Version May 2024
INTRODUCTION — The hypercortisolism of Cushing's syndrome is primarily treated surgically, regardless of its cause (ie, due to corticotropin [ACTH]-producing pituitary tumor [Cushing's disease], ectopic ACTH secretion by a nonpituitary tumor, or cortisol secretion by an adrenal adenoma or carcinoma). However, when surgery is delayed, contraindicated, or unsuccessful, medical therapy is often required. Adrenal enzyme inhibitors are the most commonly used drugs, but adrenolytic agents, drugs that target a pituitary or ectopic tumor, and glucocorticoid-receptor antagonists are also available.
The pharmacologic management of hypercortisolemia in Cushing's syndrome will be reviewed here. An overview of the treatment options for Cushing's syndrome and additional details about drugs that inhibit cortisol synthesis are discussed separately. (See "Overview of the treatment of Cushing syndrome" and "Persistent or recurrent Cushing disease: Surgical adrenalectomy".)
INDICATIONS — The main indications for medical therapy of Cushing's syndrome include (see "Overview of the treatment of Cushing syndrome"):
●Control of hypercortisolism in preparation for surgery – Although the hypercortisolism of Cushing's disease is optimally treated surgically, medical therapy is often required when surgery is delayed. (See "Overview of the treatment of Cushing syndrome", section on 'Transsphenoidal surgery'.)
●Management of hypercortisolism if surgery is contraindicated. (See "Overview of the treatment of Cushing syndrome", section on 'Medical therapy'.)
●Management of persistent or recurrent hypercortisolism after initial surgery. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Treatment if surgery fails'.)
●Patients who have undergone radiation therapy – Control of hypercortisolism while waiting for the effect of pituitary radiation in patients with corticotropin (ACTH)-secreting pituitary tumors (Cushing's disease).
●Patients with ectopic ACTH syndrome – Treatment of occult or metastatic ectopic ACTH syndrome.
Our approach is largely consistent with the Endocrine Society Clinical Practice Guideline [1].
CHOOSING THERAPIES — Medical treatment of Cushing's syndrome can be divided into two broad categories: medications that decrease cortisol production and those that antagonize the action of cortisol at the glucocorticoid receptor.
●Drugs that decrease cortisol production – Drugs that decrease cortisol production include steroidogenesis inhibitors, which act directly on the adrenal gland to inhibit enzymes involved in cortisol synthesis and may also be adrenolytic, and agents that reduce corticotropin (ACTH) secretion by pituitary corticotroph tumors or ectopic tumors, and hence reduce the adrenal stimulation for cortisol production. (See 'Adrenal enzyme inhibitors' below.)
●Glucocorticoid receptor antagonists – An example of a glucocorticoid receptor antagonist is mifepristone. (See 'Glucocorticoid-receptor antagonists' below.)
Issues for all patients
●Patients' goals and preferences – These should be explored together before choosing medical therapy. For example, a young woman's desire for pregnancy in the near future may influence a choice of adrenalectomy over medical treatment. Other potential issues include a preference for oral versus injectable route of administration; daily versus multiple daily doses; impaired memory (ie, possible reduced adherence); a desire to "get on with life," which may favor surgery or agents with a faster onset of action; insurance, availability, and affordability.
●The variability in day-to-day cortisol production – In patients with highly variable cortisol production, fixed dosing regimens may result in adrenal insufficiency alternating with normal or increased cortisol production. Instead, a "block and replace" strategy is 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.
Thus, before deciding on a specific medication, 24-hour urine cortisol secretion should be measured to determine the degree of variability of cortisol production. While no studies have identified criteria for "high" variability, one approach is to look at the percentage or fold changes in at least three pretreatment urinary free cortisol (UFC) values. If the pretreatment values differ by threefold, ideal dosing would achieve values of 20 to 60 mcg/day (within and slightly above the normal range of approximately 5 to 50 mcg/day). However, a result of 20 mcg/day implies threefold results of 0 to 60, risking adrenal insufficiency, and a value of 50 would imply possible results of 17 to 150 mcg/day, risking undertreatment. Thus, a variability criterion of no more than twofold is probably best to use when choosing a fixed-dose regimen.
