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Review Article
Hypothalamus and pituitary gland Medical Treatment of Cushing’s Syndrome
Keypoint
Endogenous Cushing’s syndrome refers to the manifestations of chronic cortisol excess. Surgical resection of the tumor is typically the first-line and preferred treatment. However, when surgery is not feasible or has been unsuccessful, medical therapies may be employed to control Cushing’s syndrome. This mini-review provides an overview of the main medical therapies currently used to treat Cushing’s syndrome, including their efficacy, safety, and management.
Laurence Guignat1orcid, Jerome Bertherat1,2
Endocrinology and Metabolism 2025;40(1):26-38.
DOI: https://doi.org/10.3803/EnM.2024.501
Published online: January 13, 2025

1Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

2Genomics and Signaling of Endocrine Tumors, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris, France

Corresponding author: Laurence Guignat. Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, F-75014, Paris, France Tel: +33-1-58-41-18-94, Fax: +33-1-58-41-18-05, E-mail: laurence.guignat@aphp.fr
• Received: July 29, 2024   • Revised: November 16, 2024   • Accepted: December 1, 2024

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Endogenous Cushing’s syndrome (CS) refers to the manifestations of chronic cortisol excess. This rare disease is associated with multiple comorbidities, impaired quality of life, and increased mortality. The management of CS remains challenging. Regardless of the underlying cause, surgical resection of the tumor is typically the first-line and preferred treatment. However, when surgery is not feasible or has been unsuccessful, medical therapies may be employed to control CS. The therapeutic strategy should be individualized based on the recommendations of a multidisciplinary team of experts and the patient’s preferences, informed by detailed information on the available options. All medications require careful monitoring, along with adequate instructions for patients and caregivers. The aim of this mini-review is to provide an overview of the main medical therapies currently used to treat CS, including their efficacy, safety, and management. Despite the availability of new drugs in recent years, the need remains for more effective specific targeted pharmacological therapies.
  • Keywords: Cushing syndrome; Cushing disease; Cortisol; Steroidogenesis
Endogenous Cushing’s syndrome (CS) refers to the manifestations of chronic cortisol excess [1]. Although rare [2], its clinical presentation closely resembles the side effects of corticosteroid therapy, also known as exogenous or iatrogenic CS. CS can arise from a variety of causes, including pituitary adenoma (Cushing’s disease [CD]), ectopic adrenocorticotropin hormone (ACTH) syndrome (EAS), and adrenal CS due to unilateral adrenocortical tumors, which may be benign (adrenocortical adenoma) or malignant (adrenocortical carcinoma); another potential cause is bilateral nodular adrenocortical disease [3]. The morbidity and mortality associated with chronic CS [4] necessitate prompt active treatment in most cases. Surgical resection of the tumor is typically the first-line approach, but it is not always possible or may be delayed. Consequently, alternative interventions, including medical therapies, are required. The availability of several drugs, some developed in the past decade, now offer a wide variety of options to patients for whom medical therapy is considered. The aim of this mini-review is to provide an overview of the main drugs used to treat CS, including their efficacy, safety, and management. Glucocorticoid receptor antagonists, the intravenous imidazole derivative etomidate, drugs in development, and potential candidates will not be covered [5,6]. Additionally, while the symptomatic treatment of comorbidities and the prevention of CS complications such as thromboembolism and infections are important, they will not be addressed in this review [7].
Excluding glucocorticoid receptor antagonists, medical therapy for CS can be classified into two main types: adrenally directed drugs and specific targeted pharmacological therapies (Table 1). Notably, the reported efficacy and side effect profiles of these drugs cannot be directly compared due to the heterogeneity of the studies [8].
Adrenally directed drugs
The drugs described below, listed from the oldest to the most recent, block cortisol production by inhibiting one or more steps of adrenal steroidogenesis (Fig. 1).

Mitotane

In the late 1940s, researchers observed that the insecticide dichlorodiphenyldichloroethane (DDD) caused selective necrosis in the adrenal cortex of dogs, primarily affecting the zona fasciculata and reticularis [9]. Mitotane, a contaminant in crude DDD preparation, was found to have potent adrenolytic properties. This drug was first administered to humans for the chemotherapeutic treatment of adrenocortical carcinomas, where it demonstrated adrenolytic effects [10], and has since been approved for the symptomatic treatment of advanced adrenocortical carcinoma (unresectable, metastatic, or recurrent). Additionally, mitotane has been used off-label in some countries, notably France, for the treatment of CD and EAS [11-14]. Mitotane has a gradual onset of action that unfolds over several weeks, is cleared slowly after discontinuation, and exerts a long-lasting effect that can persist for months or even years. A retrospective study [12] reported that disease control, defined as normalization of 24-hour urinary free cortisol (UFC), was achieved in 72% (48/67) of patients with CD after a median time of 6.7 months (range, 5.2 to 8.2), with a mean plasma mitotane concentration of 10.5±8.9 mg/L. Patients who attained a plasma mitotane level above 8.5 mg/L were found to have normalized UFC levels. This suggests that the therapeutic plasma concentration of mitotane for achieving an anticortisol effect in ACTH-dependent CS is lower than that required for the anti-tumor effect in adrenocortical carcinoma, which is above 14 mg/L. For the remaining 19 patients, mitotane was discontinued due to ineffectiveness in 10 cases and poor tolerability in nine cases. Among the patients who had well-controlled disease and stopped mitotane without receiving any other treatment, 71% (17/24) experienced a recurrence of hypercortisolism after a median of 13.2 months (range, 5.0 to 67.9) following treatment discontinuation. Mitotane can serve as an alternative to bilateral adrenalectomy if it is initially combined with fast-acting drugs in severe CS [14], and it can enable the subsequent identification of initially occult tumors [13].
Given the prevalence of adrenal insufficiency, glucocorticoid replacement therapy is typically administered using a “block-and-replace” strategy, often with hydrocortisone. The glucocorticoids are prescribed at a higher dose than what is normally used for adrenal insufficiency due to the enzyme-inducing effect of mitotane, which leads to increased catabolism of the replacement therapy [15]. Mitotane elevates cortisol-binding globulin (CBG) levels, causing serum cortisol measurements to overestimate the amount of active (free) cortisol. This can lead to an underestimation of the risk of adrenal insufficiency. Additionally, some assays may underestimate cortisol levels due to their inability to completely liberate cortisol from CBG, potentially leading to an overestimation of adrenal insufficiency risk [16]. Cross-reactivity with 11-deoxycortisol necessitates specific cortisol dosages [7]. Mitotane is known to have numerous drug interactions, which require careful selection of any concomitant therapies [17]. Its teratogenic and abortifacient effects contraindicate pregnancy as long as mitotane is detectable in the blood. In addition to adrenal insufficiency, side effects are extensive and include gastrointestinal problems (such as anorexia and nausea), hepatic and neurologic symptoms (including dizziness, apathy, general weakness, and more rarely ataxia and tremor), metabolic disturbances (dyslipidemia), endocrine problems (male hypogonadism and ovarian macrocysts), hematologic conditions (neutropenia), and dermatologic toxicities.
Despite its effectiveness as a steroidogenesis inhibitor and adrenolytic drug, the use of mitotane is currently limited in CS conditions other than advanced adrenocortical carcinoma due to its specific kinetics, highly variable bioavailability that requires close monitoring, and numerous (and sometimes serious) side effects.

