Cushing Disease

Definition and PathogenesisTop

Cushing disease is the most common cause of hypercortisolemia/Cushing syndrome in adults, caused by excess secretion of adrenocorticotropic hormone (ACTH) usually by a pituitary adenoma and very rarely by a pituitary carcinoma. This causes hypertrophy of the striatal and reticular layers of the adrenal cortex as well as increased production of cortisol and, to a lesser extent, androgens, leading to the development of the characteristic symptoms of endogenous Cushing syndrome.

Clinical FeaturesTop

Signs and symptoms are mainly related to hypercortisolemia and its complications (see Cushing Syndrome) rather than to the presence of an intrasellar tumor because pituitary adenomas (except for macroadenomas) are usually small (microadenomas) and do not cause neurologic symptoms (headaches, cranial or optic nerve compression). Menstrual irregularities and gonadal dysfunction, that is, infertility, impaired libido, and erectile dysfunction in men, are common in overt disease because hypercortisolemia inhibits gonadotropin secretion. Signs of hyperandrogenism are usually mild in women with ACTH-dependent Cushing syndrome, but they contribute to menstrual abnormalities, increased seborrhea, acne lesions, and mild hirsutism. Features of aldosterone excess may also be present, such as hypertension and hypokalemia due to high levels of ACTH.

DiagnosisTop

Diagnostic Criteria

The presence of clinical and laboratory features of hypercortisolemia (Cushing syndrome) with uninhibited ACTH secretion suppressed only with high-dose (8-mg) dexamethasone suppression test (DST; demonstrated by decreased cortisol secretion) and/or increased cortisol response to corticotropin-releasing hormone (CRH) or 1-desamino-8-D-arginine vasopressin (DDAVP) and the presence of a pituitary adenoma sized >6 mm on dynamic magnetic resonance imaging (MRI; preferably at least Tesla-3) with contrast can be diagnostic of Cushing disease. The absence of an adenoma with the above-mentioned criteria on MRI does not exclude Cushing disease and may require bilateral inferior petrosal sinus sampling (BIPSS). It is also important to exclude pseudo–Cushing syndrome, currently better known as nonneoplastic hypercortisolism (see Cushing Syndrome).

Differential Diagnosis

Differentiate with other causes of ACTH-dependent Cushing syndrome, mainly ectopic ACTH secretion. Details: see Cushing Syndrome. Computed tomography (CT) of the chest/abdomen/pelvis and molecular imaging may be needed if ectopic ACTH syndrome is suspected.

TreatmentTop

The treatment of choice is surgical removal of the pituitary adenoma through transsphenoidal surgery (TSS).

Medical therapy can be considered if there is a delay in surgery, in those with severe Cushing disease or acute complications, in patients who are not TSS candidates, in those with recurrent or persistent disease, or in those awaiting the effects of radiotherapy. The fastest-acting agents are adrenal steroidogenesis inhibitors: ketoconazole 400 to 1600 mg/d (in divided doses bid to tid) or metyrapone 500 mg to 6 g/d (in divided doses tid to qid). With this treatment vascular fragility and intraoperative bleeding may be reduced, as well as the incidence of infections and thromboembolic complications, and diabetes and hypertension may be more easily managed. Liver enzymes and liver function should be monitored and drug interactions taken into account. Osilodrostat, an inhibitor of increased adrenal cortisol synthesis by blocking 11-alpha-hydroxylase, dosed 2 to 14 mg/d (bid), may be considered. Other options for medical therapy include pituitary-directed therapies such as cabergoline (0.5-7 mg/wk) or pasireotide (second-generation somatostatin analogue; 0.6-1.8 mg/d subcutaneously or 10-30 mg IM monthly), which are less effective and slower acting. Attention to systemic aspects, complications, and comorbidities of hypercortisolemia also need to be addressed (see Cushing Syndrome).

Radiotherapy may be needed if TSS is unsuccessful and medical treatment has failed, or in patients with tumor recurrence/persistence or aggressive tumor growth, high surgical risk, and in those who refused TSS.

Rarely, bilateral adrenalectomy may be required if the disease is severe and/or complicated and rapid control is needed, which can be life-saving. With this type of therapy, there is permanent hypoadrenalism requiring lifelong glucocorticoid and mineralocorticoid replacement and the risk of Nelson syndrome (corticotroph tumor progression) is 25% to 40% after 5 to 10 years, wherefore MRI and ACTH monitoring are required.

Treatment decisions are usually made in a specialized setting.

PrognosisTop

Half of untreated individuals with Cushing disease die from complications of hypercortisolemia within 5 years of disease duration. The prognosis for cure is good: the success rate of surgery at leading neurosurgical centers exceeds 90%. Further prognosis is influenced by the severity of hypercortisolemia complications: early recognition and effective treatment can result in the resolution of diabetes and hypertension. Because of the high the risk of relapse, recurrence, or both (~20%), lifelong monitoring is required.