Approach

Do not start treatment until the diagnosis is firmly established and the source of hypercortisolism is recognized. Give patients with moderate to severe hypercortisolism therapy directed at the underlying cause. Resolution of cortisol excess in these cases has been shown to decrease mortality.[69][70]​ Weigh up the potential benefits and risk of therapy options in patients with only mild cortisol excess (biochemical evidence of hypercortisolemia but no clinical signs or symptoms of Cushing syndrome) because the benefit of surgery has not been definitively demonstrated.[52][53][71]

Cushing disease (pituitary adenoma)

Cushing disease is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumors. The ultimate goal of therapy is to remove the causative pituitary adenoma and normalize cortisol levels while preserving pituitary function.

First-line therapy is transsphenoidal (TSS) resection of the causative pituitary adenoma performed by an experienced surgeon.[26][69][72] Surgery can be done using an endoscopic or microscopic approach. Results are comparable between both techniques for microadenomas.[73] Whether there is potential incremental benefit with an endoscopic approach for macroadenomas remains unclear.[26][73]

[Figure caption and citation for the preceding image starts]: Algorithm for the treatment of Cushing disease (DST = dexamethasone suppression test. IPSS = inferior petrosal sinus sampling. ACTH = adrenocorticotropic hormone. *Pituitary surgery should be performed by an experienced surgeon. †Absence of ACTH-staining adenoma. §Lifelong monitoring for hypopituitarism and secondary neoplasia in the radiation field required. ¶On maximum tolerated dose of the drug)Fleseriu M et al. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75; used with permission [Citation ends].com.bmj.content.model.Caption@23f1e888

Many patients are supported with corticosteroids following pituitary surgery but should be assessed for remission during the first postoperative week.[71] This is done by measuring morning cortisol at least 24 hours after the last dose of corticosteroid therapy. Patients with a postoperative morning cortisol of <2 micrograms/dL are considered to be in remission and can transition into long-term follow-up. Patients with a postoperative morning cortisol of >5 micrograms/dL require further evaluation and possibly further therapy. Patients with a morning cortisol between 2 and 5 micrograms/dL should be followed with additional measurements to detect a drop in subsequent morning cortisol levels. Individuals with morning cortisols >2 micrograms/dL after surgery are 2.5 times more likely to have recurrences than those with cortisol levels <2 micrograms/dL.[74][75][76]

Postoperative hypocortisolism is predictive of remission, hence some centers advocate withholding routine corticosteroid therapy after pituitary surgery and monitoring cortisol levels every 8 hours or if symptoms of adrenal insufficiency occur.[77] If adrenal insufficiency occurs or low cortisol levels are documented, corticosteroid therapy is initiated. Other centers begin routine corticosteroid therapy immediately after surgery and evaluate for remission of hypercortisolism later in the postoperative course.[78] Corticosteroids are usually rapidly tapered to physiologic doses within 1 week or less (often by discharge from the hospital). Testing to see if the hypothalamic-pituitary-adrenal (HPA) axis has recovered can be done in follow-up by 3 months after surgery. Testing is usually a morning cortisol prior to the patient taking the morning hydrocortisone dose, if hydrocortisone therapy had been continued. Cortisol levels of >20 micrograms/dL indicate recovery of the axis. Levels <3 micrograms/dL indicate a continued need for corticosteroids. Levels between 3 micrograms/dL and 20 micrograms/dL should prompt further testing (cosyntropin stimulation testing, insulin tolerance testing, or metyrapone testing). Once recovery of HPA axis has been established, patients need to undergo testing for possible recurrence. Salivary cortisol testing seems to be a better predictor of early recurrence.[76][79]

Additional therapy should be considered in patients with failure of initial pituitary surgery or with recurrence of disease. The incidence of recurrence in Cushing disease is high, with 50% of recurrences occurring during the first 50 months after first surgery.[80] Standard therapies include repeat pituitary surgery, radiation therapy, bilateral adrenalectomy, or medical therapy.[72][81]

Success rates of these treatment options vary between 25% (for some of the medical therapies) and 100% (bilateral adrenalectomy). Treatment options have specific advantages, limitations, and side-effects so treatment decisions should be individualized according to the specific needs of the patient and risk of complications.[80][82]

Re-operation is frequently the preferred therapy if initial surgery fails. It should be considered in all patients with recurrence or persistence of disease. It is effective in about two-thirds of patients.[83][84][85] However, the risk of pituitary deficiency after re-operation is 50%. This is significantly higher than after initial surgical therapy.[83] If re-operation is ineffective, or if a patient is not a candidate for re-operation, another modality should be considered.

Radiation therapy by conventional fractionated radiation therapy or stereotactic radiosurgery is most commonly used in patients with persistent hypercortisolism after incomplete corticotroph tumor resection, particularly if the tumor is aggressive or invasive or considered unresectable.[26] Radiation therapy allows for control of hypercortisolism within 3 to 5 years in over half of patients.[86][87][88][89][90] This modality is perhaps best used as part of the therapy for patients with mild residual hypercortisolism, as full effects of therapy can take several years to be realized. Radiation of tumors located close to the optic chiasm increases the risk of damage to the optic chiasm, and this risk should be considered prior to therapy. Hypopituitarism can also occur following radiation therapy and is another risk to consider prior to initiating therapy. The exact risk of hypopituitarism after conventional fractionated radiation therapy versus stereotactic radiosurgery is unclear, but they seem similar.

