Pathophysiology Section, Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico, 155-00161 Rome, Italy
Copyright © 2012 Carlotta Pozza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cushing’s syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing’s disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ “PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.
Cushing’s syndrome (CS) is a rare but severe clinical condition caused by cortisol excess of various etiologies. It is associated with significant morbidity and mortality and leads to metabolic, cardiovascular, infectious, psychiatric, and gonadal complications (Table 1). This complex endocrine disorder is a challenge in terms of efficient treatment. This paper will focus on traditional and novel medical therapy for hypercortisolism secondary to ACTH-secreting pituitary macroadenoma or carcinoma (Cushing’s disease, CD) or to ectopic ACTH secretion.
The natural history of pituitary adenomas varies widely. In the majority of cases, ACTH-secreting pituitary adenomas are small (<1 cm in diameter) and confined within the sella turcica. Pituitary microadenomas have a typically indolent growth rate, and clinically significant invasion and malignant transformation remain uncommon. However, 4–10% of patients present with larger tumors (>1 cm in diameter). These can cause symptoms due to mass effect before any full endocrine manifestations. Moreover, they are more refractory to surgical treatment and show a more unfavorable prognosis than microadenomas. For their behavior, presentation, and outcome, ACTH secreting macroadenomas present a distinct profile compared with microadenomas, although they probably represent one end of a spectrum of tumor autonomy, with specific growth and biochemical characteristics . Morbidity and mortality are high with aggressive tumor behavior . The 2004 WHO classification of pituitary adenomas now includes an “atypical” variant, defined as an MIB-1 proliferative index greater than 3%, excessive p53 immunoreactivity and increased mitotic activity. In the absence of metastases, however, invasive or aggressive pituitary tumors are not considered malignant. Pituitary carcinomas, defined as primary tumors with intra- or extracranial metastases, are rare, encountered in less than 1% of all hypophyseal tumors. They generally secrete ACTH or Prolactin.
Ectopic ACTH Secretion (EAS) accounts for 15–20% of cases of Cushing’s syndrome and covers a spectrum of tumors from undetectable isolated lesions to extensive metastatic and aggressive malignancies. EAS is often associated with severe hypercortisolemia causing hypokalemia, diabetes, generalized infections, hypertension, and psychotic reactions. Isidori et al.  proposed a classification based on the detection of the source of ectopic secretion. EAS is defined as overt when the tumor source is easily detected during the initial endocrine and radiological investigations, covert in patients presenting with hypercortisolemia where the ectopic source is not detected during initial tests but is discovered on subsequent evaluation or during prolonged followup, and occult when the patient’s clinical features suggest CS and all tests indicate an ectopic source, but the primary lesion is not identified even after prolonged and repeated followup. Occult EAS is one of the most intriguing challenges for the clinical endocrinologist, as in some cases no tumor is found even after long-term followup or on autopsy . The overall prognosis of patients with ectopic ACTH secretion is primarily determined by the nature of the underlying malignancy and the tumor stage on diagnosis.
2. Management of Cushing’s Syndrome
Management of patients with CS requires a major effort to understand the etiology and to control hypercortisolemia as soon as the diagnosis is established. The most appropriate management of ACTH-dependent CS derives from a multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists.
The definitive treatment of CS consists in surgical resection of the tumor secreting ACTH. When the source of the excessive secretion is the pituitary gland, the standard approach is to perform an endoscopic endonasal trans-sphenoidal exploration, with excision of the tumor, if found. This surgical procedure is demanding and should only be performed in centers with extensive experience, to minimize operative risks, reduce the possibility of remission, and maintain other pituitary functions. It is successful in about 70% of cases (defined by suppressed plasma cortisol levels and normal 24 h urinary free cortisol) . Success rates can reach 90% in selective adenectomy of microadenomas (<10 mm in diameter), but decrease to 65% for macroadenomas . About 20% of tumors recur, and recurrence is more likely (and quicker) in larger than in smaller tumors.
Pituitary irradiation achieves eucortisolism in 50–60% of cases, albeit after 3–5 years , and patients can develop pituitary insufficiency, brain vascular morbidity or secondary neoplasms. Stereotactic radiosurgery (RS) proved less effective results in macroadenomas, especially if they had already infiltrate the cavernous sinus. To obtain optimal efficacy, RS should thus be reserved to small well-defined lesions. The management of aggressive adenomas invading adjacent structures is a real challenge, as they rarely respond to any treatment.
In the presence of ectopic secretion of ACTH, surgical resection of the primary tumor is recommended. This results in the complete remission, especially in cases of benign tumor. Often, however, the tumor may already have metastasized, it may not be resectable, or it may not be identified despite extensive investigation (occult).
Bilateral adrenalectomy can be chosen as a final approach, reserved for patients who do not respond to surgical exploration of the hypophysis or radiation therapy, or when the source of ectopic ACTH is not found.
Adrenalectomy necessarily requires steroid replacement therapy for the rest of the patient’s life, as with primary adrenocortical insufficiency. There is also a significant risk of developing Nelson’s syndrome, which occurs in 5–10% of the patients, likely a subset with an aggressive phenotype, after adrenalectomy for Cushing’s syndrome [4, 6]. It has been demonstrated that patients with invasive corticotrophinomas have a greater risk of subsequent (and earlier) development of Nelson’s syndrome compared with less aggressive forms . Prophylactic, conventional 3-field radiotherapy can be used to reduce the incidence of subsequent Nelson’s and it should always be considered in the management of these patients . When these approaches cannot be applied, a treatment is needed that has fewer side effects and can quickly reduce symptoms, and severe complications of hypercortisolism, aiming for the normalization of ACTH and serum cortisol values .
3. Medical Treatments
The therapeutic goal in the treatment of patients with ACTH-dependent Cushing’s syndrome is normalization of plasma ACTH and serum cortisol values, tumor shrinkage and preservation of anterior pituitary function, in cases of pituitary ACTH-secreting tumor. Medical treatment can improve the clinical condition of patients with severe hypercortisolism pending surgery, during acute diseases (infections, psychosis, etc.), or in patients undergoing radiotherapy while awaiting the effects of the radiotherapy itself. In addition, patients with ectopic secretion of ACTH may be treated while expecting confirmation of the source, in the presence of metastatic cancer, or in patients who are not candidates for surgery for some reason.
Current drug-based therapy for CS includes drugs that act on the adrenal glands to reduce steroid synthesis, which therefore do not treat the underlying cause of the disease, and neuromodulators acting at the hypothalamic-pituitary level . The existing treatments can be divided according to the site of action into adrenal acting drugs and in centrally acting drugs (Table 2).
Table 2: Medical treatments for Cushing’s syndrome (in clinical use or investigational).
3.1. Adrenal-Acting Drugs
Adrenal function must be carefully monitored, as excessive inhibition of steroidogenesis may cause adrenal insufficiency and may require the administration of small doses of glucocorticoids.
This is the most currently used drug in patients with hypercortisolism. It is a synthetic antifungal drug that works principally by inhibiting the cytochrome P450 system and 17,20-lyase, which are involved in the synthesis and degradation of steroids. It has also been suggested that this drug may directly inhibit the pituitary corticotroph function, inhibiting ACTH secretion [11–13]. This is a fast-acting drug that quickly reduces urinary free cortisol (UFC) levels . Its use has been reported as effective in 50% of patients with ectopic ACTH secretion. The most common side effects include gynecomastia, hypogonadism, gastrointestinal symptoms and reversible increases in liver enzymes. Severe liver toxicity is rare and liver function is usually restored after discontinuation. The drug does not inhibit the growth of the ACTH-secreting tumor.
3.1.2. Metyrapone and LCI699
Metyrapone predominantly inhibits 11β hydroxylase and has been used either as a monotherapy, leading to a normalization of cortisol levels in 75–80% of patients, or in combination with other steroidogenesis inhibitors or with radiation therapy, achieving even higher efficacy [15, 16]. It is able to reduce cortisol production in patients with ectopic ACTH production and Cushing’s disease. Side effects are dose-dependent, with the most common being hypertension, edema, increased acne and hirsutism in women due to its ability to inhibit the synthesis of aldosterone, resulting in an accumulation of its precursors with mineralocorticoid and weak androgen activity. However, when combined with ketoconazole, it offers a valuable and safe adjunct to control hypercortisolism. Recently, LCI699 , a novel orally active drug that inhibits at high doses the 11-beta hydroxylase activity (as well as aldosterone synthase) is under phase 2 evaluation for the management of hypercortisolism (http://clinicaltrial.gov/ identifier NCT01331239).
