Cushing Disease — Med2Date

Introduction

Cushing disease is a specific form of Cushing syndrome caused by excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma, representing 80-85% of all Cushing syndrome cases. This condition results in chronic hypercortisolism with significant morbidity and mortality if left untreated.

ℹ️

Terminology: Cushing disease specifically refers to pituitary-dependent ACTH excess, while Cushing syndrome encompasses all causes of hypercortisolism including adrenal adenomas, ectopic ACTH syndrome, and exogenous corticosteroids.

Epidemiology

In Australia, Cushing disease has an estimated incidence of 1.2-2.4 cases per million population annually, with a prevalence of approximately 40 cases per million. The condition shows a female predominance (female to male ratio 3-4:1) and typically presents in the third to fifth decades of life.

Key Demographics

Peak incidence: 30-50 years
Female predominance: 75-80%
Microadenomas: 85-90% of cases
Macroadenomas: 10-15% of cases

Clinical Significance

5-year mortality: 50% if untreated
Cardiovascular disease: Leading cause of death
Metabolic complications: Diabetes, osteoporosis
Psychiatric morbidity: Depression, anxiety

Pathophysiology

Cushing disease results from autonomous ACTH secretion by corticotroph adenomas of the anterior pituitary. These adenomas are typically small (microadenomas <10mm in 85-90% of cases) and cause bilateral adrenal hyperplasia and excessive cortisol production.

Pituitary Adenoma

Corticotroph adenoma develops with autonomous ACTH secretion

ACTH Excess

Loss of normal feedback inhibition leads to persistent ACTH elevation

Adrenal Stimulation

Bilateral adrenal hyperplasia with excessive cortisol production

Hypercortisolism

Systemic effects of chronic cortisol excess across multiple organ systems

Clinical Significance in Australia

Cushing disease presents unique challenges in the Australian healthcare context, particularly regarding access to specialised endocrine services and advanced imaging in remote areas. Early recognition and appropriate referral pathways are crucial for optimal outcomes.

⚠️

Diagnostic Delay: Average time from symptom onset to diagnosis is 3-6 years in Australia, often due to non-specific early symptoms and limited awareness among primary care providers.

Aboriginal and Torres Strait Islander Health Considerations

Access to Specialist Care

Remote communities may face delays in accessing endocrine specialists. Telehealth consultations and clear referral pathways are essential.

Cultural Considerations

Physical changes associated with Cushing disease may have particular cultural significance. Involve Aboriginal Health Workers and ensure culturally appropriate communication.

Comorbidity Management

Higher baseline rates of diabetes and cardiovascular disease may complicate diagnosis and management. Comprehensive care coordination is vital.

Guideline Scope and Objectives

These guidelines provide evidence-based recommendations for Australian healthcare providers managing Cushing disease, aligned with Therapeutic Guidelines Australia and international best practice. The guideline covers:

Clinical presentation and diagnostic criteria
Biochemical and imaging investigations
Treatment options including surgical and medical management
Long-term monitoring and follow-up care
Special population considerations
Emergency presentations and complications

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Multidisciplinary Approach: Optimal management of Cushing disease requires collaboration between endocrinologists, neurosurgeons, radiologists, and primary care providers. Early specialist referral is recommended for suspected cases.

Clinical Presentation

ℹ️

Key Point: Cushing disease presents with insidious onset of symptoms that may develop over months to years. Clinical suspicion should be high in patients with multiple features of hypercortisolism.

