Cushing's syndrome

Typical indicators of pituitary disease are raised urinary free cortisols, detectable midnight serum cortisol as well as partial suppression of serum cortisol with dexamethasone, and a detectable or elevated serum ACTH.

Pituitary MRI may or may not be obviously abnormal.

This aims to confirm pituitary origin, and aid disease lateralisation prior to surgery.

Selective venous catheterisation of the petrosal sinuses allows simultaneous sampling of central and peripheral blood to compare ACTH levels. A central to peripheral gradient of ACTH levels above 4:1 confirms a central, i.e. pituitary, source of ACTH. 

An ACTH response (greater than 30% above basal levels) to CRH testing further supports the suspicion of pituitary disease. Sampling of both sinuses simultaneously also provides evidence of disease lateralisation prior to planning surgery. 

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. 

Reassess cortisol levels with 'metyrapone day curve' at three days. Arrange weekly monitoring of liver function during treatment.

Medical treatment aims to control cortisol excess to approximate mean serum levels of 250-300nmol/l, control blood pressure and ensure good diabetes control if indicated, prior to surgery.

Trans-sphenoidal surgery is the standard treatment for pituitary disease.

Typical indicators are raised urinary free cortisol levels and detectable midnight cortisol, as well as a lack of suppression with dexamethasone, elevated basal ACTH levels, no response to CRH testing and no central to peripheral gradient on inferior petrosal sinus sampling. 

Ectopic ACTH secretion is most commonly from a bronchial tumour.

If the source of the ectopic ACTH is not obvious, consider total body imaging with octreotide or MIBG scan, followed by cross sectional imaging, for example MRI of any suspicious areas. 

Consider performing selective venous catheterisation of suspicious areas for measurements of ACTH to confirm disease localisation.

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. 

Reassess cortisol levels with 'metyrapone day curve' at three days. Arrange weekly monitoring of liver function during treatment.

Medical treatment aims to control cortisol excess to approximate mean serum levels of 250-300nmol/l, control blood pressure, and ensure good diabetes control if indicated, prior to surgery. 

Ideally, Cushing's syndrome due to ectopic ACTH should be treated by resection of the tumour after medical optimisation.

If the source of ACTH is not identified, initial management is usually to continue long term medical treatment until the source becomes apparent.

Long term use of adrenolytic therapy may be poorly tolerated however, and safe long term control can also be achieved with bilateral adrenalectomy, which should also be considered in all cases. 

Life long follow up remains necessary post adrenalectomy, with periodic surveillance imaging and biochemical assessments until source is identified.

Typical indicators are raised urinary free cortisol levels and detectable midnight cortisol as well as undetectable or low ACTH levels, and no response to high or low dose dexamethasone suppression testing. 

Adrenal androgens may also be elevated but will not suppress with dexamethasone.

Adrenal tumours are usually easily identified on CT, and their imaging characteristics and size are useful indicators of malignant potential - low Hounsfield units and small size are predictive of benign curable disease.

Patients should be prepared medically prior to surgery to optimise the safety of the procedure. Typically metyrapone 500-750mg daily in divided doses is used.

Warn patient of the symptoms of hypoadrenalism, for example nausea and dizziness at the start of treatment, and offer supply of dexamethasone for emergency use. 

Reassess cortisol levels with 'metyrapone day curve' at three days.

Arrange weekly monitoring of liver function during treatment. If control not achieved, consider adding or substituting with ketoconazole. In exceptional cases and adrenal cancer, consider use of mitotane with intensive monitoring.

Control of cortisol excess to an approximate mean serum level of 250-300nmol/l, good control of blood pressure with other agents if necessary, and optimisation of diabetes control should all be acheived during this period.

Refer to a specialist adrenal or urological multidisciplinary team for consideration of laparascopic surgical resection after six weeks medical optimisation.

With confirmed cure, patients need to commence hydrocortisone replacement therapy typically with 10mg on waking, 5mg at five hours and 5mg at nine hours. This should then be adjusted according to symptoms and hydrocortisone day curve as necessary. 

Check pre hydrocortisone dose cortisol and ACTH levels prior to all follow up assessments.

Assess control at three, six and 12 months post treatment, and then usually on an annual basis long term. 

Formally reassess for disease recurrence or re-emergence of normal hypothalomic pituitary adrenal axis with 9am cortisol, midnight cortisol, low dose dexamethasone suppression testing and 2x urinary free cortisols. Reassess at least every six months initially, or whenever their pre dose serum cortisol becomes detectable.

Ensure cardiovascular and bone health are assessed long term.

Satisfactory control is evidenced by clinical response and a mean serum cortisol, during a circadian rhythm, of 250-300nmol/l.

Two 24 hour urinary free cortisols within the normal range is an alternative reflection of adequate biochemical control while awaiting definitive treatment.

Bone densitometry should be assessed in such patients. Calcium and vitamin D should be considered in all patients, and further treatments for osteoporosis discussed.

This requires two urinary free cortisols, a 9am pre-dose cortisol and ACTH, and a low dose dexamethasone suppresssion test for cortisol. This should be performed every six months initially, and at least annually long term.

To detect and monitor Nelson's syndrome, serum ACTH should be checked both before and 120 minutes post hydrocortisone dose in patients who have undergone bilateral adrenalectomy.

Consider repeat surgery, adrenalectomy, or conventional radiotherapy if patients are not cured. 

Following pituitary radiotherapy, further surgery or radiosurgery can be considered in exceptional cases.

Patients on steroid replacement therapy require a pre dose 9am cortisol before each visit. They also require an ACTH and renin assessment prior to, and 120 minutes after, their hydrocortisone and fludrocortisone doses to guide replacement therapy and monitor for the development of Nelson’s syndrome or the emergence of an adrenal remnant.

Check pre-dose cortisol level and ACTH prior to first follow up assessment.

Assess control at three, six and 12 months post treatment, and then usually on an annual basis long term.

Formally reassess for disease recurrence or re-emergence of normal hypothalomo-pituitary-adrenal axis with 9am cortisol, midnight cortisol, low dose dexamethasone suppression testing and urinary free cortisols. Reassess at least every six months initially, or whenever their pre dose serum cortisol becomes detectable.

Patients with previous pituitary surgery or radiotherapy need to be monitored for the development of anterior pituitary failure. All patients require that cardiovascular risks and bone health are assessed long term.