Version July 2025
INTRODUCTION —
The hypercortisolism of Cushing syndrome is primarily treated surgically whenever possible, regardless of its cause (ie, whether due to a corticotropin [ACTH]-producing pituitary tumor [Cushing disease], ectopic ACTH secretion by a nonpituitary tumor, or cortisol secretion due to an adrenal adenoma, bilateral adrenal hyperplasia, or adrenal carcinoma). However, when surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required. Medical therapies for Cushing syndrome can be divided into three broad categories based on the following mechanisms of action:
●Decrease cortisol production
●Antagonize the action of cortisol at the glucocorticoid receptor, or
●Target the specific etiology of Cushing syndrome
The pharmacologic management of hypercortisolemia in Cushing syndrome due to adrenal adenoma, corticotroph tumor (Cushing disease), or ectopic ACTH-secreting tumors will be reviewed here. An overview of the treatment options for Cushing syndrome, including surgical management, is presented separately. (See "Overview of the treatment of Cushing syndrome".)
Medical treatment for Cushing syndrome due to bilateral adrenal hyperplasia and adrenal carcinoma is also discussed elsewhere.
●(See "Cushing syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Treatment'.)
●(See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Treatment'.)
●(See "Treatment of adrenocortical carcinoma".)
INDICATIONS —
The primary indications for medical therapy of Cushing syndrome are in the following settings (see "Overview of the treatment of Cushing syndrome"):
●Surgery is delayed or contraindicated. Although the hypercortisolism of Cushing disease or primary adrenal Cushing syndrome is optimally treated surgically, medical therapy may be used to normalize cortisol if surgery is delayed or contraindicated.
●Hypercortisolism persists or recurs after initial surgery. In this setting, repeat surgery is generally preferred, but medical therapy may be needed for unresectable disease.
●Severe or malignancy-related hypercortisolism. Medical therapy may be needed as emergency treatment to manage life-threatening hypercortisolism. If severe hypercortisolism markedly increases surgical risk, medical therapy may be needed to control hypercortisolism prior to surgery.
●After pituitary irradiation in patients with corticotropin (ACTH)-secreting pituitary tumors (Cushing disease). Maximum benefit of irradiation is not achieved for months to years, and interim control of hypercortisolism is needed. (See "Overview of the treatment of Cushing syndrome", section on 'Pituitary irradiation'.)
●Ectopic ACTH syndrome with occult or nonresectable tumors and/or metastatic disease. (See "Overview of the treatment of Cushing syndrome", section on 'Ectopic ACTH and CRH syndromes'.)
Our approach is largely consistent with the Endocrine Society Clinical Practice Guideline [1].
CONSIDERATIONS FOR CHOOSING AN INITIAL REGIMEN
Patient-based considerations
●Patients' goals, preferences, and comorbid conditions – Patient-based factors that may influence the approach to initial therapy include the following:
•Preference for oral versus injectable route of administration
•Willingness to adhere to multiple daily medication doses
•Impaired cognition (eg, affecting adherence to more complicated dosing regimens)
•Desire for rapid symptom improvement
●Variability in cortisol hypersecretion – Prior to choosing an initial regimen, 24-hour urinary free cortisol (UFC) should be measured several (ie, at least three) times to determine the degree of variability of cortisol production. In patients with highly variable cortisol production, fixed-dosing regimens may result in oscillation between adrenal insufficiency and inadequate control of hypercortisolism. In such individuals, a "block and replace" strategy should be used in which the medication dose is titrated to completely block cortisol secretion, with the addition of a physiologic exogenous glucocorticoid dose to "replace" cortisol. (See 'Replacement glucocorticoid therapy' below.)
Although no studies have identified criteria for "high" variability, one approach is to look at the percentage or fold changes in at least three pretreatment UFC values. For a fixed-dose regimen, a UFC variability criterion of no more than twofold is likely optimal. For example, ideal dosing would achieve UFC values of 20 to 60 mcg/day (within and slightly above the reference range of approximately 5 to 50 mcg/day). If the pretreatment UFC values differ by threefold, risks of both adrenal insufficiency and undertreatment increase. Thus, a result of 20 mcg/day with threefold variability suggests on-treatment UFC values between 0 to 60 mcg/day, risking adrenal insufficiency. Conversely, a target UFC value of 50 would suggest possible results between 17 to 150 mcg/day, risking undertreatment.
Medication-based considerations
●The cause of Cushing syndrome – Some agents are used only for pituitary Cushing or ectopic ACTH-secreting tumors.
●Likelihood of long-term normalization of signs and symptoms – Some agents are more effective when hypercortisolism is mild. Others may effectively mitigate hypercortisolism but have an adverse side-effect profile that prevents their use or limits long-term use.
●The likelihood of adrenal insufficiency.
●Drug-drug interactions. (See 'Pretreatment evaluation and drug-drug interactions' below.)
●Cost. Drug costs may vary widely across agents and may differ by region. Some options are extremely expensive.
INITIAL TREATMENT REGIMEN
Approach to treatment — The selection of an initial treatment regimen is influenced by both the etiology and severity of hypercortisolism.
Corticotroph tumor — The preferred approach to recurrent hypercortisolism due to a corticotroph tumor (Cushing disease) is repeat transsphenoidal surgery (algorithm 1). If surgery is not an option or preoperative control of hypercortisolism is needed, options for medical therapy include adrenal steroidogenesis inhibitors and corticotroph tumor-targeted treatments. A glucocorticoid receptor antagonist is also an option in some countries including the United States for patients with diabetes in whom surgery is not possible (table 1). (See 'Persistent hyperglycemia' below.)
●Mild hypercortisolism – For milder hypercortisolism (eg, urinary free cortisol [UFC] values ≤2 times the upper limit of the reference range), drugs that target a corticotroph tumor are a reasonable initial option. Occasionally, these agents might be adequate as monotherapy even in individuals with more severe hypercortisolism. (See 'Drugs that target corticotroph tumors' below.)
●Moderate hypercortisolism – For moderate hypercortisolism (eg, UFC values >2 and <10 times the upper limit of the reference range), adrenal steroidogenesis inhibitors are used most commonly as first-line treatment, and options are the same as those for treating other causes of Cushing syndrome. (See 'Adrenal steroidogenesis inhibitors' below.)
●Severe hypercortisolism – For severe hypercortisolism (eg, UFC values ≥10 times the upper limit of the reference range), initial use of combination therapy (two steroidogenesis inhibitors, or a steroidogenesis inhibitor and a pituitary-directed agent) is a reasonable approach. Alternatively, a steroidogenesis inhibitor may be used as initial monotherapy and other agent(s) added as needed. (See 'Severe or refractory hypercortisolism' below.)