Ketoconazole

Ketoconazole is an imidazole derivate, originally developed as an antifungal agent. It inhibits several steps in adrenal and gonadal steroidogenesis, particularly in the testis [18]. Cortisol synthesis is blocked at the levels of cytochrome P450 family 11 subfamily A member 1 (CYP11A1; cholesterol side-chain cleavage enzyme), cytochrome P450 family 17 subfamily A member 1 (CYP17A1; 17α-hydroxylase/17,20 lyase), and cytochrome P450 family 11 subfamily B member 1 (CYP11B1; 11β-hydroxylase) (Fig. 1). Ketoconazole monotherapy has demonstrated rapid action and prolonged beneficial effects in retrospective series [19-23]. In the largest retrospective multicenter study on this drug [23], disease control, as indicated by UFC normalization, was achieved in 49% (97/197) of patients (including 35 undergoing radiotherapy), with a mean follow-up of 20.6 months (range, 0.03 to 135) and a mean daily dose of 600 mg (range, 200 to 1,200). Notably, approximately two-thirds of the patients whose condition was not controlled did not receive the maximum dose, despite demonstrating good tolerance of the drug. In a subgroup treated for over 24 months, 65% (33/51) achieved normal UFC levels, but nearly 12% (6/51) experienced a relapse. Due to intolerance, 21.5% (41/190) of patients discontinued treatment.
Ketoconazole necessitates dosing twice or three times daily and relies on gastric acidity for its absorption. It is commonly administered using a dose titration regimen, calibrating the dosage to achieve cortisol levels within the normal range. Adrenal insufficiency has been reported in 6% of cases [24].
The most feared adverse effect of ketoconazole is hepatotoxicity, with rare cases of fatal hepatitis reported. Ketoconazole should not be initiated or continued if liver enzyme levels exceed three times the normal range. Clinicians must strictly monitor liver function at the start of treatment and after each dose adjustment. This entails weekly monitoring for at least the first month, followed by monthly monitoring for up to 6 months and routine checks thereafter. Patients should also be informed about the signs of liver toxicity [24,25]. With these precautions in place, fewer than 20% of patients experience hepatotoxicity, which is typically moderate (with liver function markers less than five times the normal range) and reversible upon timely cessation of the drug [23,25,26]. Gastrointestinal problems are among the other common adverse effects. Although ketoconazole can reduce testosterone production by the testes, side effects related to male hypogonadism are rare. Clinicians should be aware of the potential for multiple drug interactions, as many medications are contraindicated or necessitate careful monitoring when administered with ketoconazole. These include drugs that are metabolized through or that modulate the activity of the cytochrome P450 family 3 subfamily A member 4 (CYP3A4) enzymatic pathway, those that are substrates of the P-glycoprotein efflux pump, and those that carry a risk of QT prolongation. Additionally, it is necessary to address modifiable risk factors for QT prolongation, consider patient-specific risk factors, and monitor electrocardiogram findings.
Ketoconazole is approved for use in Europe to treat CS, but it is not authorized in many other countries. However, levoketoconazole, the levorotatory enantiomer of ketoconazole, received approval in the United States in 2021 for treating CS in patients for whom surgery is not an option or has not been curative. This approval followed the results of two studies. The Study Of levoketocoNazole In CS (SONICS) study was a single-arm, open-label trial consisting of three phases: a dose titration phase lasting 2 to 21 weeks, a 6-month maintenance phase, and a 6-month extended evaluation phase, involving patients with CS [27-29]. Of the 94 patients enrolled, 47 discontinued treatment for various reasons, including 16 who did so due to adverse events. Disease control, as measured by normalization of UFC levels, was achieved in 63 patients (67%) at the end of the titration phase, in 29 patients (30.9%) at the end of the maintenance phase, and in 16 patients (17%) at the end of the extended evaluation phase. The LevOketoconazole to fill a Gap In CS (LOGICS) study included an open-label dose titration and maintenance phase lasting up to 19 weeks, followed by an 8-week double-blind, placebo-controlled, randomized withdrawal phase [30]. Of the 39 patients who had normal UFC levels at the start of the randomized withdrawal phase, 18 were assigned to the placebo group and 21 to the levoketoconazole group. At the conclusion of the randomized withdrawal phase, a loss of UFC response was observed in 94.4% of the placebo group and 47.6% of the levoketoconazole group. Prespecified adverse events of special interest included hepatotoxicity, with transaminase levels at least three times normal values (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).

Metyrapone

Metyrapone is a pyridine derivative that inhibits the activity of 11β-hydroxylase (CYP11B1), blocking the conversion of the biologically inactive 11-deoxycortisol to cortisol. It also inhibits aldosterone synthase (cytochrome P450 family 11 subfamily B member 2 [CYP11B2]) and, to a lesser extent, other enzymes involved in steroidogenesis (Fig. 1) [31]. Metyrapone acts rapidly and has a prolonged beneficial effect when used alone, as demonstrated in retrospective series [22,32-35]. In the largest retrospective multicenter study on this drug [36], disease control was achieved in 43% of the 164 patients on metyrapone monotherapy, as measured by UFC normalization, and in 55% of patients as determined by the average of multiple daily serum cortisol levels, with a median dosage of 1,425 mg per day (range, 500 to 4,000). Among a subgroup of 38 patients treated for more than 6 months, 64% (9/14) achieved normal UFC levels, and 72% (18/25) attained a normal cortisol day curve. In the prospective phase III/IV PROMPT study, disease control, based on UFC normalization, was achieved in 48.6% (17/35) of patients at week 36 [37].
A block-and-replace regimen (with a replacement dose of glucocorticoid) or a titration regimen can be employed, involving multiple daily doses (ranging from twice to six times a day). Timed evening doses have been successfully used to reset the cortisol rhythm to normal in a small prospective, open-label, controlled study of patients with adrenal adenomas causing mild autonomous cortisol secretion [38].
Side effects of metyrapone include dizziness within an hour of administration, gastrointestinal problems (which may be minimized by taking the medication with food), clinical hyperandrogenism in women due to the accumulation of androgenic precursors driven by ACTH, hypertension, edema, and hypokalemia resulting from the accumulation of mineralocorticoid precursors also driven by ACTH [24]. Metyrapone may also prolong the QT interval, as noted in the precautions mentioned earlier. Cortisol levels must be monitored using assays that do not cross-react with 11-deoxycortisol, which can become markedly elevated, particularly in patients with CD. Cortisol-specific immunoassays or mass spectrometry-based methods are recommended [39].

