Treatment of Cushing's disease: a mechanistic update

in Journal of Endocrinology
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  • 1 Department of Medicine, Neuroendocrinology Clinic, Departments of Medicine and Neurological Surgery, Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, California, USA

Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus–pituitary–adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.

Abstract

Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus–pituitary–adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.

Introduction

Cushing's disease (CD) is caused by an adrenocorticotropin (ACTH)-secreting pituitary tumor that stimulates cortisol production by the adrenal glands. Morbidity and mortality are significantly increased if hypercortisolemia is left untreated. Transsphenoidal surgery, performed by an experienced neurosurgeon, is currently considered the first-line treatment. Medical treatment is commonly used to control the deleterious effects of persistent chronic glucocorticoid excess and 24-h urinary free cortisol (UFC) normalization still represents the gold standard to evaluate the efficacy of most medical treatments.

Glucocorticoid exerts effects through the glucocorticoid receptor (GR) and as the GR is expressed in almost every human tissue, conditions of glucocorticoid excess, such as CD, result in deleterious effects on cell metabolism. Pharmacological agents can be classified as adrenal steroidogenesis blockers, centrally acting drugs, and GR antagonists. Recent research has evaluated chimeric compounds that work synergistically through membrane interaction or dimerization of both somatostatin receptors (SSTRs) and dopamine D2 receptors in corticotrope cells. Although no available medical agents surpass the efficacy of surgical therapy, new treatments acting directly at the pituitary adenoma have been approved for use and highlight the importance of targeting the pituitary corticotrope. A review of the mechanisms of current and future medical treatment modalities for CD is provided.

Overview of CD therapy

Cushing's syndrome (CS) is characterized by chronic overproduction of cortisol resulting in significant morbidity and, when left untreated, increased mortality (Newell-Price et al. 2006, Dekkers et al. 2007). CS is classified as ACTH-dependent and -independent. The most common etiology (70–80%) of CS is CD, caused by an ACTH-secreting pituitary adenoma or, more rarely, by ectopic ACTH or corticotropin-releasing hormone (CRH) production that may result in corticotrope hyperplasia (Newell-Price et al. 2006, Biller et al. 2008). Chronic cortisol excess leads to a typical clinical phenotype (Table 1). Although epidemiological data on CD are limited, population-based studies indicate an incidence of 1.2–2.4 per million (Arnardottir & Sigurjonsdottir 2011, Bolland et al. 2011) with a prevalence of approximately 39 per million population (Feelders et al. 2012). Compared with the general population or patients with other pituitary adenomas, patients with hypercortisolism have a four times higher mortality risk if untreated and cardiovascular disease remains the leading cause of death (Newell-Price et al. 2006, Dekkers et al. 2007, Feelders & Hofland 2013).

Table 1

Clinical features and associated morbidity observed in Cushing's syndrome

Clinical featuresFrequency (%)
Increased weight (centripetal obesity, supraclavicular region, and upper back)80–95
Skin changes (round face, facial plethora, and skin atrophy)80–90
Decreased libido25–90
Menstrual irregularity75–80
Muscle proximal weakness60–80
Hirsutism70–75
Violaceous striae55–65
Easy bruising45–65
Associated morbidity
 Obesity40–95
 Hypertension60–80
 Glucose intolerance or diabetes mellitus50–80
 Osteoporosis40–75
 Psychiatric symptoms50–70
 Dyslipidemia40–70
 Increased infections and decreased wound healing15–30
 Renal calculi15–20
 Venous thromboembolism10–20
 Avascular necrosis in femoral head5–10
Specific for Cushing's disease
 Headaches0–37
 Visual problems (bitemporal hemianopsia)0–33
 Other anterior pituitary hormone deficiencies0–25
Alterations with severe hypercortisolism
 Weight reduction (with ectopic ACTH secretion by malignancy)10–50
 Hypoalbuminemia15–35
 Skin hyperpigmentation10–15
 Hypokalemia and metabolic alkalosis4–10

Transsphenoidal surgery is the first line therapy achieving 65–90% disease remission for microadenomas (tumors <1 cm; Biller et al. 2008, Tritos et al. 2011, Fleseriu 2012), and lower remission rates (<65%) for macroadenomas (tumors >1 cm) (Aghi 2008). The risk of CD recurrence can reach 25%, 3 years after surgery (Patil et al. 2008). Second and third line therapies such as a second pituitary surgery (Patil et al. 2008, Fleseriu 2012), pituitary irradiation (conventional and/or stereotactic) (Estrada et al. 1997, Tritos et al. 2011) and bilateral adrenalectomy (Young & Thompson 2005, Assie et al. 2007, Chow et al. 2008, Ritzel et al. 2013) have been utilized with variable results and specific complications.

Targets for medical treatment of CD

The hypothalamus–pituitary–adrenal (HPA) axis is organized into three regions: the hypothalamus, pituitary gland, and adrenal glands (Fig. 1). CD is caused by a pituitary tumor; therefore, medical therapy should ideally target the corticotrope cell adenoma. However, as glucocorticoids represent the end hormone of the HPA axis and hypercortisolism induces comorbidities, steroidogenic inhibition was the first therapy used. Indications for medical therapy in patients with CD are summarized in Table 2.

Figure 1
Figure 1

The hypothalamus–pituitary–adrenal (HPA) axis and targets of drugs used for treating Cushing's disease. Under physiological conditions, cortisol synthesis and production are tightly regulated by the HPA axis. Adrenocorticotropin (ACTH)-producing cells in the anterior pituitary respond to hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). After binding to melanocortin type 2 receptor (MC2R), ACTH induces the steroidogenic enzymes to increase the biosynthesis of cortisol and will decrease ACTH and CRH secretion. Pituitary corticotrope ACTH-secreting adenomas, however, function autonomously and overstimulate cortisol production at the adrenal cortex. The pharmacotherapies for ACTH-secreting pituitary corticotrope adenomas are categorized by the site of action into three groups: i) centrally acting agents or neuromodulators, which inhibit ACTH release from pituitary adenomas, ii) adrenal steroidogenic inhibitors, which block one or several steps in cortisol biosynthesis and iii) the glucocorticoid receptor-blocking agent mifepristone. Green arrows indicate activation and red arrows/lines indicate inhibition.

Citation: Journal of Endocrinology 223, 2; 10.1530/JOE-14-0300

Table 2

Use of medical therapy in Cushing's disease – indications and needs

Before or after pituitary surgery
 Preparation for surgery
 Patients with contraindications for surgery
 High operation risk
 Patients unwilling to undergo surgery
 After unsuccessful surgery
Amelioration or control of the metabolic effects of hypercortisolemia
 Potentially life-threatening complications
 Patients awaiting effects of pituitary radiation
 Whenever a definitive treatment is delayed
Primary medical therapy
 Low probability of surgical cure
 Unfavorable localization
 Invisible adenomas
 Adenoma without optic chiasm compression

Adrenal steroidogenesis blockers

Adrenal cortical atrophy was first documented in dogs treated with the insecticide dichlorodiphenyldichloroethane (DDD; Nelson & Woodard 1949). This observation led to the development of the use of o,p′-DDD or mitotane, initially for adrenal cancer and CS (Cueto & Brown 1958, Southren et al. 1961). Subsequently, amphonenone B (Hertz et al. 1956, Thorn et al. 1956), aminoglutethimide (Camacho et al. 1967), metyrapone (Gower 1974), trilostane (Potts et al. 1978), and ketoconazole (Pont et al. 1982) were identified as steroidogenic inhibitors (Fig. 2 and Table 3).

Figure 2
Figure 2

Adrenocortical steroidogenic pathways. A simplified diagram of adrenal steroidogenesis is depicted. Cushing's disease is almost always caused by a pituitary corticotrope adenoma that oversecretes corticotropin (ACTH). ACTH stimulates the adrenal gland to start steroid synthesis. After activation of MC2R by ACTH, the StAR protein is phosphorylated. Then, StAR facilitates cholesterol transport across the mitochondrial inner membrane. Cholesterol is the common precursor of the steroid molecules and, after several enzymatic reactions, is ultimately converted into biologically active aldosterone, cortisol, or androstenedione that is further processed to testosterone in testicles. The zona glomerulosa, fasciculata, and reticularis are the three adrenal cortex histological zones, which synthesize steroid hormones with mineralocorticoid, glucocorticoid, or androgenic properties respectively. Enzyme nomenclature is given in detail in Table 1. CYP11A1, CYP11B1, and CYP11B2 are located in the mitochondria, and the remaining enzymes are located in the smooth endoplasmic reticulum.

