New developments in the medical treatment of Cushing’s ... · REVIEW New developments in the medical treatment of Cushing’s syndrome R van der Pas, W W de Herder, L J Hoﬂand

REVIEWEndocrine-Related Cancer (2012) 19 R205–R223

New developments in the medical treatmentof Cushing’s syndrome

R van der Pas, W W de Herder, L J Hofland and R A Feelders

Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, ’s-Gravendijkwal 230, 3015 CE Rotterdam,

The Netherlands

(Correspondence should be addressed to R A Feelders; Email: [email protected])

Abstract

Cushing’s syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excessdue to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producingadrenal neoplasia. Regardless of the underlying cause, untreated CS is associated withconsiderable morbidity and mortality. Surgery is the primary therapy for all causes of CS, butsurgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatmentmodalities. The role of medical therapy in CS has been limited because of lack of efficacy orintolerability. In recent years, however, new targets for medical therapy have been identified, bothat the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factorreceptors) and the adrenal gland (ectopically expressed receptors in ACTH-independentmacronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies withdrugs that exert their action through these molecular targets, as well as already establishedmedical treatment options, will be discussed.

Endocrine-Related Cancer (2012) 19 R205–R223

Introduction

Cushing’s syndrome (CS) is characterized by chronic

overproduction of cortisol resulting in significant

morbidity and, when untreated, an increased mortality

(Lindholm et al. 2001, Newell-Price et al. 2006,

Dekkers et al. 2007, Clayton et al. 2011, Hassan-Smith

et al. 2012). Traditionally, CS is divided into

ACTH-dependent CS and ACTH-independent CS.

ACTH-dependent CS, w80% of cases, can be caused

by a corticotroph pituitary adenoma and, more rarely,

by ectopic ACTH production. ACTH-independent CS

is usually caused by a unilateral adrenal adenoma and

less frequently by an adrenal carcinoma or bilateral

micro- or macronodular adrenal hyperplasia (Boscaro

et al. 2001, Newell-Price et al. 2006).

Chronic cortisol excess leads to a typical clinical

phenotype with truncal and facial fat deposition,

plethoric facial appearance, easy bruisability, and

muscle and skin atrophy (Table 1), although the

prevalence of these symptoms can be highly variable

and in part related to the underlying cause of CS

(Newell-Price et al. 2006, Nieman et al. 2008). In

addition, chronic hypercortisolism is associated with


1351–0088/12/019–R205 q 2012 Society for Endocrinology Printed in Grea

serious morbidity including an increased cardiovas-

cular risk due to clustering of risk factors (obesity,

diabetes mellitus, hypertension, and dyslipidemia); an

increased risk of venous thromboembolism, osteoporo-

sis, and psychological and cognitive disturbances

(Newell-Price et al. 2006, Pereira et al. 2010, Stuijver

et al. 2011). This multitude of signs, symptoms, and

morbidity severely impairs quality of life in patients

with CS (Johnson et al. 2003, Webb et al. 2008). If CS

is not or suboptimally treated, continuous cortisol

excess will lead to an increased mortality in particular

due to cardiovascular disease (Plotz et al. 1952,

Lindholm et al. 2001, Dekkers et al. 2007, Clayton

et al. 2011, Hassan-Smith et al. 2012). Several

diagnostic tests are used to establish endogenous hyper-

cortisolism including urinary free cortisol (UFC)

excretion, dexamethasone suppression test(s), and mid-

night serum or salivary cortisol levels (Niemanetal. 2008).

The first-line treatment of all forms of CS is surgery.

However, additional treatment modalities are necess-

ary when surgery is not successful (e.g. in pituitary-

dependent CS), not indicated (e.g. in case of metastatic

disease), or in case of high surgical risk (e.g. in patients

with severe co-morbidity). These therapeutic options

t Britain

DOI: 10.1530/ERC-12-0191

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Table 1 Clinical features observed in Cushing’s syndrome

Feature Frequency (% of patients)

Obesity 39–96

Facial plethora 82–90

Decreased libido 24–90

Muscle weakness 60–82

Menstrual irregularity 74–80

Glucose intolerance 50–80

Hypertension 62–78

Hirsutism 72–75

Osteoporosis 38–75

Psychiatric disorders 53–70

Easy bruising 46–65

Data from: Boscaro M, Barzon L, Fallo F & Sonino N 2001Cushing’s syndrome. Lancet 357 783–791; Ilias I, Torpy DJ,Pacak K, Mullen N, Wesley RA & Nieman LK 2005 Cushing’ssyndrome due to ectopic corticotropin secretion: twenty years’experience at the National Institutes of Health. Journal ofClinical Endocrinology and Metabolism 90 4955–4962; IsidoriAM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, ReznekRH, Jenkins PJ, Monson JP, Grossman AB & Besser GM 2006The ectopic adrenocorticotropin syndrome: clinical features,diagnosis, management, and long-term follow-up. Journal ofClinical Endocrinology and Metabolism 91 371–377; andNewell-Price J, Bertagna X, Grossman AB & Nieman LK 2006Cushing’s syndrome. Lancet 367 1605–1617.

R van der Pas et al.: Developments in the medical treatment of CS

include radiotherapy, bilateral adrenalectomy, and

medical therapy. Each of these options has its

limitations due to variable response rates and compli-

cations, and in each individual patient, the pros and

cons of each second-line treatment modality should be

carefully weighed. In the past decades, the role of

medical therapy for CS was limited due to lack of

efficacy and/or safety issues. However, in recent years,

new targets for medical treatment have been identified.

Translational research and subsequent clinical studies

have opened new perspectives for medical treatment.

In this review, we will discuss the currently available

drugs to treat CS and focus on new developments in

medical therapy for CS in the context of various

treatment aims for different causes of CS.

CS etiology, clinical features, andtherapeutic approachACTH-dependent CS

Pituitary-dependent CS

Pituitary-dependent CS or Cushing’s disease (CD) is

caused by an ACTH-secreting pituitary adenoma and

accounts for w70% of all cases of endogenous CS

(Boscaro et al. 2001, Newell-Price et al. 2006, Biller

et al. 2008, Bertagna et al. 2009). Clinical symptoms

develop gradually, which often delays the diagnosis

for years. The primary treatment of CD is a

transsphenoidal resection of the adenoma. Long-term

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remission rates after surgery vary between 50 and 90%

(Atkinson et al. 2005, Biller et al. 2008, Tritos et al.

2011), but a recurrence risk of up to 26% has been

observed during 10 years of follow-up (Atkinson et al.

2005, Tritos et al. 2011). The outcome of surgery is

highly dependent on the size of the adenoma, as

macroadenomas and non-visible adenomas have a

relatively poor success rate compared with micro-

adenomas (Rees et al. 2002, Mullan & Atkinson 2008).

As repeat pituitary surgery has a relatively disappoint-

ing success rate and is often complicated by

hypopituitarism, there is a clear need for alternative

treatment modalities (Ram et al. 1994, Esposito et al.

2006, Biller et al. 2008). In case of disease recurrence

or persistent hypercortisolism after surgery, radio-

therapy can be applied to induce definitive remission.

However, it can take years for radiotherapy to become

effective, leaving the patients exposed to the toxic

effects of cortisol excess. In addition, 30–40% of

patients develop pituitary insufficiency after pituitary

irradiation (Boscaro et al. 2001, Devin et al. 2004,

Vance 2005, Biller et al. 2008, Petit et al. 2008,

Bertagna et al. 2009, Tritos et al. 2011). Medical

treatment for patients with persistent or recurrent CD

has the advantage over radiotherapy of a direct onset of

action and preserving pituitary function. Medical

treatment options for CD are discussed in ‘Medical

treatment modalities’ and ‘Medical therapy for

different causes of CS’ sections.