Osilodrostat

Osilodrostat, initially developed as a potential antihypertensive drug, inhibits 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), as well as other steroidogenesis enzymes to a lesser extent (Fig. 1) [31,40]. Unlike older medications, the efficacy and safety of osilodrostat have been evaluated in randomized, double-blind, placebo-controlled trials, including a drug withdrawal phase, in patients with CD [41]. For instance, in the LCI IN Cushing’s (LINC) 4 study—a randomized, double-blind, placebo-controlled trial—76.2% (32/42) of patients without a history of pituitary irradiation achieved disease control, as indicated by normalization of UFC, after 12 weeks of treatment, compared to only 4.5% (1/22) in the placebo group [42]. With progressive titration, UFC normalization was observed within 5 weeks in 58% of treated patients. This control was sustained over the long term. Specifically, it was maintained in 69% of patients at week 48, following 36 weeks of open-label osilodrostat treatment [42], and in 54.8% at week 72 of an optional expansion period, with a median daily dose of 4.6 mg (interquartile range, 3.7 to 9.2 mg per day) during the overall study period [43]. No correlation was observed between baseline mean UFC levels and the osilodrostat dose required to achieve UFC normalization. The efficacy of osilodrostat was also demonstrated for other causes of CS in a phase 2 single-arm open-label study, which involved five patients with adrenal adenoma, one with bilateral macronodular adrenocortical disease (BMAD), and three with EAS [44]. Additionally, its effectiveness has been reported in case studies [45-47] and small retrospective series [48-51]. It is essential to monitor cortisol levels using laboratory methods that do not exhibit cross-reactivity with 11-deoxycortisolespecially in patients with CD.
Adrenal insufficiency was reported in 54% (74/137) and 26% (19/73) of patients in the LINC 3 [28,29] and LINC 4 [43] studies, respectively. This included six (4.4%) and three (4.1%) adverse events classified as grade 3 (requiring hospitalization) or 4 (life-threatening/disabling). Adrenal insufficiency occurred not only during the titration phase but also during long-term treatment at a stable dose of osilodrostat, affecting 26.5% of patients after 72 weeks in LINC 3 and 8.5% of patients after 60 weeks in LINC 4. Furthermore, cases have been observed of prolonged control and even sustained adrenal insufficiency after discontinuation of osilodrostat, leading to the hypothesis of a potential cytotoxic effect after extended exposure. In LINC 3, UFC levels remained normalized 8 weeks after osilodrostat withdrawal in 29.4% (10/34) of patients who were randomized to placebo following a 24-week period on osilodrostat. Persistent UFC normalization or low morning serum cortisol levels were observed from 6 weeks to over 16 months after osilodrostat cessation in five patients who had been treated for 6 to 16 months. Despite elevated ACTH concentrations, low dehydroepiandrosterone sulfate (DHEA-S) and low-to-normal 11-deoxycortisol levels were observed [52,53]. Adrenal shrinkage was noted on computed tomography (CT) after 3 months of treatment in a patient with persistent ectopic ACTH secretion [54].
Given its long half-life and the risk of delayed adrenal insufficiency, a block-and-replace regimen—comprising twice-daily dosing of osilodrostat and systematic glucocorticoid supplementation—is commonly employed in current practice [51] and is even recommended [55]. The initial dose and the rate of escalation should be tailored to the patient, with a high starting dose (15 to 30 mg twice a day) and rapid increase (over a few days) for hospitalized patients with severe hypercortisolism and/or life-threatening complications [49,51]. Conversely, a low starting dose (1 or 2 mg twice daily) and gradual escalation (in increments of at least 2 weeks) are advised for other cases. Plasma drug monitoring may be particularly useful during the initiation phase or in instances of poor compliance [56]. Once low cortisol levels have been sustained for several weeks, the dose can likely be reduced to the minimum required to maintain adrenal blockade, or even temporarily discontinued, at least in some patients [53]. Patients must be informed of the potential prolonged effects of the drug, necessitating careful compliance with glucocorticoid replacement therapy and appropriate adjustments in the event of acute illness, even if osilodrostat is discontinued.
Aside from adrenal insufficiency, the most frequently reported adverse effects included gastrointestinal problems, arthralgia, dizziness, hypertension, and elevated blood testosterone levels in female patients. However, side effects associated with adrenal precursors appear to be less frequent over the long term, coinciding with the reduction of their levels, even as ACTH stimulation persists [39,43]. Symptomatic mineralocorticoid deficiency may also develop, necessitating fludrocortisone supplementation [52,53].
Osilodrostat moderately inhibits cytochrome P450 family 1 subfamily A member 2 (CYP1A2) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and weakly inhibits CYP3A4 and cytochrome P450 family 2 subfamily D member 6 (CYP2D6) [57]. It often increases the QT interval at high plasma concentrations. Therefore, careful attention should be paid to co-prescribed medicines. Additionally, it is essential to address modifiable risk factors, consider patient-related risk factors for QT prolongation, and monitor electrocardiogram signals.
Specific pharmacological therapies
In CD, various drugs have been experimentally employed to suppress pituitary ACTH oversecretion. However, only two have shown effectiveness in a subset of patients for controlling hypercortisolism and reducing tumor volume. The effects of these drugs have also been reported in the contexts of EAS and BMAD.

Cabergoline

Cabergoline has not yet been approved for the treatment of CD, despite reports of its capacity to suppress ACTH and/or cortisol levels—as well as induce tumor shrinkage—in case reports and small series, and to achieve long-term remissions in some patients with CD [58,59]. In five open-label prospective studies including a total of 86 patients with CD, disease control—defined as UFC normalization in four studies and midnight cortisol and/or a low-dose dexamethasone suppression test in one study—was achieved in 25% to 40% of patients. However, none of the 20 patients treated with increasing doses up to a median of 5 mg/week (range, 2.5 to 5) over 6 weeks displayed normalization of UFC, salivary, and serum cortisol levels [60-64]. In the largest retrospective multicenter study on this drug [65], of the 53 patients treated with cabergoline monotherapy, five (9%) developed adrenal insufficiency and 16 (30%) achieved UFC normalization (with only half of these also achieving midnight cortisol normalization) within 12 months—11 within the first 3 months and the remainder thereafter. The median dosage was 1.5 mg per week (range, 0.5 to 4.0). Sustained UFC normalization was obtained in 12 patients (23% of the entire cohort and 67% of the complete responders treated for more than a year), lasting for a median of 32.5 months (range, 19 to 105).
Cabergoline is generally well-tolerated, with mild dizziness and gastrointestinal problems being the most common side effects. However, clinicians must remain vigilant regarding rare psychiatric complications, and cardiac valve monitoring is recommended. Patients should be informed of the potential risk of cardiac valve issues and, more broadly, the risk of fibrosis. Screening recommendations for these risks vary across countries. Recent guidelines from the Pituitary Society on prolactinomas advise performing echocardiography before initiating cabergoline treatment, or within the first few months if a long-term regimen with a dose exceeding 2 mg per week is anticipated. Echocardiography should also be conducted promptly upon detection of a heart murmur, every 2 to 3 years for doses above 2 mg per week, and after 5 to 6 years for doses of 2 mg per week or less [66]. Although cabergoline has been used safely in pregnant women with macroprolactinoma, the risk-benefit balance must be considered in patients with CD.