Citation: Journal of Endocrinology 223, 2; 10.1530/JOE-14-0300

Table 3

Doses and relevant side effects of drugs used in the medical treatment for Cushing's disease

Steroidogenesis inhibitors
 Ketoconazole400–1200 mg/dayHepatitis, cholestasis, gynecomastia, gastrointestinal upset, edema, skin rash. Hypogonadism in men. Fluconazole may be better tolerated
 Fluconazole200 mg/day
 Metyrapone0.5–4.5 g/dayAcne, hirsutism, lethargy, dizziness, ataxia, nausea, hypertensive crisis, hypokalemia, edema, and adrenal insufficiency
 Mitotane2–5 g/dayGastrointestinal distress, impaired concentration and dizziness, gynecomastia, hepatitis, cholestasis, hyperlipidemia, prolongation of bleeding time, and adrenal insufficiency. Effect antagonized by spironolactone
 EtomidateBolus 0.03 mg/kg i.v.; followed by 0.1–0.3 mg/kg per hNephrotoxicity, sedation, pain at the infusion site, anaphylactic reactions, coughing, hiccups, nausea, vomiting, and myoclonus
 LCI6994–100 mg/day (investigational drug)Fatigue, nausea, headache, and hypokalemia
Centrally acting drugs
 Cabergoline0.5–7 mg/weekNasal congestion, nausea, postural hypotension, and headache. Gradual increase minimizes side effects
 Bromocriptine1–30 mg/day
 Pasireotide750–2400 μg/dayGastrointestinal-related conditions, hyperglycemia, cholelitiasis, nausea, abdominal pain, fatigue, headache, hypotension, and adrenal insufficiency
 Retinoic acid10–80 mg/day (research drug)Xerophthalmia and arthralgias
Glucocorticoid receptor antagonist
 Mifepristone300–1200 mg/dayHypokalemia, worsening of hypertension, adrenal insufficiency, endometrial hyperplasia, fetal loss, gastrointestinal complaints, fatigue, nausea, headache, arthralgia, vomiting, and edema. Contraindicated in women planning pregnancy

Ketoconazole

Introduced as an antifungal agent, ketoconazole exerts endocrine side effects indicating its possible therapeutic efficacy in lowering cholesterol levels. Indeed, the imidazole derivative ketoconazole was noted to cause gynecomastia associated with lower plasma testosterone and cortisol values (Table 3; Pont et al. 1982). Ketoconazole was first used in the treatment of a patient with a cortisol-producing adrenal adenoma in 1983 (Engelhardt et al. 1983), and has been used off-label since then. Ketoconazole inhibits the side-chain cleavage complex (P450scc, CYP11A1, or 20,22 desmolase), 11β-hydroxylase, and 17α-hydroxylase (Table 4) (Feldman 1986, Loli et al. 1986). As a result of effective inhibition of cholesterol side-chain cleavage and 17-hydroxylase/17,20 lyase activity, ketoconazole may reduce androgen synthesis; therefore, effects on hirsutism are favorable (Fig. 2). There are inhibitory effects on several cytochrome P450 enzymes, mainly CYP3A4, CYP2C9, and CYP1A2 (Feldman 1986, Feelders et al. 2010a, Fleseriu & Petersenn 2012), but minimal effect on aromatase enzyme (Miller & Crapo 1993).

Table 4

Enzymes that catalyze the initial reaction in the pathways of steroid hormone biosynthesis

Localization and common nameNomenclatureaInhibitorsReferences
PreviousCurrent
Mitochondrial
 StAR proteinStARStARImidazolesbWalsh et al. (2000)
 Side-chain cleavage (scc) enzyme or 20,22 desmolaseP450sccCYP11A1ImidazolesCamacho et al. (1967), Schulte et al. (1990), and Miller & Crapo (1993)
Etomidate
Mitotane
Aminoglutethimide
 11β-hydroxylaseP450 C11CYP11B1ImidazolesCamacho et al. (1967), Gower (1974), Feldman (1986), Loli et al. (1986), and Miller & Crapo (1993)
Mitotane
Aminoglutethimide
Metyrapone
 Aldosterone synthase, 18-hydroxylaseP450 C11ASCYP11B2MitotaneCamacho et al. (1967), Gower (1974), Miller & Crapo (1993), and Calhoun et al. (2011)
LCI699
Aminoglutethimide
Metyrapone
Smooth endoplasmic reticulum
 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase3β-HSD3β-HSDTrilostanePotts et al. (1978), Dewis et al. (1983), and Engelhardt & Weber (1994)
 17α-hydroxylase/17,20 lyaseP450 C17CYP17ImidazolesCamacho et al. (1967), Gower (1974), Feldman (1986), Loli et al. (1986), and Miller & Crapo (1993)
Aminoglutethimide
Metyrapone
 21-HydroxylaseP450 C21CYP21A2AminoglutethimideCamacho et al. (1967)
 AromataseP450 aroCYP19AminoglutethimideCamacho et al. (1967)

P450scc or CYP11A1, i.e. gene family 11, subfamily A, polypeptide 1.

Imidazoles=ketoconazole, fluconazole, econzale, and/or miconazole.

The first clinical reports on patients with CD described normalization of urinary or plasma cortisol values with ketoconazole doses of 600–1200 mg/day (Loli et al. 1986, Tabarin et al. 1991, Miller & Crapo 1993). Ketoconazole treatment is usually started at 200 mg twice a day, and biochemical effect is achieved at 600–1200 mg/day (Table 3; Nieman 2002, Fleseriu et al. 2012). It has been suggested that ketoconazole may also have inhibitory effects on ACTH secretion by corticotrope tumor cells as ACTH shows no significant increase despite confirmed reduction in cortisol levels (Loose et al. 1983, Loli et al. 1986, Jimenez-Rema et al. 1989, Tabarin et al. 1991). Escape from pharmacological control has been reported (Sonino et al. 1991). Administered as a monotherapy, ketoconazole decreases cortisol levels in 30–80% of patients (Sonino et al. 1991, Sonino & Boscaro 1999, Castinetti et al. 2008). Results from a recent large multicenter retrospective study (n=200) revealed normalization of UFC levels measured at the last follow-up in 49% of patients (Castinetti et al. 2014). Ketoconazole also blocks the GR at high concentrations in cultured hepatoma cells (Loose et al. 1983). Reportedly, hepatotoxicity (Sonino 1987, Sugar et al. 1987, Tabarin et al. 1991) was mild in the study and resolved after drug withdrawal (Castinetti et al. 2014). Ketoconazole has also been used in older patients (>75 years of age) with good tolerance and disease control (Berwaerts et al. 1998).

The use of ketoconazole has been questioned after warnings from the European Medicine Agencies and the US Food and Drug Administration (FDA) of potential hepatotoxicity (Castinetti et al. 2014). Long-term safety remains to be prospectively studied. In contrast to mitotane (which causes hypercholesterolemia), ketoconazole interferes with the conversion of lanosterol to cholesterol, leading to low cholesterol concentrations. Ketoconazole absorption requires an acidic environment, precluding the use of proton pump inhibitors or H2 receptor blockers. Currently, drug availability is limited in many countries.

Fluconazole

Fluconazole appears to have similar effects to ketoconazole; however, data are limited. Fluconazole inhibits 11β-hydroxylase and 17-hydroxylase activities (Fig. 2) and blocks cortisol production in primary cultures of human adrenocortical cells (van der Pas et al. 2012). Fluconazole has been shown to decrease 11-deoxycortisol production in H295R cells and reduce cortisol secretion in HAC15 cells and primary cultures (van der Pas et al. 2012). In cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol were increased (Fig. 2). Fluconazole slightly increased StAR protein mRNA expression (van der Pas et al. 2012). Results from clinical studies indicated that fluconazole at a dose of 100 mg twice a day successfully controlled UFC levels in two patients (Riedl et al. 2006). Together, the results of these in vitro and in vivo studies indicate that fluconazole can be used to control cortisol hypersecretion in patients with CD (Table 3).