Adrenal Cushing syndrome — The primary treatment strategy for overt Cushing syndrome due to adrenal adenoma is unilateral adrenalectomy. However, for rare individuals in whom surgery is contraindicated or delayed, medical therapy may be needed to control hypercortisolism. In this setting, treatment options are limited to adrenal steroidogenesis inhibitors. (See 'Adrenal steroidogenesis inhibitors' below.)
Medical treatment for Cushing syndrome due to bilateral adrenal hyperplasia and adrenal carcinoma is discussed elsewhere.
●(See "Cushing syndrome due to primary bilateral macronodular adrenal hyperplasia", section on 'Treatment'.)
●(See "Cushing syndrome due to primary pigmented nodular adrenocortical disease", section on 'Treatment'.)
●(See "Treatment of adrenocortical carcinoma".)
Ectopic ACTH-secreting tumor — In individuals with ectopic corticotropin (ACTH)-secreting tumors that cannot be surgically resected, adrenal steroidogenesis inhibitors are most often used to manage hypercortisolism. However, other therapies also have been used, including chemotherapy, kinase inhibitors, cabergoline, and octreotide. (See 'Adrenal steroidogenesis inhibitors' below and 'Drugs that target an ectopic ACTH-secreting tumor' below.)
Pretreatment evaluation and drug-drug interactions — Several agents used for medical management of hypercortisolism confer risks requiring pretreatment assessments and/or attention to potential drug interactions (table 1).
●Pretreatment assessments
•Liver function and biochemical tests – Liver function and biochemical tests should be performed before initiating ketoconazole or levoketoconazole. These drugs are contraindicated in patients with acute or poorly controlled chronic liver disease whose alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values are ≥3 times the upper reference range. Patients with elevated values <3 times the upper reference range often have cortisol-induced steatohepatitis that improves with treatment of hypercortisolism.
•Risk of QT interval prolongation – Levoketoconazole, ketoconazole, pasireotide, mifepristone, and osilodrostat can cause QT interval prolongation (table 2). Levoketoconazole is considered a high-risk agent. All patients should undergo electrocardiogram (ECG) and assessment for risk factors for QT prolongation before treatment initiation. Individual risk assessment is reviewed in detail separately. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'Precautions for any patient starting QT-prolonging drugs'.)
QTc-associated and metabolic interactions should be assessed by use of the drug interactions program included with UpToDate. Concomitant administration of agents that confer high risk of QT prolongation (such as cisapride, methadone, quinidine) is contraindicated for levoketoconazole, particularly if these other agents are CYP3A4 substrates; such combinations may synergize to cause life-threatening ventricular arrhythmia (table 2) [2]. If any doubt persists about the safety of medical therapy, cardiology consultation is warranted.
●Drug-drug interactions
•Concomitant medications
-Proton pump inhibitors – Ketoconazole and levoketoconazole both require an acidic environment for maximal bioavailability, which may be reduced as much as 50 percent if given with a proton pump inhibitor [3]. Proton pump inhibitors therefore should be discontinued whenever possible if ketoconazole or levoketoconazole is used. While we are not aware of reports of reduced efficacy in older individuals (who may have reduced stomach acidity), it is reasonable to consider this possibility if ketoconazole or levoketoconazole is not effective in older patients.
-CYP3A4 substrates – Ketoconazole, levoketoconazole, and mifepristone are strong inhibitors of CYP3A4. Coadministration of CYP3A4 substrates should be avoided if possible and may result in increased plasma concentrations of these drugs, with increased or prolonged therapeutic or adverse effects (table 3). For example, coadministration of certain ergot derivatives, anticoagulants, lovastatin, and alprazolam may result in dangerously elevated blood levels of those agents and is contraindicated [2]. However, coadministration of an anticoagulant may be possible if treatment is monitored carefully. (See "Clinical use of coagulation tests".)
Patients receiving ketoconazole, levoketoconazole, or mifepristone should have their medication regimen analyzed carefully for drug interactions particularly when initiating and adjusting therapy; this may be done by use of the drug interactions program included with UpToDate.
•Combination therapy regimens – Drug-drug interactions should be carefully considered prior to initiating any combination therapy regimen and can be assessed using the drug interactions program included with UpToDate. (See 'Severe or refractory hypercortisolism' below.)
For example, levoketoconazole and ketoconazole are strong CYP3A4 inhibitors, and osilodrostat is a CYP3A4 substrate. All three agents can prolong the QT interval. Therefore, if used in combination with ketoconazole or levoketoconazole, osilodrostat requires dose reduction and close monitoring. For recommended dose adjustments, refer to drug information included with UpToDate.
Adrenal steroidogenesis inhibitors
Choice of initial agent — Ketoconazole, levoketoconazole, metyrapone, osilodrostat, and mitotane are orally active medications that inhibit one or more steps in cortisol synthesis (figure 1 and table 1). These are used most often as first-line therapy to control severe corticotropin (ACTH)-dependent cortisol excess or primary adrenal etiologies of hypercortisolism [4-8].
For patients with hypercortisolism in whom medical therapy with a steroidogenesis inhibitor is indicated, we suggest ketoconazole as initial therapy. Compared with other agents, ketoconazole is well tolerated and inexpensive, but it is not available in all countries. The most commonly used agent in the United States is ketoconazole and, in the United Kingdom, metyrapone. Apart from mitotane, which is usually reserved for treating adrenocortical carcinoma, any of the steroidogenesis inhibitors is a reasonable option for initial medical therapy. The choice of initial agent is principally informed by availability, predictability of cortisol lowering, side-effect profile, and cost. (See 'Considerations for choosing an initial regimen' above.)
Steroidogenesis inhibitors may be used as monotherapy or in combination therapy regimens when needed to manage severe or refractory hypercortisolism (table 1). (See 'Severe or refractory hypercortisolism' below.)
The steroidogenesis inhibitor etomidate is the only agent for intravenous use. (See 'Patients who are NPO' below.)
Ketoconazole
●Mechanism of action – Ketoconazole is a racemic mixture of L-form and D-form enantiomers that inhibits the first step in cortisol biosynthesis (side-chain cleavage) and, to a lesser extent, the conversion of 11-deoxycortisol to cortisol; it is an even more potent inhibitor of C17-20 desmolase, decreasing androstenedione, testosterone, and estradiol production (figure 1). At therapeutic doses, it also impairs corticotroph adenylate cyclase activation and ACTH secretion in vitro [9]. However, the contribution of this effect to its action in patients with Cushing disease has not been demonstrated.
