Medical Therapy of Endogenous Cushing’s Syndrome with Steroidogenesis Inhibitors: Treatment Rationale, Available Drugs, and Therapeutic Effects

Abstract

Endogenous Cushing’s syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

Keywords

etomidate - hypercortisolism - ketoconazole - levoketoconazole - medical therapy - metyrapone - mitotane - osilodrostat

Introduction

Endogenous Cushing’s syndrome (CS) is a rare disease with an estimated annual incidence ranging between 2 and 8 cases per million people [1]. Adequate diagnosis and therapy of CS is fundamental, as prolonged glucocorticoid excess substantially increases morbidity and mortality [2]. The only curative approach is surgical removal of the underlying tumor, making surgery the first-line treatment for endogenous CS irrespective of the causative etiology.

If surgery cannot be performed or is contraindicated, second-line treatments like medical therapy, bilateral adrenalectomy (BADX) or radiotherapy may be required. Typical candidates for second-line treatments are patients with occult ectopic CS (ECS) due to adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumors or metastatic adrenocortical carcinomas (ACC), patients with Cushingʼs disease (CD) and large pituitary adenomas infiltrating the cavernous sinus (where total adenomectomy is not feasible), and patients with relevant CS-induced complications like psychosis or severe infections. Although BADX may represent a fast and definitive solution of CS, it has some important drawbacks (e. g., the risk of peri- and postoperative complications like bleeding, thrombosis or infections, and the consecutive need for life-long glucocorticoid replacement therapy due to permanent adrenal insufficiency). In contrast, medical therapy can reduce hypercortisolism fast and effectively, is usually well tolerated, and does not necessarily cause adrenal insufficiency [3] [4]. Despite various retrospective reports on steroidogenesis inhibitors [3] [4], prospective head-to-head comparative studies have not been published yet, hampering the choice of the most appropriate drug in specific cases.

The current review summarizes the main characteristics of steroidogenesis inhibitors, illustrating the individual mechanism of action, treatment efficacy, and safety of these drugs.

Currently available steroidogenesis inhibitors

Ketoconazole

Initially used as an antifungal drug, the imidazole derivative ketoconazole was withdrawn from the market (e. g., in Europe in 2013) due to relevant adverse events mainly affecting the liver. Nevertheless, the European Medicines Agency (EMA) approved ketoconazole for the treatment of endogenous CS in 2014. The rationale for this decision is that ketoconazole blocks cytochrome-P450 enzymes, thereby leading to a broad impairment of adrenal steroidogenesis (including reduced cortisol synthesis and secretion) ([Fig. 1]). Due to its short half-life of about 3.3 hours, the drug is orally administered 2 or 3 times a day (with daily doses ranging from 200–1200 mg) [3].

Fig. 1 Adrenal steroidogenesis and mechanism of action of steroidogenesis inhibitors. Abbreviations: P450scc: cholesterol side-chain cleavage enzyme, 17αOH: 17α-hydroxylase, 3βHSD: 3β-hydroxysteroid dehydrogenase, 21-OH: 21-hydroxylase, 11β-OH: 11β-hydroxylase, 18-OH: 18-hydroxylase. Figure created with BioRender.

Considering short-term effects, one study provided data from 40 patients with CS treated with ketoconazole before surgery [5]. After a mean follow-up of 4 months, 24-hour urinary free cortisol (24h-UFC) was normalized in 49% of patients and decreased by at least 50% in an additional 36% of patients. Furthermore, improvement of arterial hypertension, diabetes mellitus, clinical signs of CS, and hypokalemia was observed in 50%, 50%, 42%, and 38% of cases, respectively [5].

A recent meta-analysis reported the treatment effects of ketoconazole in 270 patients with CD and residual cortisol excess after surgery. After a mean treatment duration ranging from 4 to 66 months, biochemical control of hypercortisolism was achieved in the majority of patients (median 63%, range 39% to 89%) [6]. The variable therapeutic effectiveness was mainly attributed to differences in study design and patient cohorts. Of note, however, the largest single study included in the meta-analysis involved 200 patients and reported normalization of 24-hour 24h-UFC in 65% of patients after 24 months of treatment [5]. Accordingly, ketoconazole is effective not only as short-term, but also as a long-term therapy (see [Table 1] for a summary of published data on ketoconazole and other steroidogenesis inhibitors).

Table 1 Published data on efficacy and side effects of steroidogenesis inhibitors.