Neither ketoconazole nor fluconazole were shown to affect the mRNA levels of steroidogenic enzymes or cell number; therefore; a single dose is unlikely to have a long-term effect (van der Pas et al. 2012).

Metyrapone

Metyrapone (SU-4885; Metopirone) inhibits 11β-hydroxylase (Fig. 2) (Liddle et al. 1959) and 17α-, 18-, and 19-hydroxylase (Table 4) (Gower 1974). Cortisol levels decrease after 2 h of the first dose (Verhelst et al. 1991). Doses range from 500 mg to 4.5 g/day, or 6 g/day in divided doses (usually starting with 250 mg four times daily, Table 3; Nieman 2002, Fleseriu 2012). Notably, and similar to ketoconazole, rapid uptitration of metyrapone is essential to achieve a full effect (Kamenicky et al. 2011, Castinetti et al. 2014). The strong cortisol-lowering effect of metyrapone can be accompanied by the loss of negative feedback and ACTH inhibition (Fig. 1). Increments in ACTH secretion may override steroidogenic blockade that may occur during the first month following initiation of treatment. Nevertheless, prolonged metyrapone activity in patients with CD has been shown, despite a rise in plasma ACTH levels (Verhelst et al. 1991). ACTH also overstimulates production of adrenal androgen and mineralocorticoid precursors (e.g. desoxycorticosterone). Moreover, aldosterone biosynthesis is more severely affected than that of cortisol (Gower 1974). Therefore, several side effects related to metyrapone treatment limit its clinical use in patients with CD (Table 3). However, combination therapy has been proposed to improve tolerance and increase efficacy (Table 5; Verhelst et al. 1991, Kamenicky et al. 2011). Despite safety concerns about the use of this drug in pregnant women, metyrapone has been used sporadically during pregnancy (Lindsay et al. 2005, Karaca et al. 2010). Additional long-term studies with metyrapone in patients with CD are warranted. Currently, metyrapone has limited availability in most countries.

Table 5

Overview of agents that have been tested as combination drug therapy for Cushing's disease. Doses: cabergoline from 0.5 to 3 mg/week, ketoconazole 200 to 1200 mg/day, pasireotide 300 to 750 μg/day, mitotane 3 to 5 g/day, metyrapone 3 to 4.5 g/day, and octreotide 300 to 1500 μg/day. The studies are described in the text

ReferencesCompoundsPatients (n)UFC normalization (%)
Monotherapy Combination
Barbot et al. (2014)Ketoconazole+cabergoline1420–3080
Feelders et al. (2010b,c)Pasireotide+cabergoline+ketoconazole173050 P+C
90 P+C+K
Vilar et al. (2010)Cabergoline+ketoconazole122570
Total/average432773
Severe hypercortisolism/aggressive tumor
 Vignati & Loli (1996)Ketoconazole+octreotide400
 Bode et al. (2010)Temozolomide+pasireotide10100
 Kamenicky et al. (2011)Mitotane+metyrapone+ketoconazole11 CS (4 CD)0100
 Total/average16066

UFC, urinary free cortisol.

Mitotane

1-(o-Chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p′-DDD) (Lysodren; mitotane), an insecticide analog of dichlorodiphenyltrichloroethane has been extensively used to treat all forms of hypercortisolism (Boscaro et al. 2001). Mitotane's mechanism of action was initially described in animal studies as lipid accumulation and atrophy of fasciculate and reticularis regions of the adrenal cortex. Effects on the zona glomerulosa were only observed after prolonged therapy (Cueto & Brown 1958). Within 12 h of treatment in dogs, electron microscopy revealed rupture of mitochondrial cristae, followed by mitochondrial swelling, lysis, and cell death (Miller & Crapo 1993). Conversion of cholesterol to pregnenolone was markedly impaired indicating that side-chain cleavage of cholesterol was the major enzymatic step affected inhibiting the cytochrome P450 enzymes CYP11A1 (mitochondrial side-chain cleavage enzyme), 11β-hydroxylation (CYP11B1), and 18-hydroxylation (CYP11B2), and non-P450 enzymes (3β-hydroxysteroid dehydrogenase) (Fig. 2; Miller & Crapo 1993). Mitotane also stimulates CYP3A4 expression, reducing cortisol bioavailability (Kroiss et al. 2011). Therefore, mitotane has three effects: i) adrenocorticolytic, ii) modification of steroid metabolism, and iii) direct inhibition of steroid biosynthesis. Although used to treat adrenocortical carcinoma, mitotane has proven effective in patients with CD (Bledsoe et al. 1964, Baudry et al. 2012). Mitotane displays a relatively slow onset of action compared with other steroidogenesis inhibitors and saturation can be expected 2–3 months after initiation of therapy (Luton et al. 1979, Fleseriu & Petersenn 2012). Overall, 80% of patients achieve normalization of urinary markers; however, 60% relapsed after therapy withdrawal indicating a low level of adrenolytic action (Luton et al. 1979, Schteingart et al. 1980). Sustained remission after mitotane discontinuation has been reported in 30% of patients measured at a mean follow-up of 37 months (Miller & Crapo 1993). Doses are approximately 4 g/day, with a gradual increment from 0.5 to 1 g/day (Table 3; Luton et al. 1979). Results from a recent retrospective study revealed remission in 48 (72%) out of 67 patients treated for long-term CD after a median of 6.7 (5.2–8.2) months (Baudry et al. 2012) at lower doses compared with adrenal cancer.

Despite its effectiveness, mitotane therapy is complicated by several side effects (Table 3). Owing to an accelerated metabolism of exogenous steroids, especially hydrocortisone, replacement doses must be increased to avoid adrenal crises (Robinson et al. 1987). Mitotane may lead to restoration of gonadal function and fertility; therefore, effective contraception is advisable for female patients (Miller & Crapo 1993). Mitotane is stored in adipose tissue for 2 years after administration ends and should not be used in women considering pregnancy within 5 years of discontinuation (Leiba et al. 1989). Owing to the stimulatory effect of mitotane on cortisol-binding globulin levels (Nader et al. 2006), serum cortisol measurements are not useful and monitoring of urinary or serum free cortisol is the best index of response (Alexandraki et al. 2010). Replacement therapy requirements are higher than normal, due to interference of hormone-binding proteins as well. Mitotane combined with pituitary irradiation was shown to be efficacious in non-controlled clinical trials (Luton et al. 1979, Schteingart et al. 1980).

Etomidate

The imidazole anesthetic agent etomidate (Amidate or Hypnomidate) was observed to decrease postoperative cortisol values in patients during anesthesia (Feldman 1986). Subsequently, it was discovered that etomidate inhibits the 11β-hydroxylase enzyme (CYP11B1), 17α-hydroxylase (CYP17A1), and the cholesterol side-chain cleavage complex (P450scc, or CYP11A1, or 20,22 desmolase), thus blocking multiple steps of steroidogenesis (Fig. 2). It is the only parenteral steroidogenesis inhibitor available and provides rapid hypercortisolemia control (Allolio et al. 1988, Schulte et al. 1990). An i.v. bolus injection of etomidate at a low non-hypnotic dose (0.03 mg/kg) followed by constant infusion of 0.3 mg/kg per h for 24 h (Table 3) decreases serum cortisol in a dose-dependent manner with significant suppression after the first 5 h with a maximum effect after 11 h (Allolio et al. 1988, Schulte et al. 1990). Glucocorticoid replacement to prevent adrenal insufficiency is warranted after 24 h of etomidate infusion. Clinical use of etomidate in CS has been limited by sedative side effects, but could be safe and effective in significant biochemical disturbance, sepsis, severe psychosis, and in preoperative instability (Heyn et al. 2012, Preda et al. 2012).

