Endogenous Cushing Syndrome Treatment & Management

Updated: May 09, 2017
  • Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Treatment

Approach Considerations

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. 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 undertaken, as often occurs with ectopic adrenocorticotropic hormone (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.

In 2015, the Endocrine Society released new guidelines for Cushing syndrome: [27, 28]

  • Optimal treatment of Cushing syndrome involves direct surgical removal of the causal tumor, except in cases unlikely to cause a drop in glucocorticoids or in patients who are not candidates for surgery. Second-line therapy should be individualized.
  • Other first-line treatments include surgical resection of ectopic ACTH-secreting tumors; transsphenoidal selective adenomectomy; blocking hormone receptors in bilateral micronodular adrenal hyperplasia; and surgical removal in cases of bilateral adrenal disorders.
  • The choice of second-line treatments include medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors).
  • Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities (eg, hypertension, diabetes) by adjunctive treatments (eg, antihypertensives). Lowering cortisol levels improves hypertension, insulin resistance, dyslipidemia, and obesity.
  • In cases of benign unilateral adrenal adenoma, adrenalectomy is associated with a high cure rate in both children and adults. Adrenal carcinoma is associated with a poor prognosis; therefore, complete resection, and possibly medical treatment to stabilize cortisol levels, are necessary.
  • Long-term follow-up is recommended for osteoporosis, cardiovascular disease, and psychiatric conditions.
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Pharmacotherapy

Medications used in the management of Cushing syndrome include the following:

  • Somatostatin analogs: Pasireotide
  • Adrenal steroid inhibitors: Metyrapone, ketoconazole, etomidate
  • Glucocorticoid receptor antagonist: Mifepristone
  • Adrenolytic agents: Mitotane

Pasireotide (Signifor) is a somatostatin analog that binds and activates human somatostatin receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. It is indicated for treatment of adults with Cushing disease in whom pituitary surgery is not an option or has not been curative.

In a phase 3 trial [29]  in which 162 patients were randomly assigned to receive either 0.6 or 0.9 mg of pasireotide subcutaneously twice a day, twelve (15%) participants in the lower-dose group and 21 (26%) of the higher-dosage group met the trial's primary endpoint (free urinary cortisol levels at or below the upper limit of normal with no dose increase in 6 months). Patients with baseline levels not exceeding 5 times the upper limit of the normal range were found to achieve normal urinary free cortisol level more often than those with higher baseline levels. Other observations included improvements in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, weight, and health-related quality of life. However, 48% of patients who did not have diabetes at baseline became diabetic. Seventy-three percent of the study participants experienced hyperglycemia-related adverse events, leading to 6% leaving the study and 46% requiring a new glucose-lowering medication. Cholelithiasis was also associated with its use.

In an extension treatment study of Pasireotide from an original 15-day, phase 2 study, Pasireotide was shown to maintain the effect on lowering free urinary cortisol levels in some patients up to 24 months. This supports the extended treatment of Pasireotide in some patients with Cushing’s disease. {Ref 27}

Agents that inhibit steroidogenesis, such as mitotane, ketoconazole, metyrapone, and etomidate, have been used to cause medical adrenalectomy. These medications are often are toxic at the doses required to reduce cortisol secretion. For instance, ketoconazole's prescribing information was revised to include a black box warning regarding hepatotoxicity, including fatalities and liver transplantation. Thus, medical treatment should be initiated cautiously and, ideally, in consultation 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 is an agent that competitively inhibits a single steroidogenic enzyme. Ketoconazole acts 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 has been the most popular and effective of these agents for long-term use and usually has been the agent of choice. However, the FDA has issued a warning that states clinicians should no longer prescribe ketoconazole, except to treat some life-threatening fungal infections; this is due to increased risk for severe liver injury, adrenal insufficiency, and adverse drug interactions. Ketoconazole 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.

Patients should be informed of the hepatotoxicity risks and monitored closely while taking this drug. Drug-to-drug interaction should also be reviewed. Certain drugs when used concurrently with Ketoconazole can increase risk of prolong QT interval or changes in drug metabolism. Concomitant use with cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, and ranolazine is contraindicated due to the possible occurrence of life-threatening ventricular arrhythmias such as torsade de pointes.

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 present from increases in androgen and mineralocorticoid precursors and include hypertension, acne, and hirsutism.

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 administration by the intravenous route. However, it rapidly decreases cortisol concentration and may be used as an adjunct to impending surgical procedure.

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 for treatment of ectopic ACTH secretion.

Unfortunately, mitotane is expensive, and its utility is limited by the adverse gastrointestinal and neurologic effects, including nausea, diarrhea, dizziness, and ataxia. Other adverse effects include rash, arthralgias, and leukopenia. Mitotane 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 (Korlym) is an antiprogestational agent, which, at high doses, competitively binds to the glucocorticoid and progesterone receptors. [30] In February 2012, the FDA approved mifepristone to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery, or are not candidates for surgery.

The effect of Mifepristone was reported in a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 United States academic medical centers and three private research centers. [31] Fifty Cushing's syndrome patients were enrolled in the study. Forty-three had Cushing disease, of which 42 had prior surgery, four patients had ectopic ACTH-producing tumors and three had adrenal cancer. Response was defined as at least a 25% decrease in area under the curve for glucose on a standard oral glucose tolerance test from baseline to 24 weeks, an amount considered clinically meaningful improvement in glucose control. Twenty-nine patients enrolled in the study were glucose intolerant. Sixty percent of patients met the study’s primary endpoint. There was also a statistically significant reduction in mean HbA1c over the course of the study, from 7.43% at baseline to 6.29% at study conclusion (p<0.001). Diastolic blood pressure response, weight reduction, and waist circumference decrease were also observed in study subjects. Overall, 87% had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved.

Patients should be monitored for adrenal insufficiency, hypokalemia, prolonged QT interval. Use of mifepristone will result in termination of pregnancy. When Mifepristone is used in women with Cushing’s syndrome, pregnancy must be excluded prior to initiation of therapy. Nonhormonal form of contraception must be used during treatment and for 1 month after stopping therapy.

Agents that decrease CRH or ACTH release have been studied for the treatment of Cushing disease. Such agents include Carbegoline, bromocriptine, Cyproheptadine, valproic acid, and octreotide.

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. [32] Longer-term follow-up and a larger number of patients are needed to confirm these encouraging preliminary results.

An ongoing phase 3 study is being conducted to confirm long-term efficacy and safety of agent LCI699 for the treatment of patients with Cushing's disease. [33] LCI699 is a potent inhibitor of 11β-hydroxylase, which catalyzes the final step of cortisol synthesis. In a prior multicenter proof-of-concept 10-week study in which 12 patients were enrolled and completed the study, all 12 patients achieved urinary free cortisol level less than or equal to upper limit of normal or a 50% or greater decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. No serious side effects were reported. Common side effects were headache, fatigue, and nausea. [34]

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Surgical Therapy

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.

Other surgical interventions include the following:

  • Bilateral adrenalectomy
  • Unilateral adrenalectomy
  • Resection of carcinomas

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.

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. Lateralization of ACTH secretion via IPS catheterization and sampling is sometimes helpful in difficult cases.
  • Pituitary irradiation is employed when transsphenoidal surgery is not successful or not possible. The procedure is less successful than surgery in adults, with a 40-50% 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.
  • Individuals who undergo bilateral adrenalectomy might develop Nelson syndrome, which is symptomatic enlargement of the pituitary gland and adenoma. This 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.

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Consultations

Effective diagnosis and management of Cushing disease is often facilitated by involvement of an endocrinologist and the appropriate experienced neurosurgeon.

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