Aminoglutethimide is a potent reversible inhibitor of adrenal mineralocorticoid and glucocorticoid synthesis. It blocks cholesterol side-chain cleavage to pregnenolone, by inhibiting P450 enzymes. Side effects are skin rash, headache, a generalized pruritic rash, hypothyroidism, and goiter, and because of its toxicity is reserved for adrenal cancer.
3.1.4. Mitotane (o,p’-DDD)
It is a DDD (dichlorodiphenyldichloroethane) isomer and a derivative of DDT. A study of 177 patients showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone . Mitotane blocks several steroidogenic enzymes, thus altering peripheral steroid metabolism, directly suppressing the adrenal cortex and altering cortisone metabolism. Its adrenolytic function appears at high doses (>4 g/day). It is effective in reducing UFC levels in 83% of treated patients [19, 20]. A 2006 study confirmed that most patients under mitotane treatment in a dose ranging from 4 to 6.5 g daily had dramatic increase in CBG levels, and serum cortisol levels can be elevated even when the circulating free cortisol level is not, thus making difficult to control its biochemical effect [21, 22]. It is commonly used in patients with adrenal carcinoma. Its main use is in patients with persistent disease despite surgical resection, those who are not candidates for surgery, and patients with metastatic disease.
Serum levels should be monitored to optimize therapy. The compound is distributed in the adipose tissue and has a long half-life. Gastrointestinal and neurologic symptoms are the most common side effects.
Etomidate, an imidazole derivative, is an i.v. nonopioid anesthetic used for both induction and maintenance of anesthesia. It suppresses corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 11-β-hydroxylase and 17,20 lyase at non-hypnotic doses. It has a very rapid onset of action and can be used in acute settings in patients with CS . In addition, its intravenous administration makes it easily used in patients with no oral or enteral access. Studies and case reports support its use in patients with Cushing’s syndrome. Chronic therapeutic use of ethyl-alcohol-containing Etomidate was effective for 8 weeks in a patient with ectopic CS and peritonitis . In a 2001 case report, Etomidate was administered over 5.5 months, with daily dose modulation on the basis of serum cortisol levels. Suppression of steroidogenesis persisted for at least 14 days after cessation of the medication .
3.1.6. Mifepristone (RU486)
Mifepristone is a synthetic steroid. It is a progesterone receptor antagonist and a powerful type-2 glucocorticoid receptor (GR) antagonist. It binds to human GR with an affinity three to four times higher than that of dexamethasone and about 18 times higher than that of cortisol. Its antiglucocorticoid effects are dose dependent. Mifepristone affects both the central actions of cortisol (negative feedback on CRH/ACTH secretion) and its peripheral actions and increases plasma ACTH and cortisol levels due to the loss of negative feedback of cortisol. This drug, currently used in the interruption of early pregnancy, was recently approved in patients with hyperglycemia induced by CS who are not candidates for surgery or where surgery has failed . Medical literature suggests that mifepristone can improve clinical symptoms in 73–80% of patients  within one month after starting treatment. Castinetti et al.  reviewed the data of 37 treated CS patients (12 with EAS, 5 with Cushing’s disease, the others affected by other causes of CS). A third of these developed hypokalemia. It was suggested that this resulted from cortisol stimulation of the mineralocorticoid receptor, while GRs were blocked by mifepristone. Spironolactone and potassium chloride replacement therapy can readily restore hypokalemia and blood pressure. Followup of efficacy and the onset of adrenal insufficiency (reported in 16% of 37 patients treated with Mifepristone) should only be clinical (weight, blood pressure, skin lesions) and biological (regular blood potassium sampling). The therapeutic dose adjustments should be based on these parameters. Mifepristone is often associated with the development of endometrial hyperplasia, so regular vaginal ultrasound is recommended in long-term treatment.
3.2. Centrally Acting Drugs
In the last years several novel therapies have been studied with a view to the potential biochemical control and inhibition of pituitary tumor growth .
3.2.1. Dopamine Agonists
Dopamine (DA) is a catecholamine hormone with a wide range of functions. DA receptors have been found in a variety of organs (pituitary, adrenals, brain, kidney, gastrointestinal tract, cardiovascular system), and possibly exert an inhibitory effect when activated. D2-receptor agonists inhibit pituitary hormone secretion, particularly PRL and proopiomelanocortin-derived hormones, and drugs such as cabergoline and bromocriptine effectively inhibit PRL secretion in prolactinomas. Studies on corticotroph adenomas have shown that 80% of these tumors express D2 receptors [30, 31]. In recent decades, published case reports and case series have demonstrated the effective use of DA agonists in persistent or recurrent Cushing’s disease.
The efficacy of bromocriptine in shrinking pituitary tumors was first reported in Nelson’s syndrome and in the short-term treatment of CD [32–34]. However, the effect was not very strong, and response to long-term treatment was <30%. Cabergoline has a higher affinity for D2 receptors and a longer half-life compared to bromocriptine. In the short term  UFC levels normalized (40%) or decreased (20%) in a total cohort of 20 patients, 10 of whom underwent remission during long-term treatment (12–24 months) . More recently a study demonstrated a 25% complete response to cabergoline in 12 patients with a followup of 6 months [36, 37] and confirmed that short-term treatment of CD with cabergoline improves cortisol secretion in half the cohort studied (30 patients), while long-term followup (37 months) demonstrated sustained effectiveness of cabergoline in 30% of subjects.
There are a few documented cases of use of DA agonists in ectopic ACTH secretion. A study  describes 6 cases of ectopic tumors, three of which were not cured by surgery. UFC was normalized in two of these patients, although one exhibited treatment escape. A prospective study  evaluated the efficacy of cabergoline in monotherapy in patients with uncured CD, using sleeping midnight serum cortisol and the standard Low Dose Dexamethasone Suppression Test (LDDST) cut-off value as the response criteria. Cabergoline was effective and safe in 28% of 20 treated patients. This drug is generally well tolerated by most patients, and none of the subjects treated in these clinical trials showed signs of secondary heart dysfunction or valvulopathy, except a patient with a history of tricuspid regurgitation . Cabergoline has also been described as having potential positive metabolic effects (pressure lowering, improvement of glucose tolerance), independently of its cortisol lowering effect. These findings renew interest in the potential use of dopamine agonists in Cushing’s disease.
3.2.2. PPAR-γ Ligands
Peroxisome proliferative-activated receptor-γ (PPAR-γ), a member of the nuclear receptor superfamily, functions as a transcription factor mediating ligand-dependent transcriptional regulation . PPAR-γ is expressed in several organs, and its administration is reported to inhibit tumor cell growth in the prostate and colon [42, 43]. Heaney et al.  documented the abundant expression of PPAR-γ in a series of ACTH-secreting tumor samples compared with aactivate PPAR-γ receptors, might be effective as a treatment for Cushing’s disease. The literature evidence [44, 45] does not support this treatment, due to the lack of long-term benefit. Despite the finding of an initial reduction of ACTH and cortisol levels in a subset of patients with CD, clinical symptoms and biochemical parameters subsequently relapsed in this group of subjects. The administration of thiazolidinediones does not seem to be more effective than other currently available neuromodulators .
3.2.3. Pasireotide (SOM230)
It is a somatostatin receptor (SSR) ligand with high binding affinity for multiple receptor isoforms (SST1-3 and SST5). SST5 and SST2 are highly expressed in ACTH pituitary adenomas, and animal studies documented that SSR mediates inhibition of cAMP and regulation of ACTH secretion . A phase 2 trial  suggested that administration of Pasireotide for a 2-week period provoked a reduction in UFC in 76% of 29 patients affected by newly diagnosed, persistent or recurrent ACTH-dependent Cushing’s disease. In a double blind, phase 3 study , 162 patients were randomly assigned to receive 600 mcg or 900 mcg subcutaneously twice daily. At 12 months, 26% and 15% of patients receiving, respectively, the higher and lower Pasireotide dose showed normalization of UFC levels. Serum and salivary cortisol and plasma ACTH decreased, and clinical features of hypercortisolism diminished. Side effects of this therapy included hyperglycemia (73%) and diabetes in 34% of patients, requiring treatment with glucose lowering medications in 45%. The other common symptoms were gastrointestinal disorders (diarrhea, abdominal pain, vomiting).
The significant results described in this 12-month phase 3 study support the use of Pasireotide as a targeted therapy for ACTH-secreting tumors. It is still not known if this treatment could act on pituitary tumor size. Octreotide, which acts predominantly on SSTR2 receptors, has not proven effective in inhibiting ACTH secretion in patients with Cushing’s disease.