Ectopic ACTH syndrome

The ectopic ACTH syndrome (EAS) causes w10% of

all cases of CS (Ilias et al. 2005, Newell-Price et al.

2006, Tritos et al. 2011). EAS is predominantly caused

by neuroendocrine tumors (e.g. bronchial, thymic, or

pancreatic neuroendocrine tumors), but small-cell lung

carcinomas, pheochromocytomas, medullary thyroid

carcinomas, and neuroendocrine prostate carcinomas

are also possible sources of ectopic ACTH production

(Aniszewski et al. 2001, Ilias et al. 2005, Isidori et al.

2006, Biller et al. 2008). CS caused by bronchial

carcinoids can mimic CD with a gradual development

of symptoms, but florid CS usually develops much

faster in EAS. Because ACTH and cortisol levels are

often higher in patients with EAS than in CD,

symptoms like hyperpigmentation of the skin (due to

excessive pro-opiomelanocortin (POMC)/a-MSH

production) and mineralocorticoid effects (due to

overwhelming cortisol levels exceeding renal

11b-hydroxysteroid dehydrogenase type II capacity) like

hypertension, hypokalemia, and edema predominate in

EAS as presenting symptoms rather than the typical

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clinical phenotype (Table 2; Ilias et al. 2005, Isidori

et al. 2006). When possible, surgery is the primary

treatment option for EAS. Reported success rates of

curative surgery vary from 12 to 83%, depending on

the cause of EAS (Aniszewski et al. 2001, Ilias et al.

2005, Isidori et al. 2006). In case of metastatic disease,

alternative treatment options include radiotherapy,

radio frequency ablation, systemic chemotherapy,

bilateral adrenalectomy, and medical therapy to

decrease ACTH or cortisol production. Patients with

occult ACTH-secreting tumors can be treated with

bilateral adrenalectomy or medical therapy (Aniszewski

et al. 2001, Ilias et al. 2005, Isidori et al. 2006, Biller

et al. 2008). Medical treatment options for EAS are

discussed in ‘Medical treatment modalities’ and ‘Medical

therapy for different causes of CS’ sections.

ACTH-independent CS

ACTH-independent CS accounts for 20% of all causes

of CS and is most frequently caused by a unilateral

cortisol-producing adenoma and more rarely by

bilateral micro- or macronodular adrenal hyperplasia

(AIMAH) and a cortisol-producing adrenal carcinoma.

Adrenal adenoma and bilateral adrenal hyperplasia

Cortisol-producing adrenal adenoma and AIMAH can

occur sporadically but also as part of a genetic

syndrome like multiple endocrine neoplasia syndrome

type 1, the McCune–Albright syndrome (somatic

mutation in the a-subunit of the G-protein resulting

Table 2 Clinical features observed in 130 patients with the

ectopic ACTH syndrome

Feature Frequency (% of patients)

Muscle weakness 66–82

Weight gain 48–70

Hypertension 60–78

Menstrual irregularities 78

Acne and hirsutism 60–75

Hypokalemia 70–71

Psychiatric disorders 53–54

Easy bruising 49–52

Diabetes mellitus 37.5–50

Edema 37–38

Hyperpigmentation of the skin 19–31

Data from: Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA &Nieman LK 2005 Cushing’s syndrome due to ectopic cortico-tropin secretion: twenty years’ experience at the NationalInstitutes of Health. Journal of Clinical Endocrinology andMetabolism 90 4955–4962 and Isidori AM, Kaltsas GA, PozzaC, Frajese V, Newell-Price J, Reznek RH, Jenkins PJ, MonsonJP, Grossman AB & Besser GM 2006 The ectopic adreno-corticotropin syndrome: clinical features, diagnosis, manage-ment, and long-term follow-up. Journal of ClinicalEndocrinology and Metabolism 91 371–377.


in constitutive activation of the cAMP pathway), and

Carney complex (due to PRKAR1A mutation; Yaneva

et al. 2010). Apart from a clinically evident CS with

established hypercortisolism, adrenal adenomas and

AIMAH can also be associated with the so-called

subclinical CS (Chiodini 2011).

In AIMAH and to a lesser extent in unilateral

adenomas, cortisol production can be regulated by

ectopic stimuli. Based on ectopic hormone receptor

expression or increased eutopic hormone receptor

expression on adrenocortical cells, stimuli other than

ACTH can regulate cortisol production via abnormal

coupling between the involved receptor and steroidogen-

esis (Lacroix 2009). Ectopic/eutopic receptors associated

with AIMAH and cortisol-producing adenoma include

those for glucose-dependent insulinotropic peptide (GIP),

vasopressin, TSH, serotonin, LH, and catecholamines.

The presence of these receptors can be demonstrated by

aberrant cortisol responses to administrated stimuli (e.g.

vasopressin, LHRH, and TRH; Lacroix 2009).

Cortisol-producing adrenal adenomas are usually

small and can surgically be removed by laparoscopic

adrenalectomy. AIMAH is primarily treated surgically as

well, by bilateral adrenalectomy. Tumors larger than

6 cm are usually treated by an open adrenalectomy, in

particular when adrenal carcinoma is suspected based on

the imaging phenotype (Cuesta et al. 1996). Identifi-

cation of ectopic hormone receptor expression may offer

perspectives for medical treatment with drugs that block

the involved receptor or that inhibit production of the

endogenous ligand (see ‘Medical therapy for different

causes of Cushing’s syndrome–ACTH-independent CS’

section below). The optimal management of subclinical

CS has not been established yet (Chiodini 2011).

Adrenocortical carcinoma

Hormonal overproduction occurs in about 60% of

adrenocortical carcinomas (ACCs), and the majority of

these tumors secrete cortisol whether or not in

combination with androgens (Wajchenberg et al.

2000). Patients with hormonal overproduction can

present with CS and/or virilization. ACC are usually

large tumors and surgical resection is the only curative

treatment option. In patients with (limited) metasta-

sized disease, surgical debulking can be considered, in

combination with medical therapy (see ‘Medical

treatment modalities–Inhibitors of adrenocortical ster-

oidogenesis and Medical therapy for different causes of

Cushing’s syndrome–ACTH-independent CS’ section

below), to decrease hormone excess. After resection of

an ACC, there is a considerable recurrence risk, in

particular in case of large tumors. Adjuvant treatment

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with mitotane after radical resection of ACC may

prolong recurrence-free survival (Terzolo et al. 2007).

Indications for medical therapy

There are several treatment aims for medical therapy in

CS (Table 3; Morris & Grossman 2002, Feelders et al.

2010c). Medical treatment can be indicated because of

acute complications of CS like acute psychosis, severe

hypertension, and opportunistic infections. These

potentially life-threatening conditions are mainly

associated with the EAS (see ‘ACTH-dependent

CS–Ectopic ACTH syndrome’ section below) and

require rapid reversal of cortisol excess. Furthermore,

cortisol-lowering medical therapy is given in some

centers as pretreatment before pituitary surgery with

the aim to optimize a patient’s condition, i.e. to

decrease catabolism and improve regulation of blood

pressure and glucose homeostasis, in order to reduce

perioperative morbidity. In addition, lowering cortisol

production may decrease bleeding tendency in the

surgical area. Although this may be a rationale concept,

no studies have been performed that prove efficacy of

preoperative medical treatment (Feelders et al. 2010c).