Steroidogenesis inhibitor	Administration	Common dose range	Therapeutic efficacy (rate of patients with normalized 24h-UFC)	Most frequent treatment-related adverse events
Ketoconazole	Oral	200–1200 mg/day	45–93% [5,6,8,54,55]	Hirsutism (36%), hepatotoxicity (11–19%), adrenal insufficiency (5–19%), gastrointestinal problems (4–19%), skin rash (4–6%), and gynecomastia (new onset or worsening) (17–25%) [5,6,8,54,55]
Levoketoconazole	Oral	300–1200 mg/day	31–81% [9,10]	Nausea (29–32%), headache (23–28%), hypokalemia (11–26%), hypertension (17–24%), and QT prolongation (5–11%) [9,10]
Metyrapone	Oral	250–6000 mg/day	45–100% [3,8,11,12,14,47]	Hirsutism (5–71%), nausea (5–33%), dizziness (10–44%), edema (6–20%), decreased appetite (18%), -fatigue (14%), headache (10%), hypokalemia (6%), and hypertension (6–48%) [3,8,11,12,14,47]
Osilodrostat	Oral	4–60 mg/day	66–100% [4,14–16,39]	Fatigue (29–58%), nausea (32–42%), headache (25–34%), diarrhea (25–32%), adrenal insufficiency (28–32%), QT prolongation (4–13%), and hypertension (12%) [4,14–16,39]
Mitotane	Oral	Mean drug dose 2500–3300 g/day (according to blood concentration)	76–91% [21,27,30]	Gastrointestinal tract problems (47–65%), neurological complications (26–36%), asthenia (68%), nausea (53%), hypercholesterolemia (54%), increased transaminases (36%), and anorexia (36%) [21,27,30]
Etomidate	Intravenous	0.02–0.1 mg/kg/h	100% [31–34]*	Adrenal insufficiency (80%), myoclonus (32%), sedation, cardiac arrhythmias, central nervous system depression, and lactic acidosis [31–34]
Ketoconazole+Meyrapone	Oral	Ketoconazole 400–1200 mg/day+Metyrapone 500–4000 mg/day	73–86% [37] **	Hepatotoxicity (9%) and nausea (50%) [37]
Ketoconazole+Metyrapone+Mitotane	Oral	Ketoconazole 400–1200 mg/day+Metyrapone 500–4000 mg/day+Mitotane 3000–5000 mg/day	64% [36] ***	Hypokalemia (virtually always), increase in liver enzymes (18–82%), nausea and vomiting (64%), and adrenal insufficiency (36%) [36]

*data from case reports or small case-series **data from 22 patients ***data from 11 patients.

The most frequent side effect of ketoconazole is hepatotoxicity, which is observed in 9–19% of cases [3] [4] [7]. In one study, 18% of patients showed a more than 5-fold increase in liver enzymes [5]. Of note, the latter normalized within 2–4 weeks of drug discontinuation in nearly all patients. Only in one case, liver enzymes were initially 40-fold increased but normalized 90 days after ketoconazole withdrawal. Other relevant treatment-related adverse events are hirsutism (36%), adrenal insufficiency (5–19%), gastrointestinal problems (4–19%), and skin rash (4–6%) [3] [4] [8]. In addition, gynecomastia may occur in up to 17% of male patients [3] [8] ([Table 1]).

Levoketoconazole

Levoketoconazole is the 2 S,4 R enantiomer of ketoconazole ([Fig. 1]). Compared to the latter, levoketoconazole has been described as more effective in inhibiting 11β-hydroxylase, 17α-hydroxylase, and the cholesterol side chain cleavage enzymes [9]. In 2021, the drug was approved by the Food and Drug Administration (FDA) for the treatment of adult patients with CS for whom surgery is not an option. To date, however, it has not been approved in Europe.

Levoketoconazole is orally administered and has a half-life of 4–6 hours, allowing a twice-daily administration. The common drug dosage of levoketoconazole ranges from 300 to 1200 mg/day [3]. To date, the largest study published on the effects of levoketoconazole in endogenous CS was the phase III open-label multicenter study SONICS, including a total of 94 patients [9]. Of the 55 patients who completed the 6 months maintenance phase, 62% had a normalized 24h-UFC. In the double-blind, placebo-controlled randomized LOGICS study, 11 out of 22 patients (50%) treated with levoketoconazole had a normalized 24h-UFC at the end of the randomized withdrawal phase [10]. After one month of treatment with levoketoconazole, mean 24h-UFC decreased from 4.9x the upper limit of normal (ULN) to the normal range, and 24h-UFC remained normal within the first 6 months of maintenance therapy. In patients in whom drug dose was not increased, a normalization of 24h-UFC was observed in 48%, 50%, and 44% of cases after 1, 2, and 3 months of treatment, respectively. Furthermore, a significant improvement in glycated hemoglobin, body mass index, and cholesterol levels, but not in blood pressure, was reported [9] [10] ([Table 1]).

The typical adverse events under treatment with levoketoconazole are nausea (29–32%), headache (23–28%), hypokalemia (11–26%), hypertension (17–24%), and QT prolongation (5–11%) [4] [9] [10] ([Table 1]). As for ketoconazole, an increase in transaminases is observed in 12–45% of patients, but liver impairment is usually completely reversible within 4 weeks of drug discontinuation [10].