In most cases, pituitary adenomas are benign slow-growing tumors. However, their rate of growth can be fast and they can be resistant to standard medical, surgical and radiation treatment , especially ACTH macroadenomas. The Crooke’s cell variant of corticotroph adenoma has been described to be more aggressive and refractory to therapy, with a predisposition to malignant transformation [50–52]. When invasive tumors recur repeatedly despite radical surgery and postoperative radiotherapy, with widespread extrasellar extension, proximity to cranial nerves and critical blood vessels , combined cytotoxic therapy may be useful. It has also been suggested that early application of chemotherapy may be useful in patients who have already exhausted all surgical and radiotherapy options and are at high risk of malignant transformation [53, 54]. Kaiser et al.  reported a good response to cyclophosphamide, doxorubicin and 5-fluorouracil (5FU) in a patient with adrenocorticotroph tumor, with regression of the metastases. Kaltsas et al.  recommended the use of CCNU/5FU for relatively indolent tumor in the first instance. There have been partial and short-lasting responses to other combinations of chemotherapy agents , such as paclitaxel and etoposide in ectopic Cushing’s syndrome . In animal studies, cytotoxic hybrid compounds between the somatostatin analog vapreotide (no longer commercially available) and doxorubicin increased the effects of doxorubicin without increasing its toxicity .
Temozolomide (TMZ) is a second-generation alkylating cytostatic agent. Combined with radiotherapy, it is known to be effective in some patients with glioblastoma multiforme and cerebral metastases of malignant melanoma. It is administered orally, does not require hepatic metabolism for activation, and is able to cross the blood-brain barrier. TMZ promotes apoptosis of target cells and induces massive cell shrinkage and necrosis, depleting the DNA repair enzyme O6-methylguanine-DNA-methyl transferase (MGMT) in various cell types. Multiple studies suggest that reduced intratumor levels of MGMT predict responsiveness to TMZ. TMZ may also inhibit angiogenesis. Its use was firstly described in 2006 for the treatment of a pituitary carcinoma, and the first corticotroph adenoma was treated in 2007 . Since then, more than 30 case reports on its use in ACTH-secreting pituitary tumors have been published, and on the whole described some type of positive response. Recently Raverot et al.  described four patients with ACTH tumors with 50% positive response after only four cycles, in terms of marked shrinkage of the pituitary tumor together with a markedly reduced extension of the vertebral metastases, and a drop in ACTH levels with clinical improvement. Curtò et al.  published a case report of a patient with a corticotroph carcinoma in whom a 90% reduction in the size of the tumor, and a stabilization of the metastases volume was documented after four cycles of TMZ. Dillard et al.  described a case of an aggressive 3 cm corticotroph adenoma refractory to multiple surgery and radiotherapy which showed a 60% regression in size after TMZ administration. TMZ treatment was generally well tolerated. It has been reported  that the initial response does not always correlate with long-term control of the disease and that the absence of MGMT expression may be associated with a better response. Tumor stabilization or reduction of tumor size can improve clinical outcomes, and it remains a last-line defense for life-threatening pituitary tumors.
3.2.6. Retinoic Acid
Retinoids are a family of signaling molecules that are related to vitamin A (retinol) in terms of their chemical structure. The cell cycle is driven by complexes of cyclin-dependent kinases (CDKs) and cyclins. There is abundant evidence that retinoids, via various signaling pathways, inhibit cell-cycle progression in a variety of human cancer cells by directly or indirectly modulating cyclins, CDKs, and cell-cycle inhibitors.
Retinoic acid (RA) has been studied in various types of tumor. Páez-Pereda et al.  examined its effects on human in vitro and mouse in vivo pituitary cells. RA inhibited ACTH biosynthesis only in tumorous corticotroph cells, while normal cells were unaffected. The authors concluded that RA inhibits ACTH synthesis by inhibiting POMC transcription through its activity on AP-1 and Nur77/Nurr1 and reduces the proliferation and survival of the corticotroph adenoma. It is thus of potential therapeutic use in CD [62, 63]. Castillo et al.  published an in vivo animal study in which retinoic acid or ketoconazole was administered to 42 dogs with Cushing’s canine syndrome. A reduction in ACTH and alpha-MSH levels and pituitary adenoma volume was noted after 180 days of therapy with retinoic acid or ketoconazole, with similar results for both treatments.
3.2.7. mTOR Inhibitors
Mammalian target of rapamycin (mTOR) functions as a central element in a signaling pathway involved in the control of cell growth and proliferation. Everolimus is an mTOR inhibitor, and recent studies  have demonstrated its antineoplastic activity in several human cancers, mostly when associated with the long-acting repeatable (LAR) formulation of Octreotide in neuroendocrine tumors. Jouanneau et al.  hypothesized its use in pituitary aggressive adenomas and carcinomas. The authors described the effects of a combination therapy with everolimus (5 mg/day) and octreotide (30 mg/months) and studied mTOR expression in 1 pituitary carcinoma against 17 ACTH adenomas. Combined therapy did not control pituitary tumor growth or ACTH secretion, but the authors are waiting for more clinical cases before drawing any conclusions on this combined treatment.
3.2.8. Tyrosine Kinase Inhibitors
Epidermal growth factor receptor (EGFR) activation, due to either mutation or ligand or receptor overexpression, is associated with a variety of human cancers. Approximately 60% of pituitary tumors, including ACTH-secreting adenomas, express EGFR. In pituitary corticotroph tumors expressing EGFR, , a cyclin-dependent kinase inhibitor, is down regulated. In a recent study , the authors hypothesized that the receptor could be a novel target for treatment of Cushing’s disease, suppressing ACTH in corticotroph adenomas. In human ACTH-secreting tumors  gefitinib (a tyrosine kinase inhibitor targeting EGFR) was found to suppress in vitro POMC expression by approximately 95%. This effect was confirmed in canine corticotroph adenoma cells. Gefitinib effectively suppressed ACTH secretion and inhibited tumor growth in EGFR-expressing tumors in vivo (mouse model), in support of the in vitro results.
3.2.9. Combined Therapy
Since corticotroph adenomas express DA and SST receptors simultaneously, some authors hypothesized the use of DA agonists with SS analogues to reach a synergic effect in the treatment of ACTH-dependent CS. Recent studies  evaluated the association of cabergoline and ketoconazole, which normalized UFC in approximately 2/3 of patients not achieving a full response to cabergoline alone. In a prospective open-label, multicenter trial, Feelders et al.  administered Pasireotide in monotherapy followed by sequential addition of cabergoline and ketoconazole if UFC remained high after 28 and 60 days of treatment, respectively. At the end of the study 68% of the 17 treated patients showed complete biochemical control.
An innovative chimeric molecule that acts simultaneously on SST and DA receptors was created with a view to treatment of pituitary tumors. This compound (BIM-23A760) has been tested in a phase 1 and phase 2A study in 11 patients affected by acromegaly from GH-secreting pituitary adenoma, but the weak evidence of somatostatinergic activity led to the discontinuation of its development .
Management of persistent or recurrent CS is a challenge and medical therapy plays a critical role in the control of hypercortisolemia and associated symptoms. Unfortunately, this approach is not always successful. A multidisciplinary approach should thus be adopted, including chemotherapy, radiotherapy, neuromodulatory drugs, and hormone analogs to control tumor growth and associated symptoms. Ideally, management should be commenced in centers with appropriate experience and knowledge and involve a multidisciplinary team, including endocrinologists, neuroradiologists, dedicated neurosurgeons with expertise in pituitary tumor surgery (or general surgeons in cases of ectopic tumors), nuclear medicine physicians and oncologists.
Several studies have demonstrated that early application of medical treatment, possibly incorporating new therapeutic developments, may have improved effectiveness and led to more acceptable side effects. Nowadays, combination of tumor debulking, radiotherapy, medical treatment, and chemotherapy, appropriately and timely used, can avoid progression of an otherwise lethal condition. A better understanding of the pathogenesis of tumors underlying this puzzling syndrome is needed in order to help identify more effective and safe medical therapies. Control of hypercortisolemia should be obtained whenever possible, even in rapidly progressive disease, as small cell lung carcinomas, to reduce the associated complications (generalized infections, hypokalemia, diabetes, hypertension, psychotic reactions, and reduction of quality of life). Total bilateral adrenalectomy induces a rapid resolution of the clinical features. With low morbidity associated with laparoscopic adrenal surgery, this approach has been considered more frequently, and possibly even as main treatment in some individuals with Cushing’s disease, especially when disease is severe or because of patient preference. Unfortunately the poor prognosis of this subgroup of EAS often makes the physician give up any drug control of the disease. We hope that the several offered noninvasive medical strategies can serve as a guide for the oncologists to improve the quality of life of their patients.