●Clinical use and efficacy – Ketoconazole is used to treat hypercortisolism in patients with endogenous Cushing syndrome. For example, in a series of 200 patients with Cushing disease, 75 percent achieved either normal UFC levels (49 percent) or at least a 50 percent decrease in UFC, at a median final dose of 600 mg/day. However, 20 percent stopped the treatment due to poor tolerance [10]. In the United States, ketoconazole does not have regulatory approval and is used off-label to treat hypercortisolism.
●Adverse effects
•Reversible hepatotoxicity – Ketoconazole may cause reversible hepatotoxicity [10,11], and liver function and biochemical tests should be measured before and during treatment. (See 'Pretreatment evaluation and drug-drug interactions' above.)
ALT should be monitored weekly for the first month of treatment, monthly for three months, and less frequently thereafter. If ALT values increase to ≥3 times the upper reference range, we suggest stopping ketoconazole or reducing it to a previously well-tolerated dose.
In the study described above [10], mild (<5-fold normal values) and major (>5-fold normal values) increases in liver enzymes were observed in 13.5 and 2.5 percent of patients, respectively. In 2013, the US Food and Drug Administration (FDA) issued a warning about the risk of potentially fatal liver toxicity, even in patients without pre-existing hepatic disease [12], which was followed by a temporary withdrawal in European countries. The regulatory warnings were revised to discourage use of ketoconazole for management of fungal infections, and the drug is now widely available [13].
•Adrenal insufficiency – In individuals with endogenous Cushing syndrome, all the adrenal steroidogenesis inhibitors can cause adrenal insufficiency. (See 'Replacement glucocorticoid therapy' below.)
•Reduced sex steroid biosynthesis – Ketoconazole-induced decreases in estradiol and testosterone production may lead to gynecomastia, decreased libido, and impotence in men (those without Cushing-related hypogonadism). The effects of reduced sex steroid production are not usually clinically apparent in women because they are more likely to have hypogonadism (oligomenorrhea or amenorrhea) due to Cushing syndrome [14].
•Possible teratogenicity – Ketoconazole is teratogenic and toxic to animal embryos but has been used successfully and without harm to fetuses from as early as the seventh week of pregnancy [15,16]. However, ketoconazole is not the treatment of choice during pregnancy, because of the possibility of feminization of a male fetus. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Management'.)
•QT interval prolongation – Ketoconazole can prolong the QT interval. Consequently, an ECG should be performed before starting this agent and again after treatment initiation. The drug should not be initiated if the baseline QT interval is prolonged. (See 'Pretreatment evaluation and drug-drug interactions' above.)
Levoketoconazole
●Mechanism of action — Levoketoconazole, the pure L-form enantiomer of ketoconazole, reduces cortisol production just as ketoconazole does, by inhibiting CYP11B1 (11-beta-hydroxylase) and CYP11A1 (the cholesterol side-chain cleavage enzyme, the first step in the conversion of cholesterol to pregnenolone). It also inhibits CYP17A1 (17-alpha-hydroxylase), leading to decreased estradiol and testosterone production, and inhibits CYP3A4 with two to four times the potency of ketoconazole, so that drug-drug interactions must be considered carefully (table 3) [17,18].
●Clinical use and efficacy – Levoketoconazole is approved by the FDA for the treatment of endogenous hypercortisolemia in adult patients with Cushing syndrome when surgery is not an option or when it has not been curative. It is unavailable in some countries including Canada. Clinical trials have demonstrated normalization of 24-hour UFC in 49 percent (19 of 39) of participants with initial values of two to five times the upper limit of the reference range [19]; however, only 31 percent (29 of 94) of the entire group had this response, as patients with higher initial UFC values were less likely to respond. Patients also had improvement in quality of life, depression, and other signs of Cushing syndrome [20,21].
No trials have directly compared levoketoconazole with ketoconazole. However, it appears that the two agents have similar efficacy when UFC is elevated up to fivefold normal. Levoketoconazole has a longer half-life that allows for twice-daily administration; this is a potential advantage for patients who may be unable to adhere to the six- to eight-hour dosing interval for ketoconazole and metyrapone.
●Adverse effects – Like ketoconazole, levoketoconazole can cause reversible hepatotoxicity, adrenal insufficiency, and QT prolongation. Before and during treatment, an ECG should be performed, and liver function and biochemical tests should be measured. The drug should not be initiated if the baseline QT interval is prolonged. ALT should be monitored weekly for the first month of treatment, monthly for three months, and less frequently thereafter. If on-treatment ALT values increase to ≥3 times the upper reference range, we suggest stopping levoketoconazole or reducing it to a previously well-tolerated dose. (See 'Pretreatment evaluation and drug-drug interactions' above.)
It is not clear whether levoketoconazole causes less hepatic toxicity than ketoconazole. In the trial describe above, ALT elevation was evident in 39 of 94 patients (greater than three times the upper limit of normal in 10), dose-related QT interval prolongation in five, and adrenal insufficiency in three. (See 'Replacement glucocorticoid therapy' below.)
Metyrapone
●Mechanism of action – Metyrapone inhibits CYP11B1, leading to increases in 11-deoxycortisol, the immediate precursor of cortisol. It also inhibits CYP11B2, leading to increases in deoxycorticosterone, the immediate precursor of aldosterone (figure 2), which may cause salt retention and hypertension. Because of this enzymatic block, cortisol precursors are shunted into adrenal androgen production, which can cause hirsutism in women. (This mechanism is like that of the hyperandrogenism seen in congenital adrenal hyperplasia resulting from CYP11B2 genetic variants.)
●Clinical use and efficacy – Like ketoconazole, metyrapone is used off-label for treatment of endogenous Cushing syndrome. In the largest retrospective, multicenter series, 195 patients with Cushing syndrome (from all causes) were treated with metyrapone (as monotherapy in 84 percent) [22]. Complete normalization of cortisol secretion was achieved in approximately 50 percent of patients treated both short and long term. Among 38 patients treated long term (mean 18 months), 77 percent achieved complete normalization of cortisol secretion. Previous studies showed similar efficacy at doses of 500 to 750 mg three or four times a day. Metyrapone has been used in pregnancy with mixed efficacy [23-25].
Metyrapone is available in North America through its distributor AllianceRx Walgreens Pharmacy with order forms available on the web or by phone at 1-800-320-2112.
●Adverse effects – In the trial described above, metyrapone was generally well tolerated. The most common side effects were gastrointestinal upset (23 percent) and adrenal insufficiency (7 percent). (See 'Replacement glucocorticoid therapy' below.)
Hypokalemia, hypertension, and hirsutism were uncommon [22]. Despite the infrequent occurrence of hirsutism, some providers avoid long-term metyrapone use in women to avoid this adverse effect. Leukopenia is a rare adverse effect.