A large retrospective cohort study showed that,

compared to treatment-naı̈ve patients, patients that

are treated with cortisol-lowering therapy before

surgery seem to have a reduced risk for developing

venous thromboembolism postoperatively, although

this difference was not statistically significant (Stuijver

et al. 2011). Medical therapy can further be considered

in patients with CD with a low a priori chance on

surgical cure, i.e. in case of an adenoma with an

unfavorable localization, e.g. in the parasellar region.

The chances on cure in patients with invisible

adenomas are also lower, although surgery can still

be successful. Finally, medical therapy is indicated for

treatment of hypercortisolism: 1) after unsuccessful

surgery for pituitary-dependent CS or the EAS; 2) in

patients with metastasized disease, i.e. ACTH-producing

Table 3 Possible indications for medical therapy of Cushing’s

syndrome

Acute complications of (severe) hypercortisolism

Pretreatment before pituitary surgery

After unsuccessful surgery

Bridging therapy after pituitary irradiation

Primary medical therapy in Cushing’s disease

Adenoma with unfavorable localization

Invisible adenomas (?)

Inoperability

Metastatic disease

High operation risk

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neuroendocrine tumors and cortisol-producing ACC;

and 3) in patients with any cause of CS with a high

operation risk due to, e.g. co-morbidities or high age.

Quantitatively, patients with persistent or recurrent

pituitary-dependent CS represent the largest group that

needs medical therapy to control hypercortisolism. As

outlined in the ‘Pituitary-dependent CS’ section above,

pituitary surgery is not successful in 10–50% of

patients (Atkinson et al. 2005, Biller et al. 2008,

Tritos et al. 2011) and recurrences occur in up to 26%

of patients (Atkinson et al. 2005, Tritos et al. 2011).

In these patients, it is essential to induce long-term

normalization of cortisol production in order to reverse

co-morbidity, improve quality of life, and normalize

life expectancy (Biller et al. 2008). For this purpose,

medical therapy can be applied either as chronic

treatment or as bridging therapy during the period after

which radiotherapy becomes effective.

Medical treatment modalities

This paragraph gives a brief overview of available

drugs and their biochemical targets for treatment of CS

(Table 4). Details on dosages and combination therapy

are described in ‘Medical therapy for different causes

of CS’ section.

Pituitary-targeted drugs

Drugs with proven clinical efficacy

In recent years, dopamine receptors and somatostatin

receptors have been identified as therapeutic targets on

corticotroph adenomas (de Bruin et al. 2009b).

Approximately 80% of ACTH-secreting pituitary

adenomas express the dopamine receptor subtype 2

(D2R; Pivonello et al. 2004, de Bruin et al. 2009b).

Cabergoline is an ergot-derived dopamine agonist with

particular high affinity for the D2R. Both in vitro and

in vivo studies showed that cabergoline was efficacious

with respect to inhibition of ACTH and cortisol

secretion (discussed the ‘Medical therapy for different

causes of CS–Pituitary-dependent CS’ section below).

In an in vitro setting, Pivonello et al. (2004) found that

dopamine agonist treatment with either bromocriptine

or cabergoline inhibited ACTH secretion in 100% of

D2R-positive adenomas. Frequently occurring but

mostly transient side effects of cabergoline include

nausea, headache, dizziness, and abdominal discomfort

(Pivonello et al. 2009, Godbout et al. 2010). A point of

concern, although controversial, is the possible

association between chronic use of cabergoline and

the development of valvular heart disease. In different

studies in which patients with CD were treated with



Table 4 Dosages and most important side effects of drugs used to treat Cushing’s syndrome

Group Drug Dosage Side effects

Pituitary-targeted drugs Cabergoline Up to 7 mg/week Headache, dizziness, gastrointestinal

discomfort, and cardiac valve fibrosis

Pasireotide 750–2400 mg/day Hyperglycemia, GH deficiency, and

gastrointestinal discomfort

Inhibitors of adrenocortical

steroidogenesis

Ketoconazole 400–1600 mg/day Hepatotoxicity, gynecomastia, and


Metyrapone 0.5–4.5 g/day Dizziness, rash, gastrointestinal

discomfort, worsening of

hypertension, acne, and hirsutism

Mitotane 3–5 g/day Gynecomastia, hepatotoxicity,

hypercholesterolemia, prolonged

bleeding time, gastrointestinal

discomfort, dizziness, ataxia,

confusion, dysarthria, and memory

problems

Etomidate 0.1–0.3 mg/kg per h Nephrotoxicity

Glucocorticoid receptor

antagonists

Mifepristone 300–1200 mg/day Hypokalemia, worsening of hyperten-

sion, clinical adrenal insufficiency,

endometrial hyperplasia, and



cabergoline, dosages varying from 0.5 up to 7 mg/

week were used (Pivonello et al. 2009, Godbout et al.

2010, Vilar et al. 2010). Patients with Parkinson’s

disease are treated with much higher dosages of

cabergoline, which can cause cardiac valve fibrosis

via serotonin receptor 2B-mediated activation of

valvular fibroblasts (Schade et al. 2007, Zanettini

et al. 2007). In cabergoline-treated patients with

prolactinomas, an increased prevalence of valvular

calcification was found, but this was not accompanied

by valvular dysfunction (Delgado et al. 2011).

To date, five somatostatin receptor subtypes (sst) have

been identified (Patel 1999). Corticotroph pituitary

adenomas predominantly express the sst5 (de Bruin

et al. 2009b). In contrast to GH-producing pituitary

adenomas, which have a high degree of sst2 expression,

sst2 expression by corticotroph adenomas is low (de

Bruin et al. 2009b). This explains why the sst2-targeting

somatostatin analogs octreotide and lanreotide are

generally ineffective in the treatment of CD (Lamberts

et al. 1989, Stalla et al. 1994). The low sst2 expression is

thought to result from downregulating effects of high

circulating cortisol levels. Indeed, several in vitro studies

suggested that exposure to glucocorticoids diminishes

sst2 expression both in GH- and ACTH-secreting cell

lines (Schonbrunn 1982, Stalla et al. 1994, Xu et al.

1995, Park et al. 2003, de Bruin et al. 2009a).

Pasireotide is a somatostatin analog, which binds

sst1, 2, 3, 5 with high affinity (Bruns et al. 2002). In

particular, it has subnanomolar affinity for the sst5, the


predominant sst in corticotroph pituitary adenomas

(Bruns et al. 2002, Hofland et al. 2005). Early in vitro

studies performed by Hofland et al. showed that

pasireotide (10 nmol/l) significantly inhibited ACTH

secretion by 30–40% in 3/5 primary cultures of human

corticotroph pituitary adenomas. Three clinical studies

have shown that pasireotide in dosages between 750

and 2400 mg/day can reduce UFC levels in patients

with CD (see the ‘Medical therapy for different causes

of CS–Pituitary-dependent CS’ section below).

Induction of hyperglycemia, which may require

glucose-lowering therapy, is an important side effect

of pasireotide (Boscaro et al. 2009, Feelders et al.

2010a,b, Colao et al. 2012). In healthy volunteers,

pasireotide-induced hyperglycemia was shown to be

due to inhibition of incretin secretion with a

concomitant decreased insulin secretion (Henry et al.