Pharmacological management of Cushing's syndrome: an update
Manejo farmacológico da síndrome de Cushing: uma atualização
Cuong Nguyen Dang; Peter Trainer
Christie Hospital, Manchester, UK
Address for correspondence
The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. Drugs targeting the hypothalamic-pituitary axis have been investigated but their roles in clinical practice remain limited although PPAR-g agonist and somatostatin analogue som-230 (pasireotide) need further investigation. The only drug acting at the periphery targeting the glucocorticoid receptor remains Mifepristone (RU486). The management of Cushing syndrome may well involve combination therapy acting at different pathways of hypercortisolaemia but monitoring of therapy will remain a challenge.
Keywords: Cushing's syndrome; Drug therapy; Steroidogenesis inhibitor; Hypothalamic-pituitary modulator
O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-g e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio.
Descritores: Síndrome de Cushing; Terapia médica; Inibidores da esteroidogênese; Moduladores hipotálamo-hipofisários
CUSHING'S IS A RARE DISEASE and therefore of minimal interest to the pharmaceutical industry and hence for many years there were few developments. However in recent times there has been renewed interest in whether agents marketed for other conditions may have a role to play in the medical management of Cushing's syndrome. This review will endeavour to assess the place of the 'new' agents alongside the longer established agents.
The definitive management for Cushing's syndrome is surgical excision of the underlying cause of the hypercortisolaemia, with the exception of ACTH-independent bilateral macronodular hyperplasia where pharmacological treatment directed against the aberrant receptor can be effective (1). However, in many patients with Cushing's syndrome there is a role for medical therapy in certain specific circumstances. It is common practice to prepare patients for surgery by lowering circulating cortisol levels to reverse the metabolic consequence of cortisol excess and by implication reduce the complications of surgery. This clearly depends on the interval to surgery and disease severity. As any clinician dealing with Cushing's syndrome is aware establishing the precise aetiology is a challenge and it is not always possible to make a definitive diagnosis at first investigation, and in such cases medical therapy can be used as a stop gap to control signs and symptoms and thereby allow time for re-investigation. In patients not cured by surgery or in patients with metastatic disease medical therapy can be used to control manifestations of the disease. Pituitary radiotherapy is extremely effective at controlling hypercortisolaemia but can take several years to have its full effect and medical therapy is often required in the interim (see figure 1).
Medical therapy can be separated into agents that inhibit adrenal steroidgenesis and those that modulate pituitary ACTH release. Currently in clinical practice, the most effective, reliable and widely use agents are those that inhibit steroidgenesis.
A major challenge of medical therapy is the monitoring of its effectiveness. Urinary free cortisol (UFC) measurement is widely used but has several major limitations and is intrinsically a poor solution to the problem of disease monitoring. Only a small proportion of cortisol is excreted unaltered in urine and UFC immunoassays to varying extent detect biologically inactive cortisol metabolites, which may be raised in patients treated with agents such as metyrapone. UFC has the additional disadvantages of relying on complete collection and of being unable to detect over-treatment induced hypoadrenalism.
Although more labour intensive, measurement of serum cortisol is a more appropriate means of assessing disease activity. The best validated technique is calculation of a mean serum cortisol from multiple measurements taken during a single day. Studies comparing isotopically calculated cortisol production rates to serum levels indicate that a mean serum cortisol in the range 150300 nmol/l equates to a normal cortisol production rate, and this should be the target of medical therapy (2).
The cyclical nature of Cushing's syndrome in some patients means that even after disease control has been achieved regular treatment monitoring is required.
These agents are the most consistently effective means of controlling cortisol secretion.
In the era before it was possible to measure plasma ACTH, the metyrapone test was used to investigate suspected Cushing's syndrome and hypoadrenalism but its use now is exclusively therapeutic (3,4). It acts primarily on the final step in cortisol synthesis namely the conversion of 11-deoxycortisol to cortisol and therefore results in a dramatic increase in circulating 11-deoxycortisol levels, which can cross-react in serum and urine cortisol immunoassays. This cross-reactivity may result in spuriously elevated cortisol levels and a failure to appreciate that a patient is over-treated and hypoadrenal.
Metyrapone is the most potent, short-acting inhibitor of cortisol synthesis with a rapid onset of action. Serum cortisol levels fall within four hours of an initial dose and care is required to avoid over-treatment. The routine starting dose is 250 mg three times per day with reassessment of cortisol levels 72 hours later and dose titration as appropriate until a mean cortisol level of between 150 and 300 nmol/l is achieved. In patients with severe hypercortisolaemia up to 8 gm per day in 34 divided doses may be necessary. Most patients tolerate the drug without difficulty as long as hypoadrenalism is avoided. Nausea, anorexia and abdominal pain can occur but usually this is a sign of over-treatment. The major limitation of metyrapone is in women as the accumulation of cortisol precursors results in elevated androgens, which frequently is manifest as hirsutism and acne. Although mineralocorticoid precursors levels are elevated, hypokalaemia, hypertension and oedema are not problems, presumably because of the benefits of lower circulating cortisol levels (5,6). In patients with pituitary-dependent Cushing's disease, ACTH levels rise but there is no evidence that this results in tachyphylaxis (5,7).
Ketoconazole is an imidazole derivative developed as an oral antifungal agent that inhibits cholesterol, sex steroid and cortisol synthesis by acting on the 11b-hydroxylase and C17-20 lyase enzymes (8-11). It is the most frequently used agent in the treatment of Cushing's syndrome with the starting dose being 200 mg twice daily increasing as necessary to 1200 mg/day in four divided doses (12,13). In contrast to metyrapone it can take several weeks to see the full benefit of a dose adjustment and there is less risk of over-treatment and hypoadrenalism. With time it is effective at controlling the symptoms of Cushing's syndrome and in women its antiandrogenic properties are a virtue but in men, gynaecomastia and reduced libido have been reported. The most common side effects are gastrointestinal upset and skin rashes but liver enzyme dysfunction can occur in up to 10% of cases, which rarely has proceeded to acute liver failure and fatality (14-17). Ketoconazole has the added benefit of reducing the total cholesterol and LDL cholesterol (18).
Metyrapone and ketoconazole can be very successfully co-administered as the former controls cortisol secretion while waiting for the slower onset of action of the latter agent, which in turn lowers androgens and thus negates one of the major limitations of the former.
Mitotane reduces cortisol production by blocking cholesterol side-chain cleavage and 11b-hydroxylase (19-21). It was introduced in 1960 for the treatment of adrenal carcinoma and subsequently used for the treatment of benign causes of Cushing's syndrome. The onset of mitotane action is slow with sustained action maintained after discontinuation in up to a third of patients (22). When used to control serum cortisol levels in benign disease, mitotane is initiated at a dose of 0.51 gm per day which is increased gradually by 0.51 gm every few weeks to minimise side effects. Adverse effects such as nausea, anorexia and diarrhoea are common with doses of 2 gm per day and almost universal at doses greater than 4 gm per day (23). Adrenal insufficiency and neurological side effects including abnormal gait, dizziness, vertigo, confusion and problem of language expression are often seen at higher dose (22). Abnormal liver enzymes, hypercholesterolaemia, skin rash, hyporuricaemia, gynaecomastia in male and prolonged bleeding time are also well recognized (24,25). Changes in hormone binding globulins may result in total hormone measurement being unreliable during treatment and thus caution is required when interpreting serum cortisol levels (26,27). Mitotane increases the metabolic clearance of exogenously administered steroid and the replacement dose of steroid is increased by about a third (28). In order to minimise side effects mitotane dose should be gradually titrated up, taken with meals or at bedtime with food. Changing the schedule to once daily or alternate day may help with gastrointestinal problems. If side effects are severe mitotane can be stopped for a week and restarted at a lower dose. Mitotane may induce spontaneous abortion and is a teratogen. Its effect may persist for a number of months after discontinuation and so a female patient should avoid pregnancy for up to five years after stopping the drug (29).
Aminoglutethimide, which was introduced in 1959 as an anticonvulsant, has also been used in the treatment of breast cancer and was noticed to induce adrenal insufficiency. It inhibits the side-chain cleavage of cholesterol to pregnenolone and therefore inhibits cortisol, oestrogen and aldosterone production and additionally inhibits 11b-hydroxylase, 18-hydroxylase and aromatase activity (30,31). Initially aminoglutethimide decreases cortisol production in Cushing's syndrome but appears to be less effective in treating Cushing's disease (32). The suggested mechanism may be an increase in ACTH overcoming the enzymatic blockade or it may be induction of hepatic enzyme accelerating aminoglutethimide metabolism (33,34). Adverse effects such as lethargy, dizziness, ataxia and rashes are common on initiation and limit its use although they do resolve with time (32,35). There are better agents for controlling hypercortisolaemia and aminoglutethimide does not have a place in the modern treatment of Cushing's syndrome (36).