First- and second-generation somatostatin analogs

Pasireotide is a second-generation multireceptor-targeted somatostatin analog with a high affinity for somatostatin receptor subtype 5. In corticotroph adenomas more so than somatotroph adenomas, this receptor subtype predominates over somatostatin receptor 2; accordingly, a proof-of-concept study has demonstrated its potential involvement in treating CD [67]. In randomized double-blind studies, disease control—based on UFC normalization—was achieved at month 6 in 15% and 26% of patients administered 600 and 900 μg of pasireotide subcutaneously twice daily, respectively [68]. Additionally, approximately 40% of patients receiving 10 or 30 mg of the drug intramuscularly once a month achieved disease control at month 7 [69]. In the latter study, among patients with evaluable assessments at month 12, 45.7% achieved disease control based on UFC normalization, but only 17.4% attained control based on both UFC and late-night salivary cortisol levels [70]. In the former study, among 53 of 162 patients enrolled with measurable tumor volume, reductions in tumor volume were both dose- and time-dependent. Specifically, a reduction of more than 25% was observed in 16% (4/25) of patients treated with 600 μg twice daily at month 6, increasing to 72% (13/18) in those treated with 900 μg twice daily at month 12 [71].
The primary adverse effect is hyperglycemia, which typically manifests within 1 to 2 months and necessitates supplementary medication in about 75% of patients [24,72]. Additional side effects include gastrointestinal problems and cholelithiasis [24].
In EAS, the first-generation somatostatin analogs octreotide and lanreotide have demonstrated partial and transient efficacy in small series and case reports [73]. Specifically, in cases of EAS resulting from medullary thyroid cancer, an anti-secretory effect has been observed with the use of tyrosine kinase inhibitors, independent of their anti-tumor effect [74].
In BMAD, drugs designed to inhibit the secretion of aberrant ligands or to block illegitimate receptors have demonstrated efficacy in case reports or small series. Notably, long-acting leuprolide acetate has been effective in patients with luteinizing hormone-/human chorionic gonadotropin-dependent CS, and first-generation somatostatin analogs have shown promise in treating food-dependent CS [75].
Combination therapy
Some authors recommend combining multiple drugs that target the adrenal gland in cases of severe hypercortisolism [14,76] or when hypercortisolism remains uncontrolled by monotherapy at the maximum tolerated dose [77]. In the context of CD, a stepwise medical treatment may involve the use of cabergoline, pasireotide, and/or ketoconazole [62,63,78-80]. However, it is crucial to monitor for drug interactions and the potential for combinations to cause QT prolongation.
Medical therapies may be employed in the following situations: (1) as an adjuvant therapy in cases of pituitary surgical failure or recurrence, assuming repeat surgery is not indicated, as well as while awaiting the effectiveness of pituitary radiotherapy in CD [7]; (2) when surgery is not feasible for occult or metastatic endocrine tumors with EAS, in cases of locally advanced or metastatic adrenocortical carcinoma with hypercortisolism, or for patients who have inoperable disease or decline surgery [7]; and (3) as first-line therapy in patients with severe hypercortisolism and life-threatening complications, while reserving rescue bilateral adrenalectomy as the potential treatment of last resort [81,82], or as a “bridge therapy” while awaiting etiological curative surgery [14].
In cases of non-severe CS, preoperative medical treatment is not recommended, except when surgery must be postponed due to scheduling concerns or external factors [7,81].
Medical therapy should be individualized, incorporating numerous factors that influence the choice of drug(s) and administration strategy, as outlined in Table 2 [7,83]. These factors exist on top of variations in availability, regulatory approvals, and costs among countries. Whatever the strategy chosen, for long-term treatment, it is crucial to optimize medical therapy to potentially reverse the effects of CS. In a titration regimen, the goal is to achieve eucortisolism by normalizing UFC and nocturnal cortisol levels, while ensuring morning cortisol values do not indicate adrenal insufficiency [83]. With a block-and-replace regimen, clinicians must ensure that cortisol production is effectively blocked [83] while also fine-tuning glucocorticoid replacement, which presents its own challenges [84,85]. Over the long term, medical treatments are frequently discontinued in favor of other therapeutic options, which is at least partially due to the shortcomings of these strategies [86]. Improved outcomes may result from open communication between healthcare providers and patients; multidisciplinary care that specifically addresses pain, myopathy, and psychological issues; and patient education programs designed for individuals with CS [87].
For long-term medical treatment, monitoring of the causal lesion is essential. In cases of occult EAS, repeated imaging (CT and functional imaging) may identify the tumor after several months or even years of follow-up [73]. In patients with CD whose condition is controlled by adrenally targeted drugs, an increase in ACTH levels could indicate corticotroph tumor progression and warrant pituitary magnetic resonance imaging (MRI), as is the case after bilateral adrenalectomy [88]. MRI monitoring may prompt a transition from medical treatment, even if it is effective and well-tolerated, to initial or repeat pituitary surgery [81,86]. In the early postoperative phase, the assessment of remission or persistent disease can be challenging: prolonged preoperative normalization of cortisol levels will result in the disinhibition of normal pituitary corticotrophs, leading to eucortisolism instead of the anticipated corticotropic insufficiency following successful surgery. Additionally, low cortisol levels may be associated with sustained adrenal insufficiency caused by mitotane or osilodrostat, despite the continued excess of ACTH.
The therapeutic strategy is founded on established scientific knowledge, the expertise of a multidisciplinary team, and the patient’s preferences, which are informed by detailed information on the available options. The efficacy of the treatment on cortisol levels and clinical examination, as well as tolerance, must be evaluated regularly. The strategy should be adjusted in the event of patient non-compliance, intolerance, and/or ineffectiveness. However, with very few exceptions, medication-based approaches differ from surgery in that they cannot reestablish a normal corticotroph axis.

CONFLICTS OF INTEREST

Jérôme Bertherat’s institution has received grants from Novartis, HRA Pharma, and Recordati RD. Additionally, Jérôme Bertherat has received personal honoraria for consulting, lectures, and/or meeting attendance from these same entities: Novartis, HRA Pharma, and Recordati RD.