Osilodrostat
●Mechanism of action – Like metyrapone, osilodrostat blocks the 11-beta-hydroxylase enzymes (CYP11B1 and CYP11B2), thereby reducing the synthesis of aldosterone and cortisol [26].
●Clinical use and efficacy – In the United States, osilodrostat has regulatory approval for treating Cushing syndrome in adults who are not candidates for surgery or who have persistent disease after surgery [26-28].
•Cushing disease – The safety and efficacy of osilodrostat were evaluated in a six-month, single-arm, open-label study of 137 adults with Cushing disease who were either not surgical candidates or who had undergone noncurative transsphenoidal surgery. The starting dose of 2 mg twice daily could be increased by 1 to 2 mg every two weeks up to 30 mg twice/day. Its efficacy was similar to metyrapone; at the end of 24 weeks, approximately one-half of patients had 24-hour UFC levels less than or equal to the upper limit of the reference range [29].
In this same trial, 72 participants with normalization of 24-hour UFC at week 24, without up-titration after week 12, were eligible to enter an eight-week randomized trial of continued osilodrostat or placebo [30]. More patients maintained a complete response with osilodrostat than with placebo (86 versus 29 percent, respectively). The relatively high rate of continued response in the placebo group may reflect the potential for osilodrostat to confer prolonged suppression of adrenal steroidogenesis even after discontinuation [31].
•Ectopic ACTH secretion – Limited data support the efficacy of osilodrostat in patients with ectopic ACTH secretion [32-34]. In a retrospective study in 33 individuals with ectopic ACTH syndrome, osilodrostat was administered as first-line therapy (n = 11), second-line therapy (n = 13), or in combination with another steroidogenesis inhibitor (n = 9) [35]. When used as first-line therapy, osilodrostat monotherapy (median initial dose 10 mg daily) normalized 24-hour UFC in 9 of 11 patients (82 percent) with a median time to normalization of two weeks. In 10 individuals with persistent hypercortisolism on another enzyme inhibitor, osilodrostat monotherapy (median initial dose 4 mg daily) uniformly normalized 24-hour UFC (median 24-hour UFC 158 mcg [436 nmol] at baseline and 12 mcg [33 nmol] on osilodrostat). In the overall cohort, eight patients had at least one episode of acute adrenal insufficiency and one died of adrenal crisis.
●Adverse effects – Side effects of the drug include prolongation of the QT interval, nausea, headache, and adrenal insufficiency [27,30,36]. An ECG should be obtained prior to treatment initiation and during treatment. In contrast to metyrapone, hypocortisolism may persist after osilodrostat is discontinued [37]. In a case series of 25 patients with hypercortisolism successfully managed with osilodrostat, five patients experienced unplanned treatment interruptions [31]. In three of the five patients, hypocortisolism persisted at least four weeks after osilodrostat was discontinued, with a duration of up to nine months. Persistent hypocortisolism was evident in patients on both lower (2 mg) and higher (10 mg) daily doses of osilodrostat, underscoring the need for close monitoring and appropriate treatment of adrenal insufficiency. (See 'Pretreatment evaluation and drug-drug interactions' above and 'Replacement glucocorticoid therapy' below.)
Mitotane (rarely used)
●Mechanism of action – In addition to inhibiting adrenal enzymes, mitotane is adrenolytic. Mitotane inhibits mitochondrial CYP11B1 (11-beta-hydroxylase) and CYP11A1 (cholesterol side-chain cleavage) enzymes. A metabolite binds to macromolecules in the mitochondria, causing mitochondrial destruction and necrosis of adrenocortical cells [38]. Because of its adrenolytic action, it is used primarily for the treatment of adrenal carcinoma, which is discussed separately. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane' and 'Replacement glucocorticoid therapy' below.)
●Clinical use and efficacy – Mitotane is used primarily for the treatment of adrenocortical carcinoma and rarely for other causes of Cushing syndrome. Its use is generally confined to extremely severe, life-threatening cases of hypercortisolism. Mitotane can be used to achieve medical adrenalectomy with or without pituitary irradiation in patients with Cushing disease or as an adjunctive medication in patients with ectopic ACTH secretion [39-41]; however, it is rarely used for these purposes because of its adverse effects. Dosing in these settings begins with 0.5 g given at bedtime, adding single 0.5 g doses at a mealtime every week or so, as tolerated, to reach a maximal dose of 2 to 3 g/day. One-half of the total dose is taken at bedtime to reduce nausea. Thereafter, the concentrations are maintained by total doses of 1 to 2 g daily. At these doses, mitotane tends to spare the zona glomerulosa [42] such that mineralocorticoid replacement is not needed.
When given as adjunctive therapy after radiotherapy for Cushing disease, mitotane is stopped when UFC values normalize, on average after six to nine months. A sustained cure rate was reported in approximately 60 percent of cases at 5 to 15 years [39]. Similar findings were reported in a study of 46 patients treated with higher doses of mitotane but no pituitary irradiation [40]. In patients who do not undergo pituitary radiotherapy, mitotane treatment can lead to Nelson syndrome, although Nelson syndrome is less common after medical than surgical adrenalectomy. Monitoring for Nelson syndrome is reviewed separately. (See "Persistent or recurrent Cushing disease: Surgical bilateral adrenalectomy", section on 'Monitor for Nelson syndrome'.)
Mitotane markedly increases corticosteroid-binding globulin (CBG) levels, so serum cortisol levels cannot be used to monitor efficacy. (See 'Dose adjustments and monitoring' below.)
●Adverse effects – The major side effects are nausea, vomiting, and anorexia. Mitotane can cause adrenal insufficiency with both cortisol and mineralocorticoid deficiency. Rarer side effects include leukopenia and anemia. Mitotane treatment requires close monitoring (table 4) [43]. Additional side effects that occur with the higher doses used for adrenal carcinoma are discussed separately. (See 'Replacement glucocorticoid therapy' below and "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane'.)
Mitotane is taken up by adipose tissue and persists in plasma long after the drug is discontinued [44]. Mitotane is teratogenic and should not be given to pregnant women; women anticipating pregnancy should have mitotane levels measured after its discontinuation to ensure that it is safe to proceed with conception [45].
Risk of adrenal insufficiency — Steroidogenesis inhibitors do not usually cause adrenal insufficiency in healthy people with normal hypothalamic-pituitary-adrenal function [46] but can do so in Cushing syndrome patients due to suppression of the normal corticotrophs by hypercortisolism. (See 'Replacement glucocorticoid therapy' below.)