Trilostane is a competitive inhibitor of 3b-hydroxysteroid dehydrogenase, which is an essential enzyme in the synthesis of cortisol, aldosterone and androstenedione. It is an effective inhibitor of steroid synthesis in vitro but in man the results have been disappointing (37). However, it is used in veterinary practice as it is very effective in controlling pituitary-dependent Cushing's in dogs (38). The maximum daily dose is 1,440 mg and patients may experience side effects such as abdominal discomfort, diarrhoea and paraesthesia. Trilostane has largely fallen out of clinical use but the very fact that it is so effective in dogs may mean it justifies reconsideration in man.
Etomidate is a parenteral anaesthetic agent which when first introduced was associated with excessive mortality in patients in intensive care which was ultimately explained by the recognition it lowered circulating cortisol levels by inhibiting 11b-hydroxylase, 17-hydroxylase, c17-20 lyase as well as cholesterol side chain at cleavage (39-41). A number of case reports have shown etomidate at 2.5 mg/hour to be effective at correcting hypercortisolaemia in seriously ill patients with ectopic ACTH production (42-44). Etomidate's use is limited by the need to be given intravenously but it has a place in acutely sick patients unable to be treated orally where rapid correction of hypercortisolaemia may be life saving.
HYPOTHALAMIC-PITUITARY NEUROMODULATORY AGENTS
Pituitary ACTH secretion is regulated by a number of neurotransmitters including catecholamines, serotonin, acetylcholine, GABA and peptides. In Cushing's disease the pituitary tumour still remains partially responsive to hypothalamic stimuli, illustrated by responsiveness to exogenous CRH and dexamethasone. Reports exist advocating the virtues of various agents but, to-date, none have gained widespread acceptance. However recent data have renewed interest in the possibility of treating Cushing's disease with centrally acting drugs that modulate through dopamine, somatostatin and PPAR receptors function.
Bromocriptine is a dopamine agonist which has been widely used in the treatment of hyperprolactinaemia and acromegaly. It is unclear if the action in lowering ACTH secretion by bromocriptine is via CRH or directly on the pituitary (45-47). A single dose of bromocriptine will cause a fall in ACTH in half of the patients with Cushing's disease but unfortunately this effect is not maintained in the long term (47,48). There are reports that suggest with high dose bromocriptine (40 mg/day) there may be clinical improvement in up to 50% of patients but others have found response rate of only 12% in the long term (49,50). Potential side effects of bromocriptine include nasal congestion, nausea, postural hypotension, headaches and hallucination.
The use of cabergoline in the management of Cushing's disease remains anecdotal. In mixed pituitary tumour secreting prolactin and ACTH with florid clinical signs of Cushing's disease treatment with cabergoline resulted not only in the normalisation of prolactin but also clinical and biochemical resolution of the features of Cushing's (51). It has also been use to control Cushing's disease in failed pituitary surgery (52,53). Recently there has been renewed interest in cabergoline with the publication by Pivonello et al. of a case of lung carcinoid with Cushing's syndrome treated with a combination of lanreotide and cabergoline successfully normalising plasma ACTH and UFC levels (54). In a study of six patients with ACTH-secreting neuroendocrine tumours, dopamine D2 receptors were expressed in five patients on immunohistochemistry and treatment with cabergoline 3.5 mg/week for six months normalised UFC in two patients although one patient later did have treatment escape (55). Case reports of cabergoline use in Nelson's syndrome have been more encouraging. Casulari et al. reported a case of Nelson's syndrome with failed treatment on cyproheptadine (12 mg/day) and bromocriptine (7.5 mg/day) but cabergoline (0.5 mg twice weekly) normalised the ACTH plasma levels and induced complete resolution of the pituitary adenoma on MRI (56). There has also been a case report of cabergoline (1.5 mg/week) treatment of Nelson's syndrome for six years with normalisation of ACTH levels and stable residual pituitary tumour (57).
The role of dopamine agonists in the management of Cushing's disease remains limited to the occasional patient and long-term evidence of efficacy is very poor but interest in their use remains unabated. The available data are case based anecdote, there is a need for a controlled study before treatment can be recommended.
PPAR-g receptor agonists
In 2002, the nuclear hormone receptor, peroxisome proliferator-activated receptor-g (PPAR-g) was identified in ACTH-secreting pituitary tumour (58). In an in vivo experiment, innoculating mice with corticotroph AtT20 tumour cells, treating with extremely high dose of rosiglitazone (150 mg/kg/day) prevented the development of tumours. In mice with already established corticotroph tumours, rosiglitazone treatment decreased tumour volume in 75% of cases and prevented signs of hypercortisolaemia in all cases, with 75% reduction in ACTH level and 96% reduction in cortisol levels (58). These observations caused great interest but are yet to impact on clinical practice.
In a study of two patients with pituitary-dependent Cushing's syndrome treated with rosiglitazone 8 mg daily for 33 and 20 days (the second patient was also taking metyrapone 1 gm/day), 24 hours UFC fell in both patients although only in the patient co-treated with metyrapone did it reach statistical significance (59). In a second study of ten patients, four prior to surgery, four following relapse after surgery and two immediately after failed surgery treated with 416 mg of rosiglitazone for 18 months (median 3 months), there was no consistent reduction in urinary free cortisol, plasma ACTH or serum cortisol levels (60). Side effects reported included oedema, weight increase, somnolence and increased hirsutism. In one of the larger studies, fourteen patients with active Cushing's disease (seven untreated and seven post unsuccessful transsphenoidal pituitary surgery) were treated with 816 mg of rosiglitazone for 17 months (61). In six patients, plasma ACTH, serum cortisol and 24 hours UFC were lowered but only UFC reached significance. Two of the six patients also noted clinical improvement on follow up at seven months. No clinical side effects were noted but one patient developed hypercholesterolaemia. In a study of seven patients with Nelson's syndrome who took 8 mg of rosiglitazone for 12 weeks, no significant fall in ACTH was seen (62). Similarly in another study of six patients with Nelson's syndrome given rosiglitazone 12 mg per day for 14 weeks, there was no fall in ACTH levels (63).
Although most studies used rosiglitazone in treating Cushing's disease, pioglitazone has also been tried. In a study of five patients with Cushing's disease treated with pioglitazone 45 mg for 30 days, no alteration in 24 hours UFC, or ACTH and cortisol responses to CRH administration was seen (64).
Currently the success of PPAR agonists in treating Cushing's disease remains disappointing, failing to reproduce the success seen in the in vitro and mouse model. However with the small number of patients and short duration of treatment, further studies are still needed. The discrepancy between the in vitro and human experience may reflect the differences in the order of magnitude in the dose of rosiglitazone.
Octreotide, an analogue of somatostatin, has been used extensively to treat neuroendocrine tumours and acromegaly. In the 1990s five subtypes of somatostatin receptors were identified with expression of somatostatin receptor subtypes in mammalian corticotrophs being variable (65).
In one study all five subtype somatostatin receptors were co-localised in rat pituitary cells expressing ACTH (66). Yet in another study only 38% of corticotrophs expressed somatostatin receptor subtype 5 (sst5) and 3% expresses somatostatin receptor subtype 2 (sst2) (67). While in contrast Smith et al. found a predominance of sst2 rather than sst5 (68). It is generally accepted that sst2 and sst5 are involved in the regulation of growth hormone, prolactin and TSH (69).
In vitro studies suggested that normal corticotroph only responds to somatostatin with inhibition of ACTH release if the cells have been cultured in glucocorticoid free medium (70-74). In agreement with this is the finding that ACTH secretion in normal individuals is not affected by infusion of somatostatin or octreotide but is affected in patients with Addison's disease (75,76).
Initial reports did show that somatostatin infusion decreases plasma ACTH level by between 40% to 70% in patients with Nelson's syndrome (77). However, subsequent studies in Nelson's syndrome have been less impressive and most patients with Cushing's disease have failed to respond (78-82). The chronic treatment of rat pituitary tumour cells and mouse corticotroph cells with glucocorticoid results in decreased binding of somatostatin (83). In cultured human corticotroph, adenoma cells pre-treated with hydrocortisone resulted in abolition of octreotide-induced inhibition of basal and CRH induced ACTH release (82). The lack of clinical efficacy of octreotide may be due to the down regulation of somatostatin receptors by glucocorticoids. In fact in the mouse, sst2 gene promoter sequence is the only somatostatin receptor shown to be directly transcriptionally regulated by glucocorticoids (84,85). There has been speculation that octreotide may have a role in treating ectopic ACTH producing tumours or in Cushing's disease in combination with ketoconazole but the available evidence is unconvincing that it has any role in Cushing's disease (86,87).