LCI699

First characterized as an aldosterone biosynthesis inhibitor for primary aldosteronism and essential hypertension, LCI699 is an 18-hydroxylase (aldosterone synthase) inhibitor blocking the conversion of hydroxycorticosterone to aldosterone. It also inhibits 11β-hydroxylase (CYP11B1) in a similar manner to the R-enantiomer of fadrozole (FAD286) that blocks the hydroxylation of deoxycortisol to cortisol as well as CYP11B2 blocking the conversion of deoxycorticosterone to corticosterone (Fig. 2) (Calhoun et al. 2011). LCI699 is currently under investigation as a treatment for CD (Tritos et al. 2011, Feelders & Hofland 2013). In a phase II proof of concept study of LCI699, rapid UFC normalization in 11 out of 12 patients with CD, all achieving >50% reduction in baseline UFC, was observed. Doses ranged from 4 to 100 mg/day for 10 weeks (Bertagna et al. 2014). As expected, ACTH increased; 45% of cases had ACTH more than twice that of baseline. Most adverse events were mild or moderate (Table 3). Based on these promising results, a larger phase III trial is awaited.

Trilostane (Vetoryl), an inhibitor of 3β-hydroxysteroid, was withdrawn from human use in the USA in 1994 (Potts et al. 1978, Dewis et al. 1983, Engelhardt & Weber 1994). Aminoglutethimide (Cytadren; Camacho et al. 1967, Misbin et al. 1976) is rarely used in the treatment of patients with CD. The mechanisms of action, common doses, and main adverse effects of aminoglutethimide are listed in Tables 2 and 3.

Centrally acting drug treatments

Human corticotrope adenomas display responsiveness to neurohumoral influences such as dexamethasone suppression, lysine vasopressin, thyrotropin-releasing hormone, and metyrapone administration. Dexamethasone is a synthetic glucocorticoid extensively used to demonstrate the sensitivity of HPA axis negative feedback to glucocorticoids for differential diagnosis of CS. If the HPA axis is normal, any supraphysiological dose of dexamethasone is sufficient to suppress pituitary ACTH secretion. ACTH secretion can also be suppressed in most patients with CD as pituitary corticotrope adenomas are only relatively resistant to inhibition of glucocorticoid negative feedback. Hypophyseal ACTH secretion can be influenced by serotonin antagonists, dopamine or gamma-amino butyric acid (GABA) agonists, somatostatin receptor ligands (SRLs), retinoic acid, and temozolomide (Fig. 1). In addition to biochemical effects, CD has been associated with periodic hormonogenesis (cyclical CD) or spontaneous remission, indicating that some cases of CD may be due to altered neuroregulatory influences (Van Cauter & Refetoff 1985, Dickstein et al. 1991, Colao et al. 1997, Nieman 2002).

Somatostatin receptor ligands

Somatostatin

Somatostatin (SST) is a cyclic peptide with a circulating half-life of <3 min (Brazeau et al. 1973). The name SST originates from a supposed ‘specific’ function as an inhibitor of somatotropin (growth hormone (GH)) release, thus somatotropin release-inhibiting factor. In the CNS, SST has a key inhibitory action in the secretion of GH (Brazeau et al. 1973), prolactin (PRL; Vale et al. 1974), thyrotropin (Siler et al. 1974), and ACTH (Richardson & Schonbrunn 1981, Lamberts et al. 1989a,b) from the anterior pituitary gland. At the peripheral nervous system level, SST plays a regulatory role in the gastrointestinal tract inhibiting flow from the gallbladder, bowel motility and gastric emptying, smooth muscle contraction, and nutrient absorption from the intestine as well as in the exocrine pancreas. SST also inhibits the release of glucagon (Boden et al. 1986), insulin (Alberti et al. 1973), and pancreatic polypeptide (Koerker et al. 1974).

SST exerts action through five G protein-coupled receptor subtypes: SSTR1–SSTR5 (Batista et al. 2006, Ben-Shlomo et al. 2010, Cuevas-Ramos & Fleseriu 2014). The majority of corticotrope adenomas (>85%) express SSTR2 and SSTR5 mRNA, and to a lesser extent SSTR1 (63%) (Miller et al. 1995). The membrane density of SSTR subtypes, particularly SSTR2, is affected by hypercortisolism (Schonbrunn 1982, Stalla et al. 1994, de Bruin et al. 2009). In contrast, SSTR5 expression appears to be relatively unaffected by high cortisol levels. Therefore, in patients with active CD, SSTR5 is predominantly expressed compared with SSTR2 (de Bruin et al. 2009).

Somatostatin receptor ligands

The potent antisecretory properties of SST have made it an important pharmacological target for hormonal hypersecretion treatment. However, its short half-life, the multiple and simultaneous actions in different organs, and the need for parenteral administration hampered its clinical use. SRLs have originated after manipulation of SST key structural characteristics, which allowed several reductions of the above disadvantages. Recently, an update on SRLs and SRL's resistance has been published (Cuevas-Ramos & Fleseriu 2014).

Octreotide and lanreotide are SSTR2 SRLs with low activity in suppressing ACTH in patients with CD (Lamberts et al. 1989a,b, Biller et al. 2008). After eucortisolemia restoration, SSTR2 expression recovers, becoming similarly abundant to SSTR5, thus improving treatment responsiveness (Feelders et al. 2010a, van der Pas et al. 2013). The SSTR2 mRNA expression, however, did not correlate with protein levels. The discrepancy between mRNA and protein levels may be caused by persistent cortisol-induced disturbed translation of SSTR2 mRNA and GR on the adenoma cells still exposed to sufficiently high levels of circulating cortisol to suppress the transcription/translation of the SSTR2 gene (van der Pas et al. 2013). The recovery of SSTR2 expression may have therapeutic implications, as it may allow sequential treatment with SSTR2 ligands after induction of partial or complete remission with other drugs. Nevertheless, the predominant expression of SSTR5 mRNA in cultured human corticotrope adenoma cells prompted an alternative approach using a SSTR5 ligand (Batista et al. 2006).

Pasireotide

Pasireotide (SOM230; Signifor) is an SRL that principally binds to SSTR5, in addition to SSTR1, SSTR2, and SSTR3 (Ben-Shlomo et al. 2010). Pasireotide has a 40-fold higher affinity for SSTR5 than octreotide (Murray et al. 2004). After pasireotide treatment, in primary cultures of human corticotrope tumors, cell proliferation and ACTH secretion were suppressed (Batista et al. 2006). Notably, dexamethasone pre-treatment did not reduce cell sensitivity to pasireotide, indicating that SSTR5 is resistant to negative control by glucocorticoids (Hofland et al. 2005). Moreover, SSTR2 mRNA expression was reduced after dexamethasone treatment, whereas SSTR5 mRNA was not significantly affected (van der Hoek et al. 2005). As pituitary corticotrope ACTH-secreting adenomas predominantly express SSTR5, results obtained using primary cell cultures (Hofland et al. 2005, Batista et al. 2006), animal models (Silva et al. 2005, Ben-Shlomo et al. 2010), and clinical studies have confirmed ACTH suppression after pasireotide treatment. Overexpression of SSTR2 or SSTR5 in mouse AtT20 corticotrope adenoma cells resulted in pasireotide suppressive effects through SSTR5 but not SSTR2 (Ben-Shlomo et al. 2009). In a phase II study, proof-of-concept, open-label, single-arm, and multicenter study, using s.c. pasireotide at 600 μg twice a day for 15 days, patients who displayed normalized UFC levels with pasireotide treatment showed a 1.8-fold higher plasma concentration and 1.3-fold higher plasma exposure in comparison with non-responders, indicating that the clinical response required a plasma pasireotide level above a certain threshold for an optimal response (Boscaro et al. 2009). A subsequent double-blinded, randomized, multicenter phase III trial with pasireotide 600–900 μg twice a day revealed UFC reduction in most patients (Colao et al. 2012) and normalization in approximately one-quarter of patients. The rate of UFC normalization was higher (∼50%) in patients with mild CD. Responders can be identified within approximately 2 months of treatment (Colao et al. 2012). Serum and salivary cortisol and plasma ACTH levels were also reduced with notable clinical improvement including blood pressure, lipids, and quality of life (Colao et al. 2012). An interesting observation that warrants further investigation is the reduction in tumor volume after 12 months of high-dose pasireotide (900 μg twice daily) treatment in patients with CD (Colao et al. 2012).