Metyrapone

Metyrapone inhibits the activity of both 11β-hydroxylase and 18-hydroxylase, thereby reducing cortisol and aldosterone secretion and increasing the concentrations of mineralocorticoid precursors ([Fig. 1]). This drug is orally administered at a dosage of 250 to 6000 mg/day. Because of a short half-life of about 2 hours, dose administration is required three (or even more) times a day. While metyrapone has been approved by the EMA, it needs to be used as an off-label treatment in the USA.

The largest retrospective study on metyrapone as monotherapy included 164 patients with CS [11]. After 8 months of treatment with a median dose of 1500 mg/day, 24h-UFC and serum cortisol day curves were controlled in 43% and 55% of cases, respectively [11]. A more recent retrospective study reported normalization rates of 70% for 24h-UFC and 37% for late-night salivary cortisol (LNSC) after treatment with a median metyrapone dose of 1000 mg/day for 9 months [12]. To date, only one prospective study has been carried out (the so-called PROMPT study) but the final results have not yet been published [13]. According to preliminary data, normalization of 24h-UFC was observed in 23 of 49 (47%) patients after 12 weeks of metyrapone treatment [13] ([Table 1]).

Few published data on the short-term effects of metyrapone are available. In the largest retrospective study published so far, metyrapone was administered over a mean period of 4 months before surgery [11]. At last follow-up, a normalization of 24h-UFC and serum cortisol day curves was identified in 40% and 35% of patients, respectively [11]. A recent Italian study reported decreases of −67% (for 24h-UFC) and −57% (for LNSC) after one month of treatment with a median metyrapone dose of 750 mg/day [12]. Interestingly, the decrease from baseline was even more pronounced after 3 months of treatment (−70% for 24h-UFC and −63% for LNSC, respectively) [12]. We also recently reported early treatment effects, with 24h-UFC decreases of −21% and −38% after 2 and 4 weeks under metyrapone, respectively [14].

Of note, 66% of the patients enrolled in the PROMPT study reported an improvement or normalization of physical signs and symptoms of CS. Furthermore, lipid profile, glucose metabolism, and blood pressure also improved [13].

The most frequently reported side effects of metyrapone are nausea (5−33%), dizziness (10−44%), edema (6−20%), decreased appetite (18%), fatigue (14%), headache (10%), hypokalemia (6%), and hypertension (6%) [3] [4]. In addition, female patients often suffer from acne and hirsutism (5–71%) [3] [4] ([Table 1]).

Osilodrostat

Osilodrostat is another 11β-hydroxylase inhibitor ([Fig. 1]). It has a longer half-life than metyrapone and ketoconazole, and thus has to be administered twice a day only. Osilodrostat was approved by the EMA in 2021, making it the most recent available drug in Europe.

So far, most data on its effects are derived from prospective clinical trials. In the phase III study LINC3, 72 out of 137 patients (53%) were completely controlled after 12 weeks of treatment without any up-titration of dosages [15]. After 24 weeks on osilodrostat (with doses ranging from 4 to 60 mg/day), 68% of patients were in remission [15]. Therapeutic efficacy was confirmed in the phase III study LINC4. Here, a remission rate of 77% was observed after 12 weeks of treatment [16] ([Table 1]).

Data on the short-term effects of osilodrostat are still limited. From the LINC4 study [16], it could be extrapolated that the mean 24h-UFC levels normalized after 8 and 12 weeks of treatment. If the short-term effects of metyrapone and osilodrostat were analyzed, we observed 24h-UFC decreases of −68% and −50% after 2 and 4 weeks, respectively [14]. Of note, 50% of our patients had a normalized 24h-UFC after 12 weeks of treatment. This is well in line with a more recent study on 11 patients with ECS and osilodrostat as monotherapy. Here, biochemical remission was observed in 9 patients after a median treatment duration of 2 weeks [17] ([Table 1]).

Interestingly, as osilodrostat results in lower blood pressure, the number of antihypertensives may decrease already within the first month of treatment [14] [17]. Body weight, glucose metabolism, and quality of life were also found to improve [3] [15].

The most reported adverse event of osilodrostat are fatigue (29–58%), nausea (32–42%), headache (25–34%), adrenal insufficiency (28–32%) and diarrhea (25–32%) [3] [4] ([Table 1]). Other relevant side effects are hypokalemia (13%) and QT prolongation (4%) [3] [15]. Of note, it has recently been shown that adrenal insufficiency may persist even for several months after stopping osilodrostat treatment [18] [19] [20].