Cardinal Clinical Features

PATHOGNOMONIC

Highly Specific Signs

• Purple striae (>1cm wide)
• Proximal myopathy
• Easy bruising
• Facial plethora

Present in >80% of cases

COMMON

Frequent Manifestations

• Central obesity
• Moon facies
• Buffalo hump
• Hypertension
• Glucose intolerance

Present in 60-80% of cases

VARIABLE

Associated Features

• Depression/mood changes
• Osteoporosis
• Menstrual irregularities
• Hirsutism
• Poor wound healing

Present in 30-60% of cases

System-Based Clinical Assessment

System	Clinical Features	Frequency (%)	Clinical Significance
Appearance	Central obesity, moon facies, buffalo hump, purple striae	85-95	Most obvious presenting features
Musculoskeletal	Proximal myopathy, osteoporosis, compression fractures	70-90	Significant functional impairment
Cardiovascular	Hypertension, cardiac arrhythmias, heart failure	80-85	Major cause of morbidity
Metabolic	Diabetes mellitus, glucose intolerance, dyslipidaemia	70-80	Cardiovascular risk factor
Dermatological	Easy bruising, poor wound healing, acne, hirsutism	75-85	Early diagnostic clues
Neuropsychiatric	Depression, anxiety, cognitive impairment, psychosis	50-70	Quality of life impact
Reproductive	Menstrual irregularities, infertility, decreased libido	70-80	Often presenting complaint
Immunological	Increased susceptibility to infections	40-60	Opportunistic infections possible

Special Population Considerations

👶

Paediatric Presentation:

• Growth retardation (most common)

• Weight gain despite poor linear growth

• Delayed puberty

• Behavioural changes

Consider if growth velocity <3rd percentile with weight gain

🤰

Pregnancy Considerations:

• Rare in pregnancy due to infertility

• Gestational diabetes risk

• Pre-eclampsia risk

• Fetal growth restriction

Requires specialist endocrine management

👴

Elderly Patients:

• More subtle presentation

• Higher fracture risk

• Cardiovascular complications

• Cognitive impairment prominent

May be misattributed to normal aging

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Clinical Pearls: The absence of classic cushingoid features does not exclude Cushing disease, particularly in mild or early disease. Consider subclinical Cushing syndrome in patients with difficult-to-control diabetes, osteoporosis, or hypertension.

Red Flag Symptoms

🚨

Urgent Assessment Required:

Rapid onset of symptoms (weeks rather than months)
Severe muscle weakness or paralysis
Severe psychiatric symptoms or psychosis
Unexplained hypokalaemia with hypertension
Features suggestive of ectopic ACTH syndrome
Compression fractures in young patients

Differential Diagnosis Considerations

Pseudo-Cushing States

Alcohol excess
Depression
Metabolic syndrome
Polycystic ovary syndrome

Other Causes of Hypercortisolism

Adrenal adenoma
Adrenal carcinoma
Ectopic ACTH syndrome
Exogenous glucocorticoids

Aboriginal and Torres Strait Islander Health Considerations

Higher Diabetes Risk

ATSI populations have higher baseline diabetes prevalence. Cushing disease may be masked by or complicate existing diabetes management.

Cultural Considerations

Body shape changes may have cultural significance. Discuss appearance changes sensitively and involve cultural liaisons when appropriate.

Access to Specialist Care

Remote communities may require telehealth consultations or patient travel for specialist endocrine assessment. Coordinate with specialist centres early.

Investigations

ℹ️

Investigation Approach: Diagnosis requires confirmation of hypercortisolism followed by determination of ACTH-dependent vs ACTH-independent causes. Cushing disease (pituitary adenoma) accounts for 80% of Cushing's syndrome cases.

Initial Screening Tests

Essential

24-hour Urine Free Cortisol (UFC)

Normal: <165 nmol/24h (60 μg/24h). Collect 2-3 samples. Elevated in 95% of Cushing's syndrome cases. False positives: depression, alcoholism, severe illness.

Essential

Late-night Salivary Cortisol

Normal: <7.5 nmol/L (2.7 ng/mL). Collect at 11 PM on 2 separate nights. Patient collects at home - more convenient than urine collection.

Essential

1mg Overnight Dexamethasone Suppression Test

Give 1mg dexamethasone at 11 PM, measure cortisol at 8 AM. Normal: cortisol <50 nmol/L (1.8 μg/dL). Screening test - low specificity.

