Lucan · Conditions

Cushing's syndrome

Australian guidance: eTG Endocrinology — Adrenal Disorders

1. Definition and epidemiology

Cushing's syndrome is the clinical state resulting from prolonged exposure to excess glucocorticoids, whether from endogenous overproduction or exogenous administration. Endogenous Cushing's syndrome is rare in Australia, with an estimated incidence of 2 to 3 cases per million population per year; iatrogenic disease from prescribed corticosteroids is far more common in everyday practice. Pituitary-dependent hypercortisolism (Cushing's disease) accounts for approximately 70% of endogenous cases, with adrenal adenoma and ectopic adrenocorticotrophic hormone (ACTH) secretion accounting for most of the remainder. Women are affected roughly three to four times more often than men in pituitary-dependent disease.

2. Pathophysiology

The hypothalamic-pituitary-adrenal (HPA) axis normally maintains cortisol within a diurnal rhythm through corticotrophin-releasing hormone (CRH) stimulating pituitary ACTH, which drives adrenal cortical production of cortisol; cortisol exerts negative feedback at both the hypothalamus and pituitary (Robbins Ch 24). In Cushing's disease, a corticotroph adenoma secretes ACTH autonomously with partial resistance to feedback, driving bilateral adrenal hyperplasia and cortisol excess. In adrenal adenoma or adrenocortical carcinoma, autonomous cortisol suppresses ACTH, causing contralateral adrenal atrophy. In ectopic ACTH syndrome, typically from small-cell lung carcinoma, bronchial carcinoid, or pancreatic neuroendocrine tumour, ACTH is secreted entirely independent of the HPA axis, often at very high levels. Glucocorticoid excess acts through glucocorticoid receptors in virtually every tissue: catabolism of muscle and bone matrix, central fat redistribution, immune suppression, insulin antagonism, and stimulation of renal mineralocorticoid receptors causing hypokalaemia and hypertension.

3. Clinical presentation and diagnostic criteria

The clinical syndrome reflects the broad tissue distribution of glucocorticoid receptors. Central obesity with a buffalo hump (dorsocervical fat pad), moon facies, and a supraclavicular fat pad are classic but not universal. Skin fragility manifests as easy bruising, wide (greater than 1 cm) violaceous abdominal striae, poor wound healing, and skin thinning. Proximal myopathy produces difficulty rising from a chair or climbing stairs. Hypertension, hypokalaemia, and glucose intolerance or overt diabetes reflect metabolic and mineralocorticoid effects. Osteoporosis, often presenting as vertebral compression fracture, results from glucocorticoid suppression of osteoblast activity and intestinal calcium absorption. Menstrual irregularities, hirsutism, and acne occur in women. Neuropsychiatric features including depression, emotional lability, and cognitive impairment are common and frequently underrecognised. Immunosuppression increases susceptibility to opportunistic infections. In children, growth retardation is a prominent feature.

Diagnostic confirmation requires biochemical demonstration of hypercortisolism using at least two of the following screening tests: late-night salivary cortisol (on two separate nights), 24-hour urinary free cortisol (UFC) on two occasions, or low-dose overnight dexamethasone suppression test (1 mg dexamethasone at 11 pm with serum cortisol measured at 8 am the following morning). A serum cortisol of 50 nmol/L or above after overnight dexamethasone is considered a positive screen. Cyclical Cushing's syndrome may require repeated testing over weeks to months if initial results are inconclusive.

4. Investigations and AU-specific cutoffs

The investigation sequence follows a two-step approach: confirm hypercortisolism, then determine its cause.

1. Screening tests (at least two required): late-night salivary cortisol greater than the laboratory-specific upper reference limit on two occasions; UFC greater than three times the upper limit of normal on two separate 24-hour collections; or serum cortisol above 50 nmol/L following 1 mg overnight dexamethasone.
2. Plasma ACTH: a suppressed plasma ACTH (less than 10 pg/mL or 2 pmol/L) indicates an ACTH-independent adrenal cause, whereas a normal or elevated ACTH indicates ACTH-dependent disease.
3. High-dose dexamethasone suppression test (2 mg every 6 hours for 48 hours, or 8 mg overnight): greater than 50% suppression of UFC or serum cortisol supports pituitary origin; failure to suppress suggests ectopic ACTH.
4. MRI pituitary with gadolinium: first-line imaging for ACTH-dependent disease. Microadenomas are often below MRI resolution; a normal MRI does not exclude pituitary disease.
5. CT chest and abdomen: required when ectopic ACTH is suspected clinically (rapid onset, severe hypokalaemia, very high cortisol) or when pituitary MRI is negative.
6. Inferior petrosal sinus sampling (IPSS): the gold standard to distinguish pituitary from ectopic ACTH when non-invasive localisation is inconclusive. A central to peripheral ACTH gradient of 2 or above at baseline (or 3 or above post-CRH stimulation) strongly supports pituitary origin.
7. CT or MRI adrenal: for ACTH-independent disease to characterise adrenal mass.
8. Additional bloods: serum potassium (hypokalaemia more pronounced in ectopic ACTH), fasting glucose, bone mineral density (DXA scan), full blood count (often shows polycythaemia and lymphopenia).