2011). Glucose levels were most effectively lowered

with glucagon-like peptide 1 agonists or dipeptidyl

peptidase 4 (an enzyme that inactivates the incretins)

inhibitors (Henry et al. 2011). Other than hyper-

glycemia, pasireotide might cause gastrointestinal side

effects (Boscaro et al. 2009, Colao et al. 2012).

Finally, the alkylating chemotherapeutic drug

temozolomide, which is used to treat malignant

brain tumors, has been reported to be of value in

case of aggressive corticotroph pituitary adenomas

that are refractory to surgery or pituitary irradi-

ation (Mohammed et al. 2009, Curto et al. 2010, Raverot

et al. 2010, Dillard et al. 2011, McCormack et al. 2011).

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Drugs with promising in vitro results

Retinoic acid has been shown to inhibit POMC

transcription and ACTH secretion both in the murine

AtT20 cell-line and in the primary cultures of human

corticotroph pituitary adenoma cells (Paez-Pereda

et al. 2001). In addition, this study showed that retinoic

acid inhibited AtT20 cell proliferation by inducing

apoptosis. Finally, both pretreatment of AtT20 cells

with retinoic acid before injection and treating retinoic

acid-naı̈ve AtT20 tumor cells resulted in inhibition of

AtT20 tumor formation in nude mice inoculated with

these AtT20 cells (Paez-Pereda et al. 2001).

A subsequent study performed by the same group showed

that, without inducing toxicity, retinoic acid decreased

urinary cortisol/creatinine ratios, plasma ACTH, and

pituitary adenoma size in dogs with CD (Castillo et al.

2006). Preliminary data from a recent pilot study in

humans demonstrated that treatment with retinoic acid in

dosages up to 80 mg during 6–12 months normalized

UFC in 4/7 patients (Pecori Giraldi et al. 2012).

A recent study evaluated the possible role of the

epidermal growth factor receptor (EGFR) as a thera-

peutic target for CD (Fukuoka et al. 2011). In this study,

the in vitro effects of gefitinib, a tyrosine kinase inhibitor

that targets the EGFR, on human, canine, and murine

corticotroph tumor cells were assessed. It was found that

gefitinib dose dependently inhibited POMC mRNA

expression in primary cultures of human corticotroph

adenoma cells. In addition, gefitinib decreased POMC

mRNA expression in 6/10 and inhibited ACTH

secretion in 4/12 cultures of canine corticotroph

adenomas. Moreover, in nude mice inoculated with

AtT20 cells stably transfected with the EGFR, gefitinib

inhibited tumor growth by 40% compared with vehicle-

treated animals. Serum corticosterone levels were also

decreased by gefitinib, which was accompanied by

improvement of clinical signs, e.g. fat accumulation,

hyperglycemia, and weight gain (Fukuoka et al. 2011).

Although not yet evaluated in humans, the EGFR may

be a promising target.

In addition to D2R and sst5, corticotroph pituitary

adenomas have been shown to express peroxisome

proliferator-activated receptor g (PPARg). Although

initial studies showed that high dosages of the thiazoli-

dinediones were able to inhibit tumor growth and ACTH

and corticosterone levels in mice (Heaney et al. 2002), the

results of thiazolidinedione treatment in patients with CD

and Nelson’s syndrome (NS) have been rather dis-

appointing (Ambrosi et al. 2004, Suri & Weiss 2005,

Mullan et al. 2006, Pecori Giraldi et al. 2006, Munir et al.

2007, Kreutzer et al. 2009). Therefore, PPARg agonists

do not play a role in the medical treatment of CD.

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Although serotonin receptor antagonists and

vasopressin receptor antagonists were initially

believed to decrease ACTH secretion in patients with

CD, they have not proven their clinical efficacy and are

therefore not recommended in the treatment of CD

(Biller et al. 2008).

Inhibitors of adrenocortical steroidogenesis

Ketoconazole is an imidazole derivative that was

originally developed to treat fungal infections.

However, ketoconazole has also been shown to inhibit

adrenocortical steroidogenesis when administered in

high dosages, i.e. between 400 and 1600 mg/day

(Castinetti et al. 2008). Its main mechanism of action

is inhibition of the steroidogenic enzymes

17-hydroxylase and 17,20-lyase and it is one of

the most frequently used cortisol-lowering drugs

(Engelhardt et al. 1985, Loli et al. 1986, Lamberts

et al. 1987, McCance et al. 1987, Sonino 1987, Farwell

et al. 1988, Sonino et al. 1991, Biller et al. 2008,

Castinetti et al. 2008). Ketoconazole is hepatotoxic,

can cause gynecomastia, and has serious, mainly

gastrointestinal, side effects, which together can limit

its long-term use (McCance et al. 1987, Sonino et al.

1991, Como & Dismukes 1994, Nieman 2002,

Castinetti et al. 2008). Ketoconazole may also have

inhibitory effects on ACTH secretion by corticotroph

tumor cells (Stalla et al. 1988, Feelders et al. 2010c).

This might explain the absence of a rise in ACTH

levels during ketoconazole treatment in response to a

decrease in cortisol levels. Although an increase in

ACTH production upon ketoconazole treatment was

found in rats (Burrin et al. 1986), several studies show

no rise in ACTH concentrations in patients with CD

following treatment with ketoconazole (Loli et al.

1986, Terzolo et al. 1988, Sonino et al. 1991). In recent

clinical trials, ketoconazole has been combined with

either pituitary-targeted medical therapy or other

adrenal-blocking drugs (Feelders et al. 2010a,b, Vilar

et al. 2010, Kamenicky et al. 2011). Combination

therapy for CS will be discussed in ‘Medical therapy

for different causes of CS’ section.

Metyrapone is another frequently used inhibitor

of steroidogenesis. Its main site of action is

11b-hydroxylase, as Verhelst et al. (1991) found a

concomitant decrease in cortisol concentrations and

increase in 11-deoxycortisol levels in 91 CS patients

treated with metyrapone. Side effects that occur

during metyrapone therapy include dizziness, rash,

and gastrointestinal complaints (Tritos et al. 2011).

In addition, concentrations of mineralocorticoid

precursors and adrenal androgens can increase due to




the 11b-hydroxylase block and the subsequent increase

in ACTH production, which stimulates steroidogenesis

(Nieman 2002, Tritos et al. 2011). As a result,

metyrapone administration might be accompanied by

worsening of hypertension, acne, and hirsutism

(Verhelst et al. 1991, Nieman 2002, Feelders et al.

2010c). In contrast to ketoconazole, metyrapone does

not cause gynecomastia. Hence, metyrapone might

preferably be used in males, whereas ketoconazole

may be more appropriate to treat female patients with

CS (Stewart & Petersenn 2009). However, although

metyrapone treatment often has a good short-term

response, long-term efficacy data are scarce. Metyr-

apone is not commercially available in the US. Similar

to ketoconazole, metyrapone has been used in

combination with other pituitary- or adrenocortical-

targeted drugs (Thoren et al. 1985, Kamenicky et al.

2011). Studies addressing combination therapy will be

further detailed in ‘Medical therapy for different causes

of CS’ section.

Mitotane or o,p’-DDD is a derivative of DDT

(dichlorodiphenyltrichloroethane) and is mainly used

in the treatment of ACCs because of its adrenolytic

properties (Veytsman et al. 2009, Fassnacht et al.

2011). It has been shown to inhibit cortisol production

via inhibition of multiple steroidogenic enzymes and to

be efficacious in the treatment of CD (Young et al.

