Adrenal Hyperfunction

Adrenal Hyperfunction: Cushing's Syndrome

Cushing’s Syndrome – a persistent, inappropriate excess of cortisol

Named for Harvey Cushing, M.D.; born and buried in Cleveland; educated at Harvard Med; Father of Neurosurgery

Cushing’s Syndrome refers to:

excessive glucocorticoid production by adrenal cortex

complications from prolonged glucocorticoid therapy (e.g., prednisone)

Clinical Features

Truncal obesity – Ý cortisol leads to insulin resistance; resulting Ý insulin levels are lipogenic

also leads to redistribution of fat (e.g., "buffalo hump" or "moon-face")

Hyperglycemia – glucocorticoids Ý hepatic glucose production

Striae/thin skin – look like stretch marks but are due to subcutaneous wasting

Proximal muscle weakness – due to effect of glutocorticoids on protein metabolism

Hirsutism – excessive hair growth

if sex steroids are produced as well, women will get "male pattern baldness"

hypertension – due to electrolyte imbalances (may be due to Ý mineralcorticoids), hypervolemia and sodium retention

Menstrual dysfunction

Easy bruisability and Poor wound healing – due to capillary fragility

Osteoporosis – a major complication, due to Ý bone resorption and ß formation

Behavioral changes – depression is a common symptom in Cushing’s

in children: generalized obesity and growth retardation are the most common features

Etiology – can be ACTH dependent or ACTH independent

(1) ACTH Dependent – bilateral adrenal hyperplasia stimulated by inappropriate ACTH

Cushing’s Disease (a subset of Cushing’s syndrome) – due to microadenoma of the pituitary secreting ACTH

occurs most frequently in women of child-bearing age

Ectopic ACTH Syndrome – ACTH made by non-pituitary tumor, usually small cell carcinoma of the lung (oat cell)

more common in men, possibly associated with smoking

Ectopic CRH syndrome – CRH made by a non-hypothalamic tumor which stimulates pituitary to release ACTH

(2) ACTH Independent – primary adrenal tumor – either adenoma (most common cause in children) or carcinoma

(3) Other – Nodular adrenal hyperplasia

Establishing a Diagnosis – if you suspect hyperfunction do a suppression test (e.g. Dexamethasone suppression test)

To establish hyperfunction:

Dexamethasone Suppression Test – dexamethasone is a glucocorticoid that can provide neg. feedback to ß ACTH

small dose will suppress cortisol production in normal people but will not suppress excessive cortisol production from adrenal tumor or autonomous ACTH secretion

following overnight dextromethasone, serum cortisol will be <5 m g/dL in normal subjects, >10m g/dL in Cushing’s patients.

24 hr urine cortisol – normal <100 m g Cushing’s >100 m g

To distinguish ACTH-dependent from ACTH-independent secretion:

Measure ACTH Level – if patient is hypercortisolemic then even a normal ACTH is high (it should be low by negative feedback), so if it ain't low it's high

an ACTH level will help determine if the process is ACTH-dependent or -independent.

Þ if ACTH-independent – then it’s an adrenal tumor – next step is radiology

Þ if ACTH-dependent – need to distinguish between ectopic vs. pituitary ACTH production before treatment

To distinguish pituitary from ectopic ACTH secretion:

High Dose Dexamethasone Test – ACTH will be suppressed with pituitary but not ectopic ACTH secretion

Measure Local ACTH Levels –sample blood near the pituitary and compare with peripheral levels

more near pituitary suggests pituitary secretion of ACTH, more in periphery suggests an ectopic source of ACTH

Treatment

Treatment for Cushing’s Disease (pituitary hypersecretion of ACTH)

Surgery – transsphenoid microsurgical selective removal of pituitary adenomas

if successful, patient will initially be adrenally insufficient post-operatively until the axis regains homeostasis

Drugs – agents that inhibit cortisol synthesis (e.g. Ketoconazole)

Radiation – should be restricted to patients for whom all other modalities have failed

Treatment for Ectopic ACTH Syndrome

1^st treat primary tumor; 2^nd treat hypokalemia; 3^rd control hypercortisolism with drugs; 4^th remove adrenals (last resort)

Treatment for Adrenal Tumors

Adenoma – unilateral adrenalectomy and glucocorticoid support pending recovery of suppressed pituitary

Carcinoma – adrenalectomy (metastases common and surgical cures are rare, de-bulk the tumor) and drugs