pituitary-targeted medical therapy of cushing's disease

Review

10.1517/13543780802005780 © 2008 Informa UK Ltd ISSN 1354-3784 669

Endocrine & Metabolic

Pituitary-targetedmedicaltherapyofCushing’sdiseaseKrystallenia I Alexandraki & Ashley B Grossman†

St. Bartholomew’s Hospital, Department of Endocrinology, London EC1A 7BE, UK

Background: The goals of ideal medical therapy for Cushing’s disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current ‘gold standard’ treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found. Objective: To summarise pituitary-targeted medical treatment of Cushing’s disease. Methods: Compounds with neuro-modulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo–pituitary regulation have been investigated. Results: The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushing’s disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently. Conclusion: Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation.

Keywords: bromocriptine, cabergoline, Cushing’s disease, Cushing’s syndrome, medical therapy, pasireotide

Expert Opin. Investig. Drugs (2008) 17(5):669-677

1. Introduction

Cushing’s disease is the most frequent cause of endogenous hypercortisolaemia [1]. The goals of treatment, as in other cases of Cushing’s syndrome, are the normali-sation of cortisol levels with a reversal of clinical symptoms and minimalisation of the long-term consequences of hypercortisolism. Therefore, surgical removal of the adenoma is the current first-line therapeutic approach, which may be followed by radiotherapy in cases of surgical failure [2]. Medical treatment is the next step in Cushing’s disease, but it has not played as major a role as it has done in other secretory pituitary tumours, such as with prolactinomas or acromegaly. However, drugs still need to be considered in the therapeutic approach under certain circumstances. It is essential to treat glucocorticoid excess in order to reverse the uncontrolled metabolic consequences and poor healing in severely affected patients, and this may be required before surgery. In cases in which surgical treat-ment fails, drugs are an alternative as monotherapy or in addition to radiotherapy while awaiting its delayed effects. Finally, medical treatment may be considered in patients who cannot be submitted to surgical procedures because of comorbidities, or who are unwilling to receive other types of treatment.

To be as successful as possible a therapy should target to the aetiology of the disorder. Therefore, the ideal drug for Cushing’s disease should target the source of the problem, the pituitary. This is the case for compounds with neuromodulatory prop-erties, including dopamine agonists and somatostatin (SST) analogues, GABA agonists, serotonin antagonists and drugs targeting different nuclear hormone receptor

1. Introduction

2. Somatostatin analogues

3. Dopaminergic neuromodulators

4. Other neuromodulatory

compounds and ligands

of different nuclear

hormone receptors

5. Conclusions

6. Expert opinion

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.

Pituitary-targetedmedicaltherapyofCushing’sdisease

670 ExpertOpin.Investig.Drugs(2008) 17(5)

ligands involved in hypothalamo–pituitary regulation (e.g., thiazolidinediones and retinoic acid). On the other hand, compounds that target glucocorticoid synthesis (adrenal secretion inhibitors or adrenolytic drugs such as aminoglutethimide, metyrapone, ketoconazole, etomidate, mitotane, trilostane) or function (glucocorticoid antagonists, e.g., mifepristone) have so far been the principal means of control for the deleterious effects of hypercortisolaemia.

This review summarises pituitary-targeted medical treat-ment for Cushing’s disease, highlighting SST analogues and dopamine agonists that are the most promising drugs for the management of this disorder at present.