Patients with unsuccessful re-operation who manifest severe hypercortisolism should be evaluated for therapy with medical therapy, bilateral adrenalectomy, or a combination of these therapies. The advantage to these approaches is the rapid onset of decreased cortisol levels or blockade of cortisol action.

Medical treatment with a somatostatin analog (pasireotide), a dopamine agonist (cabergoline), a steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate), or a glucocorticoid receptor antagonist (mifepristone) has been increasingly used in clinical practice. Medical therapy is indicated to control cortisol secretion in patients with mild hypercortisolism, as a short term adjunct for severe hypercortisolism before other therapies are undertaken, preoperatively to bridge the time period until control of hypercortisolism is achieved by radiation therapy, in cases with persistent or recurrent hypercortisolism after surgery, or where surgery is declined or not feasible (e.g., high surgical risk, metastatic disease).[91][92][93][94] However, there is a paucity of high-quality studies of medical therapy in Cushing disease, and caution should be employed when comparing efficacy rates owing to the variability in study design and quality.[94] Individualize medical therapy for patients with Cushing disease based on the clinical scenario, including the severity of hypercortisolism.[26] In patients with severe disease, treat aggressively to normalize cortisol concentrations (or cortisol action). Use multiple serial tests of both urinary free cortisol and late-night salivary cortisol to monitor treatment outcomes.

  • Pasireotide is a somatostatin analog that selectively targets somatostatin receptors in corticotroph adenomas and is now being used to medically treat Cushing disease.[92][93] Pasireotide binds to a wide variety of somatostatin receptors, but with greater affinity to receptor 5, which is predominantly expressed in patients with corticotroph adenomas. The use of the regular-release formulation of pasireotide has been shown to decrease cortisol levels in most patients with Cushing disease, but only normalizes cortisol levels in 25% of patients.[95] The long-acting formulation of pasireotide showed normalization in approximately 40% of patients, but hyperglycemia was noted in up to 80% of patients.[96] In one study, tumor shrinkage was noted in 62.5% of patients after 6 months of pasireotide treatment.[97] Salivary cortisol also decreased after treatment; thus, salivary cortisol may be a more convenient biomarker to follow in assessing response to treatment in patients with Cushing disease.[98] One 10-year single-center experience with pasireotide reported sustained biochemical and clinical benefit in about 60% of patients with Cushing disease.[99] This is a pituitary-targeted therapy and should only be used in patients with hypercortisolism due to ACTH-secreting pituitary tumors.[100] There is a high risk of hyperglycemia, which requires careful patient selection, and a risk of QTc prolongation.[26]

  • Cabergoline, a dopamine agonist, has been used off-label in the treatment of Cushing disease in some countries with limited results.[92][93][101]

  • Steroidogenesis inhibitors (agents that decrease adrenal corticosteroid production, such as osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate) can be used (though off-label in some countries, except osilodrostat) in the treatment of Cushing syndrome.[26][92][93]

    • Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase) that is approved in the US for the treatment of Cushing disease in patients where pituitary surgery is not an option or has not been curative, and in Europe and Japan for the treatment of endogenous Cushing syndrome.[26][102] Osilodrostat rapidly reduces urinary free cortisol with associated improvements in clinical signs of hypercortisolism, and is generally well tolerated.[102] There is a risk of hypocortisolism, hypokalemia, and QTc prolongation; careful monitoring for hyperandrogenism is needed in women.[26]

    • Ketoconazole has a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause idiopathic severe liver injury and adrenal insufficiency.[93][103][104] Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104]

    • Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107]

    • Metyrapone provides rapid onset of inhibition and can be obtained for compassionate use in the US.

    • Mitotane has adrenostatic and adrenolytic properties, but has delayed efficacy due to slow onset of action and a narrow therapeutic window.[93] It is rarely used for Cushing syndrome due to causes other than adrenal carcinoma.

    • Etomidate is a potent adrenostatic agent with a rapid onset of action. It is used only in emergencies (e.g., hypercortisol-induced psychosis), and must be given intravenously.[93]

  • Mifepristone, a glucocorticoid receptor antagonist, blocks the effect of cortisol at the receptor level and should be considered in patients who have clinical and metabolic derangements of continued hypercortisolism with hyperglycemia and/or diabetes. The US Food and Drug Administration has approved mifepristone for the treatment of hyperglycemia associated with Cushing syndrome in patients with type 2 diabetes mellitus. Cortisol and ACTH levels may increase with the use of mifepristone due to feedback inhibition.[108] As such, cortisol levels should not be used to guide therapy in patients treated with mifepristone.[109]