⚠️

Screening Limitations: At least 2 abnormal screening tests required. Single abnormal test insufficient for diagnosis. Consider pseudo-Cushing's syndrome in depression, alcoholism, or severe illness.

Confirmatory Testing

Essential

48-hour Low-dose Dexamethasone Suppression Test

0.5mg dexamethasone every 6 hours × 48h. Measure cortisol and dexamethasone levels. Normal: cortisol <50 nmol/L. Gold standard for confirming hypercortisolism.

Alternative

Midnight Serum Cortisol

Requires hospital admission. Normal: <207 nmol/L (7.5 μg/dL). Used when other tests inconclusive or patient factors interfere.

Differential Diagnosis - ACTH Dependent vs Independent

Test	Pituitary (Cushing Disease)	Ectopic ACTH	Adrenal	PBS Status
Plasma ACTH (9 AM)	15-100 ng/L (normal-high)	>100 ng/L (elevated)	<10 ng/L (suppressed)	✔ PBS
High-dose Dex Suppression	>50% suppression	<50% suppression	N/A	✔ PBS
CRH Stimulation Test	ACTH rises >50%	No response	N/A	✗ Not PBS

Localisation Studies

Essential

Pituitary MRI with Gadolinium

Identifies adenoma in 60-70% of cases. Microadenomas (<1cm) may not be visible. Macroadenomas (>1cm) usually visible. Essential for surgical planning.

Specialist

Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

Gold standard when MRI negative or equivocal. Central:peripheral ACTH ratio >2 (baseline) or >3 (post-CRH) confirms pituitary source. Specialist procedure.

If Indicated

Chest CT

For suspected ectopic ACTH syndrome. Look for lung tumours (bronchial carcinoid, small cell lung cancer). Pancreatic islet cell tumours.

Additional Laboratory Tests

Investigation	Purpose	Expected Findings
Full Blood Count	Assess metabolic effects	Neutrophilia, lymphopenia, eosinopenia
Electrolytes	Mineralocorticoid effects	Hypokalaemia, metabolic alkalosis
Glucose/HbA1c	Diabetes screening	Hyperglycaemia in 75% of cases
Lipid Profile	Cardiovascular risk	Dyslipidaemia common
Bone Density (DEXA)	Osteoporosis assessment	Reduced bone density in 50%
Ophthalmology Review	If macroadenoma	Visual field defects

Investigation Timeline

Week 1-2

Initial Screening: UFC (×2-3), late-night salivary cortisol (×2), overnight dexamethasone suppression test

Week 3-4

Confirmation: If screening positive - 48h low-dose dexamethasone suppression test, plasma ACTH

Week 5-6

Localisation: High-dose dexamethasone suppression, CRH stimulation test, pituitary MRI

Week 7-8

Specialist Referral: If diagnosis unclear - BIPSS consideration, multidisciplinary team review

✅

Key Points: Diagnosis requires systematic approach: screen → confirm hypercortisolism → determine ACTH-dependent vs independent → localise source. Early endocrinologist involvement recommended for complex cases or when initial investigations inconclusive.

Treatment

First-Line

Transsphenoidal Surgery

Selective adenomectomy or hemihypophysectomy for microadenomas and macroadenomas

Specialist neurosurgical centre

Second-Line

Medical Management

When surgery contraindicated, failed, or recurrent disease

Endocrinologist management

Third-Line

Radiation Therapy

Stereotactic radiosurgery or conventional radiotherapy

Radiation oncology centre

Surgical Management

✓

First-Line Treatment: Transsphenoidal surgery is the treatment of choice for Cushing disease with 65-90% cure rates for microadenomas and 65% for macroadenomas.

