ACTH-secreting pituitary tumors are relatively rare, making up only 4% of functioning tumors. It is a dangerous condition with a poor 5-year survival rate if untreated. There is a high female to male ratio of 8:1.
Lesions associated with excess circulating cortisol produce the manifestations of Cushing's syndrome. This can be due to lesions of the adrenal cortex, to extrapituitary, "ectopic" production of ACTH by neoplasms, to excessive corticotrophin-releasing hormone (CRH) production, and to pituitary-dependent ACTH excess. The latter, termed "Cushing's disease", was recognized and described by Harvey Cushing in 1932. The syndrome is characterized by centripetal obesity, plethoric moon-shaped facies, hirsutism, acne, diabetes, hypertension, muscle weakness, bruising, mental disorders, amenorrhea and osteoporosis, all due to gluco-corticoid hypersecretion. Hyperpigmentation is associated with ectopic ACTH production and, in severe cases, with pituitary-dependent ACTH excess. This is because the pro-hormone from which ACTH is eventually cleaved (pro-opiomelanocortin) also contains the amino acid sequences for melanocyte-stimulating hormone. Left untreated, Cushing's disease leads to severe complications.
The most common cause of pituitary-dependent Cushing's disease is a basophilic microadenoma.
Biochemical Investigations Loss of diurnal rhythm of plasma (or salivary) cortisol, with increased excretion of urinary free cortisol and lack of overnight suppression of cortisol in response to a low dose (1 mg) of dexamethasone, confirms cortisol overproduction. A combined low-dose and high-dose (8 mg) suppression test usually distinguishes between Cushing's disease and adrenal overproduction. In the former, suppression occurs, but not usually in the case of adrenal adenoma or ectopic production of ACTH. This is because the pituitary adenoma cells still have some susceptibility to negative feedback.
The presence of detectable levels of ACTH suggests ACTH-dependent disease - either pituitary or ectopic. In ectopic ACTH secretion, usually from an oat-cell carcinoma of the bronchus, very high levels of ACTH, pigmentation and hypokalemic alkalosis are found.
If an adenoma is not detected on imaging, then inferior petrosal sinus sampling after CRH injection is justified. With such sampling, peripheral blood ratios of more than 2.0 in the basal state and more than 3.0 following CRH injection are strongly suggestive of a pituitary origin. It does not guarantee the side of the gland where the occult microadenoma may be located because of trans-cavernous sinus veins that allow mixing of the blood from each side. CRH testing can be helpful in differential diagnosis, where a 100 g injection of CRH-41 will produce a normal or exaggerated response in Cushing's disease, but will make no difference in cases of ectopic ACTH secretion and adrenal adenoma.
Radiological Investigations As with the other pituitary tumors, good-quality MRI and plain films usually suffice, supplemented by petrosal sampling if required.
The definitive treatment for Cushing's disease is surgery. For those in whom surgery is not possible or has failed, radiotherapy is usually given. This may be accompanied by adrenalec-tomy and steroid replacement. Adrenalectomy carries a 20% risk of Nelson's syndrome (pituitary hyperplasia and autonomous production of ACTH) and thus medical rather than surgical adrenalectomy is usually the first choice. The 11 p-hydroxylase inhibitor metyrapone is the most commonly used agent. Ketoconazole, which inhibits steroid production and release of ACTH, may also be used, or mitotane, which destroys adrenal tissue. All of these agents have potentially serious side-effects, particularly ketoconazole and mitotane, which my cause liver damage and hypercholesterolemia respectively. Another group of agents acts centrally by enhancing the activity of endogenous inhibitors, or by antagonizing endogenous ACTH stimulators. The most commonly used agents are bromocriptine (dopamine agonist), cyproheptadine (a serotinin antagonist) and the GABA transaminase inhibitor sodium val-proate. Responses to these agents are unpredictable and idiosyncratic.