Cushing syndrome results from effects of supraphysiologic glucocorticoid levels originating from either exogenous administration or endogenous overproduction by the adrenal gland (adrenocorticotropic hormone [ACTH]-dependent) or by abnormal adrenocortical tissues (ACTH-independent).
ACTH-dependent Cushing syndrome (80% of all Cushing syndrome cases) is usually caused by overproduction of ACTH by the pituitary gland, causing adrenal hyperplasia. Pituitary adenomas account for ~85% of these cases (Cushing disease). Ectopic ACTH-secreting tumors and non-neoplastic corticotropin hypersecretion cause the remaining 20% of ACTH-dependent cases.
Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or non-endocrine tumor, usually of the pancreas, thyroid, or lung (eg, small-cell lung cancer).
ACTH-independent Cushing syndrome is usually caused by adrenal adenomas and carcinomas.
The most common findings in Cushing syndrome are central obesity and facial rounding (90% of patients). Peripheral obesity and fat accumulation occur in 50% of patients. Fat accumulation in the dorsocervical area (buffalo hump) is nonspecific, but increased supraclavicular fat pads are more specific for Cushing syndrome. Patients are often described as having moon faces and a buffalo hump.
Other findings may include myopathy or muscular weakness, abdominal striae, hypertension, glucose intolerance, psychiatric changes, gonadal dysfunction, and amenorrhea and hirsutism in women. Up to 60% of patients develop Cushing-induced osteoporosis; ~40% present with back pain, and 20% progress to spinal compression fractures.
Hypercortisolism can be established with a 24-hour urinary free cortisol (UFC), midnight plasma cortisol, late-night (11 pm) salivary cortisol, and/or low-dose dexamethasone suppression test (DST). Other tests to determine etiology are plasma ACTH test; adrenal vein catheterization; metyrapone stimulation test; adrenal, chest, or abdominal computed tomography (CT); corticotropin-releasing hormone (CRH) stimulation test; inferior petrosal sinus sampling; and pituitary magnetic resonance imaging (MRI). Adrenal nodules and masses are identified using high-resolution CT scanning or MRI.
Goals of treatment are toLimit morbidity and mortality and return the patient to a normal functional state by removing the source of hypercortisolism while minimizing pituitary or adrenal deficiencies.
Treatment of choice for both ACTH-dependent and ACTH-independent Cushing syndrome is surgical resection of offending tumors. Transsphenoidal resection of the pituitary tumor is the treatment of choice for Cushing disease. Pituitary irradiation provides clinical improvement in ~50% of patients within 3 to 5 years, but improvement may not be seen for 6 to 12 months, and pituitary-dependent hormone deficiencies (hypopituitarism) can occur.
Laparoscopic adrenalectomy may be preferred in patients with unilateral adrenal adenomas or for whom transsphenoidal surgery and pituitary radiotherapy have failed or cannot be used.
Pharmacotherapy is generally used as secondary treatments in preoperative patients or as adjunctive therapy in postoperative patients awaiting response. Rarely, monotherapy is used as a palliative treatment when surgery is not indicated.
Steroidogenic Inhi bitors
Metyrapone inhibits 11 β-hydroxylase, thereby inhibiting cortisol synthesis. Initially, patients can demonstrate increased plasma ACTH concentrations because of a sudden drop in cortisol. This can increase androgenic and mineralocorticoid hormones, resulting in hypertension, acne, and hirsutism. Nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash have been reported after oral administration. Metyrapone is currently available through the manufacturer only for compassionate use.
Ketoconazole inhibits cytochrome P-450 enzymes, including 11 β-hydroxylase and 17 α-hydroxylase. It is effective in lowering serum cortisol levels after several weeks of therapy. It also has antiandrogenic activity, which may be beneficial in women but can cause gynecomastia and decreased libido in men. The most common adverse effects are reversible elevation of hepatic transaminases, GI discomfort, and dermatologic reactions. Ketoconazole may be used concomitantly with metyrapone to achieve synergistic reduction in cortisol levels; in addition, ketoconazole’s antiandrogenic actions may offset the androgenic potential of metyrapone.
Etomidate is an imidazole derivative similar to ketoconazole that inhibits 11 β-hydroxylase. Because it is only available in a parenteral formulation, use is limited to patients with acute hypercortisolemia requiring emergency treatment.
Aminoglutethimide inhibits cortisol synthesis by blocking conversion of cholesterol to pregnenolone early in the cortisol pathway. Side effects of severe sedation, nausea, ataxia, and skin rashes limit aminoglutethimide use in many patients. Other steroidogenesis inhibitors offer greater efficacy with fewer side effects; if aminoglutethimide is used, it should be coadministered with another steroidogenesis inhibitor (usually metyrapone) due to high relapse rates with aminoglutethimide monotherapy.
Mitotane is a cytotoxic drug that inhibits the 11-hydroxylation of 11-desoxycortisol and 11-desoxycorticosterone in the adrenal cortex, reducing synthesis of cortisol and corticosterone. Similar to ketoconazole, mitotane takes weeks to months to exert beneficial effects. Sustained cortisol suppression occurs in most patients and may persist after drug discontinuation in up to one third of patients. Mitotane degenerates cells within the zona fasciculata and reticularis; the zona glomerulosa is minimally affected during acute therapy but can become damaged after long-term treatment.
Mitotane can cause significant neurologic and GI side effects, and patients should be monitored carefully or hospitalized when initiating therapy. Nausea and diarrhea are common at doses greater than 2 g/day and can be avoided by gradually increasing the dose and/or administering it with food. Lethargy, somnolence, and other CNS effects are also common. Reversible hypercholesterolemia and prolonged bleeding times can occur.
Neuromodulators of Acth Release
Pituitary secretion of ACTH is normally mediated by neurotransmitters such as serotonin, γ-aminobutyric acid (GABA), acetylcholine, and catecholamines. AlthoughACTH-secreting pituitary tumors (Cushing disease) self-regulate ACTH production to some degree, these neurotransmitters can still promote pituitary ACTH production.
Consequently, agents that target these transmitters have been proposed for treatment of Cushing disease, including cyproheptadine, bromocriptine, cabergoline, valproic acid, octreotide, rosiglitazone, and tretinoin. None of these drugs have demonstrated consistent clinical efficacy for treating Cushing syndrome.
Cyproheptadine can decrease ACTH secretion in some patients with Cushing disease. However, side effects such as sedation and weight gain significantly limit its use.
Pasireotide is a somatostatin analogue that binds and activates somatostatin receptors, thereby inhibiting ACTH secretion, leading to decreased cortisol secretion. It is approved for treatment of adults with Cushing disease for whom pituitary surgery is not an option or has not been curative.
Glucocorticoid -Receptor Bloc king Agents
Mifepristone (RU-486) is a progesterone- and glucocorticoid-receptor antagonist that inhibits dexamethasone suppression and increases endogenous cortisol and ACTH levels in normal subjects. Evidence suggests that mifepristone is highly effective in reversing the manifestations of hypercortisolism. Its use for treatment of Cushing syndrome remains investigational.