Fig. 1.
Sites of action of adrenally directed drugs. CYP11A1, cholesterol side-chain cleavage enzyme; MIT, mitotane; KET, ketoconazole; CYP17A1, cytochrome P450 family 17 subfamily A member 1; DHEA, dehydroepiandrosterone; 3β-HSD2, 3 b-hydroxysteroid dehydrogenase; CYP21A2, cytochrome P450 family 21 subfamily A member 2; CYP11B2, cytochrome P450 family 11 subfamily B member 2; MET, metyrapone; OSI, osilodrostat; CYP11B1, cytochrome P450 family 11 subfamily B member 1.
enm-2024-501f1.jpg
Table 1.
Main Characteristics of Medical Therapies
Drug Common doses Onset of action Efficacy in Cushing’s disease Adverse effects Monitoring considerations
Mitotane 500 mg to 6 g total per day, given orally three times a day Months UFC normalization in 72% of patients in a retrospective study Teratogenic, abortifacient, numerous adverse effects (gastrointestinal, hepatic, neurologic, metabolic, endocrine, hematologic, dermatologic, etc.) Many drug interactions; highly variable bioavailability (monitor mitotanemia); serum cortisol measurement overestimates active (free) cortisol, with potential for overestimation or underestimation by certain assays
Ketoconazole 200 to 1,200 mg total per day, given orally twice or three times a day A few days UFC normalization in 65% of patients in a retrospective study Hepatotoxicity, gastrointestinal problems Many drug interactions; requires gastric acidity; monitor liver function test and electrocardiogram
Metyrapone 500 mg to 6 g total per day, given orally one to six times a day A few hours UFC normalization in 64% of patients in a retrospective study and in 49% of patients in a prospective study Dizziness, gastrointestinal problems, clinical hyperandrogenism in women, hypertension, edema, hypokalemia Drug interactions; take medication with food; monitor electrocardiogram; monitor cortisol with assays that do not exhibit cross-reactivity with 11-deoxycortisol
Osilodrostat 2 to 14 mg total per day, given orally twice a day. For patients with moderate hepatic impairment and Asian patients, the recommended starting dose is 1 mg twice daily, while for patients with severe hepatic impairment, it is 1 mg once daily in the evening. The maximum recommended maintenance dosage is 60 mg per day, but daily doses up to 80 mg have been used. A few hours to days UFC normalization in 76% of patients in a randomized double-blind study Gastrointestinal problems, arthralgia, dizziness, hypertension, hyperandrogenism in women Drug interactions; monitor electrocardiogram; consider risk of delayed adrenal insufficiency; monitor cortisol with assays that do not exhibit cross-reactivity with 11-deoxycortisol
Cabergoline 0.5 to 4 mg total per week, given orally Weeks to months Disease control in 25% to 40% of patients in retrospective studies Mild dizziness and gastrointestinal problems, rare psychiatric complications Conduct cardiac valve monitoring
Pasireotide 0.3 to 0.9 mg twice daily, given subcutaneously. For patients with moderate hepatic impairment, the recommended starting dose is 0.3 mg twice daily, while the maximum dose is 0.6 mg twice daily. Do not use in cases of severe hepatic impairment. Weeks to months UFC normalization in 15% to 26% of patients in a randomized double-blind study High risk of hyperglycemia, gastrointestinal problems, cholelithiasis, fatigue Monitor glycemia, liver function test, and electrocardiogram
Pasireotide, long-acting release 10 to 40 mg per month, given intramuscularly. For patients with moderate hepatic impairment, the recommended starting dose is 10 mg per month, while the maximum dose is 20 mg per month. Do not use in cases of severe hepatic impairment. Weeks to months UFC normalization in 40% of patients in a randomized double-blind study High risk of hyperglycemia, gastrointestinal problems, cholelithiasis, fatigue Monitor glycemia, liver function test, and electrocardiogram

Due to the heterogeneity of the studies, the data regarding efficacy and adverse effects cannot be directly compared between drugs.

UFC, urinary free cortisol.