Considerations for individual medications — These issues are discussed below:
●The cause of Cushing's syndrome – Some agents are used only for pituitary Cushing's or ectopic ACTH-producing 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.
INITIAL THERAPY
Adrenal enzyme inhibitors — Ketoconazole, metyrapone, and mitotane are orally active medications that inhibit one or more steps in cortisol synthesis (figure 1). They are most often used to control corticotropin (ACTH)-dependent cortisol excess [2-6]. These drugs are not available in all countries. The most commonly used agent is ketoconazole in the United States and metyrapone in the United Kingdom. Other drugs that inhibit adrenal enzymes but are either no longer available (aminoglutethimide and trilostane), or rarely used (fluconazole), will not be considered further. These drugs usually do not cause adrenal insufficiency in patients with normal hypothalamic-pituitary-adrenal function [7] but can do so in those with limited pituitary or adrenal reserve. (See 'Replacement glucocorticoid therapy' below.)
In addition to inhibiting adrenal enzymes, mitotane is adrenolytic and is used for the treatment of adrenocortical carcinoma (see "Treatment of adrenocortical carcinoma"). The steroidogenesis inhibitor etomidate is the only agent for intravenous use.
Ketoconazole — Ketoconazole is a racemic mixture of L-form and S-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 [8]. However, the contribution of this effect to its action in patients with Cushing's disease has not been demonstrated.
In a series of 200 patients with Cushing's disease, 75 percent achieved either normal free cortisol (UFC) levels (49 percent) or at least a 50 percent decrease, at a median final dose of 600 mg/day. However, 20 percent stopped the treatment due to poor tolerance [9].
Ketoconazole may cause reversible hepatotoxicity [9,10]. In the study described above [9], 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 [11], 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 [12]. In the United States, it is an off-label use for the treatment of Cushing's syndrome.
●Liver function tests should be performed before initiation of ketoconazole. The drug is contraindicated in patients with liver disease whose alanine aminotransferase (ALT) values are ≥3 times the upper normal range. Patients with elevated values <3 times the upper normal range often have cortisol-induced nonalcoholic hepatosteatosis that improves with ketoconazole treatment.
●ALT should be monitored weekly for the first month, monthly for three months, and less frequently thereafter.
●If ALT values increase to ≥3 times the upper normal range, we suggest stopping the ketoconazole or reducing it to a previously well-tolerated dose.
Ketoconazole-induced decreases in estradiol and testosterone production may lead to gynecomastia, decreased libido, and impotence in men but usually are not clinically apparent in women because of the oligomenorrhea or amenorrhea associated with Cushing's syndrome [13].
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 [14,15]. However, ketoconazole is not the treatment of choice during pregnancy. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Management'.)
Ketoconazole requires an acidic environment for maximal absorption; its bioavailability may be reduced as much as 50 percent if it is given with a proton pump inhibitor [16]. Such agents should be discontinued, if at all possible, if ketoconazole is used.
Ketoconazole is a strong inhibitor 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. For example, coadministration of certain ergot derivatives, lovastatin, and alprazolam may result in dangerous elevations of those agents and is contraindicated [17].
Ketoconazole can prolong the QT interval; thus concomitant administration of other agents that also prolong the QT interval (such as cisapride, methadone, quinidine) is contraindicated as they may synergize to cause life-threatening ventricular arrhythmia [17].
Levoketoconazole — Levoketoconazole, comprised of the pure L-form enantiomer of ketoconazole, inhibits adrenal steroidogenesis via inhibition of CYP3A4 with two to four times the potency of ketoconazole [18,19]. It is approved by the FDA for the treatment of endogenous hypercortisolemia in adult patients with Cushing's syndrome when surgery is not an option or when it has not been curative.
Clinical trials have demonstrated normalization of 24-hour urinary free cortisol levels in 49 percent (19 of 39) of subjects with initial values of two to five times the upper limit of normal [20]; however, only 31 percent (29 of 94) of the entire group had this response, as patients with higher initial UFC were less likely to respond. Patients also had improvement in quality of life, depression, and other signs of Cushing's syndrome [21,22]. Adverse events included increased ALT in 39 patients (greater than three times the upper limit of normal in 10), dose-related QT interval prolongation in five, and adrenal insufficiency in three.
