Cushings syndrome entails a variety of charsacteristic clinical abnormalities associated with excessive chronic exposure to cortisol or related corticosteroids. Symptoms include hypertension, hyperglycemia, proximal muscle weakness, polyuria, hirsutism, moon facies, dorsocervical fat-pad (buffalo hump), supraclavicular fullness, abdominal striae, acne, hyperpigmentation, central obesity, menstrual irregularities and neuropsychiatric dysfunction. Cushings syndrome may result from administration of exogenous glucocorticoids for the treatment of various diseases, or it may result from endogenous hypercortisolism. Endogenous hypercortisolism may result from hyperfunctioning adrenal glands or may be the result of excessive adrenal stimulation by ACTH (adrenocorticotrophic hormone). Excess ACTH may be the result of overproduction by the pituitary gland in which case the disorder is called Cushings disease, or ACTH may be produced from an ectopic malignant source. Sources of ectopic ACTH include bronchial carcinoids, small-cell lung cancers, thymic tumors, islet-cell pancreatic tumors, pancreatic cancer, ovarian cancer, prostate cancer, medullary carcinomas of the thyroid, pheochromocytomas and metastatic lesions.
The initial step in the work up of Cushings syndrome is to establish a state of hypercortisolism. This is most effectively and accurately done by collecting a twenty four hour urine sample for determination of the free cortisol value on several occasions or a midnight salivary cortisol determination. Some physicians employ the dexamethasone suppression test for the initial step although the 24 hour urine cortisol level is preferred. Once hypercortisolism is established, the next step is to determine if the pathologic state is secondary to adrenal hyperfunction or excessive adrenal stimulation. This is done by measuring the serum ACTH level. A low value in the face of hypercortisolism indicates autonomous adrenal hyperfunction whereas a high value is consistent with pituitary (Cushings disease) or ectopic production of ACTH.
If the ACTH level is low indicating adrenal pathology, then the next step entails imaging the adrenals with CT. Potential adrenal pathology includes neoplasia (most common and usually benign), primary pigmented nodular hyperplasia (an autoimmune disease) or macronodular hyperplasia. All three are indications for adrenalectomy.
If the ACTH level is normal or elevated in the face of hypercortisolism, then the Cushingoid state is said to be ACTH dependent, and the source of excess ACTH must be identified. ACTH dependent Cushing's syndrome (if ectopic source) or Cushings disease (if pituitary source) is a challenging dilemma for the physician. A pituitary MRI is often erroneously obtained to check for pituitary pathology. However, benign pituitary adenomas are quite common and usually asymptomatic, also Cushing's disease is often secondary to a corticotrophic microadenoma which would not be detected by MRI. This allows for a great degree of uncertainty in establishing the source of excess ACTH. Therefore, the next step in the workup of ACTH dependent hypercortisolism is not pituitary imaging, but inferior petrosal sinus sampling for ACTH and exclusion of malignancies which may produce ectopic ACTH. The pituitary drains directly into the inferior petrosal sinus, so if a gradient exists between the concentration of ACTH in the petrosal sinus sample and the peripheral blood, the pathology is located in the pituitary and transphenoidal pituitary microsurgery is indicated. If the gradient between the two samples is less than two, an ectopic source should be aggressively sought. However, it would be just as efficient, and probably more cost effective, to rule out ectopic sources of ACTH secretion first (bronchial carcinoid, small-cell lung cancers, thymic tumors, islet-cell pancreatic tumors, pancreatic cancer, prostate cancer, medullary carcinoma of the thyroid, pheochromocytoma, and metastatic cancer) via appropriate lab tests (24 hour urine metanephrines, serum chromagranin A, sputum cytology, CA 19-9, PSA, serum calcitonin) along with MRI of the chest and abdominal CT than to initiate the work-up with inferior petrosal sinus sampling first. Plus, petrosal sinus sampling is not universally available thus making a search for an ectopic source an easier approach in the work-up.
During the workup of excess cortisol, which may be time consuming, hypercortisolism may be treated with either ketoconazole or metyrapone or both. Ketoconazole inhibits adrenal enzymes necessary for cortisol production. 11-beta-hydroxylase, the enzyme necessary for the final step of cortisol production, is inhibited by metyrapone. Surgical correction of the underlying etiology is curative.