Table 2.
Strategy for Medical Therapies
Clinical problem Drugs/approach suggested Drugs not recommended
Women of childbearing age who desire pregnancy Consider bilateral adrenalectomy All available drugs are contraindicated or not recommended.
Some experts suggest using cabergoline or metyrapone [7].
Clinical hyperandrogenism in women Ketoconazole or osilodrostat (in the long term) Metyrapone
Severe hypercortisolism and/or life-threatening complications Metyrapone or osilodrostat monotherapy or combined ketoconazole/metyrapone
Cushing’s disease with residual tumor Cabergoline and/or pasireotide may be considered in a stepwise medical treatment and subsequently associated with an adrenally directed drug if necessary.
Cyclical Cushing’s syndrome Osilodrostat (on block-and-replace regime) or metyrapone (during phases of hypercortisolism)
Patients who exhibit poor compliance or are difficult to monitor Metyrapone may be comparatively safe. Ketoconazole (requires hepatic monitoring and vigilance for drug interactions)
Osilodrostat (carries risk of acute adrenal insufficiency if glucocorticoid replacement treatment is discontinued or is not properly adapted to acute illness)
Diabetes Pasireotide
History of bipolar or impulse control disorder Cabergoline
Liver impairment Ketoconazole, pasireotide
Achlorhydria, H2 antagonists, proton pump inhibitors Ketoconazole
Pre-existing QT prolongation or medications that could increase the risk of QT prolongation Ketoconazole, metyrapone, osilodrostat
Co-prescribed medicines: eplerenone, lovastatin, simvastatin, atorvastatin, oral anticoagulants, anxiolytics, hypnotics, antipsychotics (not exhaustive) Ketoconazole
Co-prescribed medicines: tizanidine, duloxetine, zolmitriptan (not exhaustive) Osilodrostat
  • 1. Tabarin A, Assie G, Barat P, Bonnet F, Bonneville JF, Borson-Chazot F, et al. Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing’s syndrome. Ann Endocrinol (Paris) 2022;83:119–41.ArticlePubMed
  • 2. Wengander S, Trimpou P, Papakokkinou E, Ragnarsson O. The incidence of endogenous Cushing’s syndrome in the modern era. Clin Endocrinol (Oxf) 2019;91:263–70.ArticlePubMedPDF
  • 3. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet 2015;386:913–27.ArticlePubMed
  • 4. van Haalen FM, Broersen LH, Jorgensen JO, Pereira AM, Dekkers OM. Management of endocrine disease: mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol 2015;172:R143–9.ArticlePubMed
  • 5. Tritos NA. Adrenally directed medical therapies for Cushing syndrome. J Clin Endocrinol Metab 2021;106:16–25.ArticlePubMedPDF
  • 6. Wei W, Xu Q, Wu L, Gong G, Tian Y, Huang H, et al. Drug development and potential targets for Cushing’s syndrome. Eur J Med Chem 2024;270:116333.ArticlePubMed
  • 7. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol 2021;9:847–75.PubMedPMC
  • 8. Broersen LH, Jha M, Biermasz NR, Pereira AM, Dekkers OM. Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary 2018;21:631–41.ArticlePubMedPMCPDF
  • 9. Nelson AA, Woodard G. Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2,2-bis(parachlorophenyl)-1,1-dichloroethane (DDD or TDE). Arch Pathol (Chic) 1949;48:387–94.PubMed
  • 10. Hertz R, Bergenstal DM, Lubs HA, Jackson SJ. Observations on adrenal carcinoma with special reference to the effects of amphenone. Cancer 1957;10:765–76.ArticlePubMed
  • 11. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture M, Simon D, et al. Treatment of Cushing’s disease by O,p’DDD: survey of 62 cases. N Engl J Med 1979;300:459–64.ArticlePubMed
  • 12. Baudry C, Coste J, Bou Khalil R, Silvera S, Guignat L, Guibourdenche J, et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur J Endocrinol 2012;167:473–81.ArticlePubMed
  • 13. Donadille B, Groussin L, Waintrop C, Abbas H, Tenenbaum F, Dugue MA, et al. Management of Cushing’s syndrome due to ectopic adrenocorticotropin secretion with 1,ortho-1, para’-dichloro-diphenyl-dichloro-ethane: findings in 23 patients from a single center. J Clin Endocrinol Metab 2010;95:537–44.ArticlePubMed
  • 14. Kamenicky P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 2011;96:2796–804.ArticlePubMed
  • 15. Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O’Neil DM, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metab 2013;98:161–71.ArticlePubMedPDF
  • 16. Hawley JM, Owen LJ, Lockhart SJ, Monaghan PJ, Armston A, Chadwick CA, et al. Serum cortisol: an up-to-date assessment of routine assay performance. Clin Chem 2016;62:1220–9.ArticlePubMedPDF
  • 17. Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2011;75:585–91.ArticlePubMed
  • 18. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med 1987;317:812–8.ArticlePubMed
  • 19. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347–52.ArticlePubMed
  • 20. Moncet D, Morando DJ, Pitoia F, Katz SB, Rossi MA, Bruno OD. Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing’s syndrome. Medicina (B Aires) 2007;67:26–31.PubMed
  • 21. Castinetti F, Morange I, Jaquet P, Conte-Devolx B, Brue T. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing’s disease. Eur J Endocrinol 2008;158:91–9.ArticlePubMed
  • 22. van den Bosch OF, Stades AM, Zelissen PM. Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing’s disease. Clin Endocrinol (Oxf) 2014;80:184–90.PubMed
  • 23. Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab 2014;99:1623–30.ArticlePubMed
  • 24. Castinetti F. How best to monitor the specific side effects of medical treatments of Cushing’s disease. Best Pract Res Clin Endocrinol Metab 2022;36:101718.ArticlePubMed
  • 25. Young J, Bertherat J, Vantyghem MC, Chabre O, Senoussi S, Chadarevian R, et al. Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol 2018;178:447–58.PubMed
  • 26. Chien RN, Yang LJ, Lin PY, Liaw YF. Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology 1997;25:103–7.ArticlePubMed
  • 27. Fleseriu M, Pivonello R, Elenkova A, Salvatori R, Auchus RJ, Feelders RA, et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol 2019;7:855–65.ArticlePubMed
  • 28. Fleseriu M, Auchus RJ, Greenman Y, Zacharieva S, Geer EB, Salvatori R, et al. Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes. Eur J Endocrinol 2022;187:859–71.ArticlePubMedPMCPDF
  • 29. Fleseriu M, Newell-Price J, Pivonello R, Shimatsu A, Auchus RJ, Scaroni C, et al. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur J Endocrinol 2022;187:531–41.ArticlePubMedPMCPDF
  • 30. Pivonello R, Zacharieva S, Elenkova A, Toth M, Shimon I, Stigliano A, et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 2022;25:911–26.ArticlePubMedPMCPDF
  • 31. Creemers SG, Feelders RA, de Jong FH, Franssen GJ, de Rijke YB, van Koetsveld PM, et al. Osilodrostat is a potential novel steroidogenesis inhibitor for the treatment of Cushing syndrome: an in vitro study. J Clin Endocrinol Metab 2019;104:3437–49.ArticlePubMedPDF
  • 32. Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser GM. Metyrapone in long-term management of Cushing’s disease. Br Med J 1977;2:215–7.ArticlePubMedPMC
  • 33. Thoren M, Adamson U, Sjoberg HE. Aminoglutethimide and metyrapone in the management of Cushing’s syndrome. Acta Endocrinol (Copenh) 1985;109:451–7.ArticlePubMed
  • 34. Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman AB, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1991;35:169–78.ArticlePubMed
  • 35. Valassi E, Crespo I, Gich I, Rodriguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol (Oxf) 2012;77:735–42.PubMed
  • 36. Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015;100:4146–54.ArticlePubMedPMC
  • 37. Nieman LK, Boscaro M, Scaroni CM, Deutschbein T, Mezosi E, Driessens N, et al. Metyrapone treatment in endogenous Cushing’s syndrome: results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III/IV study. J Endocr Soc 2021;5(Suppl 1):A515.ArticlePDF
  • 38. Debono M, Harrison RF, Chadarevian R, Gueroult C, Abitbol JL, Newell-Price J. Resetting the abnormal circadian cortisol rhythm in adrenal incidentaloma patients with mild autonomous cortisol secretion. J Clin Endocrinol Metab 2017;102:3461–9.ArticlePubMedPMC
  • 39. Bonnet-Serrano F, Poirier J, Vaczlavik A, Laguillier-Morizot C, Blanchet B, Baron S, et al. Differences in the spectrum of steroidogenic enzyme inhibition between osilodrostat and metyrapone in ACTH-dependent Cushing syndrome patients. Eur J Endocrinol 2022;187:315–22.ArticlePubMedPDF
  • 40. Valentin-Goyco J, Liu J, Peng HM, Oommen J, Auchus RJ. Selectivity of osilodrostat as an inhibitor of human steroidogenic cytochromes P450. J Steroid Biochem Mol Biol 2023;231:106316.ArticlePubMedPMC
  • 41. Perosevic M, Tritos NA. Clinical utility of osilodrostat in Cushing’s disease: review of currently available literature. Drug Des Devel Ther 2023;17:1303–12.ArticlePubMedPMCPDF
  • 42. Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab 2022;107:e2882–95.ArticlePubMedPMCPDF