1973, Luton et al. 1979). Mitotane has a slow onset of

action and based on its lipophilic nature, it is stored in

adipose tissue, ensuring a long half-life of 18–159 days

(Nieman 2002). Consequently, mitotane remains

present in the body, even up to 2 years after

withdrawing the drug (Nieman 2002, Tritos et al.

2011). Especially when administered in high dosages,

mitotane has many side effects including gastrointes-

tinal (anorexia, nausea, vomiting, and diarrhea) and

neurological (dizziness, ataxia, confusion, dysarthria,

and memory problems) complaints (Nieman 2002,

Fassnacht & Allolio 2009, Schteingart 2009) that

require close monitoring of the patient and plasma

mitotane concentrations. Other frequently reported

adverse events are gynecomastia, hepatotoxicity,

hypercholesterolemia, and prolonged bleeding time.

Owing to its adrenolytic nature, mitotane often causes

adrenal insufficiency necessitating concomitant hydro-

cortisone substitution (Fassnacht & Allolio 2009).

Similar to ketoconazole, etomidate is an imidazole

derivative (Allolio et al. 1983). Originally used as an

anesthetic agent, etomidate, which is administered i.v.,

was soon reported to cause adrenocortical insufficiency

in critically ill patients (Fellows et al. 1983).

Subsequent studies showed that etomidate can be

used to induce eucortisolemia in patients with


CS (Schulte et al. 1990, Krakoff et al. 2001). Its

suggested mechanism of action is inhibition of the

11b-hydroxylase and cholesterol side-chain cleavage

enzymes (Lamberts et al. 1987, Schteingart 2009).

Currently, etomidate infusion is used to obtain rapid

control of hypercortisolism in severe cases of CS

(e.g. in case of glucocorticoid-induced psychosis),

in which oral cortisol-lowering agents are ineffective

or oral therapy is impossible (Biller et al. 2008).

Aminoglutethimide was first reported to success-

fully reduce cortisol levels in patients with functional

ACCs (Schteingart et al. 1966). The same group

reported that, due to increased ACTH levels overriding

the cortisol-lowering effect, aminoglutethimide only

had temporary suppressive effects in patients with

ACTH-dependent CS (Schteingart & Conn 1967).

Since 2007, aminoglutethimide is no longer available

(Schteingart 2009).

LCI699, a novel inhibitor of 11b-hydroxylase, has

been introduced very recently. The efficacy of this

agent has been assessed in a small number of patients

with CD (Bertagna et al. 2012). Like other adrenal-

targeted drugs, this novel compound obviously does

not target the cause of the disease in these patients. The

clinical applicability and optimal dosage of LCI699

have to be further elucidated.

Glucocorticoid receptor antagonists

Mifepristone is the only glucocorticoid receptor (GR)

antagonist that is currently available (Castinetti et al.

2009) and counteracts the effect of cortisol at tissue

level. It was initially developed as a compound with

antiprogestin activity by blocking the progestin

receptor. Subsequently, antiglucocorticoid effects

were recognized because mifepristone binds to the

GR with an 18-fold higher affinity than cortisol

(Fleseriu et al. 2012). As a consequence, cortisol

cannot exert its negative feedback effects at the

hypothalamic and pituitary level, which can lead to an

increase in ACTH secretion with a concomitant

increased cortisol production. A disadvantage of

mifepristone is that there is no biochemical parameter

available according to which the mifepristone dose can

be adjusted. Consequently, clinical adrenal insuffi-

ciency can develop after overtreatment, which may

require dose interruption and corticosteroid replace-

ment. In female patients, mifepristone can cause endo-

metrial hyperplasia, which requires ultrasonic

monitoring. In addition, increasing cortisol levels dur-

ing mifepristone treatment can cause mineralocorticoid

effects with induction or worsening of hypokalemia and

hypertension (Castinetti et al. 2009, Tritos et al. 2011,

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Fleseriu et al. 2012). Theoretically, long-term use of

mifepristone could provoke NS in patients with CD.

Dose titration of mifepristone should be performed

according to clinical signs and serum potassium levels

(Castinetti et al. 2009).

Medical therapy for different causes of CS

Pituitary-dependent CS

Optimal medical therapy for CD would normalize

ACTH and cortisol production without escape,

stabilize, or reduce tumor growth; reverse morbidity

and mortality; and improve quality of life (Biller et al.

2008). Unfortunately, to date, no long-term efficacy

and safety data are available of any available drug.

As already described in ‘Pituitary-targeted drugs’

section, ACTH-secreting pituitary adenomas predomi-

nantly express D2R and sst5, which can serve as targets

for medical therapy (Pivonello et al. 2004, de Bruin

et al. 2009b). Recently, three studies were published in

which the effects of cabergoline monotherapy in

patients with CD were evaluated (Pivonello et al.

2009, Godbout et al. 2010, Vilar et al. 2010). The first

study was performed in 20 patients with persistent CD

after surgery. After 3 months of treatment, ACTH

concentrations had decreased by more than 25% in

15 of these patients. After 2 years of treatment, 7/20

patients had escaped from cabergoline therapy and

8/20 (40%) were in sustained remission with a median

cabergoline dosage of 3.5 mg/week (Pivonello et al.

2009). A retrospective analysis of 30 patients treated

with cabergoline monotherapy showed a 50% response

rate (either complete or partial) after 6 months of

treatment with cabergoline in a mean dose of

1.5 mg/week (Godbout et al. 2010). Long-term

analysis showed a sustained normalization of UFC

excretion in 9/30 (30%) patients after a mean of

37 months treated with, on average, 2.1 mg/week

(range 0.5–6 mg/week). However, in the group of

non-responders, the mean cabergoline dose was only

2 mg/week (range 1–4.5 mg/week) for an average

period of 4 months (range 1–9 months). The relatively

low dose of cabergoline that was used in most patients

in this study might have underestimated the maximal

inhibitory effect (Godbout et al. 2010). Another

recently published study prospectively evaluated the

effects of low-dose cabergoline (up to 3 mg/week) in

12 patients with persistent CD after unsuccessful

surgery. After 6 months, UFC excretion had

normalized in three patients (25%; Vilar et al. 2010).

In the other patients, cabergoline decreased UFC

excretion by 15–48%. Again, the modest cabergoline

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dosage might have caused underestimation of the

maximal inhibitory effect (Vilar et al. 2010). In this

study, low-dose ketoconazole (200–400 mg daily) was

added to cabergoline in case of persistent hypercorti-

solism after 6 months of cabergoline monotherapy.

Interestingly, UFC excretion normalized in 6/9 patients

with cabergoline and low-dose ketoconazole com-

bination therapy after an additional 6 months of

treatment (Vilar et al. 2010).

The efficacy of pasireotide, which targets the sst5, in

a clinical setting was first evaluated by Boscaro et al.

(2009). In this study, 29 patients with pituitary-

dependent CS were treated with pasireotide 600 mg

s.c. twice daily during 15 days. On average, UFC

excretion decreased by 44.5% compared with baseline.

Overall, UFC decreased in 22/29 patients and five

patients (17%) reached normal UFC excretion after

15 days of treatment (Boscaro et al. 2009). The results

of a large, multicenter phase III study, in which the

long-term efficacy of pasireotide was examined, have

recently been published (Colao et al. 2012). In this

study, 162 patients were included and randomized to

treatment with pasireotide s.c. in a dose of either 600 or

900 mg twice daily. After 3 months of treatment, these

dosages were increased by 300 mg (to either 900 or

1200 mg twice daily) in patients in whom UFC

excretion did not fall below two times the upper limit

of normal (ULN) or, in case baseline UFC excretion

did not exceed two times ULN, in whom UFC had

increased after 3 months compared with baseline. On

average, UFC excretion decreased by 48% after

6 months of treatment (Fig. 1; Colao et al. 2012).