As there has been no head-to-head comparison to ketoconazole, it is not clear whether levoketoconazole offers an advantage in terms of reduction of hepatic toxicity. However, it appears that the two agents have similar efficacy when urine free cortisol is elevated up to five-fold 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.
Metyrapone — We do not suggest metyrapone as the first-line drug for women with Cushing's disease requiring long-term control of hypercortisolism. However, its use is not precluded in women for projected short-term use (for example, for treatment before surgery), or when ketoconazole is not a good alternative.
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. As a consequence of decreasing cortisol levels, ACTH secretion from a pituitary tumor may increase, stimulating increases in adrenal androgen production, which can cause hirsutism in women.
When given in a dose of approximately 4 g/day, metyrapone decreases cortisol secretion, but usually not to normal, in patients with Cushing's disease [23]. Thus, like the other adrenal enzyme inhibitors, metyrapone is most useful as adjunctive therapy in patients with mild disease or after pituitary irradiation, which prevents a further increase in ACTH secretion [2,24-27]. A dose of 500 to 750 mg three or four times a day is usually required in these patients. Metyrapone has been used in pregnancy with mixed results efficacy [28-30]. (See "Diagnosis and management of Cushing syndrome during pregnancy", section on 'Management'.)
In the largest retrospective, multicenter series, 195 patients with Cushing's syndrome (all causes) were treated with metyrapone (as monotherapy in 84 percent) [31]. 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. The drug was generally well tolerated: gastrointestinal upset (23 percent) and hypoadrenalism (7 percent) were the most frequent side effects; hypokalemia, hypertension, and hirsutism were very seldom found.
Metyrapone is currently available in North America through its distributor HRA Pharma (Paris, France) via its specialty pharmacy Direct Success Inc with order forms available on the web (www.metopirone.us) or by phone at 1-855-674-7663. Like ketoconazole, its use for treatment of Cushing's syndrome is an off-label use.
Osilodrostat — Osilodrostat is an oral agent that has been approved for adults with Cushing's disease who are not candidates for pituitary surgery or who have undergone transsphenoidal surgery but have persistent disease [32-34]. Like metyrapone, it blocks the 11-beta-hydroxylase enzymes (CYP11B1 and CYP11B2), thereby reducing the synthesis of aldosterone and cortisol [32]. Osilodrostat's safety and effectiveness for treating adults with Cushing's disease was evaluated in a six-month, single-arm, open-label study of 137 adult patients with Cushing's disease, who were either not surgical candidates or who had undergone transsphenoidal surgery but were not cured. The starting dose for all was 2 mg twice daily that could be increased by 1 to 2 mg every two weeks up to 30 mg twice/day. 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 normal (ULN) [35].
In this same trial, subjects who achieved a 24-hour UFC less than or equal to ULN at week 24, without up-titration after week 12, entered into an 8-week randomized trial of continued osilodrostat or placebo [36]. Of the 137 patients initially enrolled, 72 were eligible for the randomized trial. More patients maintained a complete response with osilodrostat than placebo (86 versus 29 percent, respectively).
Side effects of the drug include hypocortisolism, prolongation of the QT interval, nausea, headache, and adrenal insufficiency [33,36,37]. There are limited data on a faster dose escalation strategy or use of the agent in patients without Cushing's disease. In one report of three patients with ectopic ACTH secretion, the dose was increased by 1 mg every two to five days, based on morning plasma cortisol levels [38].
Mitotane — Mitotane is an adrenolytic drug that acts on adrenocortical cell mitochondria to inhibit CYP11B1 (11-beta-hydroxylase) and cholesterol side-chain cleavage (CYP11A1) enzymes. A metabolite binds to important macromolecules in the mitochondria, causing mitochondrial destruction and necrosis of adrenocortical cells [39]. Because of its adrenolytic action, it is used primarily for the treatment of adrenal carcinoma, which will not be considered further here. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane' and 'Replacement glucocorticoid therapy' below.)