Pre-operative Preparation

Optimise cortisol levels, manage comorbidities (diabetes, hypertension), DVT prophylaxis

Surgical Approach

Endoscopic transsphenoidal adenomectomy (preferred) or microscopic approach

Post-operative Care

Monitor for diabetes insipidus, CSF leak, assess cortisol levels

Medical Management

Medical therapy is indicated when surgery is contraindicated, unsuccessful, or for recurrent disease. Options include steroidogenesis inhibitors, pituitary-directed agents, and glucocorticoid receptor blockers.

Steroidogenesis Inhibitors

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Metyrapone

Metopirone® · 11β-hydroxylase inhibitor · First-line medical therapy

Adult Dose 250-750 mg PO 6-8 hourly

Starting Dose 250 mg PO TDS, titrate based on UFC

Maximum 6 g daily in divided doses

Monitoring 24hr UFC, serum cortisol, ACTH, K+

PBS Status ⚬ PBS Authority Required

💊

Ketoconazole

Generic · CYP17A1 inhibitor · Second-line option

Adult Dose 200-400 mg PO BD-TDS

Maximum 1200 mg daily

Monitoring LFTs monthly, cortisol levels

Contraindications Hepatic impairment, QT prolongation

PBS Status ✗ Not PBS Listed

💊

Osilodrostat

Isturisa® · 11β-hydroxylase inhibitor · Newer agent

Adult Dose 2 mg PO BD, titrate up to 7 mg BD

Titration Increase by 1-2 mg BD every 1-2 weeks

Monitoring UFC, cortisol, ACTH, ECG (QT)

PBS Status ⚬ PBS Authority Required

⚠️

Adrenal Insufficiency Risk: All steroidogenesis inhibitors can cause adrenal insufficiency. Monitor closely and provide patient education on sick day rules.

Pituitary-Directed Therapy

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Pasireotide

Signifor® · Somatostatin analogue · Pituitary-targeted

Adult Dose 0.6-0.9 mg SC BD

Starting Dose 0.6 mg SC BD, increase if inadequate response

Maximum 0.9 mg SC BD

Monitoring UFC, glucose, HbA1c, ECG, gallbladder

PBS Status ⚬ PBS Authority Required

🧬

Cabergoline

Dostinex® · Dopamine agonist · Adjunctive therapy

Adult Dose 0.25-3 mg PO weekly (divided doses)

Starting Dose 0.25 mg PO twice weekly

Efficacy Limited effectiveness as monotherapy

PBS Status ✓ PBS General Benefit

Glucocorticoid Receptor Blocker

🛡️

Mifepristone

Korlym® · GR blocker · Severe hypercortisolism

Adult Dose 300-1200 mg PO daily

Indication Severe Cushing syndrome with diabetes

Monitoring Cannot use cortisol levels for monitoring

PBS Status ✗ Not Available in Australia

Radiation Therapy

Stereotactic Radiosurgery (Gamma Knife/CyberKnife)

Single-fraction high-dose radiation
Cure rates: 65-85% at 5 years
Faster response than conventional RT
Lower risk of hypopituitarism
Requires visible adenoma on MRI

Conventional Fractionated Radiotherapy

45-54 Gy in 25-30 fractions
Cure rates: 60-80% at 10 years
Delayed response (2-5 years)
Higher risk of hypopituitarism (50-100%)
Can be used without visible adenoma

Bilateral Adrenalectomy

⚠️

Last Resort Option: Bilateral adrenalectomy is reserved for patients with persistent severe hypercortisolism who have failed other treatments. Results in lifelong adrenal insufficiency and risk of Nelson syndrome.

Special Populations

🤰

Pre-conception Planning:

Ideally achieve biochemical remission before pregnancy. High maternal cortisol associated with IUGR, preterm delivery, and gestational diabetes.

Pregnancy Management:

• Monitor cortisol levels - normal pregnancy increases cortisol
• UFC >3x upper limit normal concerning
• Multidisciplinary care with maternal-fetal medicine

Treatment Options:

Metyrapone
250-500 mg TDS oral
⚠ Not PBS Listed

Preferred over ketoconazole. Surgery deferred unless life-threatening.