Consequently, all patients initiating treatment with a steroidogenesis inhibitor should be provided with emergency injectable glucocorticoid (eg, 100 mg vials of hydrocortisone), along with needles and syringes for injection, as well as a supply of hydrocortisone tablets. Patients should be instructed to use emergency glucocorticoid treatment if they develop symptoms concerning for acute cortisol deficiency or experience major physiologic stress. Indications for emergency glucocorticoid use are reviewed in detail separately. (See "Treatment of adrenal insufficiency in adults", section on 'Emergency precautions'.)
Dose adjustments and monitoring — Unless mitotane is given in adrenolytic doses, adrenal steroidogenesis inhibitors do not permanently cure hypercortisolism, which recurs when the drug is discontinued. As a result, these medications must be continued indefinitely until definitive treatment is complete (eg, bilateral adrenalectomy, tumor excision, or therapeutic effect of pituitary radiotherapy) (table 1).
●Baseline cortisol measurement – Prior to treatment initiation, baseline measurement of 24-hour UFC should be performed. Additional assessments depend on whether late-night salivary cortisol and/or serum cortisol level also will be used for treatment monitoring.
•UFC with or without late-night salivary cortisol – UFC is used most often for monitoring medical therapy. In two analyses in patients with Cushing disease treated with medical therapy, the greatest improvement in clinical parameters of hypercortisolism was evident when mean values for both UFC and late-night salivary cortisol were below the upper limit of the reference range [47,48]. Notably, this analysis found substantial intra-individual variability in both metrics and used the mean of three UFC values or two late-night salivary cortisol values to assess treatment response.
•Serum cortisol – Serum cortisol is an option for monitoring treatment with any steroidogenesis inhibitor except mitotane. At the outset of treatment with steroidogenesis inhibitors, we measure a morning serum cortisol level on the day that a 24-hour urine collection is returned for UFC measurement. This allows the two results to be correlated, so subsequent monitoring can entail morning serum cortisol measurement only and avoid the inconvenience of repeated urine collections. If serum cortisol levels are used to monitor treatment, they should be correlated with urinary cortisol excretion, both at baseline and after any dose adjustments.
UFC is necessary for monitoring treatment with mitotane. Mitotane increases CBG levels, so on-treatment serum cortisol levels increase and do not reliably reflect biologically active free levels [49].
●Treatment targets – Medication dose adjustments are based on target values for serum cortisol and/or 24-hour UFC and late-night salivary cortisol. Treatment targets depend in part on whether the treatment strategy involves near-normalization of cortisol levels or a "block and replace" strategy, in which the goal is to completely suppress endogenous cortisol production and provide cortisol replacement therapy.
•Fixed-dose schedule – For patients with relatively invariant cortisol production, a fixed-dose schedule can be used with the goal of "normalization" of cortisol. A serum cortisol target of 7 to 12 mcg/dL (193 to 331 nmol/L) can be used as an alternative or if awaiting a UFC result. (This range reflects the mean cortisol value over 24 hours in a healthy person and assumes that patients with Cushing syndrome lose diurnal variation in cortisol secretion.) The goal for 24-hour UFC is a value in the middle to slightly above the upper limit of the reference range. While this approach minimizes the chance of adrenal insufficiency, patients nevertheless should receive education about signs and symptoms of adrenal insufficiency and how to administer emergency doses of glucocorticoid. (See "Treatment of adrenal insufficiency in adults", section on 'Patient education and safety'.)
•Block and replace – For patients requiring a "block and replace" strategy, the medication dose is progressively increased until serum or urine cortisol is in the low normal range (outpatients) or undetectable (inpatients), at which time a glucocorticoid is added for cortisol replacement. For patients with detectable cortisol levels, the steroidogenesis inhibitor dose is then increased further until serum or urine cortisol values are very low or undetectable. (See 'Replacement glucocorticoid therapy' below.)
●Frequency of monitoring and dose adjustment
•Ketoconazole and metyrapone – Doses of ketoconazole and metyrapone can be increased every three to seven days based on serum cortisol and/or 24-hour UFC.
Metyrapone administration increases 11-deoxycortisol, which may cross-react with the antibodies in some cortisol immunoassays, while tandem mass spectrometry results are not affected [50]. If urine or serum cortisol measurement by tandem mass spectrometry is not available, a cortisol immunoassay that does not cross-react with 11-deoxycortisol should be used.
•Osilodrostat – In clinical trials, the osilodrostat dose was adjusted every two weeks; this dose adjustment period is recommended in the FDA label. Like metyrapone, osilodrostat administration increases 11-deoxycortisol; therefore, urine or serum cortisol should be measured by tandem mass spectrometry. If such assays are not available, a cortisol immunoassay that does not cross-react with 11-deoxycortisol should be used.
•Mitotane – In the absence of very severe or life-threatening hypercortisolism, doses of mitotane are generally increased more slowly, due to its long half-life. However, in severe hypercortisolism, mitotane may be given in higher doses in combination with other agents [51]. (See 'Principles of combination therapy' below.)
After an optimal dose of any steroidogenesis inhibitor has been achieved, monitoring may occur less often, usually monthly and occasionally less frequently.
Long-term monitoring for Nelson syndrome (Cushing disease only) — All patients with Cushing disease who are on long-term therapy with steroidogenesis inhibitors require surveillance for Nelson syndrome, a disorder of corticotroph tumor progression. Tumor progression has been reported with use of steroidogenesis inhibitors including mitotane and osilodrostat [52,53]. (See "Persistent or recurrent Cushing disease: Surgical bilateral adrenalectomy", section on 'Monitor for Nelson syndrome'.)
Drugs that target corticotroph tumors — The somatostatin analog, pasireotide, and the dopamine agonist, cabergoline, have shown benefit against corticotroph tumors (table 1); other agents that are not effective include bromocriptine, cyproheptadine, and valproate.
Cabergoline
●Mechanism of action – Cabergoline is a long-acting dopamine D2 receptor agonist.
●Clinical use and efficacy – Cabergoline may be most effective when Cushing disease is associated with UFC values up to twice normal; however, cabergoline monotherapy may be sufficient to manage more severe hypercortisolism [54].
In two studies, chronic cabergoline therapy (1 mg once weekly to 1 mg daily) decreased 24-hour UFC to ≤125 percent of normal in 12 of 42 patients with Cushing disease [55,56]. Normalization of UFC was achieved in 30 percent of patients with up to five years of follow-up [56]. A meta-analysis found that patients with milder hypercortisolism were more likely to respond [57]. Cabergoline also has been used in a small number of pregnant women with good outcomes [58]. Treatment "escape" has been described during cabergoline therapy as patients who achieve an initial therapeutic response may experience recurrent hypercortisolism during treatment [59].