Mitotane also can be used to achieve medical adrenalectomy with or without pituitary irradiation in patients with Cushing's disease or as an adjunctive medication in patients with ectopic ACTH secretion [40-42]. Mitotane treatment of Cushing's syndrome not caused by adrenocortical cancer should be started with 0.5 g given at bedtime, adding single 0.5 g doses at a mealtime every week or so, as the patient's tolerance permits, to reach a maximal dose of 2 to 3 g/day, one-half of which is taken at bedtime to reduce nausea. Thereafter, the concentrations are maintained by doses of 1 to 2 g daily. At these doses, mitotane tends to spare the zona glomerulosa [43] so that mineralocorticoid replacement is not needed.
The major side effects are nausea, vomiting, and anorexia. Additional side effects that occur with the higher doses used for adrenal carcinoma are discussed separately. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane'.)
When given as adjunctive therapy after radiotherapy for Cushing's disease, mitotane is stopped when cortisol levels 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 [40]. Similar findings were reported in a study of 46 patients treated with higher doses of mitotane but no pituitary irradiation [41]. Four of 92 patients developed Nelson syndrome.
Mitotane is taken up by adipose tissues 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 levels measured after its discontinuation to ensure that it is safe to proceed [45].
Dose adjustments and monitoring — Unless mitotane is given in adrenolytic doses, these medications do not permanently cure the hypercortisolism, leading to recurrence when the drug is discontinued. As a result, they must be continued indefinitely until bilateral adrenalectomy is performed, or a tumor is found and excised or pituitary radiotherapy is effective.
●Ketoconazole/metyrapone/osilodrostat – Doses of ketoconazole and metyrapone can be increased every three to seven days based on serum cortisol and/or urine cortisol excretion. In clinical trials, the osilodrostat dose was adjusted every two weeks; this dose adjustment period is recommended in the FDA label. At the outset of treatment with these steroidogenesis inhibitors, we recommend measurement of a morning serum cortisol level on the day that urine is returned for cortisol measurement. This allows the two to be correlated, allowing later use of the morning cortisol only, as most patients find a blood draw to be more convenient than urine collection.
●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 while awaiting the urine result, with a goal urine 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 adrenal insufficiency signs and symptoms and how to administer emergency doses of glucocorticoid. (See "Treatment of adrenal insufficiency in adults".)
●For patients requiring a "block and replace" strategy, the dose of drug(s) is increased at intervals until serum or urine cortisol is in the normal range, at which time a glucocorticoid is added. The dose is increased further until serum or urine cortisol values are very low or undetectable. (See 'Replacement glucocorticoid therapy' below.)
●Once the dose appears to be optimal, monitoring may occur less often, perhaps monthly or less frequently.
●Metyrapone administration increases 11-deoxycortisol, which may cross-react with the antibodies in some cortisol immunoassays, while tandem mass spectrometry results are not affected [46]. 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.
●Mitotane – Doses of mitotane are increased more slowly, due to its long half-life. Urinary cortisol excretion is the optimal measure of the efficacy of mitotane therapy. Mitotane increases cortisol-binding globulin (CBG) levels, so that serum cortisol levels increase and do not reliably reflect biologically active free levels [47]. If serum cortisol levels are used to monitor treatment, they should be correlated with urinary cortisol excretion, at least initially and after dose changes.
Replacement glucocorticoid therapy — In a block and replace strategy, patients must receive replacement glucocorticoid therapy when the serum or urine cortisol is in the normal range.
●When ketoconazole, osilodrostat, and/or metyrapone are used to decrease cortisol levels, any glucocorticoid replacement can be used in the usual way (see "Treatment of adrenal insufficiency in adults"). If hydrocortisone is used, urine collections to assess efficacy must be done after switching to dexamethasone, which does not cross-react in cortisol assays. Alternatively, a pre-hydrocortisone serum cortisol level can be used to monitor therapeutic effectiveness, with a goal of very low or undetectable level of urine or serum cortisol.
●When mitotane is used, one cannot predict when a patient will become hypocortisolemic. As a result, replacement glucocorticoid, usually 5 mg of prednisone or 0.5 mg of dexamethasone each day, should be started when cortisol in urine or saliva begin to decrease. Mitotane increases the metabolism of dexamethasone [48], fludrocortisone, and cortisol and induces an increase in CBG levels [5]. Thus, replacement dose hydrocortisone usually requires a two- to threefold increase in the usual dose after long-term therapy with mitotane. (See "Treatment of adrenocortical carcinoma", section on 'Adjuvant mitotane'.)