Mitotane

Although the mechanism of action of mitotane on adrenal cells is still not completely understood, it is known to have an adrenolytic effect, inhibit mitochondrial enzymes involved in the steroidogenesis (like the 11β-hydroxylase), and block the cholesterol side chain cleavage ([Fig. 1]) [21] [22] [23]. Furthermore, mitotane activates cytochrome P4503A4 enzymes, thereby leading to a rapid metabolic clearance of steroidal hormones (including glucocorticoids) [21] [22]. Because of its long half-life and its accumulation in adipose tissue, treatment effects of mitotane may be observed even several months after its discontinuation [22]. To date, mitotane is the only approved drug for the treatment of adrenocortical carcinoma both in Europe and the USA [24] [25] [26].

The largest study on mitotane for the treatment of endogenous CS included 76 patients with CD [21]. After a median treatment duration of 7 months, 72% of patients were in remission [21] ([Table 1]). At this time, the mean mitotane dose was 2.7 g/day, and the authors suggested a mitotane plasma concentration of 8.5 mg/l as an indicator of disease control. Data on short-term effects of mitotane were not reported in this study. Another study described the treatment efficacy of mitotane in 23 ECS patients. After a mean of 4 months under a mean mitotane dose of 3.3 g/day, CS was controlled in 21 patients (91%) [27]. In the 12 patients with available data, the mean plasma mitotane concentration was 10.4 µg/mL.

Importantly, mitotane is associated with several adverse events, including a broad range of gastrointestinal (47–65%) or neurological (26–36%) complications. Hypercholesterolemia (54%), increased liver enzymes (36%), and anorexia (36%) are also commonly observed [21] [27] [28] [29] ([Table 1]). Other reported side effects include mild neutropenia and gynecomastia [21] [30].

Etomidate

Etomidate is an imidazole derivative that inhibits 11β-hydroxylase at low concentrations, while higher levels block the cholesterol side chain enzymes [4]. It is the only steroidogenesis inhibitor that can be administered intravenously, making it very useful in particular settings (e. g., in patients with sustained hypertensive crises or relevant psychosis). The half-life of etomidate is 3–5 hours, and doses usually range from 0.02 to 0.2 mg/kg/h [4] [31]. Because of its sedative effect and the high risk of adrenal insufficiency, etomidate should only be administered in an intensive care setting.

Published data on its therapeutic effects are usually derived from case reports or small case series describing a fast normalization of hypercortisolemia (which is usually observed in less than 24 hours) [31] [32] [33] [34]. In 6 CS patients, mean serum cortisol concentrations decreased from 1374 nmol/L to 188 nmol/L after 11 hours of etomidate infusion and remained low until the end of treatment, while 11-deoxycortisol levels increased [34].

The most relevant side effect of etomidate is adrenal insufficiency (occurring in up to 80% of patients) ([Table 1]). In addition, myoclonus (32%), sedation, cardiac arrhythmias, depression, and lactic acidosis may occur [31] [35].

Combination of oral steroidogenesis inhibitors

Combination of oral steroidogenesis inhibitors may be performed if remission cannot be achieved by a single agent. In case of severe hypercortisolemia, an oral combination therapy may also represent a possible alternative to etomidate (and may then be applied outside an intensive care setting as well). In 11 patients with severe ACTH-dependent CS who were treated with a combination of ketoconazole (400–1200 mg/day), metyrapone (3000–4500 mg/day), and mitotane (3000–5000 mg/day), a remission rate of 64% was observed [36] ([Table 1]). A combination of ketoconazole and metyrapone was used in a small series with severe CS due to ECS or ACC. Here, 73% of patients with ECS and 86% with ACC achieved remission from hypercortisolism under ketoconazole plus metyrapone at dosages of 400–1200 and 500–4500 mg/day, respectively [37] ([Table 1]).

Recently, the outcome of a combination therapy with ketoconazole (600 mg/day) and osilodrostat (30 mg/day) in a patient with CS due to primary bilateral macronodular adrenocortical hyperplasia was reported. Apart from an excellent control of hypercortisolism, a rapid improvement of arterial hypertension, potassium levels, and diabetes mellitus was observed (without reporting any adverse events) [38].

When a dose-dependent adverse event occurs or is suspected, a shift from a monotherapy to a combination therapy may represent an alternative. It has already been shown that a dose reduction of one steroidogenesis inhibitor and adding a complementary drug with different mechanism of action may reduce the risk of side effects that are typically observed if a single drug is administered at higher dosages [39].

The most frequently reported adverse events of combination therapies with steroidogenesis inhibitors were: hypokalemia (observed in virtually all patients), increased liver enzymes (18–82%), nausea and/or vomiting (64%), and adrenal insufficiency (36%) [36] ([Table 1]).