●Adverse effects – Cabergoline is generally well tolerated. In the two studies above, gastrointestinal side effects, particularly nausea (14 percent), and dizziness were most common; severe adverse effects included adrenal insufficiency and hypotension. In one multicenter study, approximately 10 percent of patients taking cabergoline monotherapy developed adrenal insufficiency [54].
Pasireotide
●Mechanism of action – The somatostatin analog pasireotide binds to somatostatin receptors and blocks the release of corticotropin (ACTH) from the corticotrophs via its high affinity for somatostatin receptor subtype 5 [60].
●Clinical use and efficacy – Pasireotide injection has regulatory approval in the United States, Europe, Canada, and parts of Asia and South America and is recommended for the treatment of patients with Cushing disease for whom surgery has been unsuccessful or who are not surgical candidates [1,61]. It is available as a short-acting subcutaneous preparation for twice-daily use and as a once-monthly intramuscular (IM) injection.
In a study of 162 patients with Cushing disease receiving subcutaneous pasireotide (0.6 or 0.9 mg twice daily for six months), 24-hour UFC decreased by a mean of 48 percent in the whole group and normalized in 21 of 80 (26 percent) and 12 of 82 (15 percent) of those receiving the 0.9 and 0.6 mg dose, respectively [62]. Patients who achieved UFC control also experienced other clinical improvements, including a decrease in total and low-density lipoprotein cholesterol [63]. Reductions in blood pressure and body mass index occurred even without normalization of UFC.
A sustained response for up to five years has been reported in three individuals [64,65]. A long-term study of 53 patients showed a tumor volume reduction of at least 20 percent at 6 and 12 months. Reduction in tumor size was more common in those taking the 0.9 mg than the 0.6 mg subcutaneous dose (75 and 89 percent versus 44 and 50 percent, respectively) [66].
In a trial of 150 patients receiving either 10 or 30 mg once-monthly IM pasireotide for 12 months, approximately 40 percent in each group reached the primary endpoint (UFC value less than or equal to upper limit of the reference range by seven months) [67].
●Dosing and monitoring – The recommended initial dose of the short-acting formulation is 0.6 mg subcutaneously twice daily, which may be increased to 0.9 mg twice daily if UFC does not normalize after one to two months of therapy. If there is no clinical response to 0.9 mg, a different agent should be started, or combined therapy should be considered. (See 'Severe or refractory hypercortisolism' below.)
The recommended starting dose for once-monthly, IM pasireotide is 10 mg. The monthly preparation may be useful for patients who have difficulty remembering to take medications.
●Adverse effects – Pasireotide can cause hyperglycemia, gastrointestinal side effects, and adrenal insufficiency [68]. Pasireotide also can cause QT interval prolongation. (See 'Pretreatment evaluation and drug-drug interactions' above.)
The most common side effect of pasireotide is hyperglycemia, which can manifest as overt diabetes. Due to the high rate of hyperglycemia, patients with diabetes require close monitoring during pasireotide treatment and may need intensified glucose-lowering therapy. The initial pasireotide warning and precaution for hyperglycemia and diabetes has been updated to include ketoacidosis [69]. Nonetheless, with clinical and biochemical reversal of hypercortisolism, pasireotide-associated hyperglycemia can remit [65]. Pasireotide promotes hyperglycemia through decreases in both insulin secretion and incretin hormone responses (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), but pasireotide does not affect hepatic/peripheral insulin sensitivity [70].
In the study above in 162 patients with Cushing disease, hyperglycemia occurred in 118 patients (73 percent) and 74 of 118 patients (63 percent) required initiation of a glucose-lowering medication. In the trial of IM pasireotide in 150 patients, adverse events included hyperglycemia (47 to 49 percent), diarrhea (35 to 43 percent), gallstones (20 to 45 percent), and type 2 diabetes (19 to 24 percent). In an open-label extension study that enrolled 81 of the 150 patients, the safety profile was similar to that reported in the first 12 months [71].
Other side effects are like those of other somatostatin analogs (eg, gastrointestinal symptoms and gallstones). (See "Treatment of acromegaly".)
Drugs that target an ectopic ACTH-secreting tumor
●Chemotherapy – Chemotherapy may reduce corticotropin (ACTH) and cortisol levels in patients with ectopic ACTH secretion due to carcinoid tumors or small cell lung cancer [72,73]. However, chemotherapy confers risks of both an acute rise in ACTH (and hence cortisol) [73] and adrenal insufficiency.
●Other treatment options – Targeted treatment with kinase inhibitors has been effective in some patients with ectopic ACTH-dependent hypercortisolism due to medullary thyroid cancer [74-76]. A few patients have been successfully treated with octreotide and/or cabergoline [77-79]. However, these data are confined to case reports or small series, and the overall efficacy of these approaches is not known. (See "Overview of the treatment of Cushing syndrome", section on 'Ectopic ACTH and CRH syndromes'.)
●Risks and monitoring – Patients with ectopic ACTH-dependent hypercortisolism have risks attendant to severe endogenous hypercortisolism (unusual infections, hypokalemia), as well as risk of adrenal insufficiency with successful treatment. As a result, joint management by providers with expertise in oncology and endocrinology is optimal.
Patients with ectopic ACTH-dependent Cushing require close monitoring. In addition to 24-hour UFC and serum cortisol, routine monitoring should include measurement of serum potassium and kidney function.
REPLACEMENT GLUCOCORTICOID THERAPY
●Timing of replacement glucocorticoid initiation – In a block and replace strategy, patients must receive replacement glucocorticoid therapy when the serum or urine cortisol is within the low reference range. If a fixed-dose schedule is used, we monitor patients closely for signs and symptoms of adrenal insufficiency and initiate cortisol replacement therapy if these develop. Signs and symptoms of adrenal insufficiency are reviewed in detail separately. (See "Clinical manifestations of adrenal insufficiency in adults".)
When mitotane is used, the timing of hypocortisolism onset is unpredictable. As a result, replacement glucocorticoid therapy should be started when 24-hour urinary free cortisol (UFC) values begin to decrease.
●Choice of replacement regimen – When ketoconazole, osilodrostat, and/or metyrapone are used to decrease cortisol levels, standard glucocorticoid replacement regimens can be used. (See "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid replacement for all patients'.)
Mitotane increases the metabolism of dexamethasone [80], fludrocortisone, and cortisol and induces an increase in corticosteroid-binding globulin (CBG) levels [7]. Thus, after long-term therapy with mitotane, replacement hydrocortisone doses usually require a two- to threefold increase compared with standard dosing. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane'.)