There is renewed interest in somatostatin analogues in Cushing's disease because of encouraging data emerging from early studies with SOM-230 (pasireotide, Novartis Pharmaceuticals UK Ltd). It is a new somatostatin analogue with affinity to all the somatostatin receptor subtypes but with 40 fold higher affinity for sst5 than octreotide (88-90).
Compared to octreotide, SOM-230 is more potent at suppressing ACTH release and at inhibiting CRH-induced ACTH release in corticotroph tumour cells (91-93). Dexamethasone (10 nM) pre-treatment of mouse corticotroph cells fails to suppress SOM-230 inhibition of CRH-induced ACTH release whereas the suppressive effect of octreotide is blocked (92).
The preliminary results of an open label, single arm phase 2 study of fourteen patients with persistent or recurrent Cushing's disease treated with pasireotide 600 mg subcutaneously twice daily for fifteen days, were reported as an abstract at ENDO 2006 (94). Pasireotide normalised UFC in 3 patients (21%) and in a further 7 patients there was at least 40% reduction in UFC compared to baseline. There was significant improvement in symptoms including weight loss, facial rubor, abdominal obesity, fatigue and proximal weakness in over 40% of patients. The drug was well tolerated but common side effects were mild to moderated gastrointestinal upset, injection site reaction and a transient increase in fasting blood glucose with one pre-existing diabetes mellitus patient stopping treatment early. Although the results of this preliminary study are encouraging the final results are awaited and further studies will be required to confirm these results.
Cyproheptadine is a non-selective histamine and serotonin antagonist. In a small series, at a dose of 24 mg/ day, it was effective at reducing ACTH in three patients with Cushing's disease (95). There is disagreement on whether cyproheptadine acts either directly on the pituitary or through the inhibition of CRH (96-99). It is rarely effective and has no place in current practice. Its main side effect is sedation.
Ritanserin is a specific 5-HT2 antagonist which has been used in a few patients but its effects do not appear to be sustained in most patients (100,101).
Sodium valproate is mainly used as an anti-epileptic agent. Evidence for its effectiveness in treating Cushing's disease remains conflicting. There are reports suggesting it is successful at suppressing ACTH at a daily dose of 600 mg, but more recent data have failed to demonstrate benefit either as primary therapy or after failed pituitary surgery (102,103). However, it may have a role as add on therapy to metyrapone at a daily dose of 12 g (104,105).
Since the 1980's retinoic acid derivatives are widely used by dermatologists in the treatment of acne and psoriasis as well as in certain malignancy such as acute promyelocytic leukaemia (106,107). Retinoic acid is a ligand for Nur77/Nurr1 receptor which is involved in the physiological stimulation of ACTH by CRH (108). Retinoic acid inhibits cell proliferation and induces cell death in ACTH secreting tumours but not in normal pituitary cells. In the adrenal cortex it inhibits corticosterone secretion and cell proliferation, while in a mouse model, it blocks tumour growth and reduces circulating ACTH and cortisol. The dose was 10 mg/kg which is within the dose range in human cancer therapy (108). Studies in rodents and dogs models of Cushing's disease have been successful but there is now a need for studies in human (108,109).
Agents blocking cortisol action
Mifepristone (RU486) is a potent antagonist of the glucocorticoid and progesterone receptors (110). In man mifepristone blocks glucocorticoid action resulting in negative feedback at the hypothalamic-pituitary level leading to a rise in ACTH, arginine-vasopressin and therefore cortisol (111). Mifepristone, at doses of up to 20 mg/kg, has been successfully used to treat a small number of patients with ectopic ACTH syndrome and there is every reason to believe that it could be successfully used in all patients if it were not for the problem of monitoring therapy (112). As a receptor antagonist it does not lower circulating cortisol levels, which in fact rise, and therefore it is very difficult to dose titrate and judge effectiveness. The GH receptor antagonist pegvisomant has gained widespread acceptance as a treatment for acromegaly because its effectiveness can be judged by monitoring IGF-1. Unfortunately, the HPA axis lack a marker analogous to IGF-I. Even with short term use, a number of patients did develop symptoms of hypoadrenalism, which is problematic as there is no effective method of monitoring over treatment (113). There has also been report of a case of mifepristone causing severe hypokalaemia that is attributed to excess cortisol activation of mineralcorticoid receptor which responded to spironolactone therapy (114). With caution, mifepristone may have a role in the treatment of Cushing's syndrome and could be first line treatment if a biochemical measure of disease were identified (115).
A number of drugs have been used in the management of Cushing's syndrome. Regardless of the aetiology, steroid biosynthesis remains the most effective and widely used agent. The preferred treatments are metyrapone or ketoconazole as monotherapy, or in combination. Careful monitoring of therapy is important as all agents have the potential of causing hypoadrenalism.
Currently drugs acting on the hypothalamic-pituitary pathways have been less successful in clinical practice and their role is likely to be limited to add on therapy on an individual basis. However, with the identification of new receptors and development of agent blocking these receptors, there remains the hope that they may still prove to be useful in the future.
1. Christopoulos S, Bourdeau I, Lacroix A. Aberrant expression of hormone receptors in adrenal Cushing's syndrome. Pituitary 2004;7:225-35. [ Links ]
2. Trainer PJ, Eastment C, Grossman AB, Wheeler MJ, Perry L, Besser GM. The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushing's syndrome. Clin Endocrinol (Oxf) 1993;39:441-3. [ Links ]
3. Newell-Price J, Grossman AB. The differential diagnosis of Cushing's syndrome. Ann Endocrinol (Paris) 2001;62:173-9. [ Links ]
4. Liddle GW, Estepe HL, Kendall JWJ, Williams WCJ, Townes A. Clinical application of a new test of pituitary reserve. J Clin Endocrinol Metab 1959;19:875-94. [ Links ]
5. Verhelst JA, Trainer PJ, Howlett TA, Perry L, Rees LH, Grossman AB, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome. Clin Endocrinol (Oxf) 1991;35:169-78. [ Links ]
6. Connell JM, Cordiner J, Davies DL, Fraser R, Frier BM, McPherson SG. Pregnancy complicated by Cushing's syndrome: potential hazard of metyrapone therapy. Case report. Br J Obstet Gynaecol 1985;92:1192-5. [ Links ]
7. Orth DN. Metyrapone is useful only as adjunctive therapy in Cushing's disease. Ann Intern Med 1978;89:128-30. [ Links ]
8. Engelhardt D, Dorr G, Jaspers C, Knorr D. Ketoconazole blocks cortisol secretion in man by inhibition of adrenal 11 beta-hydroxylase. Klin Wochenschr 1985;63:607-12. [ Links ]
9. Oelkers W, Bahr V, Hensen J, Pickartz H. Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells. Acta Endocrinol (Copenh) 1986;113:370-7. [ Links ]
10. Sonino N. The endocrine effects of ketoconazole. J Endocrinol Invest 1986;9:341-7. [ Links ]
11. Weber MM, Luppa P, Engelhardt D. Inhibition of human adrenal androgen secretion by ketoconazole. Klin Wochenschr 1989;67:707-12. [ Links ]
12. Angeli A, Frairia R. Ketoconazole therapy in Cushing's disease. Lancet 1985;1:821. [ Links ]
13. Sonino N, Boscaro M, Paoletta A, Mantero F, Ziliotto D. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347-52. [ Links ]