Without needing up-titration of the dose of pasireotide,

33 patients (20.4%; 14.6% in the 600 mg group and

26.3% in the 900 mg group) reached normal UFC

excretion levels after 6 months (Colao et al. 2012).

Parallel with the decrease in UFC, improvements were

observed in blood pressure, weight, and quality of life

(Webb et al. 2008, Colao et al. 2012). Hyperglycemia

was the most important adverse event in this study, as

glycated hemoglobin levels increased from 5.8 to 7.2%

or 7.4%, depending on the dosage of pasireotide used.

Other side effects included abdominal discomfort,

headache, and cholelithiasis (Colao et al. 2012).

Pasireotide was recently approved in the EU for

treatment of CD after unsuccessful surgery.

Thus, monotherapy with either cabergoline or

pasireotide induces complete biochemical remission

in about 25% of patients. We performed a prospective

open-label trial in which 17 patients with CD were

treated in a stepwise manner with pasireotide mono or

combination therapy with cabergoline and low-dose

ketoconazole during 80 days (Feelders et al. 2010a,b).



Figure 1 Urinary free cortisol excretion levels at baseline and after 6 months of treatment with pasireotide. Urinary free cortisol wasavailable at baseline and at month 6 in a total of 103 patients; 61 patients had a reduction of at least 50% in urinary free cortisol levelsat month 6. The black dashed line represents the upper limit of the normal range (ULN; 145 nmol/24 h (52.5 mg/24 h)). Reproducedwith permission from Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills D, Salgado LR &Biller BM 2012 A 12-month phase 3 study of pasireotide in Cushing’s disease. New England Journal of Medicine 366 914–924.

Figure 2 Mean levels of urinary free cortisol in five patientstreated with pasireotide monotherapy, four patients treated withcombination therapy with pasireotide plus cabergoline, and eightpatients treated with pasireotide plus cabergoline and ketocona-zole. Cabergoline was added to pasireotide if the level of urinaryfree cortisol had not normalized at day 28. Ketoconazole wasadded to pasireotide and cabergoline at day 60 if the patient hadpersistent hypercortisolism. The upper limit of the normal range isindicated by the dashed line. Bars indicate the S.E.M. Reproducedwith permission from Feelders RA, de Bruin C, Pereira AM,Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM,van Heerebeek R, de Jong FH, van der Lely AJ et al. 2010bPasireotide alone or with cabergoline and ketoconazole inCushing’s disease. New England Journal of Medicine 3621846–1848.


The rationale of this approach was that the majority of

corticotroph adenomas do co-express sst5 and D2R

(de Bruin et al. 2009b) and that combined treatment

with sst5 and D2R targeting compounds may have

synergistic effects (Rocheville et al. 2000, Baragli

et al. 2007). All patients started with pasireotide

monotherapy in a dosage of 100 mg s.c. thrice daily.

After 10 days, this dosage was increased to 250 mg s.c.

thrice daily in case UFC excretion remained elevated.

UFC excretion was measured again at day 28, after

which, in case of persistent hypercortisolism, cabergo-

line (1.5 mg every other day) was added to pasireotide.

If UFC remained elevated at day 56, ketoconazole

(200 mg thrice daily) was added to pasireotide and

cabergoline. Using this treatment regimen, 15/17

patients (88%) achieved biochemical remission after

80 days. As can be seen in Fig. 2, patients with more

severe hypercortisolism at baseline needed more drugs

to normalize UFC excretion (Feelders et al. 2010a,b).

Apart from biochemical remission from CD, decreases

in weight and blood pressure were observed (Feelders

et al. 2010a,b). Again, hyperglycemia was the most

important side effect; glycated hemoglobin levels

increased from 5.8 to 6.7% after 80 days of treatment.

Moreover, nine patients were insulin-like growth factor

1 (IGF1) deficient at the end of the study period

(Feelders et al. 2010a,b). In ‘Pituitary-targeted drugs’

section, it was described that the expression level of

the sst2 is relatively low in corticotroph pituitary


adenomas, probably due to downregulating effects of

high concentrations of circulating glucocorticoids.

After pasireotide mono or combination therapy, a

subset of patients was operated and in vitro studies

showed that sst2 mRNA expression levels of adenomas

from these patients, who were all in remission, were

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Figure 3 Changes in glucose-related outcomes in patients withCushing’s syndrome after treatment with mifepristone atdosages between 300 and 1200 mg daily. (A) HbA1c signi-ficantly decreased from baseline to week 24 or early termination(ET; P!0.001); (B and C) a significant reduction in area underthe curve (AUC) for insulin (B) and significant improvements inhomeostatic model assessment of insulin resistance(HOMA-IR; C) were also observed. Data are shown asmeanGS.D. To convert insulin values to picomoles per liter,multiply by 6.945. Reproduced with permission from Fleseriu M,Biller BM, Findling JW, Molitch ME, Schteingart DE & Gross C2012 Mifepristone, a glucocorticoid receptor antagonist,produces clinical and metabolic benefits in patients withCushing’s syndrome. Journal of Clinical Endocrinology andMetabolism 97 2039–2049.


significantly higher than those of adenomas from

patients with elevated preoperative UFC excretion

(Feelders et al. 2010a). This suggests that glucocorti-

coid-induced sst2 downregulation is a dynamic process

that might be reversed by cortisol-lowering therapy.

One preliminary study describes a further decrease in

UFC in four ketoconazole-treated patients after

addition of octreotide (Vignati & Loli 1996). It might

thus be an interesting concept to treat CD patients with

cortisol-lowering therapy, which, in case of reappear-

ing sst2 expression, is followed by treatment with a sst2targeting somatostatin analog. Future studies should

investigate the efficacy of such a treatment regimen.

With respect to adrenal blocking drugs, ketocona-

zole, metyrapone, and mitotane are most frequently

used for CD. In a retrospective study, ketoconazole

treatment, in a dose between 200 and 1000 mg/day,

resulted in control of hypercortisolism in 17 out of

33 patients within 3 months with a concomitant clinical

improvement. In five other included patients, ketoco-

nazole was stopped within the first week of treatment

because of intolerance (Castinetti et al. 2008). One

older study with 28 patients showed that ketoconazole

treatment was successful in 93% of patients, but this

result was biased as patients had been treated before

with radiotherapy (Sonino et al. 1991). Metyrapone, at

dosages between 750 and 6000 mg/day, can effectively

control cortisol overproduction in w75% of patients

during short-term treatment, i.e. up to 16 weeks,

whereas long-term treatment resulted in biochemical

remission in about 80% of patients, although these

patients were also treated with radiotherapy (Verhelst

et al. 1991). Mitotane, at lower dosages, can be useful

in the treatment of CD (Luton et al. 1979, Schteingart

et al. 1980, Kamenicky et al. 2011). Schteingart et al.

(1980) reported clinical and biochemical remission of

CD in 80% of patients treated with mitotane and

pituitary irradiation. Another study showed control of

hypercortisolemia using mitotane monotherapy in

38/46 patients, whereas mitotane and pituitary irradi-

ation combination therapy was successful in 100% of

patients (Luton et al. 1979). Mitotane has, however,

multiple side effects, which may limit long-term use.