Except for a higher degree and frequency of hyperglycemia, adverse effects are similar to those of other SRLs (Table 3). Hyperglycemia-related adverse events occurred in 73% of patients and 6% of patients discontinued the study treatment because of such events. Glucose and HbA1c levels increased soon after the initiation of treatment with pasireotide, necessitating the administration of medications to manage these complications. Of the patients who did not have diabetes at baseline 48% had a HbA1c level of 6.5% or more at the end of the study.

The mechanism of pasireotide-induced hyperglycemia in healthy volunteers is mediated by incretin hormone, glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide, reduction and therefore insulin secretion decline. Glucagon secretion, however, seems to be mildly inhibited (Henry et al. 2011). A dipeptidyl peptidase 4 inhibitor or a GLP1 agonist was shown to be particularly effective in countering increased glucose levels in healthy volunteers; however, further studies in CD are required (Henry et al. 2011, Colao et al. 2014).

The absence of expression of SSTR5 mRNA in 40% of ACTH-secreting pituitary adenomas (de Bruin et al. 2009) might explain the different responses to pasireotide. It remains to be determined whether any correlation exists between the degree of SSTR2/SSTR5 receptor expression and the in vivo response to pasireotide in patients with CD.

Pasireotide was approved (in the USA and in Europe) for the treatment of patients with CD for whom surgery has failed or is not possible (Fleseriu & Petersenn 2012, Feelders & Hofland 2013, Colao et al. 2014).

Additionally, somatropim (DG3173) is a novel SRL that selectively binds SSTR2, SSTR4, and SSTR5. It has a well-demonstrated effect in GH suppression (Plöckinger et al. 2012, Fleseriu & Petersenn 2013). Further research is necessary to evaluate the effects on ACTH.

Dopamine agonists

Dopamine is the main catecholamine neurotransmitter in the human brain involved in the regulation of locomotor activity, food intake, and endocrine function (Missale et al. 1998). The dopamine receptor (DR) family consists of five receptor subtypes, two with preferentially stimulatory effects (D1 and D4) and three with inhibitory properties (D2, D3, and D5) (Missale et al. 1998). D2 (DRD2) and, to a lesser extent, D4 (DRD4) are the DR subtypes that are expressed in the anterior pituitary gland. The D2 subtype has a long (D2long) and a short (D2short) isoforms and both variants are expressed in lactotrope and melanotrope cells (Pivonello et al. 2004). Inhibition of PRL secretion is the most well-known action of dopamine in the anterior pituitary. However, results of recent studies have indicated that the D2 receptor is expressed in 80% of corticotrope adenomas (Lamberts et al. 1980, Pivonello et al. 2004, Gatto & Hofland 2011). The D2 receptor is not negatively regulated by cortisol (de Bruin et al. 2009). Consistently, dopamine agonists, bromocriptine, and cabergoline have shown inhibitory effects in vitro on ACTH secretion in corticotrope tumor cells (Pivonello et al. 2004) and apoptosis in an ACTH-secreting mouse cell line; therefore, in vivo effectiveness can also be suspected (Lamberts et al. 1980, Yin et al. 1994). In the pituitary gland, pro-opiomelanocortin (POMC) is cleaved by prohormone convertases (PCs) 1 and 2 (Bertagna 1994). PC1 (PCSK1) is expressed in both the anterior and intermediate pituitary lobes, whereas PC2 (PCSK2) expression is restricted to the intermediate lobe, which is believed to regress soon after birth and, therefore, is absent in adults (Bertagna 1994, Iino et al. 2010). Lamberts and colleagues showed that D2 receptor agonist-responsive tumors located in the region consisted of basophilic adenomatous tissue or multiple microadenomas accompanied by hyperplastic cell nests (Lamberts et al. 1980, 1982). PC2 expression at the intermediate lobe, and the phosphorylation of its cell-signaling molecule Akt, have been identified as clinical markers of an increased rate of tumor growth in CD (Iino et al. 2010). Compared with corticotrope pituitary tumors that were histologically classified as pure adenomas, tumors identified as adenomatous hyperplasia or hyperplasia of ACTH-producing cells have higher PC2 expression and, although not statistically significant, higher neurofilament (NF) protein expression. Together, these results led to the hypothesis that CD may originate not only from corticotrope adenomas of the anterior lobe, but also from an adenoma or adenomatous hyperplasia of ACTH-producing cells of the intermediate zone because the PC2 enzyme is predominantly expressed in this region of the pituitary gland (Iino et al. 2010). In addition, increases in the levels of alpha-melanocyte-stimulating hormone, which is a PC2 processing product, in the inferior petrosal sinus were higher in these patients. Finally, increased NF expression indicates close proximity of these lesions to the posterior pituitary lobe. PAX7, a protein restricted to the melanotrope lineage of the intermediate pituitary lobe that is not expressed in the anterior corticotrope cells, was identified as a key regulator that drives POMC-positive pituitary cells toward melanotrope differentiation (Budry et al. 2012). In the intermediate lobe, cells of rat pituitary glands lacking PAX7 showed downregulation of melanotrope-specific genes (e.g. POMC, PC2, and D2R (DRD2)) and these cells switched towards the corticotrope lineage. Similar observations were made using AtT20 mice corticotrope adenoma cells (Budry et al. 2012). The hypothesis that adenomatous hyperplasia or corticotrope hyperplasia is particularly sensitive to dopamine D2 receptor agonists (Lamberts et al. 1982), and SSTR5 expression appears to be lower than that in the pure adenomas awaits further confirmation (Budry et al. 2012).

Cabergoline

Cabergoline (Caberlin, Dostinex, or Cabaser) is a D2 receptor agonist, currently approved in the USA to treat hyperprolactinemia. It has a long half-life and a very high affinity and specificity for D2 receptors. Cabergoline has been evaluated as a potential therapy in patients with CD who have failed surgery (de Bruin et al. 2009). Initial response is up to 75% (Pivonello et al. 2009); however, 30–40% of these patients will have a sustained response over a 2-year period (Pivonello et al. 2009, Lila et al. 2010). A retrospective study reported complete response to cabergoline therapy in 37% of cases using an initial dose of 0.5–1 mg/week with a further increment up to 6 mg/week. At a mean dose of 2.1 mg/week, 30% (nine out of 30 cases) persisted with sustained control after 3 years (Godbout et al. 2010). Acute cabergoline response does not predict long-term disease control. Approximately 25% of patients present with cabergoline escape phenomenon at 2–5 years. Doses range from 0.5 to 7.0 mg/week (median 3.5 mg) raising potential concerns about long-term safety (Table 3). By activating valvular fibroblasts through serotonin receptor 2B, valve calcification was observed in patients with prolactinomas treated with cabergoline. However, this finding was not associated with cardiac valve dysfunction after 2 years of follow-up (Delgado et al. 2012). Long-term studies, however, are required to elucidate potential cardiac involvement at long-term high doses.

Bromocriptine

The effectiveness of bromocriptine (Parlodel, Cycloset, or Brotin) was initially reported in small studies of patients with CD (Lamberts & Birkehager 1976, Miller & Crapo 1993). Out of 23 patients with CD treated with 1.25–30 mg/day for 3–180 weeks, approximately 40% achieved urinary or plasma glucocorticoid levels normalization, and ACTH levels decreased by more than 50% in 20% of patients (Table 3; Miller & Crapo 1993). Subsequent consecutive studies on the effects of bromocriptine in patients with CD have not confirmed relevant efficacy (Biller et al. 2010).

Chimeric compounds

Corticotrope cells coexpress both SSTRs and D2 receptors, which work synergistically through membrane interaction or dimerization (Fig. 3; Rocheville et al. 2000, Ren et al. 2003, de Bruin et al. 2009). Studies on different tumor models, including pituitary adenomas, revealed a higher potency of BIM-23A779, BIM-23A760, and BIM-23A781 (chimeric molecules containing both SST and dopamine structural elements) in controlling tumor cell growth (Ferone et al. 2013). Further studies of patients with CD are required.