Delivery Planning:

Stress-dose hydrocortisone if recent treatment or bilateral adrenalectomy history.

👶

Clinical Presentation:

Growth retardation most common. Obesity, hirsutism, and mood changes prominent. Striae and muscle weakness less common than adults.

Diagnostic Considerations:

• Age-adjusted cortisol reference ranges essential
• 24-hour UFC collection challenging
• Salivary cortisol preferred for screening

Treatment Approach:

Pituitary surgery preferred when feasible. Medical therapy weight-adjusted dosing with pediatric endocrinology guidance.

Ketoconazole (if required)
5-10 mg/kg/day divided BD-TDS
⚠ Not PBS Listed

Monitor LFTs monthly. Hepatotoxicity risk.

👵

Surgical Considerations:

• Higher perioperative risk
• Careful anesthetic assessment
• Consider medical management as primary therapy
• Post-operative monitoring for complications

Medical Therapy Adjustments:

Ketoconazole
Start 200 mg daily, titrate slowly
⚠ Not PBS Listed

Increased sensitivity to side effects. Monitor for drug interactions with polypharmacy.

Comorbidity Management:

Aggressive treatment of diabetes, hypertension, and osteoporosis. Higher fracture risk.

🫘

Diagnostic Impact:

• 24-hour UFC unreliable in severe CKD
• Salivary cortisol preferred
• Dexamethasone clearance may be altered

Drug Dosing:

Ketoconazole
No dose adjustment in CKD
Monitor for accumulation of metabolites

Cabergoline
Use with caution in severe CKD
⚠ PBS Authority Required

Monitoring:

Enhanced monitoring for fluid retention and electrolyte disturbances.

🫀

Contraindications:

Ketoconazole: Contraindicated in active liver disease or ALT >3x ULN
Cabergoline: Use with caution in hepatic impairment

Alternative Approaches:

Metyrapone
Preferred in hepatic impairment
250 mg BD-TDS, titrate to effect
⚠ Not PBS Listed

Monitoring Requirements:

Baseline and monthly LFTs if using hepatically metabolized agents. Consider surgical intervention earlier.

🛡️

Infection Risk:

• Hypercortisolism increases infection risk
• Opportunistic infections possible
• Screen for latent TB before treatment
• Consider PJP prophylaxis in severe cases

Post-Treatment:

Monitor for adrenal insufficiency. May require stress-dose steroids during illness or procedures.

Vaccination:

Avoid live vaccines during active hypercortisolism. Update routine vaccinations when biochemically controlled.

⚠️

Perioperative Steroid Coverage: All patients with treated Cushing disease require stress-dose steroid coverage for surgery, regardless of apparent recovery, due to potential HPA axis suppression.

ℹ️

Specialist Consultation: Endocrinology consultation recommended for all special populations. Multidisciplinary care involving relevant specialists (obstetrics, pediatrics, nephrology) essential for optimal outcomes.

Aboriginal and Torres Strait Islander Health

Geographic Access

Limited specialist endocrinology services in remote areas. Telehealth consultations and liaison with urban centers essential. Consider medical therapy over surgery when specialist surgical expertise unavailable.

Cultural Considerations

Include family and community in decision-making. Respect traditional healing practices alongside medical treatment. Use interpreters when required and provide culturally appropriate education materials.

Comorbidity Management

Higher baseline rates of diabetes and cardiovascular disease. Integrated care approach essential. Monitor for medication interactions with traditional medicines. Enhanced diabetes management during treatment.

Follow-up Challenges

Arrange flexible appointment scheduling. Use local healthcare workers for monitoring when possible. Simplified treatment regimens preferred. Consider longer-acting medications where available.

