Red flags.

• Severe hypokalaemia, psychosis, sepsis (including Pneumocystis jirovecii) or venous thromboembolism.
• Rapid onset with marked hypokalaemia and pigmentation suggests ectopic ACTH.

• Confirm hypercortisolism with at least two of: late night salivary cortisol (two samples), 24-hour urinary free cortisol (two collections), and 1 mg overnight dexamethasone suppression with 8 am cortisol over 50 nmol/L (1.8 micrograms/dL).
• ACTH-dependent if morning plasma ACTH is 10 ng/L (2 pmol/L) or more (under 5 ng/L is ACTH-independent).
• Pituitary MRI with contrast (positive in about 60%). If MRI is normal or the lesion is under 6 mm, perform bilateral inferior petrosal sinus sampling: central to peripheral ACTH ratio 2 or more at baseline or 3 or more after corticotrophin releasing hormone or desmopressin.
• A high dose (8 mg) dexamethasone test suppressing cortisol by over 50% and a corticotrophin releasing hormone test (ACTH rise 35% or more) support a pituitary source.

Differential diagnosis.

• Ectopic ACTH syndrome (bronchial or thymic carcinoid, small cell lung cancer, pancreatic neuroendocrine tumour, medullary thyroid carcinoma, phaeochromocytoma).
• Pseudo-Cushing states (depression, heavy alcohol use, severe obesity, poorly controlled diabetes).
• Exogenous glucocorticoid exposure and adrenal causes (ACTH suppressed).
• Pituitary incidentaloma in a patient with an ectopic source.

• Transsphenoidal selective adenomectomy is first line. Remission is suggested by a morning cortisol under 138 nmol/L (5 micrograms/dL) within 7 days (under 50 nmol/L, or 1.8 micrograms/dL, is stronger), measured before glucocorticoid cover.
• After surgery give hydrocortisone replacement until the axis recovers, which may take 6 to 18 months, with periodic morning cortisol testing. Give low molecular weight heparin perioperatively.
• Drugs to control cortisol when surgery fails or is awaited: osilodrostat 2 mg twice daily up to 30 mg twice daily; metyrapone 250 mg three times daily up to 6 g daily; ketoconazole 200 mg twice daily up to 1200 mg daily with liver tests; pasireotide 0.6 mg subcutaneously twice daily up to 0.9 mg twice daily (raises glucose); cabergoline 0.5 to 3 mg weekly; mifepristone 300 mg daily up to 1200 mg daily (cortisol cannot be used to monitor).
• Repeat surgery, stereotactic radiotherapy or bilateral adrenalectomy for persistent disease. After adrenalectomy watch for progressive corticotroph tumour growth.
• Treat hypertension, diabetes, osteoporosis and thromboembolic risk. Consider pneumocystis prophylaxis with co-trimoxazole in severe hypercortisolism.

Special groups. Pregnancy: rare; metyrapone is the usual drug, and surgery is preferred in the second trimester. Avoid ketoconazole and osilodrostat.

Monitoring. Cortisol and ACTH response after surgery, then annual late night salivary or urinary cortisol for life because late recurrence occurs. Drug treatment: cortisol, potassium, liver tests and glucose.

Referral and escalation. Specialist pituitary centre; urgent review for sepsis, psychosis, severe hypokalaemia or thromboembolism.