Figure 3
Figure 3

Potential novel therapeutic targets for CD. From left to right; the effect of V3 receptor-specific antagonists that could lead to a new class of agents that can suppress ACTH secretion in corticotrope adenomas (Ferone et al. 2013). After blocking of EGFR, a tyrosine kinase receptor, POMC expression is attenuated, and inhibition of corticotrope cell proliferation and apoptosis can be induced (Fukuoka et al. 2011). Through membrane interaction or dimerization (Rocheville et al. 2000), the G-protein-coupled somatostatin receptor (SSTR) and dopamine D2 receptor (D2R) have a synergistic effect on controlling tumor cell growth and ACTH secretion (de Bruin et al. 2009, Ferone et al. 2013). The main proteins of each receptor signaling pathway are depicted. The leading effect of such pathways is cell cycle arrest with a decrease in tumor growth. Interestingly, using a cyclin-dependent kinase 2 (CDK2)/cyclin E inhibitor in animal models, the ACTH and corticosterone levels were suppressed, and xenografted pituitary tumor growth was restrained (Liu et al. 2011b). Red lines/arrows indicate inhibition, whereas green lines/arrows indicate induction. PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; GSK3, synthase kinase 3 beta; Rb, retinoblastoma protein; E2F, E2 transcription factors.

Citation: Journal of Endocrinology 223, 2; 10.1530/JOE-14-0300

Retinoic acid

Retinoic acid type II nuclear receptors are important drug targets for cancer therapy. In animal studies and in vitro experiments, an effective inhibitory effect has been shown on corticotrope tumor growth, POMC transcription, plasma ACTH, and corticosterone secretion from human ACTH-secreting pituitary tumors, but not in normal cells (Fig. 1). Retinoic acid also increased caspase-3-activity-induced cell death (Labeur et al. 2009). Retinoic acid exhibits peripheral activity at the level of the adrenal and induced bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor beta superfamily that plays a central role during pituitary organogenesis and transcription (Labeur et al. 2009). The antiproliferative action of retinoic acid is considered to be mediated by BMP4. Such preliminary results promoted a randomized treatment with retinoic acid vs ketoconazole in dogs with CD (Labeur et al. 2009). Recently, seven patients with CD were treated with 10–80 mg of retinoic acid in a longitudinal, non-controlled, non-randomized, multicenter study (Pecori Giraldi et al. 2012). After 6–12 months, three patients displayed normalized UFC with mild adverse effects (Table 3). These results need further confirmation in larger studies.

Temozolomide

Temozolomide (Temodar, Temodal, or Temcad) is an orally administrated second-generation alkylating chemotherapeutic agent. It is a methyl-triazenoimidazole-carboxamide derivative that methylates DNA at the O6 position of guanine causing a mismatch with thymine during the next DNA replication cycle, leading to cell apoptosis (Fig. 1). Drug efficacy relies on O6-methylguanine-DNA methyltransferase (MGMT) enzyme activity. MGMT reverses alkylation, and it has been initially suggested that low MGMT expression could predict a better response to temozolomide. After treatment with temozolomide, tumors become soft and friable, and display better differentiation, less mitoses, and a lower Ki-67 index, indicative of surgical benefits as well as a reduction in cell proliferation (Syro et al. 2011). Temozolomide could be an efficacious drug in cases of aggressive CD, but the predictive role of MGMT expression remains to be determined (Syro et al. 2011, Dillard et al. 2011).

Cyproheptadine

Cyproheptadine (Periactin or Peritol) has anti-serotonergic, anti-histaminic, and anti-cholinergic properties, and it has been studied for treatment of CD and Nelson's syndrome since 1975 (Krieger et al. 1975, Nieman 2002, Fleseriu 2012). In normal subjects, cyproheptadine may alter the feedback regulation of ACTH to different stimuli such as metyrapone and insulin-induced hypoglycemia (Cavagnini et al. 1975). These responses are independent of the effects on basal ACTH levels, and patients treated with cyproheptadine therapy have documented normalization of low-dose dexamethasone suppression, metyrapone response, insulin tolerance test, CRH response, and diurnal cortisol patterns (Ferrari et al. 1977). It has been postulated that ACTH secretion was also under serotoninergic control and a direct inhibitory effect on CRH and arginine vasopressin (AVP) secretion from the hypothalamus has been confirmed (Suda et al. 1983). However, clinical studies showed disappointing results (Nieman 2002, Biller et al. 2008). Control of CD activity with cyproheptadine has been described in case reports (Tanakol et al. 1996) at doses varying from 12 to 24 mg/day. Main side effects are somnolence, hyperphagia, and weight gain. Other serotonin antagonists, metergoline, ketanserine, and ritanserine, have been evaluated in very few patients with limited results (Cavagnini et al. 1975, Sonino et al. 1992, Miller & Crapo 1993).

Valproic acid (valproate)

The neurotransmitter GABA has an inhibitory effect on ACTH release (Maraka & Stark 1974). GABA inhibits the functioning of the HPA axis in vivo, reducing CRH levels in hypophyseal portal blood after i.c.v. administration (Fig. 1; Plotsky et al. 1987). Valproic acid (sodium valproate or valproate) is an antiepileptic agent that inhibits GABA aminotransferase. Patients with seizures treated with valproate showed suppression of ACTH. Valproate blocks GABA reuptake enhancing GABA inhibition of hypothalamic CRH release. Clinical reports of valproate-responsive patients with CD have emerged (Cavagnini et al. 1984, Koppeschaar et al. 1986, Colao et al. 1997). However, chronic administration and placebo-controlled studies failed to confirm the ACTH-lowering effects of valproate (Reincke et al. 1988, Colao et al. 1997).

Peroxisome proliferator-activated receptor gamma ligands

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that functions as a transcription factor. It is highly expressed in ACTH-secreting adenomas (Heaney 2004, Mannelli et al. 2010). PPARγ ligands, thiazolidinediones, have been shown to increase insulin sensitivity and also inhibit the growth of many tumors, including breast, colon, and prostate cancer cells (Mannelli et al. 2010). In addition, antiproliferation with G0/G1 cell cycle arrest, and apoptotic effects in murine cell model of corticotrope adenoma cells and inhibition of POMC transcription were demonstrated using PPARγ ligands (Heaney et al. 2002). However, the antiproliferative effects were observed at very high doses. The PPARγ agonist rosiglitazone was evaluated as a possible therapy for patients with CD. Despite initial results indicating that rosiglitazone could be an effective treatment for patients with CD (Ambrosi et al. 1990), further reports confirmed that PPARγ ligands have no efficacy (Kreutzer et al. 2009), a sustained ACTH decrease is rare, and ACTH levels may rebound (Suri & Weiss 2005, Morcos et al. 2007). Current information is insufficient to support the routine clinical use of rosiglitazone or pioglitazone in patients with CD (Biller et al. 2008, Mannelli et al. 2010). Moreover, side effects such as edema, hypertension, weight gain, somnolence, hirsutism, and bruisability are significant, and there have also been concerns related to possible increased cardiovascular disease risks (Nissen & Wolski 2010).

Alpha 1 adrenergic receptor antagonists

Alpha 1 adrenergic receptor antagonists have been suggested as a novel therapy for pituitary adenomas (Fernando & Heaney 2005). In murine pituitary tumor cells, doxazosin (Cardura, Cardura XL) reduced phosphorylated retinoblastoma protein levels and induced G0–G1 cell cycle arrest with decreased tumor growth and reduced plasma ACTH levels (Fernando & Heaney 2005). Further research is required to support the observations.

GR antagonism

As almost every human cell expresses GRs, conditions with glucocorticoid excess, such as CD, result in the deleterious effects on cell metabolism. Therefore, blocking GRs seem to be a promising and attractive approach to treat CD. GRs are classically classified as type I with mineralocorticoid effects and type II with glucocorticoid effects. GR protein is encoded by the NR3C1 gene, which is located on chromosome 5 (5q31). Two isoforms of the GR have been identified, GRα and GRβ (Bamberger et al. 1996).