Drug dosing

If a steroidogenesis inhibitor is applied, a “block and replace” or a “dose titration” approach may be used [39]. The first approach causes a complete (and not only a partial) block of adrenal cortisol secretion. For this, the respective drug is usually administered in higher doses than if the dose is titrated according to cortisol concentrations and the clinical outcome. If endogenous cortisol secretion is substantially blocked (as illustrated by low levels of e. g., 24h-UFC or serum cortisol), concomitant oral glucocorticoid replacement therapy should be initiated (e. g., with a hydrocortisone equivalent of at least 20 mg/day), aiming to reduce the risk of clinically relevant adrenal insufficiency and to provide a more physiological cortisol curve over the day. Of note, in some cases, hydrocortisone doses of more than 30 mg/day may be required to prevent from developing a clinically relevant glucocorticoid withdrawal syndrome. As 11β-hydroxylase inhibitors also cause an increase in mineralocorticoid precursors, an additional dose of fludrocortisone is rarely necessary [40]. The “dose titration” approach usually involves lower drug doses at the time of treatment initiation, which are then escalated according to the biochemical and clinical outcome. In order to achieve a more physiological secretion pattern of cortisol, slightly lower drug doses in the morning compared to the rest of the day may be useful. Of note, both treatment approaches can be applied to all steroidogenesis inhibitors.

Drug monitoring

Monitoring the therapeutic effects of steroidogenesis inhibitors can sometimes be difficult and often requires a simultaneous evaluation of biochemical and clinical parameters.

Biochemical tests used to assess the treatment efficacy of steroidogenesis inhibitors are morning serum cortisol, 24h-UFC, and LNSC. Each diagnostic tool has certain advantages and disadvantages. A main limitation of all laboratory tests is that their results might be affected by analytical interference. For instance, 11β-hydroxylase inhibitors may lead to an increase of 11-deoxycortisol [4], which could cross-react with some immunoassays, thereby leading to an overestimation of cortisol levels [40]. This is particularly true for serum cortisol [41]. Nevertheless, repetitive blood sampling over a day may allow for serum cortisol day curves, which provide a robust estimate of the endogenous cortisol secretion capacity over 24 h. 24h-UFC is also widely used in the monitoring of steroidogenesis inhibitors [40], but a high intra-patient coefficient of variation has to be considered [42] [43]. Furthermore, a recent publication reported that ketoconazole and metyrapone may alter the urinary excretion of steroid metabolites, thereby leading to a high risk of overestimating their biochemical impact [44]. With respect to LNSC, a high intra-patient variation of almost 50% has been reported [43].

In addition to the measurement of classical hormonal parameters, treatment effects of steroidogenesis inhibitors can also be assessed indirectly. For instance, a relevant improvement of hyperglycemia, dyslipidemia, and hypokalemia is a common finding after treatment initiation [9] [10] [13]. However, as mineralocorticoid precursors often increase under 11β-hydroxylase inhibitors, potassium levels may also worsen during treatment [3]. Alterations of hematological parameters observed in patients with CS (e. g., neutrophilia, lymphopenia, anemia in males) typically improve after remission of hypercortisolism [45] [46]. However, detailed information on the distinct changes in hematological parameters during medical therapy has not been reported yet.

Finally, the treatment effects of steroidogenesis inhibitors should ideally be monitored clinically as well. Arterial hypertension, for instance, usually improves already within the first weeks of therapy, whereas clinical signs typical for CS (like plethora and centripetal obesity) often persist even for months after biochemical control [40].

Comparison of the steroidogenesis inhibitors

Although steroidogenesis inhibitors belong to the same drug family and are therefore characterized by a similar mechanism of action, these drugs have some specific features that need to be considered. Large studies directly comparing different drugs with each other have not been published yet but would certainly be of interest. The first retrospective series comparing CS patients under metyrapone and osilodrostat showed a comparable therapeutic efficacy [13]. Although the study cohorts were small, osilodrostat appeared to reduce cortisol levels and blood pressure faster than metyrapone [14]. According to preliminary results of a large multicentric study that compared metyrapone, ketoconazole, and osilodrostat, the latter allowed for the best control of blood pressure [47]. Recently, two studies reported higher levels of 11-deoxycortisol, androstenedione, and other androgens under metyrapone compared to osilodrostat [48] [49]. Such differences in the treatment-induced changes of the biochemical profile most likely explain the different therapeutic effects and adverse events.

The choice of the most appropriate steroidogenesis inhibitor in a certain setting

Currently, large-scale comparative data on steroidogenesis inhibitors are lacking. Therefore, the choice of a specific drug for treating different clinical scenarios in the context of endogenous CS may be difficult. Some factors may help to identify the most appropriate drug in a certain setting:

• Drug availability: Ketoconazole, metyrapone, and osilodrostat have been approved by the EMA and are therefore available in Europe. In the USA, however, only osilodrostat and levoketoconazole have been approved by the FDA.

• Arterial hypertension: 11β-hydroxylase inhibitors cause an increase in mineralocorticoid precursors and may, therefore, induce or exacerbate arterial hypertension, as reported in up to 48% of patients under metyrapone and up to 12% of patients under osilodrostat [3] ([Table 1]). However, osilodrostat (which was first developed as an antihypertensive drug) may also induce a fast reduction of blood pressure if hypertension is already present at baseline [14]. As a consequence, osilodrostat may be the drug of choice in patients with known (severe) arterial hypertension. In case of a hypertensive crisis, intravenous etomidate infusion may be considered.