Very recently, the efficacy of LCI699, a novel

inhibitor of 11b-hydroxylase, was evaluated in

11 patients with CD at a dose of 2–50 mg twice

daily. After 10 weeks of treatment, 8/9 patients that

completed the study period had normalized UFC

excretion (Bertagna et al. 2012). Like other adrenal-

targeted drugs, this novel compound obviously does

not target the cause of the disease in these patients. The

clinical applicability and optimal dosage of LCI699

have to be further elucidated.

www.endocrinology-journals.orgR214


Figure 4 Serial UFC levels in patients before and during therapywith mitotane, metyrapone, and ketoconazole. The gray areaindicates the normal range of UFC excretion (10–65 mg/24 h).Note the log scale of the y-axis. D, day after start of therapy;M, months; open diamonds, UFC excretion determined withouthydrocortisone withdrawal; solid diamonds, UFC excretiondetermined during hydrocortisone withdrawal. Reproduced withpermission from Kamenicky P, Droumaguet C, Salenave S,Blanchard A, Jublanc C, Gautier JF, Brailly-Tabard S,Leboulleux S, Schlumberger M, Baudin E et al. 2011 Mitotane,metyrapone, and ketoconazole combination therapy as analternative to rescue adrenalectomy for severeACTH-dependent Cushing’s syndrome. Journal of ClinicalEndocrinology and Metabolism 96 2796–2804.


A recently published study by Fleseriu et al. showed

beneficial effects of treatment with the GR antagonist

mifepristone. In this study, 50 patients with CS

(43 with CD) were treated for 24 weeks with

mifepristone at dosages between 300 and 1200 mg

daily (Fleseriu et al. 2012). Clear metabolic improve-

ments were achieved with this treatment, as reflected

by decreased glucose levels after oral glucose tolerance

tests, decreased glycated hemoglobin levels, and

increased insulin sensitivity (Fig. 3). Moreover, body

weight significantly decreased and quality of life

significantly improved after 24 weeks of treatment.

As was expected, plasma concentrations of ACTH and

cortisol increased at least twofold in 72% of the

patients with CD. This illustrates the most important

drawback of this treatment, as therapy with mifepris-

tone does not target the pituitary adenoma. In this

study, only one patient experienced an increase in

adenoma size after 24 weeks of treatment, but as the

authors emphasize in their paper, it is uncertain

whether the risk of tumor growth increases with longer

treatment duration. Frequently encountered adverse

effects included fatigue, headache, abdominal dis-

comfort, decreased serum potassium, and peripheral

edema (Fleseriu et al. 2012). Mifepristone was recently

approved in the U.S. for the treatment of hyperglyce-

mia in patients with CS and type II diabetes if surgery

is not an option or unsuccessful. Mifepristone might

also be used to treat patients with CS that have an

acute psychosis, in order to rapidly counteract the

GR-mediated effects (van der Lely et al. 1991).

The optimal order and combination of drugs to treat

CD is not known yet. Pasireotide and cabergoline have

the advantage that they both target the underlying

pituitary adenoma. However, the hyperglycemic

effects of pasireotide are a point of concern for long-

term treatment in a condition that is already accom-

panied by glucose intolerance. Further study on the

mechanism and management of pasireotide-induced

hyperglycemia is clearly needed. The adverse event

profiles of adrenal blocking drugs and mifepristone can

limit their long-term use. It should be emphasized that

patients with CD and moderate-to-severe hypercorti-

solism need combination therapy to control cortisol

excess. In this respect, combination of pasireotide and

cabergoline may have synergizing effects. Another

rationale for combination therapy may be to use

lower drug dosages in order to reduce side effects

of either agent like in the study of Vilar et al. (2010)

in which cabergoline was combined with low-dose

ketoconazole. Finally, combination therapy is

indicated when symptomatology requires rapid

reversal of cortisol excess, e.g. in case of psychosis.


Thus, a tailor-made approach should be aimed in each

patient according to individual characteristics. For

instance, a patient with poorly regulated diabetes

mellitus should not be treated with pasireotide, whereas

in a patient with severe hypertension and hypokalemia,

metyrapone would not be the first choice.

Ectopic ACTH syndrome

As outlined in the ‘ACTH-dependent CS–Ectopic

ACTH syndrome’ section above, EAS is frequently

accompanied by severe hypercortisolism, which can

lead to hypertension, hypokalemia, acute psychosis,

and thromboembolic complications. In addition, due to

immunosuppressive effects, these patients are at risk

for (opportunistic) infections and can rapidly deterio-

rate because of overwhelming sepsis. Apart from

maximal supportive therapy (i.e. treatment with an

aldosterone receptor antagonist, thromboprophylaxis,

and antibiotic prophylaxis), cortisol production or its

tissue effects should aggressively be decreased.

Kamenicky et al. (2011) recently performed a

study in which patients with severe CS were treated

with medical combination therapy. In their series,

11 patients were included, four of which had CD and

seven had EAS. Patients had severe (e.g. pulmonary,

cardiovascular, or infectious) complications that

needed immediate intervention. Treatment was

initiated with mitotane (3 g/24 h) and, as mitotane

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has a slow onset of action, ketoconazole (800 mg/24 h)

and metyrapone (2.25 g/24 h). These dosages were

adjusted based on the clinical signs. Patients were

reported to experience clear improvement of their

Cushingoid features. Interestingly, UFC (near-)

normalized in all patients within the first 3 days

(Fig. 4; Kamenicky et al. 2011). This treatment

regimen was generally well tolerated, but main side

effects were gastrointestinal complaints, hypokalemia,

and increases in cholesterol and liver enzyme values.

Considering its efficacy, this approach might be an

alternative to emergency bilateral adrenalectomy, in

particular for critically ill patients in whom surgery

(bilateral adrenalectomy) is contraindicated. Recently,

Sharma and Nieman reported four patients with EAS in

whom prolonged remission was achieved with keto-

conazole mono- or combination therapy with mitotane

and/or metyrapone. Interestingly, in two patients

sustained remission was observed after cessation of

ketoconazole and metyrapone, which may in part be

explained by effects of these drugs on tumoral ACTH

secretion (Sharma & Nieman 2012). Finally, in the

intensive care setting, the anesthetic drug etomidate, at

dosages between 0.1 and 0.3 mg/kg per h, can be used

Figure 5 [111In-DTPA0]octreotide and CT imaging results in a patie(A and B) and after 6 months of therapy with mifepristone (C, D anda small nodule in the right upper lung (white arrow), which was not vmifepristone therapy, the CT scan shows the same lesion (white arepeat [111In-DTPA0]octreotide scan that shows pathological uptakwith permission from de Bruin C, Hofland LJ, Nieman LK, van KoetsSW, de Herder WW & Feelders RA 2012 Mifepristone effects on tuCushing’s syndrome due to ectopic ACTH secretion. Journal of Cli

R216

to rapidly suppress cortisol production in complicated

EAS (Schulte et al. 1990).