14. Zollner E, Delport S, Bonnici F. Fatal liver failure due to ketoconazole treatment of a girl with Cushing's syndrome. J Pediatr Endocrinol Metab 2001;14:335-8. [ Links ]
15. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology 1984;86:503-13. [ Links ]
16. Stricker BH, Blok AP, Bronkhorst FB, Van Parys GE, Desmet VJ. Ketoconazole-associated hepatic injury. A clinicopathological study of 55 cases. J Hepatol 1986;3:399-406. [ Links ]
17. Knight TE, Shikuma CY, Knight J. Ketoconazole-induced fulminant hepatitis necessitating liver transplantation. J Am Acad Dermatol 1991;25:398-400. [ Links ]
18. Miettinen TA. Cholesterol metabolism during ketoconazole treatment in man. J Lipid Res 1988;29:43-51. [ Links ]
19. Hart MM, Straw JA. Effect of 1-(0-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane on adrenocorticotropic hormone-induced steroidogenesis in various preparations in vitro of dog adrenal cortex. Biochem Pharmacol 1971; 20:1679-88. [ Links ]
20. Young RB, Bryson MJ, Sweat ML, Street JC. Complexing of DDT and o,p'DDD with adrenal cytochrome P-450 hydroxylating systems. J Steroid Biochem 1973;4:585-91. [ Links ]
21. Caticha O, Odell WD, Wilson DE, Dowdell LA, Noth RH, Swislocki AL, et al. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinol Metab 1993;77:494-7. [ Links ]
22. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-201. [ Links ]
23. Hutter AM Jr, Kayhoe DE. Adrenal cortical carcinoma. Results of treatment with o,p'DDD in 138 patients. Am J Med 1966; 41:581-92. [ Links ]
24. Maher VM, Trainer PJ, Scoppola A, Anderson JV, Thompson GR, Besser GM. Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia. Q J Med 1992; 84:671-9. [ Links ]
25. Haak HR, Caekebeke-Peerlinck KM, van Seters AP, Briet E. Prolonged bleeding time due to mitotane therapy. Eur J Cancer 1991;27:638-41. [ Links ]
26. Bledsoe T, Island DP, Ney RL, Liddle GW. An effect of o,p'-DDD on the extra-adrenal metabolism of cortisol in man. J Clin Endocrinol Metab 1964;24:1303-11. [ Links ]
27. van Seters AP, Moolenaar AJ. Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh) 1991;124:526-33. [ Links ]
28. Hague RV, May W, Cullen DR. Hepatic microsomal enzyme induction and adrenal crisis due to o,p'DDD therapy for metastatic adrenocortical carcinoma. Clin Endocrinol (Oxf) 1989;31:51-7. [ Links ]
29. Leiba S, Weinstein R, Shindel B, Lapidot M, Stern E, Levavi H, et al. The protracted effect of o,p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo. Ann Endocrinol (Paris) 1989;50:49-53. [ Links ]
30. Dexter RN, Fishman LM, Ney RL, Liddle GW. Inhibition of adrenal corticosteroid synthesis by aminoglutethimide: studies of the mechanism of action. J Clin Endocrinol Metab 1967;27:473-80. [ Links ]
31. Shaw MA, Nicholls PJ, Smith HJ. Aminoglutethimide and ketoconazole: historical perspectives and future prospects. J Steroid Biochem 1988;31:137-46. [ Links ]
32. Misbin RI, Canary J, Willard D. Aminoglutethimide in the treatment of Cushing's syndrome. J Clin Pharmacol 1976; 16:645-51. [ Links ]
33. Zachmann M, Gitzelmann RP, Zagalak M, Prader A. Effect of aminoglutethimide on urinary cortisol and cortisol metabolites in adolescents with Cushing's syndrome. Clin Endocrinol (Oxf) 1977;7:63-71. [ Links ]
34. Sonino N, Boscaro M. Medical therapy for Cushing's disease. Endocrinol Metab Clin North Am 1999;28:211-22. [ Links ]
35. Miller JW, Crapo L. The medical treatment of Cushing's syndrome. Endocr Rev 1993;14:443-58. [ Links ]
36. Child DF, Burke CW, Burley DM, Rees LH, Fraser TR. Drug controlled of Cushing's syndrome. Combined aminoglutethimide and metyrapone therapy. Acta Endocrinol (Copenh) 1976;82:330-41. [ Links ]
37. Dewis P, Anderson DC, Bullock DE, Earnshaw R, Kelly WF. Experience with trilostane in the treatment of Cushing's syndrome. Clin Endocrinol (Oxf) 1983;18:533-40. [ Links ]
38. Sieber-Ruckstuhl NS, Boretti FS, Wenger M, Maser-Gluth C, Reusch CE. Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependant hyperadrenocorticism treated with trilostane. Domest Anim Endocrinol 2006;31:63-75. [ Links ]
39. Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983;1:1270. [ Links ]
40. Weber MM, Lang J, Abedinpour F, Zeilberger K, Adelmann B, Engelhardt D. Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis. Clin Investig 1993;71:933-8. [ Links ]
41. Allolio B, Stuttmann R, Fischer H, Leonhard W, Winkelmann W. Long-term etomidate and adrenocortical suppression. Lancet 1983;2:626. [ Links ]
42. Allolio B, Schulte HM, Kaulen D, Reincke M, Jaursch-Hancke C, Winkelmann W. Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in Cushing's syndrome. Klin Wochenschr 1988;66:361-4. [ Links ]
43. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM. Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis. J Clin Endocrinol Metab 1998;83:3542-4. [ Links ]
44. Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK. Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic Cushing's syndrome. J Clin Endocrinol Metab 2001;86:4104-8. [ Links ]
45. Lamberts SW, de Lange SA, Stefanko SZ. Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushing's disease: differences in the regulation of hormone secretion. J Clin Endocrinol Metab 1982;54:286-91. [ Links ]
46. Croughs RJ, Koppeschaar HP, van't Verlaat JW, McNicol AM. Bromocriptine-responsive Cushing's disease associated with anterior pituitary corticotroph hyperplasia or normal pituitary gland. J Clin Endocrinol Metab 1989;68:495-8. [ Links ]
47. Boscaro M, Benato M, Mantero F. Effect of bromocriptine in pituitary-dependent Cushing's syndrome. Clin Endocrinol (Oxf) 1983;19:485-91. [ Links ]
48. Lamberts SW, Klijn JG, de Quijada M, Timmermans HA, Uitterlinden P, de Jong FH, et al. The mechanism of the suppressive action of bromocriptine on adrenocorticotropin secretion in patients with Cushing's disease and Nelson's syndrome. J Clin Endocrinol Metab 1980; 51:307-11. [ Links ]
49. Mercado-Asis LB, Yasuda K, Murayama M, Mune T, Morita H, Miura K. Beneficial effects of high daily dose bromocriptine treatment in Cushing's disease. Endocrinol Jpn 1992;39:385-95. [ Links ]
50. Morris D, Grossman A. The medical management of Cushing's syndrome. Ann N Y Acad Sci 2002;970:119-33. [ Links ]
51. T'Sjoen G, Defeyter I, Van De SJ, Rubens R, Vandeweghe M. Macroprolactinoma associated with Cushing's disease, successfully treated with cabergoline. J Endocrinol Invest 2002;25:172-5. [ Links ]
52. Miyoshi T, Otsuka F, Takeda M, Inagaki K, Suzuki J, Ogura T, et al. Effect of cabergoline treatment on Cushing's disease caused by aberrant adrenocorticotropin-secreting macroadenoma. J Endocrinol Invest 2004;27:1055-9. [ Links ]
53. Illouz F, Dubois-Ginouves S, Laboureau S, Rohmer V, Rodien P. Use of cabergoline in persisting Cushing's disease. Ann Endocrinol (Paris) 2006;67:353-6. [ Links ]
54. Pivonello R, Ferone D, Lamberts SW, Colao A. Cabergoline plus lanreotide for ectopic Cushing's syndrome. N Engl J Med 2005;352:2457-8. [ Links ]
55. Pivonello R, Ferone D, de Herder WW, Faggiano A, Bodei L, de Krijger RR, et al. Dopamine receptor expression and function in corticotroph ectopic tumors. J Clin Endocrinol Metab 2007;92:65-9. [ Links ]
56. Casulari LA, Naves LA, Mello PA, Pereira NA, Papadia C. Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res 2004;62:300-5. [ Links ]
57. Shraga-Slutzky I, Shimon I, Weinshtein R. Clinical and biochemical stabilization of Nelson's syndrome with long-term low-dose cabergoline treatment. Pituitary 2006;9:151-4. [ Links ]
58. Heaney AP, Fernando M, Yong WH, Melmed S. Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 2002;8:1281-7. [ Links ]
59. Hull SSA, Sheridan B, Atkinson AB. Pre-operative medical therapy with rosiglitazone in two patients with newly diagnosed pituitary-dependent Cushing's syndrome. Clin Endocrinol (Oxf) 2005;62:259-61. [ Links ]