• Hypokalemia: 11β-hydroxylase inhibitors cause an increase in mineralocorticoid precursors, potentially leading to a relevant lowering of potassium levels. However, hypokalemia is not a common side effect of ketoconazole and levoketoconazole ([Table 1]). Therefore, if severe hypokalemia is observed under metyrapone or osilodrostat, a switch to ketoconazole or levoketoconazole may be helpful.

• Optimal drug absorption: Ketoconazole is better absorbed in an acid milieu. If a proton pump inhibitor is used, an alternative drug should therefore be evaluated or ketoconazole should be taken with an acidic beverage [40].

• Gastrointestinal tract: If liver enzymes are more than 3-fold elevated, ketoconazole should be avoided [40].

• Androgenetic and demasculinizing effects: 11β-hydroxylase inhibitors may cause an increase in adrenal androgens. In women, this may lead to hirsutism and acne (rates under metyrapone and osilidrostat of up to 36% and 11%, respectively, were reported) [4]. On the other hand, gynecomastia may occur in up to 17% of men treated with ketoconazole (caused by a decrease in testosterone due to the inhibition of cytochrome P450 enzymes) [3]. Accordingly, sex-specific effects need to be considered (e. g., using an 11β-hydroxylase inhibitor in males with low testosterone levels).

• Electrocardiogram: ketoconazole, levoketoconazole, and osilodrostat may increase the QT interval, thereby leading to a higher risk for torsades de pointes and mortality [14] [39]. For this reason, an electrocardiogram should be performed before starting any medical therapy. If the QT-interval is prolonged, metyrapone seems to be the most appropriate drug since QT alterations are not among the typical adverse events. During treatment with ketoconazole, levoketoconazole, and osilodrostat, electrocardiograms should be performed periodically.

• Drug interaction: Ketoconazole may interact with several drugs due to its strong inhibition of cytochrome P450 3AE enzymes [40]. Accordingly, the bioavailability of other drugs may be altered, thereby increasing the risk of (relevant) treatment-related adverse events. Although to a weaker extent than for ketoconazole, osilodrostat inhibits cytochrome P450 3A4 enzymes as well. This needs to be considered if other drugs than steroidogenesis inhibitors are administered [50].

• Drug pharmacokinetics: In some patients, drugs with longer half-life, like levoketoconazole and osilodrostat, need to be considered (e. g., to reduce to number of pills or drug intakes per day) [40].

Possible new candidates for drug therapy for Cushingʼs syndrome

To date, there are no ongoing studies on new steroidogenesis inhibitors (at least to our knowledge). The only adrenal-directed drug under clinical investigation is ATR-101 (Nevanimibe) [51]. This drug does not act directly on adrenal steroidogenesis but on acyl-coenzyme A (ACAT1), a transmembrane enzyme involved in cholesterol metabolism [51]. ACAT1 is involved in the synthesis of cholesterol esters from fatty acid and free cholesterol. Initially, it was believed that the inhibition of ACAT1 through ATR-101 may be a potential target in the therapy of hypercholesterolemia and atherosclerosis [51] [52]. However, in vivo studies in different animal models showed that ATR-101 induced adrenocortical degeneration and necrosis of the zona fasciculate and reticularis [51] [52]. Due to its adrenolytic effects, ATR-101 has been proposed as a novel medical treatment of CS. In 2017, a phase II, randomized, double-blind, placebo-controlled trial was started to evaluate its efficacy and safety in endogenous CS (clinicaltrials.gov code: NCT03053271) [51]. The study was closed in August 2019 due to slow enrollment. We are not aware of any preliminary data on the trial results.

Relacorilant is a new drug under investigation in a phase III study (NCT03697109). It is an oral, highly selective, non-steroidal modulator of the glucocorticoid receptor. The block of the glucocorticoid receptor impairs the translocation of the ligand-receptor complexes to the nucleus and the consequent gene transcription. The main advantage of this drug is that, unlike the well-known glucocorticoid receptor antagonist mifepristone, no effects on the progesterone receptor have been observed. As a consequence, pregnancy termination and endometrial hypertrophy are not expected adverse events of relacorilant [4].

In April 2023, a Phase 1b/2a, first-in-disease, open-label, multiple-ascending dose exploration study was initiated to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic biomarker responses associated with CRN04894 (an ACTH receptor antagonist). The study is currently ongoing.

Two clinical trials have focused on SPI-62, an inhibitor of 11β-hydroxysteroid dehydrogenase enzymes that catalyze the conversion of inactive cortisone into active cortisol. These enzymes are present in key metabolic tissues of the body, including the liver, adipose tissue, kidney, and lungs. Both trials evaluated the efficacy, safety, and pharmacological effects of SPI-62 in different study cohorts (i. e., subjects with hypercortisolism due to a benign adrenal tumor in study NCT05436639, and subjects with ACTH-dependent Cushing's syndrome in study NCT05307328) [53].