Blockade of cortisol tissue effects with mifepristone

administration can also be an efficacious treatment for

EAS. A recently published retrospective study reported

improvement of clinical signs in 15/20 patients with CS

of different etiologies after treatment with mifepristone

(Castinetti et al. 2009). Most of these patients could be

controlled with daily mifepristone dosages between

400 and 800 mg. An advantage of mifepristone is its

rapid onset of action. Indeed, in this retrospective

cohort, psychiatric symptoms improved within a week

in 4/5 patients (Castinetti et al. 2009). This paper also

summarized earlier published case reports on mifepris-

tone treatment showing clinical improvement in 9/9

patients with EAS. Dosages higher than 1000 mg/day

seem to be associated with more side effects, in

particular hypokalemia and clinical adrenal insuffi-

ciency (Castinetti et al. 2009). Glucocorticoid antag-

onizing therapy may also modulate sst2 expression of

ACTH-producing neuroendocrine tumors. We recently

described two patients with an occult bronchial

neuroendocrine tumor in whom the initially negative

somatostatin receptor scintigram became positive after

nt with ectopic ACTH production by a bronchial carcinoid beforeE). Before mifepristone therapy was started, CT scan (A) showsisible at the [111In-DTPA0]octreotide scan (B). After 6 months ofrrow) in the right lung (C), which can now be visualized with ae at the site of the lesion (D and E; black arrows). Reproducedveld PM, Waaijers AM, Sprij-Mooij DM, van Essen M, Lambertsmor somatostatin receptor expression in two patients withnical Endocrinology and Metabolism 97 455–462.




treatment with mifepristone during 6 and 12 months

respectively (Fig. 5; de Bruin et al. 2012). These

patients were subsequently operated and immunohis-

tochemical studies showed strong sst2 expression. This

observation demonstrates that glucocorticoid-mediated

suppression of sst2 expression can be reversed by

blockade of the GR. Further studies are needed to

evaluate whether glucocorticoid-antagonizing or -low-

ering therapy can improve the diagnostic yield of

somatostatin receptor scintigraphy and can increase

therapeutic efficacy of sst2-preferring compounds.

These somatostatin analogs can be of use in the

treatment of EAS when sst2 is sufficiently expressed,

although treatment escapes have been described

(Hofland & Lamberts 2003). Dopamine receptors can

also be expressed by ACTH-producing neuroendocrine

tumors, and in small case series, complete responses

were observed after treatment with cabergoline, either

as monotherapy (Pivonello et al. 2007) or in

combination with the sst2-preferring somatostatin

analog lanreotide (Pivonello et al. 2005). Future

studies should further explore the efficacy of combined

targeting of sst2 and D2R in EAS.

In summary, EAS that is complicated by severe CS

should be treated aggressively. If patients cannot

undergo curative or palliative surgery, medical therapy

should be applied with mifepristone or combination

therapy with inhibitors of steroidogenesis according to

individual patient characteristics (e.g. presence of

psychosis and disturbed liver function). In selected

cases, somatostatin analogs and dopamine agonists

may be effective. Further studies are needed on the

optimal combination and doses of available drugs in

the treatment of EAS.

ACTH-independent CS

Medical treatment in ACTH-independent CS is

predominantly used for cortisol-producing ACC to

Table 5 Medical treatment options for identified aberrant adrenal h

Aberrant receptor In vivo screening protocol

GIP receptor Mixed meal; oral glucose

Vasopressin receptor Upright posture

Administration of arginine vasopres

b-Adrenergic receptor Upright posture; isoproterenol infus

LH/hCG receptor GNRH administration; hCG, recomb

5-HT4 receptor Administration of 5-HT4 agonists

AT-1 receptor Upright posture; angiotensin infusio

GIP, glucose-dependent insulinotropic peptide; GIPR, GIP receptoAT-I, angiotensin I. Reproduced with permission from Lacroix A 20Best Practice & Research. Clinical Endocrinology & Metabolism 23


treat acute complications of CS and/or in patients with

advanced disease. Mitotane is the first-choice treat-

ment for ACC considering its antiproliferative and

antisecretory effects (Veytsman et al. 2009, Fassnacht

et al. 2011). When hypercortisolism cannot be

controlled by mitotane monotherapy or when the

late-onset effects of mitotane cannot be awaited for,

other adrenal blocking drugs, e.g. ketoconazole or

metyrapone, or the GR antagonist mifepristone can

be added (Castinetti et al. 2009, Fassnacht et al. 2011).

In case of progressive disease under mitotane

treatment, chemotherapy with etoposide, doxorubicin,

and cisplatin can be considered (Fassnacht et al. 2012),

although there might be a high risk on infections in the

neutropenic phase because of the hypercortisolemic

state. Currently, tyrosine kinase inhibitors, IGF-1

receptor blockers, and interferon-b are evaluated in

in vitro and/or in vivo models of ACC.

As outlined in ‘Adrenal adenoma and bilateral

adrenal hyperplasia’ section, AIMAH is usually treated

by bilateral adrenalectomy, whether or not preceded by

medical therapy with steroidogenesis inhibitors.

However, the identification of ectopic hormone

receptors in AIMAH may provide perspectives for

specific medical treatment by targeting the involved

receptor or production of the endogenous ligand

(Lacroix 2009). For instance, in AIMAH associated

with catecholamine-responsive CS, treatment with

b-adrenergic receptor antagonists can result in sus-

tained control of cortisol overproduction (Lacroix et al.

1997). In AIMAH with ectopic LH receptor

expression, inhibition of LH production with long-

acting leuprolide acetate successfully reversed hyper-

cortisolism (Lacroix et al. 1999), whereas in patients

with food-dependent CS due to ectopic expression of

the glucose-dependent insulinotropic peptide (GIP)

receptor, treatment with octreotide led to biochemical

improvement via inhibition of postprandial GIP release

ormone receptors using an in vivo screening protocol in AIMAH

Medical treatment options

Octreotide; GIPR antagonist

Vasopressin receptor antagonist

sin or desmopressin

ion b-Blockers

inant LH Long-acting GNRH agonist

5-HT4 receptor antagonist

n AT-1 receptor antagonist

r; hCG, human chorionic gonadotropin; 5-HT4, serotonin;09 ACTH-independent macronodular adrenal hyperplasia.245–259.

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(Table 5; Reznik et al. 1992, de Herder et al. 1996).

Thus, specific medical therapy for AIMAH can be

considered after screening for aberrant receptors,

although further study is needed on long-term efficacy

of different treatment modalities. In this respect, a

possible role for medical therapy in AIMAH associated

with subclinical CS should also be examined.

Conclusions and future developments

Although surgery is still the primary treatment of most

cases of CS, recent years have brought several

developments in the medical treatment of different

causes of CS. In CD, pituitary-targeted therapy with

cabergoline and pasireotide has been shown to be

efficacious in w20–40% of patients with CD when

used as monotherapy. Higher success rates have been

obtained not only by combination therapy with

pasireotide, cabergoline, and ketoconazole but also

by combining only cabergoline and ketoconazole. GR

antagonizing therapy with mifepristone can result in

rapid clinical and metabolic improvement. Preclinical

studies with retinoic acid and the EGFR-directed

tyrosine kinase inhibitor gefitinib have shown promis-

ing results, but future studies should examine their

clinical applicability.

With respect to ACTH-independent macronodular

adrenal hyperplasia, an increasing amount of data

has become available showing promising results of

drugs targeting different aberrantly expressed receptors

at the level of the adrenal cortex. Such receptor-

directed therapy could be an alternative to bilateral

adrenalectomy in these patients.

Medical therapy for CS should be given with a

tailor-made approach, involving relevant patient

characteristics, in which potential clinical efficacy of

a drug should be carefully weighed against its potential

side effects.

Declaration of interest

R A Feelders and W W de Herder have performed

consultancy activities for Novartis.

Funding

This review did not receive any specific grant from any

funding agency in the public, commercial or not-for-profit

sector.

R218

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Received in final form 18 August 2012Accepted 30 August 2012Made available online as an Accepted Preprint30 August 2012

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