●Monitoring
•Replacement therapy with hydrocortisone – Hydrocortisone is molecularly identical to cortisol and therefore detected in all cortisol assays. If hydrocortisone is used for glucocorticoid replacement therapy, a serum cortisol level drawn before the morning hydrocortisone dose can be used to monitor the efficacy of cortisol-lowering therapy. Alternatively, 24-hour UFC can be measured after switching to dexamethasone, which does not cross-react in cortisol assays.
•Replacement therapy with dexamethasone – Dexamethasone is generally not preferred for glucocorticoid replacement therapy. However, if dexamethasone is used for replacement therapy during mitotane administration, a dose increase up to three to seven times the usual dose may be required. If mineralocorticoid replacement is needed, similar increases in fludrocortisone dose also may be required. In such cases, clinical assessments alone are used to guide glucocorticoid replacement. Symptoms and signs of volume status (postural hypotension, systemic hypertension, or edema), serum electrolytes, and plasma renin activity are used to guide mineralocorticoid replacement. These assessments are reviewed in detail separately. (See "Treatment of adrenal insufficiency in adults", section on 'Glucocorticoid therapy monitoring' and "Treatment of adrenal insufficiency in adults", section on 'Mineralocorticoid therapy monitoring'.)
●Discontinuation of replacement glucocorticoid therapy – If medical therapy for Cushing syndrome is discontinued, glucocorticoid replacement therapy is no longer required. However, replacement therapy cannot be discontinued immediately after treatment with mitotane or osilodrostat. Mitotane levels may remain measurable for months after its discontinuation due to storage in adipose tissue with gradual release. Prolonged hypocortisolism also has been observed after osilodrostat discontinuation. As a result, these medications require slow taper of replacement glucocorticoid therapy based on serum cortisol levels over a period of several weeks to months.
SEVERE OR REFRACTORY HYPERCORTISOLISM
Principles of combination therapy — Combination therapy may provide additive or synergistic therapeutic effects of two or three medications at lower individual doses, thereby minimizing side effects. This approach may be chosen if side effects emerge at higher doses of a single agent or if monotherapy is ineffective. Patients with severe hypercortisolism (eg, urinary free cortisol [UFC] 10-fold the upper limit of the reference range) may not respond to monotherapy; in this setting, combination therapy may be used as an initial treatment strategy.
The most commonly used regimen for combination therapy is ketoconazole and metyrapone. However, a variety of other combinations have been reported, and no data exist to support the superiority of any specific combination or sequence of treatment (table 1). In such cases, treatment should be provided through referral to or consultation with endocrinologists who have extensive experience with such patients whenever possible, as no single algorithm applies to these rare presentations.
Regimens for any cause of Cushing syndrome — Agents used for medical management of hypercortisolism have the potential for drug-drug interactions. These interactions should be carefully considered prior to beginning any combination therapy regimen and can be assessed using the drug interactions program included with UpToDate. (See 'Pretreatment evaluation and drug-drug interactions' above.)
●Dual-agent therapy
•Initial therapy with ketoconazole – If ketoconazole alone does not control cortisol secretion, it should be maintained at a total dose of 1200 to 1600 mg/day and metyrapone and/or another steroidogenesis inhibitor (mitotane or osilodrostat) should be added. We suggest adding metyrapone at a dose of 250 mg two to four times a day (administered at the same times as ketoconazole) and increasing rapidly, to a maximum dose of approximately 4.5 g/day [3]. Most patients show near-maximal responses at a daily dose of 2 g. (See 'Metyrapone' above.)
Particularly in patients with severe hypercortisolism, it is important to control cortisol synthesis quickly. In these patients, the doses should be increased every two or three days based on serum cortisol results.
Osilodrostat is a CYP3A4 substrate and must be initiated at a reduced dose if used in combination with ketoconazole or levoketoconazole. For recommended dose adjustments, refer to drug information included with UpToDate. Ketoconazole, levoketoconazole, and osilodrostat can cause QT interval prolongation and require electrocardiogram (ECG) monitoring. (See 'Pretreatment evaluation and drug-drug interactions' above and 'Ketoconazole' above and 'Osilodrostat' above and 'Levoketoconazole' above.)
•Initial therapy with metyrapone – An alternative approach is to begin treatment with metyrapone and add ketoconazole if cortisol is not adequately controlled.
●Triple-agent therapy – Very limited data are available for triple-agent regimens. In a series of 11 cases of Cushing syndrome in the acute care setting, the combination of mitotane (3 to 5 g/24 hours), metyrapone (3 to 4.5 g/24 hours), and ketoconazole (400 to 1200 mg/24 hours) rapidly corrected severe hypercortisolism [51]. In one study of 11 individuals with severe hypercortisolism in whom adrenalectomy was not feasible, triple-agent therapy with mitotane, metyrapone, and ketoconazole similarly normalized UFC [51].
Regimens for corticotroph tumors — In individuals with Cushing disease, drugs that specifically target corticotroph tumors may be used in combination with each other or with adrenal steroidogenesis inhibitors. Cabergoline may help achieve adequate control of hypercortisolism when used in combination with a steroidogenesis inhibitor and/or pasireotide. Small studies support the use of various combination regimens, as follows:
●In three studies with a total of 32 patients in whom steroidogenesis inhibitor monotherapy was inadequate, cabergoline (0.5 to 3.5 mg/week) normalized UFC in 24 patients when combined with either ketoconazole (200 to 1200 mg daily) or metyrapone (3750 to 6000 mg daily) [54,55,81].
●In a report of 17 patients with Cushing disease, pasireotide, followed by cabergoline, and, if necessary, ketoconazole, achieved normalization in UFC in five (29 percent for pasireotide alone), four (53 percent for pasireotide and cabergoline), and six patients (88 percent for three drugs) [82].
SPECIAL CIRCUMSTANCES
Patients who are NPO — Etomidate, a substituted imidazole anesthetic drug that blocks CYP11B1 synthesis of cortisol, is the only available agent for hospitalized patients unable to take medication by mouth (nil per os [NPO]) (figure 1 and table 1) [83]. Etomidate is infused intravenously, initially with a low, nonhypnotic dose of 0.04 to 0.05 mg/kg per hour (approximately 2.5 to 3 mg/hour) and dose titration based upon serum cortisol (up to 0.1 to 0.3 mg/kg/hour). This approach has been effective in approximately 30 adults and children who were acutely ill [84]. In a study of a standardized protocol in seven patients with severe hypercortisolism, etomidate was given with an optional 5 mg intravenous bolus and an infusion dose of 0.02 mg/kg/hour. Infusion rates were adjusted in increments of 0.01 to 0.02 mg/kg/hour based upon serum cortisol measurements every six hours; rapid control of hypercortisolemia was achieved in all patients [85].