Conclusion

In endogenous CS, oral steroidogenesis inhibitors represent an important and effective alternative to surgery. In emergency situations where rapid control of CS is needed, intravenous etomidate administered in an intensive care setting or combination therapy with oral drugs may represent established and useful therapeutic options. As CS is a complex and heterogeneous disorder, the individual setting (e. g., comorbidities and preferences) needs to be considered to identify the most appropriate drug for each patient. Large comparative studies on steroidogenesis inhibitors would certainly be of help in improving the medical treatment of endogenous CS.

Conflict of Interest

MD and BA have nothing to declare. TD received travel costs from Recordati Rare Diseases and honoraria for scientific board activities from HRA Pharma. Furthermore, he served as a principal investigator and national study coordinator for clinical studies for Corcept Pharmaceuticals.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Reincke M, Fleseriu M. Cushing syndrome: A review. JAMA 2023; 330: 170-181
• 2 Pivonello R, Isidori AM, De Martino MC. et al. Complications of Cushing's syndrome: State of the art. Lancet Diabetes Endocrinol 2016; 4: 611-629
• 3 Pivonello R, Simeoli C, Di Paola N. et al. Cushing's disease: Adrenal steroidogenesis inhibitors. Pituitary 2022; 25: 726-732
• 4 Gilis-Januszewska A, Boguslawska A, Rzepka E. et al. Individualized medical treatment options in Cushing disease. Front Endocrinol (Lausanne) 2022; 13: 1060884
• 5 Castinetti F, Guignat L, Giraud P. et al. Ketoconazole in Cushing's disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
• 6 Viecceli C, Mattos ACV, Hirakata VN. et al. Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: Systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14: 1145775
• 7 Young J, Bertherat J, Vantyghem MC. et al. Hepatic safety of ketoconazole in Cushing's syndrome: Results of a Compassionate Use Programme in France. Eur J Endocrinol 2018; 178: 447-458
• 8 Pivonello R, De Leo M, Cozzolino A. et al. The treatment of Cushing's disease. Endocr Rev 2015; 36: 385-486
• 9 Fleseriu M, Pivonello R, Elenkova A. 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: 855-865
• 10 Pivonello R, Zacharieva S, Elenkova 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: 911-926
• 11 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of metyrapone in treating Cushing's syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
• 12 Ceccato F, Zilio M, Barbot M. et al. Metyrapone treatment in Cushing's syndrome: A real-life study. Endocrine 2018; 62: 701-711
• 13 Nieman LK, BM Scaroni CM, Deutschbein T. 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: A515
• 14 Detomas M, Altieri B, Deutschbein T. et al. 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
• 15 Pivonello R, Fleseriu M, Newell-Price J. et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): A multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020; 8: 748-761
• 16 Gadelha M, Bex M, Feelders RA. et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab 2022; 107: e2882-e2895
• 17 Dormoy A, Haissaguerre M, Vitellius G. et al. Efficacy and safety of osilodrostat in paraneoplastic Cushing syndrome: A real-world multicenter study in France. J Clin Endocrinol Metab 2023; 108: 1475-1487
• 18 Ferriere A, Salenave S, Puerto M. et al. Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism. Eur J Endocrinol 2024; 190: L1-L3
• 19 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: 629-630
• 20 Poirier J, Bonnet-Serrano F, Thomeret L. et al. Prolonged adrenocortical blockade following discontinuation of Osilodrostat. Eur J Endocrinol 2023; 188: K29-K32
• 21 Baudry C, Coste J, Bou Khalil R. et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol 2012; 167: 473-481
• 22 Altieri B, Kimpel O, Megerle F. et al. Recovery of adrenal function after stopping mitotane in patients with adrenocortical carcinoma. Eur J Endocrinol 2024; 190: 139
• 23 Altieri B, Lalli E, Faggiano A. Mitotane treatment in adrenocortical carcinoma: Mechanisms of action and predictive markers of response to therapy. Minerva Endocrinol (Torino) 2022; 47: 203-214
• 24 Detomas M, Pivonello C, Pellegrini B. et al. MicroRNAs and long non-coding RNAs in adrenocortical carcinoma. Cells 2022; 11: 2234
• 25 Fassnacht M, Dekkers OM, Else T. et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018; 179: G1-G46
• 26 Calabrese A, Basile V, Puglisi S. et al. Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence. Eur J Endocrinol 2019; 180: 387-396
