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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
Endocrine-Related Cancer (2012) 19 R205–R223
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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Endocrine-Related Cancer (2012) 19 R205–R223
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.
www.endocrinology-journals.org
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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R van der Pas et al.: Developments in the medical treatment of CS
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
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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
gastrointestinal discomfort
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
gastrointestinal discomfort
Endocrine-Related Cancer (2012) 19 R205–R223
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
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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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R van der Pas et al.: Developments in the medical treatment of CS
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
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Endocrine-Related Cancer (2012) 19 R205–R223
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
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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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R van der Pas et al.: Developments in the medical treatment of CS
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).
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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.
Endocrine-Related Cancer (2012) 19 R205–R223
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
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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.
R van der Pas et al.: Developments in the medical treatment of CS
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.
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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.
Endocrine-Related Cancer (2012) 19 R205–R223
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.
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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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R van der Pas et al.: Developments in the medical treatment of CS
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
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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.
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Endocrine-Related Cancer (2012) 19 R205–R223
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
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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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R van der Pas et al.: Developments in the medical treatment of CS
(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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