Bilateral adrenalectomy provides an immediate cure to any cause of endogenous hypercortisolism, at the expense of causing permanent adrenal insufficiency (requiring cortisol and mineralocorticoid replacement) and creating a risk of Nelson syndrome (corticotroph tumor growth after adrenalectomy). This progression can cause hyperpigmentation from excessive ACTH and intracranial compressive symptoms from growth of the tumor outside the sella. Newer laparoscopic methods of adrenalectomy allow for more rapid recovery and tolerability.[110] One meta-analysis of 37 studies (1320 patients, 82% with Cushing disease, 13% with ectopic Cushing syndrome, and 5% with primary adrenal hyperplasia) showed that bilateral adrenalectomy is relatively safe and provides adequate success.[111] Although residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in up to 34% of patients, less than 2% had a relapse of Cushing syndrome. Symptoms of hypercortisolism (e.g., hypertension, obesity, or depression) improved in the majority of the patients after bilateral adrenalectomy. The number of adrenal crises per 100 patient years was 9.3, and Nelson syndrome occurred in 21% of the patients. Excess mortality within the first year after surgery suggests that intensive clinical care for patients after bilateral adrenalectomy is warranted.

For replacement of non-glucocorticoid pituitary hormones following pituitary surgery (any combination of deficiencies may occur):[112]

  • Levothyroxine is used to achieve a free T4 in the upper half of the normal range. A thyroid-stimulating hormone should not be used to guide therapy.

  • Testosterone therapy is used to achieve a testosterone level in the normal range.

  • Women with an intact uterus taking estrogen replacement also need 10 days of progestin each month in addition to estrogen replacement therapy.

  • Decision to treat with growth hormone should be individualized for each patient based on symptoms, benefits, and risk of therapy. Dose titration should occur every month to achieve clinical response (i.e., energy level, sense of well-being, and lean body mass) and an insulin-like growth factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

  • Desmopressin is titrated to control symptomatic excessive urine output. This is based on patient preference. Serum sodium and symptoms are monitored periodically to evaluate adequacy of treatment.

ACTH-independent Cushing syndrome

The most common cause of adrenal cortisol overproduction is a unilateral autonomous adrenal adenoma. First-line therapy is almost always unilateral adrenalectomy of the affected adrenal gland. Laparoscopic adrenalectomy is the preferred method in most cases. Removal of the affected adrenal gland is curative in all patients with unilateral adrenal disease. Adrenalectomy has a beneficial effect on cardiovascular risk factors in patients with subclinical Cushing syndrome overall and compared with conservative management.[113]

Rare causes of ACTH-independent disease generally cause bilateral adrenal disease from autonomous nodule formation or bilateral hyperplasia.[19][92] In these cases first-line therapy generally requires bilateral adrenalectomy. Steroidogenesis inhibitor therapy (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate), or a glucocorticoid receptor antagonist (mifepristone) can be used for patients who wish to avoid bilateral adrenalectomy.[19][93][114] Osilodrostat rapidly reduces urinary free cortisol with associated improvements in clinical signs of hypercortisolism, and is generally well tolerated.[26][102] Ketoconazole has a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] Metyrapone provides rapid onset of inhibition and can be obtained for compassionate use in the US. Mitotane has slow onset of action, has a narrow therapeutic window, and is generally only used in adrenal carcinoma.[72] Etomidate, used only in emergencies, has rapid onset but must be given intravenously.[72] Mifepristone blocks cortisol action, resulting in attenuation of cortisol effects.

Adrenal carcinoma is an exceedingly rare cause of ACTH-independent Cushing syndrome. First-line therapy in many patients is surgical resection; however, at the time of diagnosis the disease has often progressed beyond the point where surgical therapy is effective. The effectiveness of chemotherapy and adjunctive therapies in both early- and late-stage disease has shown mixed results in clinical trials; however, patients should be considered for treatment with mitotane and enrollment in clinical trials (if available).[10]

Ectopic ACTH syndrome

The optimal first-line therapy involves locating and surgically resecting the ACTH-producing tumor. Not infrequently, complete resection of these tumors is not possible. Where surgical resection is not possible, second-line therapies include a glucocorticoid receptor antagonist (mifepristone), steroidogenesis inhibitor therapy (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate), or bilateral adrenalectomy.[92] Bilateral adrenalectomy is definitive therapy, but patients with ectopic ACTH-producing tumors may have extremely severe hypercortisolism, and require reduction in cortisol before proceeding to surgery. In these cases, mifepristone or steroidogenesis inhibitor therapy can be used to block cortisol action or lower cortisol levels in preparation for bilateral adrenalectomy. Osilodrostat rapidly reduces urinary free cortisol with associated improvements in clinical signs of hypercortisolism, and is generally well tolerated.[26][102] Ketoconazole has a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[104] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the US.[105][106][107] Metyrapone provides rapid onset of inhibition and can be obtained for compassionate use in the US. Mitotane has slow onset of action, has a narrow therapeutic window, and is generally only used in adrenal carcinoma.[72] Etomidate, used only in emergencies, has rapid onset but must be given intravenously.[72] Mifepristone blocks cortisol action, resulting in attenuation of cortisol effects.

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