Follow-Up & Prevention

ℹ️

Long-term Care: Cushing disease requires lifelong monitoring due to high recurrence rates and potential for multiple endocrine complications. Coordinate care between endocrinologist, neurosurgeon, and primary care.

Post-Surgical Follow-Up Schedule

1-2 weeks

Immediate post-operative assessment
• Wound healing assessment
• Neurological examination
• Serum cortisol (8am) and electrolytes
• Assess for diabetes insipidus

6-12 weeks

Early remission assessment
• 24-hour UFC or midnight salivary cortisol
• Dexamethasone suppression test
• Pituitary hormone assessment
• MRI pituitary (if clinically indicated)

6 months

Comprehensive endocrine review
• Full pituitary function testing
• HbA1c and lipid profile
• Bone density scan (DEXA)
• Cardiovascular risk assessment

12 months

Annual comprehensive assessment
• MRI pituitary with contrast
• Complete metabolic and hormonal profile
• Ophthalmology review
• Mental health screening

Long-term Monitoring Protocol

Essential

Biochemical Recurrence Screening

24-hour UFC, midnight salivary cortisol, or late-night salivary cortisol every 6-12 months for first 5 years, then annually

Essential

MRI Pituitary

Contrast-enhanced study annually for first 2 years, then every 2-3 years if stable

Available

Pituitary Function

TSH, T4, prolactin, IGF-1, LH/FSH, testosterone/estradiol annually

Available

Metabolic Monitoring

HbA1c, lipids, blood pressure, weight every 6 months

Available

Bone Health

DEXA scan every 2 years, vitamin D level annually

Management of Post-Surgical Complications

💊

Hydrocortisone

Cortef® · Replacement therapy

Adult Dose 15-25 mg daily (10-15 mg morning, 5-10 mg evening)

Route Oral

Duration Until HPA axis recovery (6-18 months)

PBS Status ✔ PBS General Benefit

💊

Desmopressin

Minirin® · ADH replacement

Adult Dose 100-400 mcg daily (intranasal) or 100-800 mcg daily (oral)

Route Intranasal or oral

Indication Post-operative diabetes insipidus

PBS Status ✔ PBS General Benefit

Recurrence Management

⚠️

Recurrence Risk: 10-20% of patients experience recurrence within 10 years. Early detection through biochemical monitoring is crucial for optimal outcomes.

Biochemical Confirmation

Repeat 24-hour UFC, midnight salivary cortisol, and dexamethasone suppression test. Confirm with at least two abnormal tests.

Imaging Assessment

MRI pituitary with contrast to assess for residual or recurrent adenoma. Consider 11C-methionine PET if MRI inconclusive.

Treatment Options

Repeat transsphenoidal surgery (if feasible), stereotactic radiosurgery, or medical therapy with cabergoline/pasireotide.

Preventive Care Strategies

Complication	Prevention Strategy	Monitoring Frequency
Osteoporosis	Calcium 1200 mg + Vitamin D 1000 IU daily, weight-bearing exercise	DEXA every 2 years
Diabetes Mellitus	Diet modification, regular exercise, weight management	HbA1c every 6 months
Hypertension	Low sodium diet, ACE inhibitor/ARB if indicated	BP monitoring every 3 months
Infection Risk	Annual influenza vaccination, pneumococcal vaccination	Clinical assessment
Mental Health	Regular screening, psychological support, antidepressants if needed	Every 6 months

Patient Education Priorities

Key Educational Points

Signs and symptoms of cortisol deficiency and excess
Importance of medication compliance with hormone replacement
Sick day rules for stress dosing of hydrocortisone
When to seek urgent medical attention
Lifestyle modifications for cardiovascular and bone health
Importance of regular follow-up and screening
Medical alert bracelet/card for emergency situations

✓

Remission Definition: Sustained normalization of 24-hour UFC, midnight salivary cortisol, and normal response to low-dose dexamethasone suppression test for >12 months without anti-hypercortisolemic therapy.

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