Mifepristone

Mifepristone is an 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one competitive antagonist of androgen, progestin, and GRs (Bertagna et al. 1984, Bertagna et al. 1986). Mifepristone is the first potent glucocorticoid antagonist available for clinical use, which has affinity for GRs and very little agonist effect (Fig. 1). In normal subjects, mifepristone inhibits dexamethasone suppression and raises endogenous cortisol and ACTH values (Bertagna et al. 1984). It has been suggested that mifepristone may upregulate SSTR2 on corticotrope adenomas, which may then be treated with a SSTR2 ligand (octreotide or lanreotide; de Bruin et al. 2012). Symptomatic improvement was reported at doses of 5–20 mg/kg per day (Nieman et al. 1985), including prompt reversal of neuropsychiatric symptoms (Van der Lely et al. 1991, Johanssen & Allolio 2007). Early in the 2000s, a few patients with CS had been treated with mifepristone and the first patient with CD was treated with mifepristone in 2001 (Chu et al. 2001). Results of further studies of treatment of additional CD cases with mifepristone confirmed clinical improvement (Castinetti et al. 2009). In a large prospective study (Fleseriu 2012), mifepristone showed clinical efficacy at doses of 300–1200 mg/day (mean 900 mg) for over 6–4 months (Table 3). Diabetes control improved significantly, with reduction in the mean HbA1c (7.4–6.3%) in addition to an overall decrease in antidiabetic medications (Fleseriu et al. 2012). Body weight and waist circumference also improved significantly after 24 weeks and mean percentage total body fat also declined. As a result of the mechanism of action, cortisol concentrations (up to sevenfold) and ACTH (up to twofold) tend to increase (Sonino & Boscaro 1999, Fleseriu et al. 2012). Side effects are described in Table 3 (Fleseriu 2012). The authors of the main study concluded that the drug had an acceptable benefit–risk profile (Fleseriu 2012, Fleseriu & Petersenn 2013). Nevertheless, some physicians consider mifepristone use only in specific situations such as in patients with severe hypercortisolism, when the chance of surgical cure is low, and in those waiting for the maximal efficacy of radiotherapy (Castinetti et al. 2009, Feelders & Hofland 2013). The development of a selective GR without antiprogestin effects could also represent an important step in the long-term treatment of women with CD. Mifepristone should not be administered with drugs that are metabolized by CYP3A or CYP2C (e.g. simvastatin, cyclosporine, fentanyl, ciprofloxacin, non-steroidal anti-inflammatory drugs, and warfarin) because of an increased toxicity risk (Fleseriu & Petersenn 2013). In the USA, in 2012, mifepristone (Korlym) was FDA approved for the treatment of glucose intolerance or diabetes in patients with CS.

Mechanistic approach for combination therapy

Combination medical therapy is an option that is gaining momentum and increased attention (Feelders et al. 2010b,c, Vilar et al. 2010, Kamenicky et al. 2011). It is possible that drug doses may be decreased with fewer adverse events and synergistic or additive effects on ACTH-secretion inhibition (Sonino & Boscaro 1999, Feelders & Hofland 2013) are possible; however, there is no treatment strategy valid for all cases (Table 5). Owing to coexpression of SSTR2 and D2 receptor that frequently occurs in corticotrope pituitary adenomas (Fig. 3), there is a rationale for treating patients with CD with a combination of drugs that target these receptors (Table 5). A prospective study is going on (Fleseriu et al. 2014).

Medical therapy should be selected according to drug properties and each patient's particular clinical situation (Table 2). A ketoconazole and octreotide effect was shown to be additive with improved clinical features and reduced cortisol production; however, a minimal proportion of cases exhibited normalized UFC (Vignati & Loli 1996). In two studies, after 3–6 months of combined therapy, a complete response was shown in 67% and 90% of patients with a stepwise combination of pasireotide and cabergoline or pasireotide, cabergoline, and ketoconazole respectively (Feelders et al. 2010b,c, Vilar et al. 2010). In contrast to previously reported cases during long-term cabergoline monotherapy, patients on combined pasireotide–cabergoline treatment did not exhibit escapism (Feelders & Hofland 2013). It would seem that UFC normalization in combination therapies remains at approximately 80% regardless of which drug is administered first: cabergoline with ketoconazole or, ketoconazole with cabergoline (Barbot et al. 2014).

A triple-drug combination has been recently evaluated as an alternative to urgent adrenalectomy (Kamenicky et al. 2011). A group of 11 patients with severe CD were simultaneously treated with mitotane (3–5 g/day), metyrapone (3–4.5 g/day), and ketoconazole (400–1200 mg/day, Table 5). Within days, UFC decreased significantly and clinical improvement permitted pituitary surgery in five patients. Although side effects were present, they were tolerable (Kamenicky et al. 2011). Ketoconazole with metyrapone might cause mineralocorticoid hypertension. Blood pressure should be monitored if this therapeutic approach is applied.

Pasireotide with temozolomide administered over 12 months revealed sustained control of tumor growth and ACTH secretion in a pituitary carcinoma, indicating that such a combination may be a promising option for aggressive pituitary tumors (Bode et al. 2010).

The degree of hypercortisolism at baseline could predict the doses needed to control cortisol excess (Vilar et al. 2010, Feelders & Hofland 2013). Combination treatments that have been evaluated for CD treatment are summarized in Table 5.

Novel targets for treatment of CD

Epidermal growth factor receptor inhibitors

Epidermal growth factor receptor (EGFR) has been studied as a therapeutic target for ACTH-secreting pituitary adenomas (Fukuoka et al. 2011). Normal pituitary and corticotrope adenomas express EGFR, which controls POMC expression. After blocking of EGFR with gefitinib, a tyrosine kinase inhibitor, POMC expression was attenuated, with inhibition of corticotrope cell proliferation and induced apoptosis (Fig. 3). The results were confirmed using canine and human corticotrope tumors as well as an athymic nude mouse model, indicating that inhibiting EGFR signaling with gefitinib may be a novel strategy for treating CD (Fukuoka et al. 2011). However, confirmation of efficacy in patients with CD requires clinical trials.

Cell cycle regulators

Animal and cell models have provided insights into mechanisms underlying the pathogenesis of ACTH-secreting pituitary adenomas, mostly due to cell cycle disruption. A classic example indicating the association of cell cycle regulators and pituitary tumorigenesis is derived from the heterozygous Rb mouse (Melmed 2003). The Rb (Rb1) gene encodes a tumor suppressor that controls the G1/S cell cycle checkpoint. Rb phosphorylation by cyclin-dependent kinases (CDKs) releases the E2F transcription factor enabling S-phase progression (Fig. 3) (Liu et al. 2011a,b). Inhibitors of CDK4 (INK4) type (p16, p15, p18, and p19) and CIP/KIP type (p21, p27, and p57) suppress the action of CDK. Sequential activation and inactivation of protein kinase complexes regulate cell cycle progression (Melmed 2003). Heterozygous Rb+/− mice developed intermediate lobe POMC cell tumors at 12 months with 100% penetrance. Deletion of p27Kip1 (Cdkn1b) or p21 (Cdkn1a) enhances intermediate lobe tumorigenesis in Rb+/− mice (Park et al. 1999). These results motivate the pharmacological assessment of a CDK2/cyclin E inhibitor, R-roscovitine (seliciclib; CYC202) in corticotrope pituitary adenomas. In transgenic POMC-pituitary tumor-transforming gene (PTTG (PTTG1)) zebrafish embryos and in a mouse model of ACTH-secreting pituitary adenomas, R-roscovitine suppressed ACTH expression/production and inhibited tumor growth (Liu et al. 2011b). Molecular analyses in vitro and in vivo showed upregulation of p27, p21, and p57 (CDKN1C), and downregulation of cyclin E expression (Fig. 3). The results indicate that use of selective CDK inhibitors may effectively target corticotrope tumor growth and hormonal secretion (Liu et al. 2011b).

Therapeutic role of microRNA's

MicroRNAs (or miRNAs) are noncoding, single-stranded RNAs constituting a novel class of gene regulators. miRNAs control diverse biological processes including cell growth, differentiation, and apoptosis by post-transcriptional regulation of target gene expression (He & Hannon 2004). miRNA mutations or misexpression correlate with several human cancers indicating that miRNAs can function as tumor suppressors. Real-time PCR in corticotrope adenomas compared with normal pituitary tissue revealed downregulation of several miRNAs, including miR-15a (MIR15A), miR-16, and Let-7a among others (Amaral et al. 2009). Interestingly, miR-15a and miR-16 genes are colocalized with the Rb tumor suppressor on chromosome 13q14, which is commonly deleted in corticotropinomas. Let-7 miRNA negatively regulates high-mobility group A2 protein, which is highly expressed in pituitary adenomas, increasing aggressiveness of corticotrope adenomas and, therefore, contributing to pituitary tumorigenesis and progression (Qian et al. 2009). Genetic manipulation of miRNAs may induce tumor regression and decrease the activity of corticotrope adenomas.