If dexamethasone is used for replacement therapy during mitotane administration, it may be necessary to increase its dose (and that of fludrocortisone, if it is required) to three to seven times the usual dose; in these cases, amelioration of symptoms of hypocortisolism or normalization of UFC values must be used to guide glucocorticoid replacement, while symptoms and signs of volume depletion or excess (postural hypotension, systemic hypertension, or edema), serum electrolytes, and plasma renin activity are used to guide mineralocorticoid replacement. (See "Treatment of adrenal insufficiency in adults".)
Because mitotane levels may remain measurable for months after its discontinuation due to release from adipose tissue, cortisol levels may remain suppressed so that replacement glucocorticoid may have to be tapered over a period of several weeks to months.
Combination therapy — Combinations of these drugs often have additive or synergistic therapeutic effects at lower individual doses, thereby minimizing side effects.
●If ketoconazole does not control cortisol secretion, it should be maintained at a total dose of 1200 mg/day and metyrapone and/or mitotane should be added.
●We suggest adding metyrapone at a dose of 250 mg two or three times a day and increasing rapidly, to a maximum dose of approximately 4.5 g/day [16]. 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 if laboratory results are available.
●An alternative approach is to begin treatment with metyrapone and add ketoconazole if cortisol is not adequately controlled.
●In one study of 11 cases of severe hypercortisolism in whom adrenalectomy was not feasible, triple drug therapy with mitotane, metyrapone, and ketoconazole normalized UFC [49].
Intravenous etomidate — Etomidate is a substituted imidazole anesthetic drug that blocks CYP11B1 synthesis of cortisol and is the only available agent for hospitalized patients unable to take medication by mouth (figure 3). 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), with 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 [50]. 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 [51].
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 to date.
OTHER AGENTS
Drugs that target a pituitary tumor — Only the somatostatin analogue, pasireotide, and the dopamine agonist, cabergoline, have shown benefit; other agents that are not effective include bromocriptine, cyproheptadine, and valproate.
Cabergoline — Cabergoline is useful when Cushing's disease is associated with urinary free cortisol (UFC) values up to twice normal. In two studies, chronic cabergoline therapy (1 mg once weekly to 1 mg orally every day) decreased 24-hour UFC to ≤125 percent of normal in 12 of 42 patients with Cushing's disease [52,53]. Normalization of UFC was achieved in 30 percent of patients with up to five years of follow-up [53]. A meta-analysis found that patients with milder hypercortisolism were more likely to respond [54]. Gastrointestinal side effects, particularly nausea (14 percent) and dizziness were most common; severe adverse effects included adrenal insufficiency and hypotension. The agent has been used in a small number of pregnant women with good outcomes [55].
Pasireotide — 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 [56]. Pasireotide injection has been approved in the United States, Europe, Canada, and parts of Asia and South America and is recommended for the treatment of patients with Cushing's disease for whom surgery has been unsuccessful or who are not surgical candidates [1,57]. 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's 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 it in 21 of 80 (26 percent) and 12 of 82 (15 percent) of those in the 0.9 or 0.6 mg group, respectively [58]. Patients who achieved UFC control also experienced other clinical improvements, including a decrease in total and low-density lipoprotein cholesterol [59]. Reductions in blood pressure and body mass index occurred even without normalization of UFC. Hyperglycemia was common, occurring in 118 of 162 patients (73 percent); 74 of 162 patients (63 percent) required initiation of a glucose-lowering medication. Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), but not to changes in hepatic/peripheral insulin sensitivity [60]. Other side effects were similar to other somatostatin analogs (gastrointestinal symptoms and gallstones). (See "Treatment of acromegaly".)
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, treatment should either be stopped or combined therapy should be considered. A sustained response for up to five years has been reported in three individuals [61,62]; two had initially developed glucose intolerance with pasireotide, but with clinical and biochemical reversal of their hypercortisolism, they were eventually able to discontinue all diabetes pharmacotherapy [62].
A long-term study of 53 patients showed a tumor volume reduction of at least 20 percent at 6 and 12 months that was more common in those taking the 0.9 mg dose than the 0.6 mg dose (75 and 89 percent versus 44 and 50 percent) [63].