60. Giraldi FP, Scaroni C, Arvat E, Martin M, Giordano R, Albiger N, et al. Effect of protracted treatment with rosiglitazone, a PPARgamma agonist, in patients with Cushing's disease. Clin Endocrinol (Oxf) 2006;64:219-24. [ Links ]
61. Ambrosi B, Dall'Asta C, Cannavo S, Libe R, Vigo T, Epaminonda P, et al. Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease. Eur J Endocrinol 2004;151:173-8. [ Links ]
62. Mullan KR, Leslie H, McCance DR, Sheridan B, Atkinson AB. The PPAR-gamma activator rosiglitazone fails to lower plasma ACTH levels in patients with Nelson's syndrome. Clin Endocrinol (Oxf) 2006;64:519-22. [ Links ]
63. Munir A, Song F, Ince P, Walters SJ, Ross R, Newell-Price J. Ineffectiveness of rosiglitazone therapy in Nelson's syndrome. J Clin Endocrinol Metab 2007;92:1758-63. [ Links ]
64. Suri D, Weiss RE. Effect of pioglitazone on adrenocorticotropic hormone and cortisol secretion in Cushing's disease. J Clin Endocrinol Metab 2005;90:1340-6. [ Links ]
65. Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2003; 2:999-1017. [ Links ]
66. O'Carroll AM, Krempels K. Widespread distribution of somatostatin receptor messenger ribonucleic acids in rat pituitary. Endocrinology 1995;136:5224-7. [ Links ]
67. Day R, Dong W, Panetta R, Kraicer J, Greenwood MT, Patel YC. Expression of mRNA for somatostatin receptor (sstr) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis. Endocrinology 1995; 136:5232-5. [ Links ]
68. Mezey E, Hunyady B, Mitra S, Hayes E, Liu Q, Schaeffer J, et al. Cell specific expression of the sst2A and sst5 somatostatin receptors in the rat anterior pituitary. Endocrinology 1998; 139:414-9. [ Links ]
69. Shimon I, Taylor JE, Dong JZ, Bitonte RA, Kim S, Morgan B, et al. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J Clin Invest 1997;99:789-98. [ Links ]
70. Brown MR, Rivier C, Vale W. Central nervous system regulation of adrenocorticotropin secretion: role of somatostatins. Endocrinology 1984;114:1546-9. [ Links ]
71. Kraicer J, Gajewski TC, Moor BC. Release of pro-opiomelanocortin-derived peptides from the pars intermedia and pars distalis of the rat pituitary: effect of corticotrophin-releasing factor and somatostatin. Neuroendocrinology 1985;41:363-73. [ Links ]
72. Voigt KH, Fehm HL, Lang RE, Beinert KE, Pfeiffer EF. Suppression of ACTH secretion by synthetic MSH-release inhibiting factor Pro-Leu-Gly-NH2 in Addison's disease. Horm Metab Res 1977;9:150-2. [ Links ]
73. Nicholson SA, Adrian TE, Gillham B, Jones MT, Bloom SR. Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro. J Endocrinol 1984;100:219-26. [ Links ]
74. Lamberts SW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988;9:417-36. [ Links ]
75. Invitti C, Pecori GF, Dubini A, Piolini M, Cavagnini F. Effect of sandostatin on CRF-stimulated secretion of ACTH, beta-lipotropin and beta-endorphin. Horm Metab Res 1991; 23:233-5. [ Links ]
76. Stafford PJ, Kopelman PG, Davidson K, McLoughlin L, White A, Rees LH, et al. The pituitary-adrenal response to CRF-41 is unaltered by intravenous somatostatin in normal subjects. Clin Endocrinol (Oxf) 1989;30:661-6. [ Links ]
77. Tyrrell JB, Lorenzi M, Gerich JE, Forsham PH. Inhibition by somatostatin of ACTH secretion in Nelson's syndrome. J Clin Endocrinol Metab 1975;40:1125-7. [ Links ]
78. Lamberts SW, Uitterlinden P, Klijn JM. The effect of the long-acting somatostatin analogue SMS 201-995 on ACTH secretion in Nelson's syndrome and Cushing's disease. Acta Endocrinol (Copenh) 1989;120:760-6. [ Links ]
79. Julesz J, Laczi F, Janaky T, Laszlo F. Effects of somatostatin and bromocryptine on the plasma ACTH level in bilaterally adrenalectomized patients with Cushing's disease. Endokrinologie 1980;76:68-72. [ Links ]
80. Petrini L, Gasperi M, Pilosu R, Marcello A, Martino E. Long-term treatment of Nelson's syndrome by octreotide: a case report. J Endocrinol Invest 1994;17:135-9. [ Links ]
81. Ambrosi B, Bochicchio D, Fadin C, Colombo P, Faglia G. Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion. J Endocrinol Invest 1990;13:257-61. [ Links ]
82. Stalla GK, Brockmeier SJ, Renner U, Newton C, Buchfelder M, Stalla J, et al. Octreotide exerts different effects in vivo and in vitro in Cushing's disease. Eur J Endocrinol 1994; 130:125-31. [ Links ]
83. Schonbrunn A. Glucocorticoids down-regulate somatostatin receptors on pituitary cells in culture. Endocrinology 1982; 110:1147-54. [ Links ]
84. Kraus J, Woltje M, Hollt V. Regulation of mouse somatostatin receptor type 2 gene expression by glucocorticoids. FEBS Lett 1999;459:200-4. [ Links ]
85. Kraus J, Woltje M, Schonwetter N, Hollt V. Alternative promoter usage and tissue specific expression of the mouse somatostatin receptor 2 gene. FEBS Lett 1998;428:165-70. [ Links ]
86. Bertagna X, Favrod-Coune C, Escourolle H, Beuzeboc P, Christoforov B, Girard F, et al. Suppression of ectopic adrenocorticotropin secretion by the long-acting somatostatin analog octreotide. J Clin Endocrinol Metab 1989;68:988-91. [ Links ]
87. Vignati F, Loli P. Additive effect of ketoconazole and octreotide in the treatment of severe adrenocorticotropin-dependent hypercortisolism. J Clin Endocrinol Metab 1996;81:2885-90. [ Links ]
88. Boerlin V, van der HJ, Beglinger C, Poon KW, Hartmann S, Dutreix C, et al. New insights on SOM230, a universal somatostatin receptor ligand. J Endocrinol Invest 2003; 26(suppl 8):14-6. [ Links ]
89. Lewis I, Bauer W, Albert R, Chandramouli N, Pless J, Weckbecker G, et al. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J Med Chem 2003;46:2334-44. [ Links ]
90. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol 2002; 146:707-16. [ Links ]
91. Hofland LJ, van der HJ, Feelders R, van Aken MO, van Koetsveld PM, Waaijers M, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol 2005;152:645-54. [ Links ]
92. van der HJ, Waaijers M, van Koetsveld PM, Sprij-Mooij D, Feelders RA, Schmid HA, et al. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am J Physiol Endocrinol Metab 2005; 289:E278-87. [ Links ]
93. Strowski MZ, Dashkevicz MP, Parmar RM, Wilkinson H, Kohler M, Schaeffer JM, et al. Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells. Neuroendocrinology 2002;75:339-46. [ Links ]
94. Boscaro M, Petersenn S, Atkinson AB, et al. Pasireotide (SOM-230), the novel multi-ligand somatostatin analogue, is a promising medcal therapy for patients with Cushing's disease: preliminary safety and efficacy results of a phase 2 study. ENDO 2006. (Abstract) [ Links ]
95. Krieger DT, Amorosa L, Linick F. Cyproheptadine-induced remission of Cushing's disease. N Engl J Med 1975;293:893-6. [ Links ]
96. Suda T, Tozawa F, Mouri T, Shibasaki T, Demura H, Shizume K. Effects of cyproheptadine, reserpine, and synthetic corticotropin-releasing factor on pituitary glands from patients with Cushing's disease. J Clin Endocrinol Metab 1983; 56:1094-9. [ Links ]
97. Waveren Hogervorst CO, Koppeschaar HP, Zelissen PM, Lips CJ, Garcia BM. Cortisol secretory patterns in Cushing's disease and response to cyproheptadine treatment. J Clin Endocrinol Metab 1996;81:652-5. [ Links ]
98. Tanakol R, Alagol F, Azizlerli H, Sandalci O, Terzioglu T, Berker F. Cyproheptadine treatment in Cushing's disease. J Endocrinol Invest 1996;19:242-7. [ Links ]
99. Whitehead HM, Beacom R, Sheridan B, Atkinson AB. The effect of cyproheptadine and/or bromocriptine on plasma ACTH levels in patients cured of Cushing's disease by bilateral adrenalectomy. Clin Endocrinol (Oxf) 1990;32:193-201. [ Links ]
100.Sonino N, Boscaro M, Fallo F, Fava GA. Potential therapeutic effects of ritanserin in Cushing's disease. JAMA 1992; 267:1073. [ Links ]
101.Sonino N, Fava GA, Fallo F, Franceschetto A, Belluardo P, Boscaro M. Effect of the serotonin antagonists ritanserin and ketanserin in Cushing's disease. Pituitary 2000;3:55-9. [ Links ]