  • 43. Gadelha M, Snyder PJ, Witek P, Bex M, Belaya Z, Turcu AF, et al. Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: results from the LINC 4 study extension. Front Endocrinol (Lausanne) 2023;14:1236465.ArticlePubMedPMC
  • 44. Tanaka T, Satoh F, Ujihara M, Midorikawa S, Kaneko T, Takeda T, et al. A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease. Endocr J 2020;67:841–52.ArticlePubMed
  • 45. Bessiene L, Bonnet F, Tenenbaum F, Jozwiak M, Corchia A, Bertherat J, et al. Rapid control of severe ectopic Cushing’s syndrome by oral osilodrostat monotherapy. Eur J Endocrinol 2021;184:L13–5.ArticlePubMed
  • 46. Malik RB, Ben-Shlomo A. Adrenal Cushing’s syndrome treated with preoperative osilodrostat and adrenalectomy. AACE Clin Case Rep 2022;8:267–70.ArticlePubMedPMC
  • 47. Blew K, Van Mater D, Page L. Successful management of Cushing syndrome from ectopic ACTH secretion in an adolescent with osilodrostat. JCEM Case Rep 2023;1:luad101.ArticlePubMedPMCPDF
  • 48. Haissaguerre M, Puerto M, Nunes ML, Tabarin A. Efficacy and tolerance of osilodrostat in patients with severe Cushing’s syndrome due to non-pituitary cancers. Eur J Endocrinol 2020;183:L7–9.ArticlePubMed
  • 49. Tabarin A, Haissaguerre M, Lassole H, Jannin A, Paepegaey AC, Chabre O, et al. Efficacy and tolerance of osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas. Eur J Endocrinol 2022;186:K1–4.ArticlePubMed
  • 50. Detomas M, Altieri B, Deutschbein T, Fassnacht M, Dischinger U. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing’s syndrome: results from a single center cohort study. Front Endocrinol (Lausanne) 2022;13:903545.ArticlePubMedPMC
  • 51. Dormoy A, Haissaguerre M, Vitellius G, Do Cao C, Geslot A, Drui D, et al. Efficacy and safety of osilodrostat in paraneoplastic cushing syndrome: a real-world multicenter study in France. J Clin Endocrinol Metab 2023;108:1475–87.ArticlePubMedPMCPDF
  • 52. Poirier J, Bonnet-Serrano F, Thomeret L, Bouys L, Bertherat J. Prolonged adrenocortical blockade following discontinuation of osilodrostat. Eur J Endocrinol 2023;188:K29–32.ArticlePubMedPDF
  • 53. Ferriere A, Salenave S, Puerto M, Young J, Tabarin A. Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism. Eur J Endocrinol 2024;190:L1–3.ArticlePubMedPDF
  • 54. Sawabe F, Hayafusa R, Kosugi R, Ariyasu H. A case of an ectopic ACTH-producing tumor with adrenal shrinkage during osilodrostat administration. JCEM Case Rep 2024;2:luae008.ArticlePubMedPMCPDF
  • 55. Castinetti F, Amodru V, Brue T. Osilodrostat in Cushing’s disease: the risk of delayed adrenal insufficiency should be carefully monitored. Clin Endocrinol (Oxf) 2023;98:629–30.ArticlePubMedPDF
  • 56. Balakirouchenane D, Vasseur A, Bonnet-Serrano F, Choi M, Khoudour N, Puszkiel A, et al. LC-MS/MS method for simultaneous quantification of osilodrostat and metyrapone in human plasma from patients treated for Cushing’s syndrome. J Pharm Biomed Anal 2023;228:115316.ArticlePubMed
  • 57. Armani S, Ting L, Sauter N, Darstein C, Tripathi AP, Wang L, et al. Drug interaction potential of osilodrostat (LCI699) based on its effect on the pharmacokinetics of probe drugs of cytochrome p450 enzymes in healthy adults. Clin Drug Investig 2017;37:465–72.ArticlePubMedPMCPDF
  • 58. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev 2015;36:385–486.ArticlePubMedPMCPDF
  • 59. Nguyen JT, Ferriere A, Tabarin A. Case report: complete restoration of the HPA axis function in Cushing’s disease with drug treatment. Front Endocrinol (Lausanne) 2024;15:1337741.ArticlePubMedPMC
  • 60. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009;94:223–30.ArticlePubMed
  • 61. Lila AR, Gopal RA, Acharya SV, George J, Sarathi V, Bandgar T, et al. Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. Endocr Pract 2010;16:968–76.ArticlePubMed
  • 62. Vilar L, Naves LA, Azevedo MF, Arruda MJ, Arahata CM, Moura E Silva L, et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 2010;13:123–9.ArticlePubMedPDF
  • 63. Barbot M, Albiger N, Ceccato F, Zilio M, Frigo AC, Denaro L, et al. Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment: should we start with cabergoline or ketoconazole? Pituitary 2014;17:109–17.ArticlePubMedPDF
  • 64. Burman P, Eden-Engstrom B, Ekman B, Karlsson FA, Schwarcz E, Wahlberg J. Limited value of cabergoline in Cushing’s disease: a prospective study of a 6-week treatment in 20 patients. Eur J Endocrinol 2016;174:17–24.ArticlePubMed
  • 65. Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, et al. Cabergoline for Cushing’s disease: a large retrospective multicenter study. Eur J Endocrinol 2017;176:305–14.ArticlePubMed
  • 66. Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BM, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 2023;19:722–40.ArticlePubMedPDF
  • 67. Boscaro M, Ludlam WH, Atkinson B, Glusman JE, Petersenn S, Reincke M, et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009;94:115–22.PubMed
  • 68. Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012;366:914–24.ArticlePubMed
  • 69. Lacroix A, Gu F, Gallardo W, Pivonello R, Yu Y, Witek P, et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endocrinol 2018;6:17–26.PubMed
  • 70. Newell-Price J, Pivonello R, Tabarin A, Fleseriu M, Witek P, Gadelha MR, et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease. Eur J Endocrinol 2020;182:207–17.ArticlePubMedPMC
  • 71. Lacroix A, Gu F, Schopohl J, Kandra A, Pedroncelli AM, Jin L, et al. Pasireotide treatment significantly reduces tumor volume in patients with Cushing’s disease: results from a Phase 3 study. Pituitary 2020;23:203–11.ArticlePubMedPMCPDF
  • 72. Feldt-Rasmussen U, Bolanowski M, Zhang SL, Yu Y, Witek P, Kalra P, et al. Predictive factors and the management of hyperglycemia in patients with acromegaly and Cushing’s disease receiving pasireotide treatment: post hoc analyses from the SOM230B2219 study. Front Endocrinol (Lausanne) 2024;15:1250822.ArticlePubMedPMC
  • 73. Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A. Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol 2020;182:R29–58.ArticlePubMed
  • 74. Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing’s syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med 2013;369:584–6.Article
  • 75. Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenicky P, Lacroix A. Clinical, pathophysiologic, genetic, and therapeutic progress in primary bilateral macronodular adrenal hyperplasia. Endocr Rev 2023;44:567–628.ArticlePubMedPDF
  • 76. Corcuff JB, Young J, Masquefa-Giraud P, Chanson P, Baudin E, Tabarin A. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol 2015;172:473–81.ArticlePubMed
  • 77. Amodru V, Brue T, Castinetti F. Synergistic cortisol suppression by ketoconazole-osilodrostat combination therapy. Endocrinol Diabetes Metab Case Rep 2021;2021:21–0071.ArticlePubMedPMC
  • 78. Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 2010;362:1846–8.ArticlePubMed
  • 79. van der Pas R, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, et al. Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease. Pituitary 2013;16:536–44.ArticlePubMedPDF
  • 80. Feelders RA, Fleseriu M, Kadioglu P, Bex M, Gonzalez-Devia D, Boguszewski CL, et al. Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing’s disease. Front Endocrinol (Lausanne) 2023;14:1165681.ArticlePubMedPMC
  • 81. Castinetti F. Pharmacological treatment of Cushing’s syndrome. Arch Med Res 2023;54:102908.ArticlePubMed
  • 82. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing’s syndrome. Lancet 2023;402:2237–52.ArticlePubMed
  • 83. Castinetti F, Nieman LK, Reincke M, Newell-Price J. Approach to the patient treated with steroidogenesis inhibitors. J Clin Endocrinol Metab 2021;106:2114–23.ArticlePubMedPMCPDF
  • 84. Mazziotti G, Formenti AM, Frara S, Roca E, Mortini P, Berruti A, et al. Management of endocrine disease: risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects. Eur J Endocrinol 2017;177:R231–48.ArticlePubMed
  • 85. Caetano CM, Malchoff CD. Daily glucocorticoid replacement dose in adrenal insufficiency, a mini review. Front Endocrinol (Lausanne) 2022;13:897211.ArticlePubMedPMC
  • 86. Ghalawinji A, Drezet L, Chaffanjon P, Muller M, Sturm N, Simiand A, et al. Discontinuation of drug treatment in Cushing’s disease not cured by pituitary surgery. J Clin Endocrinol Metab 2024;109:1000–11.ArticlePubMedPDF
  • 87. Halstrom A, Lin IH, Lin A, Cohen M, Tabar V, Geer EB. Different patient versus provider perspectives on living with Cushing’s disease. Pituitary 2024;27:141–50.ArticlePubMedPMCPDF
  • 88. Fontaine-Sylvestre C, Letourneau-Guillon L, Moumdjian RA, Berthelet F, Lacroix A. Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing’s disease. Pituitary 2021;24:207–15.ArticlePubMedPDF