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 concentration less than or equal to upper limit of normal by seven months) [64]. Adverse events include 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 [65]. The recommended starting dose for pasireotide is 10 mg.
The monthly preparation may be useful for patients who have difficulty remembering to take medications, but is not a first-line choice for patients with diabetes.
The pasireotide warning and precaution for hyperglycemia and diabetes has been updated to include ketoacidosis [66].
Drugs that target an ectopic ACTH-secreting tumor — Chemotherapy or immunotherapy may reduce corticotropin (ACTH) and cortisol levels in patients with ectopic ACTH secretion [67-69]. A few patients have been successfully treated with octreotide and/or cabergoline [70-72]. However, these are case reports or small series, and the overall efficacy of these approaches is not known.
Combination therapy — In a report of 17 patients with Cushing's disease, the somatostatin analog 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), respectively [73].
In another report, for patients in whom cabergoline therapy (3 mg/week) provided a suboptimal response, addition of ketoconazole (200 to 400 mg daily) achieved a normal UFC in six of nine patients [52].
In another study, cabergoline (n = 6, dose up to 3 mg weekly) or ketoconazole (n = 8, daily dose of 200 to 600 mg) was the first agent for four to six months [74]. UFC remained abnormal with the initial treatment but normalized in 13 patients on combination therapy.
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) was able to rapidly correct severe hypercortisolism in a series of 11 cases of Cushing's syndrome in acute care situations [49].
Glucocorticoid-receptor antagonists — 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. Currently, mifepristone is the only available glucocorticoid antagonist, although other agents are in clinical trials.
Mifepristone is approved in the United States as a once-daily oral medication to control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome and type 2 diabetes or glucose intolerance who have failed surgery or are not candidates for surgery [75]. Because patients were not categorized as clinically normal during treatment, the role of mifepristone apart from treatment of hyperglycemia is not clear [76].
Mifepristone may be a reasonable short-term intervention for patients with Cushing's syndrome who have an acute crisis, such as cortisol-induced psychosis, as symptoms improve rapidly in response to the glucocorticoid receptor blockade [77,78].
Mifepristone also blocks the action of 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.
Because mifepristone blocks cortisol action, the levels of ACTH and cortisol increase in patients with Cushing's disease [79] and are variable in patients with ectopic ACTH secretion [80], so that 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 each 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's syndrome and then monitor these regularly, increasing the dose of the medication if they do not improve.
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
●The hypercortisolism in Cushing's 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: in preparation for surgery, persistence or recurrence of hypercortisolism after surgery, while waiting for the effect of pituitary radiation, occult ectopic corticotropin (ACTH) syndrome, severe or malignancy-related hypercortisolism, and when surgery is contraindicated. (See 'Indications' above.)
●Among patients with hypercortisolism in whom medical therapy is indicated, we suggest ketoconazole as initial therapy (Grade 2C). Liver function tests must be carefully monitored because of rare occurrences of hepatotoxicity (see 'Ketoconazole' above). If ketoconazole does not control cortisol secretion, we suggest adding metyrapone (Grade 2C). (See 'Initial therapy' above.)
●An alternative approach is to start with metyrapone and add ketoconazole if cortisol secretion is not controlled. (See 'Issues for all patients' above.)
●Mitotane is an adrenocorticolytic drug that is used primarily for the treatment of adrenal carcinoma. (See 'Mitotane' above.)
●Mitotane also can be used to as adjunctive therapy during or after pituitary irradiation in patients with Cushing's disease. The usual duration of mitotane therapy in patients with Cushing's disease is six to nine months. (See 'Mitotane' above.)
●Mitotane has significant side effects. However, important advantages over surgical adrenalectomy include a possible decreased risk of developing Nelson syndrome and the possibility of not requiring mineralocorticoid replacement. (See 'Mitotane' above.)
●Drugs directed at reducing ACTH levels in Cushing's disease include the dopamine agonist, cabergoline (off-label use), and the parenteral somatostatin analog pasireotide (approved for therapy of Cushing's disease). (See 'Cabergoline' above and 'Pasireotide' above.)
●Mifepristone, a glucocorticoid-receptor antagonist, is approved in the United States for treatment of hyperglycemia in Cushing's syndrome patients who cannot undergo surgery. (See 'Other agents' above.)
DISCLOSURE — 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.
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