• 27 Donadille B, Groussin L, Waintrop C. 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: 537-544
• 28 Altieri B, Sbiera S, Herterich S. et al. Effects of germline CYP2W1*6 and CYP2B6*6 single nucleotide polymorphisms on mitotane treatment in adrenocortical carcinoma: A multicenter ENSAT study. Cancers (Basel) 2020; 12: 359
• 29 Altieri B, Kimpel O, Quinkler M. et al. Adverse events of mitotane treatment in patients with adrenocortical carcinoma. Endocrine Abstracts 2021; 73
• 30 Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: A focus on novel therapies. Pituitary 2016; 19: 643-653
• 31 Pence A, McGrath M, Lee SL. et al. Pharmacological management of severe Cushing's syndrome: The role of etomidate. Ther Adv Endocrinol Metab 2022; 13 20420188211058583
• 32 Greening JE, Brain CE, Perry LA. et al. Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing's disease. Horm Res 2005; 64: 140-143
• 33 Vergara Molina N, Ruiz Andres N, Casas Martin N. et al. Etomidate in the treatment of Cushing syndrome. Rev Esp Anestesiol Reanim (Engl Ed) 2023; 70: 473-476
• 34 Schulte HM, Benker G, Reinwein D. et al. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990; 70: 1426-1430
• 35 Payen JF, Dupuis C, Trouve-Buisson T. et al. Corticosteroid after etomidate in critically ill patients: A randomized controlled trial. Crit Care Med 2012; 40: 29-35
• 36 Kamenicky P, Droumaguet C, Salenave S. 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: 2796-2804
• 37 Corcuff JB, Young J, Masquefa-Giraud P. et al. Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole. Eur J Endocrinol 2015; 172: 473-481
• 38 Amodru V, Brue T, Castinetti F. Synergistic cortisol suppression by ketoconazole-osilodrostat combination therapy. Endocrinol Diabetes Metab Case Rep 2021; 2021: 21-0071
• 39 Castinetti F. Pharmacological treatment of Cushing's syndrome. Arch Med Res 2023; 54: 102908
• 40 Castinetti F, Nieman LK, Reincke M. et al. Approach to the patient treated with steroidogenesis inhibitors. J Clin Endocrinol Metab 2021; 106: 2114-2123
• 41 Monaghan PJ, Owen LJ, Trainer PJ. et al. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11beta-hydroxylase inhibitor metyrapone. Ann Clin Biochem 2011; 48: 441-446
• 42 Petersenn S, Newell-Price J, Findling JW. et al. High variability in baseline urinary free cortisol values in patients with Cushing's disease. Clin Endocrinol (Oxf) 2014; 80: 261-269
• 43 Newell-Price J, Pivonello R, Tabarin A. et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease. Eur J Endocrinol 2020; 182: 207-217
• 44 Vega-Beyhart A, Laguna-Moreno J, Diaz-Catalan D. et al. Ketoconazole- and metyrapone-induced reductions on urinary steroid metabolites alter the urinary free cortisol immunoassay reliability in Cushing syndrome. Front Endocrinol (Lausanne) 2022; 13: 833644
• 45 Detomas M, Deutschbein T, Tamburello M. et al. Erythropoiesis in Cushing syndrome: Sex-related and subtype-specific differences. Results from a monocentric study. J Endocrinol Invest 2024; 47: 101-113
• 46 Detomas M, Altieri B, Chifu I. et al. Subtype-specific pattern of white blood cell differential in endogenous hypercortisolism. Eur J Endocrinol 2022; 187: 439-449
• 47 Detomas M, Ceccato F, Aulinas A. et al. Comparison of Metyrapone, OSilodrostat and KEToconazolE in the short-term thERapy of endogenous Cushing’s syndrome: Preliminary results of the MOSKETEER study. Endocrine Abstracts 2023; 90: 811
• 48 Nowotny HF, Braun L, Vogel F. et al. 11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing's disease. Eur J Endocrinol 2022; 187: 663-673
• 49 Bonnet-Serrano F, Poirier J, Vaczlavik A. 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: 315-322
• 50 Fleseriu M, Biller BMK. Treatment of Cushing's syndrome with osilodrostat: Practical applications of recent studies with case examples. Pituitary 2022; 25: 795-809
• 51 Pivonello R, Ferrigno R, De Martino MC. et al. Medical treatment of Cushing's disease: An overview of the current and recent clinical trials. Front Endocrinol (Lausanne) 2020; 11: 648
• 52 LaPensee CR, Mann JE, Rainey WE. et al. ATR-101, a selective and potent inhibitor of acyl-CoA acyltransferase 1, induces apoptosis in H295R adrenocortical cells and in the adrenal cortex of dogs. Endocrinology 2016; 157: 1775-1788
• 53 Wu N, Katz DA, An G. A Target-mediated drug disposition model to explain nonlinear pharmacokinetics of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 in healthy adults. J Clin Pharmacol 2021; 61: 1442-1453

Publication History

Received: 01 February 2024
Received: 18 April 2024

Accepted Manuscript online:
30 April 2024

Article published online:
14 June 2024