Cushing Syndrome Treatment & Management

Treatment of Cushing syndrome is directed by the primary cause of the syndrome. In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism. A culprit tumor should be removed if possible. The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy.

When surgery is not successful or cannot be used, as often occurs with ectopic ACTH or metastatic adrenal carcinoma, control of hypercortisolism may be attempted with medication. However, medication failures are common, and adrenalectomy may be indicated in ACTH-mediated Cushing syndrome. Pituitary radiation may be useful if surgery fails for Cushing disease.^[11]

The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid.

Medical care for Cushing syndrome can be summarized as follows:

• Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to cause medical adrenalectomy. These medications are used rarely and often are toxic at the doses required to reduce cortisol secretion. Thus, medical treatment should be initiated cautiously and, ideally, in conjunction with a specialist. Efficacy of these medical interventions can be assessed with serial measurements of 24-hour urinary free cortisol.
• Patients receiving these medications may require glucocorticoid replacement to avoid adrenal insufficiency. Patients should be counseled on the signs and symptoms of adrenal insufficiency when starting these drugs.
• Metyrapone and trilostane are agents that competitively inhibit a single steroidogenic enzyme. Ketoconazole and aminoglutethimide act at several sites. In ACTH-dependent Cushing syndrome, ACTH secretion continues to stimulate steroidogenesis, which counters the actions of these medications.
• Because ACTH production may persist or increase in patients with Cushing disease, radiation therapy of the pituitary is often required after unsuccessful initial therapy, either surgical or medical. These agents have higher efficacy when used in combination because they may act synergistically.
• Ketoconazole is probably the most popular and effective of these agents for long-term use and usually is the agent of choice. It acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol.

  • A daily dose of 600-800 mg often decreases cortisol production. If this agent is ineffective at controlling hypercortisolism, the dose may be maintained while another steroid enzyme inhibitor, typically metyrapone, is initiated.
  • Adverse effects of ketoconazole include headache, sedation, nausea, irregular menses, decreased libido, impotence, gynecomastia, and elevated liver function tests. The drug is contraindicated during pregnancy.
  • Ketoconazole is less effective in patients on H2 blockers or proton-pump inhibitors because gastric acidity is required for metabolism.
• Metyrapone blocks 11-beta-hydroxylase activity, the final step in cortisol synthesis. Therapy is begun at 1 g/d divided into 4 doses and increased to a maximum dose of 4.5 g/d. Adverse effects are from increases in androgen and mineralocorticoid precursors, including hypertension, acne, and hirsutism.
• Aminoglutethimide is an anticonvulsant agent that blocks cholesterol side-chain cleavage to pregnenolone. It is a relatively weak adrenal enzyme inhibitor at doses that patients can tolerate. Aminoglutethimide is typically initiated at 250 mg twice daily, and doses of 1-2 g daily are often used.

  • Adverse effects of aminoglutethimide include somnolence, headache, a generalized pruritic rash, hypothyroidism, and goiter.
  • In rare cases, it may cause bone marrow suppression.
  • Aminoglutethimide increases the metabolism of dexamethasone but not cortisol.
• Trilostane is not widely available and is not as well studied. Trilostane inhibits the conversion of pregnenolone to progesterone, which decreases the synthesis of cortisol, aldosterone, and androstenedione. It is not a first-choice agent because it is a weak inhibitor of steroidogenesis. In addition, trilostane interacts with some assays, causing a false elevation of cortisol measurements.
• Etomidate, an imidazole-derivative anesthetic agent, blocks 11-beta-hydroxylase. It is used intravenously at 0.3 mg/kg/h. Its use is limited by the requirement for chronic administration by the intravenous route.
• Mitotane is an adrenolytic agent that acts by inhibiting 11-beta hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis. For this reason, it is used in treatment of adrenal cancer at doses of 2-4 g daily. Its survival benefit is unclear. It can be used in addition to radiation therapy for treatment of Cushing disease and in combination with metyrapone or aminoglutethimide for treatment of ectopic ACTH secretion.

  • Unfortunately, mitotane is expensive, and its utility is limited by adverse gastrointestinal and neurologic effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia.
  • It is taken up by adipose tissues and persists in the circulation long after discontinuation.
  • It is a potential teratogen and can cause abortion; therefore, it is relatively contraindicated in women interested in remaining fertile.
• Mifepristone (RU 486) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors. It currently is used only on an investigational basis for treatment of Cushing syndrome.^[12]
• Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include bromocriptine, cyproheptadine, valproic acid, and octreotide. Currently, use of these agents is investigational.

Treatment options for patients with persistent or recurrent Cushing disease have included pituitary irradiation and repeat surgery. A small study found that a percentage of such patients respond to cabergoline therapy.^[13] Mechanism of action, longer-term follow-up, and a larger number of patients are needed to confirm these encouraging preliminary results.

• Cushing disease

  • Treatment of choice for classic Cushing disease is transsphenoidal surgery by an experienced neurosurgeon. The goal of surgery is to remove the adenoma, preserving as much pituitary function as possible.
  • The more extensive the mass and the resulting resection, the greater the risk for loss of pituitary function. Successful amelioration of hypercortisolism occurs in 60-80% of cases. Both open and laparoscopic techniques are possible. If unsuccessful, MRI-guided pituitary surgery, a new procedure, may be indicated. Lateralization of ACTH secretion via IPS catheterization and sampling is sometimes helpful in difficult cases.^[14]
  • Pituitary irradiation is employed when transsphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 45% cure rate in adults and 85% cure rate in children. Late-onset adverse effects include hypopituitarism.
  • Bilateral adrenalectomy is an option if transsphenoidal surgery, pituitary irradiation, and medical therapy fail or if rapid normalization of cortisol levels is required. The patient then requires lifelong glucocorticoid and mineralocorticoid therapy.
  • In individuals who undergo bilateral adrenalectomy, Nelson syndrome, that is symptomatic enlargement of the pituitary gland and adenoma, may occur in one quarter to one half of adults not treated with pituitary irradiation and in as many as one quarter of patients pretreated with radiation therapy.
• Ectopic adrenocorticotropic production

  • Surgical resection of the source of ACTH production may not always be possible. Ectopic ACTH-producing tumors are often difficult to locate.
  • Medical therapy or bilateral adrenalectomy may be required.
• Adrenal source

  • Adenomas may be removed with unilateral adrenalectomy, often with a laparoscopic approach.
  • Carcinomas should be resected for possible cure and palliation.
  • Micronodular or macronodular hyperplasia causing Cushing syndrome may be treated effectively by bilateral adrenalectomy. Unilateral or subtotal adrenalectomy may lead to recurrence.
• Hormone replacement

  • Patients with endogenous Cushing syndrome who undergo resection of pituitary, adrenal, or ectopic tumors should receive stress doses of glucocorticoid in the intraoperative and immediate postoperative period.
  • Typically, hydrocortisone is infused intravenously, either continuously (10 mg/h) or in boluses (80-100 mg q8h) starting prior to surgery and for the first 24 hours afterward.
  • If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-2 days and replaced with an oral formulation. The rate of steroid taper may be slowed if severe preoperative hypercortisolism was present.
  • In the event of pituitary destruction or bilateral adrenalectomy, lifelong glucocorticoid replacement is necessary. Lifelong mineralocorticoid replacement is also necessary in those patients who undergo bilateral adrenalectomy.

Effective diagnosis and management of Cushing disease is often facilitated by involvement of an endocrinologist and the appropriate experienced neurosurgeon, general surgeon, or urologist.