Etomidate administration increases 11-deoxycortisol; therefore, during etomidate treatment, urine or serum cortisol should be measured by tandem mass spectrometry. If such assays are not available, a cortisol immunoassay that does not cross-react with 11-deoxycortisol should be used. Monitoring in an intensive care unit is suggested when using etomidate. Intravenous hydrocortisone is added if complete block rather than cortisol normalization is the goal. Sedation, a theoretical side effect of this drug, was not observed in the few patients studied.
Persistent hyperglycemia — Mifepristone (RU-486) is an anti-progestational drug that is best known as an abortifacient. At much higher doses, it acts as a glucocorticoid receptor antagonist. Mifepristone is the only available glucocorticoid antagonist, although other agents are being tested in clinical trials.
Mifepristone can prolong the QT interval. An electrocardiogram (ECG) should be performed before starting this agent. (See 'Pretreatment evaluation and drug-drug interactions' above.)
●Clinical use
•Hyperglycemia – In the United States, mifepristone has regulatory approval as a once-daily oral medication to control hyperglycemia in adults with endogenous Cushing syndrome in whom surgery was unsuccessful or is contraindicated [86]. The role of mifepristone apart from treatment of hyperglycemia is not clear [87].
•Acute hypercortisolism – Mifepristone may be a useful short-term intervention for patients with Cushing syndrome who have an acute crisis, such as cortisol-induced psychosis, as symptoms improve rapidly in response to the glucocorticoid receptor blockade [88,89].
●Treatment monitoring – Mifepristone blocks cortisol action, so the levels of corticotropin (ACTH) and cortisol increase in patients with Cushing disease [90] and are variable in patients with ectopic ACTH secretion [91]. As a result, hormonal measurement cannot be used to judge either therapeutic efficacy or adrenal insufficiency. Instead, the goal is normalization of clinical and biochemical manifestations of hypercortisolism in the individual. For example, if hypertension, weight gain, and diabetes are signs/symptoms for a specific patient, monitoring should ensure that these improve and then resolve. It may be helpful to develop a list of each patient's signs and symptoms of Cushing syndrome and then monitor these regularly, increasing the dose of the medication if they do not improve.
Serum potassium should be monitored closely during treatment, as mifepristone can cause hypokalemia due to cortisol-mediated activation of mineralocorticoid receptors.
●Management of adrenal insufficiency – Mifepristone blocks the action of both endogenous and exogenous glucocorticoids, making it difficult to treat symptoms of adrenal insufficiency. Should symptoms of adrenal insufficiency occur, we suggest giving dexamethasone 4 mg to overcome the blockade.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Cushing syndrome (The Basics)")
●Beyond the Basics topics (see "Patient education: Cushing syndrome (Beyond the Basics)" and "Patient education: Cushing syndrome treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications – The hypercortisolism in Cushing syndrome is primarily treated surgically, regardless of its cause. However, when surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required. (See 'Indications' above.)
The main indications for pharmacologic control of hypercortisolism include:
•Surgery is delayed or contraindicated
•Hypercortisolism persists or recurs after initial surgery
•While awaiting the effect of pituitary irradiation
•Occult ectopic corticotropin (ACTH) syndrome
•Severe or malignancy-related hypercortisolism (including emergency management of life-threatening hypercortisolism)
●Initial therapy – The choice of initial therapy depends in part on the cause and severity of hypercortisolism (table 1). For Cushing disease with mild to moderate hypercortisolism, drugs that target corticotroph tumors are reasonable choices. For adrenal Cushing syndrome and ectopic ACTH-secreting tumors, adrenal steroidogenesis inhibitors are used most often as first-line therapy. (See 'Approach to treatment' above.)
•Pretreatment evaluation and drug-drug interactions – Several agents used for medical management of hypercortisolism confer risks requiring pretreatment assessments and/or attention to potential drug interactions. (See 'Pretreatment evaluation and drug-drug interactions' above.)
•Adrenal steroidogenesis inhibitors – For patients with hypercortisolism in whom medical therapy with a steroidogenesis inhibitor is indicated, we suggest ketoconazole as initial therapy (Grade 2C). This agent is relatively well tolerated and inexpensive. Liver function tests must be carefully monitored because of rare occurrences of hepatotoxicity. Levoketoconazole appears to have similar effectiveness and side effects but is unavailable in some countries. (See 'Ketoconazole' above and 'Levoketoconazole' above.)
An alternative approach is to start with metyrapone and add ketoconazole if cortisol secretion is not controlled. (See 'Metyrapone' above.)
Mitotane is an adrenolytic drug that has been used only in rare instances for Cushing disease and is used primarily for the treatment of adrenal carcinoma. For causes of Cushing syndrome other than adrenal carcinoma, mitotane largely has been supplanted by steroidogenesis inhibitors or cabergoline in Cushing disease. (See 'Mitotane (rarely used)' above.)
•Drugs that target corticotroph tumors – The somatostatin analog, pasireotide, and the dopamine agonist, cabergoline, have shown benefit against corticotroph tumors. Cabergoline is a cost-effective option for patients with Cushing disease who have mild recurrent or persistent post-surgical hypercortisolism (algorithm 1). (See 'Drugs that target corticotroph tumors' above.)
●Replacement glucocorticoid therapy – In a block and replace strategy, patients must receive replacement glucocorticoid therapy when the serum or urine cortisol is within the reference range. If a fixed-dose schedule is used, we monitor patients closely for signs and symptoms of adrenal insufficiency and initiate cortisol replacement therapy if these develop. (See 'Replacement glucocorticoid therapy' above.)
●Severe or refractory hypercortisolism – Combination therapy may provide additive or synergistic therapeutic effects of two or three medications at lower individual doses, thereby minimizing side effects. This approach may be chosen if side effects emerge at higher doses of a single agent or if monotherapy is ineffective. Patients with severe hypercortisolism may not respond to monotherapy; in this setting, combination therapy may be used as an initial treatment strategy. (See 'Dose adjustments and monitoring' above and 'Severe or refractory hypercortisolism' above.)
If ketoconazole does not control cortisol secretion as initial monotherapy, we suggest combining with metyrapone (Grade 2C). Osilodrostat or mitotane is a reasonable alternative. (See 'Regimens for any cause of Cushing syndrome' above.)
In individuals with Cushing disease, drugs that specifically target corticotroph tumors may be used in combination with each other or with adrenal steroidogenesis inhibitors. (See 'Regimens for corticotroph tumors' above.)
●Hyperglycemia – Mifepristone, a glucocorticoid-receptor antagonist, is approved in the United States for treatment of hyperglycemia in Cushing syndrome patients who cannot undergo surgery. (See 'Persistent hyperglycemia' above.)
ACKNOWLEDGMENT —
The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