Figure & Data

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    Figure
    • 0
    Medical Treatment of Cushing’s Syndrome
    Image
    Fig. 1. Sites of action of adrenally directed drugs. CYP11A1, cholesterol side-chain cleavage enzyme; MIT, mitotane; KET, ketoconazole; CYP17A1, cytochrome P450 family 17 subfamily A member 1; DHEA, dehydroepiandrosterone; 3β-HSD2, 3 b-hydroxysteroid dehydrogenase; CYP21A2, cytochrome P450 family 21 subfamily A member 2; CYP11B2, cytochrome P450 family 11 subfamily B member 2; MET, metyrapone; OSI, osilodrostat; CYP11B1, cytochrome P450 family 11 subfamily B member 1.

    Fig. 1.

    Medical Treatment of Cushing’s Syndrome
    Drug Common doses Onset of action Efficacy in Cushing’s disease Adverse effects Monitoring considerations
    Mitotane 500 mg to 6 g total per day, given orally three times a day Months UFC normalization in 72% of patients in a retrospective study Teratogenic, abortifacient, numerous adverse effects (gastrointestinal, hepatic, neurologic, metabolic, endocrine, hematologic, dermatologic, etc.) Many drug interactions; highly variable bioavailability (monitor mitotanemia); serum cortisol measurement overestimates active (free) cortisol, with potential for overestimation or underestimation by certain assays
    Ketoconazole 200 to 1,200 mg total per day, given orally twice or three times a day A few days UFC normalization in 65% of patients in a retrospective study Hepatotoxicity, gastrointestinal problems Many drug interactions; requires gastric acidity; monitor liver function test and electrocardiogram
    Metyrapone 500 mg to 6 g total per day, given orally one to six times a day A few hours UFC normalization in 64% of patients in a retrospective study and in 49% of patients in a prospective study Dizziness, gastrointestinal problems, clinical hyperandrogenism in women, hypertension, edema, hypokalemia Drug interactions; take medication with food; monitor electrocardiogram; monitor cortisol with assays that do not exhibit cross-reactivity with 11-deoxycortisol
    Osilodrostat 2 to 14 mg total per day, given orally twice a day. For patients with moderate hepatic impairment and Asian patients, the recommended starting dose is 1 mg twice daily, while for patients with severe hepatic impairment, it is 1 mg once daily in the evening. The maximum recommended maintenance dosage is 60 mg per day, but daily doses up to 80 mg have been used. A few hours to days UFC normalization in 76% of patients in a randomized double-blind study Gastrointestinal problems, arthralgia, dizziness, hypertension, hyperandrogenism in women Drug interactions; monitor electrocardiogram; consider risk of delayed adrenal insufficiency; monitor cortisol with assays that do not exhibit cross-reactivity with 11-deoxycortisol
    Cabergoline 0.5 to 4 mg total per week, given orally Weeks to months Disease control in 25% to 40% of patients in retrospective studies Mild dizziness and gastrointestinal problems, rare psychiatric complications Conduct cardiac valve monitoring
    Pasireotide 0.3 to 0.9 mg twice daily, given subcutaneously. For patients with moderate hepatic impairment, the recommended starting dose is 0.3 mg twice daily, while the maximum dose is 0.6 mg twice daily. Do not use in cases of severe hepatic impairment. Weeks to months UFC normalization in 15% to 26% of patients in a randomized double-blind study High risk of hyperglycemia, gastrointestinal problems, cholelithiasis, fatigue Monitor glycemia, liver function test, and electrocardiogram
    Pasireotide, long-acting release 10 to 40 mg per month, given intramuscularly. For patients with moderate hepatic impairment, the recommended starting dose is 10 mg per month, while the maximum dose is 20 mg per month. Do not use in cases of severe hepatic impairment. Weeks to months UFC normalization in 40% of patients in a randomized double-blind study High risk of hyperglycemia, gastrointestinal problems, cholelithiasis, fatigue Monitor glycemia, liver function test, and electrocardiogram
    Clinical problem Drugs/approach suggested Drugs not recommended
    Women of childbearing age who desire pregnancy Consider bilateral adrenalectomy All available drugs are contraindicated or not recommended.
    Some experts suggest using cabergoline or metyrapone [7].
    Clinical hyperandrogenism in women Ketoconazole or osilodrostat (in the long term) Metyrapone
    Severe hypercortisolism and/or life-threatening complications Metyrapone or osilodrostat monotherapy or combined ketoconazole/metyrapone
    Cushing’s disease with residual tumor Cabergoline and/or pasireotide may be considered in a stepwise medical treatment and subsequently associated with an adrenally directed drug if necessary.
    Cyclical Cushing’s syndrome Osilodrostat (on block-and-replace regime) or metyrapone (during phases of hypercortisolism)
    Patients who exhibit poor compliance or are difficult to monitor Metyrapone may be comparatively safe. Ketoconazole (requires hepatic monitoring and vigilance for drug interactions)
    Osilodrostat (carries risk of acute adrenal insufficiency if glucocorticoid replacement treatment is discontinued or is not properly adapted to acute illness)
    Diabetes Pasireotide
    History of bipolar or impulse control disorder Cabergoline
    Liver impairment Ketoconazole, pasireotide
    Achlorhydria, H2 antagonists, proton pump inhibitors Ketoconazole
    Pre-existing QT prolongation or medications that could increase the risk of QT prolongation Ketoconazole, metyrapone, osilodrostat
    Co-prescribed medicines: eplerenone, lovastatin, simvastatin, atorvastatin, oral anticoagulants, anxiolytics, hypnotics, antipsychotics (not exhaustive) Ketoconazole
    Co-prescribed medicines: tizanidine, duloxetine, zolmitriptan (not exhaustive) Osilodrostat
    Table 1. Main Characteristics of Medical Therapies

    Due to the heterogeneity of the studies, the data regarding efficacy and adverse effects cannot be directly compared between drugs.

    UFC, urinary free cortisol.

    Table 2. Strategy for Medical Therapies

    Table 1.

    Table 2.

    Endocrinol Metab : Endocrinology and Metabolism
    © Korean Endocrine Society.
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