5. Management

Management is directed at the underlying cause and guided by eTG Endocrinology and specialist endocrinology consensus.

For pituitary-dependent Cushing's disease, transsphenoidal adenomectomy by an experienced pituitary neurosurgeon is the first-line treatment and achieves remission in approximately 70 to 80% of cases with a discrete resectable adenoma. Remission is confirmed by a post-operative morning serum cortisol below 50 nmol/L within 1 to 7 days of surgery, reflecting return of feedback suppression. Patients with post-operative adrenal insufficiency require hydrocortisone replacement until HPA axis recovery, which may take 6 to 18 months. Repeat transsphenoidal surgery or pituitary radiotherapy (stereotactic radiosurgery preferred) is considered for persistent or recurrent disease. Bilateral adrenalectomy is a definitive but non-pituitary option for medically refractory cases, with the risk of Nelson's syndrome (ACTH-secreting pituitary tumour expansion due to loss of cortisol feedback) requiring lifelong pituitary surveillance.

For adrenal adenoma, laparoscopic adrenalectomy is curative. The contralateral adrenal is atrophied and glucocorticoid replacement is required post-operatively until recovery of the axis.

For ectopic ACTH syndrome, treatment of the primary tumour is the goal. Medical steroidogenesis inhibition is often required as a bridge or in inoperable cases.

6. Pharmacology and AU PBS notes

Medical therapy is used to normalise cortisol while awaiting surgery, in post-operative recurrence, or in inoperable disease.

Ketoconazole is the most widely used steroidogenesis inhibitor in Australia. It inhibits multiple CYP450 enzymes in the cortisol synthesis pathway (CYP11A1, CYP11B1). Starting dose is 200 mg two to three times daily, titrated to UFC and serum cortisol to a maximum of 1200 mg daily. Hepatotoxicity requires LFT monitoring at baseline, monthly for three months, then quarterly. Not PBS-listed (off-label); may require Special Access Scheme approval. AU brand: Nizoral.

Metyrapone inhibits CYP11B1 (the final step of cortisol synthesis) and is available via Special Access Scheme. Starting dose 750 mg daily, titrated up to 6 g daily in divided doses. Adverse effects include nausea, hirsutism in women from androgen precursor accumulation, and hypertension from mineralocorticoid precursors. Not PBS-listed.

Osilodrostat (CYP11B1 and CYP11B2 inhibitor) received TGA approval in Australia for Cushing's disease not suitable for surgery. Starting dose 2 mg twice daily, titrated to normalise UFC. Key risks are QTc prolongation and adrenal insufficiency. Requires specialist initiation; confirm PBS listing at the time of prescribing.

Glucocorticoid replacement post-operatively: hydrocortisone 15 to 20 mg daily in divided doses (10 mg morning, 5 mg early afternoon) until HPA axis recovery. Patients require a steroid emergency card and sick-day rules. AU brand: Hysone.

7. Complications and monitoring

Untreated or undertreated Cushing's syndrome carries significant morbidity and increased mortality, predominantly from cardiovascular disease, infection, and thromboembolic events.

Key complications include: - Osteoporosis and fragility fractures: DXA scan at diagnosis; calcium and vitamin D supplementation; bisphosphonate therapy for established osteoporosis. - Venous thromboembolism: risk is elevated perioperatively and during active hypercortisolism; thromboprophylaxis is required peri-operatively. - Hypertension and dyslipidaemia: these often persist partially after cure and require ongoing cardiovascular risk management. - Diabetes mellitus: glucose intolerance may persist after cure in predisposed individuals; monitor fasting glucose or HbA1c annually. - Pituitary insufficiency: following transsphenoidal surgery, all pituitary axes (thyroid, gonadal, growth hormone) should be formally assessed 3 to 6 months post-operatively. - Nelson's syndrome: after bilateral adrenalectomy for Cushing's disease, 6-monthly ACTH levels and annual pituitary MRI are required for life.

Surveillance schedule in remission: - Serum cortisol or UFC: 3 months post-operatively, then 6-monthly for 2 years, then annually. - Pituitary MRI: 3 months post-operatively, then annually for 5 years in Cushing's disease. - Bone mineral density: DXA at diagnosis and 2 years after achieving remission. - Blood pressure, fasting glucose, and fasting lipids: annually. - HPA axis recovery: morning cortisol or short Synacthen test every 3 to 6 months until confirmed.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.