Potential future therapeutic targets

Several transgenic mouse models have contributed important knowledge to understanding of human pituitary disease. Transgenic mice with metallothionein (mMT)-promoter-driven overexpression of CRH exhibited disruption of the HPA axis with elevated plasma ACTH and glucocorticoid levels, and development of CS (Stenzel-Poore et al. 1992).

Desmopressin (1-desamino-8-d-arginine vasopressin, DDVAP), a long-acting synthetic AVP analog, stimulates ACTH secretion from human pituitary corticotrope adenomas through V3 pituitary receptor stimulation. The V3 pituitary receptor is located mainly in the anterior pituitary gland (Fig. 3) and has been previously classified as the V1b AVP receptor. Transgenic mice expressing the human AVP V3 receptor under the control of rat Pomc promoter sequences showed increased basal concentrations of corticosterone; however, no corticotrope tumors developed (Rene et al. 2002). AVP antagonists (vaptans) showed mainly antidiuretic effects, as they are selective V2 renal receptor antagonists. However, development of V3-receptor-specific antagonists could lead to a new class of agents that suppress ACTH secretion in corticotrope adenomas (Fig. 3; Ferone et al. 2013).

Manipulation of leukemia inhibitory factor (LIF) and the ATPase subunit of the chromatin remodeling Swi/Snf complex Brg1 may be good therapeutic targets for controlling hypercortisolism. LIF is a pleiotropic cytokine that enhances POMC transcription, ACTH secretion, and corticotrope cell proliferation, and is an essential protein for POMC repression (Auernhammer & Melmed 2000). Brg1 stabilizes the interaction between GR and Nur77 (NGFI-B), a nuclear orphan receptor that is also essential for POMC transrepression (Bilodeau et al. 2006).

Testicular orphan nuclear receptor 4 (TR4) has been recently identified as another potential target for CD treatment. TR4 (NR2C2) was overexpressed in human corticotrope tumors and in human and mouse corticotrope tumor cell lines (Du et al. 2013). Consistently, TR4 overexpression in human and murine tumor cells increased POMC transcription, ACTH secretion, cellular proliferation, and tumor invasiveness. TR4 activated POMC transcription through a MAPK-mediated pathway (Du et al. 2013).

Vascular endothelial growth factor receptor 2 (VEGFR2 (KDR)), PTTG, and fibroblast growth factor expressions are associated with extrasellar extension and greater pituitary adenoma proliferative potential. These data provide useful information for novel targeted treatments. For example, treatment of a corticotrope carcinoma with bevacizumab, a monoclonal antibody that blocks VEGFRs, stopped tumor progression and induced CD control (Ortiz et al. 2012).

The rapamycin (mTOR) pathway is upregulated in pituitary adenomas. Human ACTH-secreting pituitary adenomas, however, express MTOR and its active phosphorylated isoform at levels similar to those of normal pituitary tissue. In addition, AtT-20 mice corticotrope adenoma cells were shown to be resistant to rapamycin. Interestingly, such resistance can effectively be overcome using octreotide as a cotreatment. If CD is treated first with an SRL, and then with an mTOR inhibitor, control of hypercortisolism may be more easily achieved (Ferone et al. 2013).

Summary

CD is a severe pituitary endocrine disorder with related long-term complications and increased mortality if not appropriately treated. Transsphenoidal surgery is the first-line treatment of choice; however, surgery does not result in a long-term cure for many patients. Recently, approved medical therapies target the corticotrope adenoma itself (i.e. pasireotide) or block cortisol effects in the periphery (i.e. mifepristone), thus providing new approaches and treatment options. The most commonly utilized clinical inhibitors of steroid biosynthesis are ketoconazole, metyrapone, and mitotane. Mitotane's mechanism of action seems to be multifactorial. Other steroidogenesis inhibitors interfere with cytochrome-P450-catalysed reactions. This mechanism of action has little selectivity and extra-adrenal adverse effects are likely. Daily doses should be titrated to maintain urinary and serum cortisol in the normal range, avoiding excessive suppression of adrenal function. However, glucocorticoid replacement is sometimes recommended with a ‘block and replace’ approach. A relatively new adrenal steroidogenesis inhibitor, LCI699, seems to be efficient and well tolerated; clinical trials are ongoing. Finally, in recent years, new molecular targets have been identified on corticotrope adenomas including EGFR, cell cycle regulators, and miRNAs.

Declaration of interest

D C-R declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

M F has received research grants to Oregon Health and Science University from Corcept Therapeutics, Ipsen, and Novartis and has been an ad hoc consultant/advisor for Genentech, Ipsen, Novartis, and Pfizer.

Acknowledgements

The authors thank Shirley McCartney, PhD, for editorial assistance.

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    The hypothalamus–pituitary–adrenal (HPA) axis and targets of drugs used for treating Cushing's disease. Under physiological conditions, cortisol synthesis and production are tightly regulated by the HPA axis. Adrenocorticotropin (ACTH)-producing cells in the anterior pituitary respond to hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). After binding to melanocortin type 2 receptor (MC2R), ACTH induces the steroidogenic enzymes to increase the biosynthesis of cortisol and will decrease ACTH and CRH secretion. Pituitary corticotrope ACTH-secreting adenomas, however, function autonomously and overstimulate cortisol production at the adrenal cortex. The pharmacotherapies for ACTH-secreting pituitary corticotrope adenomas are categorized by the site of action into three groups: i) centrally acting agents or neuromodulators, which inhibit ACTH release from pituitary adenomas, ii) adrenal steroidogenic inhibitors, which block one or several steps in cortisol biosynthesis and iii) the glucocorticoid receptor-blocking agent mifepristone. Green arrows indicate activation and red arrows/lines indicate inhibition.

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    Adrenocortical steroidogenic pathways. A simplified diagram of adrenal steroidogenesis is depicted. Cushing's disease is almost always caused by a pituitary corticotrope adenoma that oversecretes corticotropin (ACTH). ACTH stimulates the adrenal gland to start steroid synthesis. After activation of MC2R by ACTH, the StAR protein is phosphorylated. Then, StAR facilitates cholesterol transport across the mitochondrial inner membrane. Cholesterol is the common precursor of the steroid molecules and, after several enzymatic reactions, is ultimately converted into biologically active aldosterone, cortisol, or androstenedione that is further processed to testosterone in testicles. The zona glomerulosa, fasciculata, and reticularis are the three adrenal cortex histological zones, which synthesize steroid hormones with mineralocorticoid, glucocorticoid, or androgenic properties respectively. Enzyme nomenclature is given in detail in Table 1. CYP11A1, CYP11B1, and CYP11B2 are located in the mitochondria, and the remaining enzymes are located in the smooth endoplasmic reticulum.

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    Potential novel therapeutic targets for CD. From left to right; the effect of V3 receptor-specific antagonists that could lead to a new class of agents that can suppress ACTH secretion in corticotrope adenomas (Ferone et al. 2013). After blocking of EGFR, a tyrosine kinase receptor, POMC expression is attenuated, and inhibition of corticotrope cell proliferation and apoptosis can be induced (Fukuoka et al. 2011). Through membrane interaction or dimerization (Rocheville et al. 2000), the G-protein-coupled somatostatin receptor (SSTR) and dopamine D2 receptor (D2R) have a synergistic effect on controlling tumor cell growth and ACTH secretion (de Bruin et al. 2009, Ferone et al. 2013). The main proteins of each receptor signaling pathway are depicted. The leading effect of such pathways is cell cycle arrest with a decrease in tumor growth. Interestingly, using a cyclin-dependent kinase 2 (CDK2)/cyclin E inhibitor in animal models, the ACTH and corticosterone levels were suppressed, and xenografted pituitary tumor growth was restrained (Liu et al. 2011b). Red lines/arrows indicate inhibition, whereas green lines/arrows indicate induction. PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; GSK3, synthase kinase 3 beta; Rb, retinoblastoma protein; E2F, E2 transcription factors.

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