2. Somatostatinanalogues

SST analogues are presently in frequent use in the treatment of acromegaly [3] and of symptomatic gastroenteropancreatic neuroendocrine tumours [4]. SST is a neuropeptide whose actions are mediated through five different membrane-bound receptors (SSTR1 – 5) [5]. Although the heterogeneity of the studies performed and the differences in methodology have resulted in some contradictory findings, human corticotroph adenomas express multiple SSTR subtypes with subtypes 1, 2 and 5 being the most frequently expressed receptors, and with SSTR5 as the predominant receptor, particularly being more highly expressed compared with SSTR2 [6-8]. Native SST and octreotide inhibit in vitro basal and stimulated adrenocorticotropin (ACTH) secretion in animal-derived and human corticotroph adenoma cell lines [8-12]. In patients with Cushing’s disease most experience has been gained with octreotide, which is predominantly an SSTR2-selective ligand, having only moderate affinity for SSTR5; however, this has been shown to be virtually ineffective in Cushing’s disease, certainly in the great majority of patients [13-16]. Pasireotide, or SOM-230 (Novartis, Basel, Switzerland), is a new multi-ligand SST analogue with high binding affinity to SSTR5, 1, 2 and 3 subtypes [17]. SSTR1, 2, 4 and 5 inhibit cell proliferation via a phosphotyrosine-phosphatase-dependent pathway and interact with the MAPK pathway [5,18], although recent data suggest an additional interaction with a serine-threonine phosphatase [19]. SSTR3 is cytotoxic and causes cell death or apoptosis through a phosphotyrosine-phosphatase-dependent mechanism and activation of p53 and Bax proteins [18]. In vitro studies and animal models implicate both SSTR2 and 5 in the regulation of ACTH release, whereas SSTR2-knockout mice resulted in increased ACTH levels [8-11,20]. Pasireotide inhibited basal and stimulated ACTH release from human ACTH-secreting pituitary adenomas and the murine corticotroph tumour cell line AtT-20 in vitro, but it did not inhibit AtT-20 cell proliferation, nor did it induce apoptosis or inhibit pro-opiomelanocortin (POMC) synthesis, suggesting a possible blockade of ACTH release or an increased breakdown of ACTH [8,9]. The different behaviour of these SST analogues has been extensively studied.

The functional activity of pasireotide compared with octreotide has been found 30-, 11- and 158-fold higher on SSTR 1, 3 and 5 respectively, and ∼ 7-fold lower on SSTR2 [17], being more potent compared with octreotide in inhibiting basal ACTH release [8]. In in vitro studies in both human and AtT-20 cell line ACTH-secreting adenomas, pasireotide suppressed ACTH secretion and corticotrophin-releasing hormone (CRH)-induced ACTH release more than octreotide [8,9]. In the first place, this fact may be attributed to the relatively low levels of SSTR2 mRNA [9]. Furthermore, preincubation with dexamethasone did not affect the ability of pasireotide to inhibit CRH-induced ACTH release, whereas the suppressive action of octreotide was virtually lost [8,9]. SSTR2A and 2B, but not SSTR5, mRNA levels were also significantly suppressed after 24 and 48 h, respectively, of dexamethasone treatment [8]. These findings suggest that glucocorticoids differentially affect SSTR expression [13,15-17,21], with SSTR2 being down-regulated and SSTR5 resistant to corticosteroid modulation. Sensitivity to SST inhibition of ACTH secretion is possibly observed only when the physiological feedback regulation of ACTH release by glucocorticoids fails [22]. This hypothesis is supported by the absence of any effect on ACTH levels after experimental infusions of natural SST or octreotide in normal individuals [23,24], as well as by their suppression in patients with adrenal insufficiency or adrenalectomy [13,25-27]. A direct effect on transcriptional level or on mRNA stability might be also implicated. The regulation of the gene pro-moter sequence of SSTR2 by glucocorticoids has been experimentally demonstrated, but only in the mouse [28]. In rats, pasireotide inhibited both CRH-induced ACTH secretion and corticosterone release, but octreotide inhibited only ACTH release, and to a lesser extent compared to pasireotide [29]. Recently, pasireotide was shown to signifi-cantly suppress cell proliferation (in the range of 10 – 70%) as well as ACTH secretion in human corticotroph tumours [7], but possibly via independent mechanisms, as no correlation was found between these effects. Another mechanism for its action might be an indirect influence of growth by decreasing secretion of pituitary hormones and/or growth factors [30]. Recently, the use of pasireotide in the treatment of Cushing’s disease was investigated in a Phase II, open-label, single-arm, multi-centre pilot study [31]. Twenty-nine patients self-administered subcutaneous pasireotide 600 μg b.i.d. for 15 days. The results are encouraging, demonstrating remission of urinary cortisol to within the normal reference range in 17.2% of patients and a reduction in urinary-free cortisol levels in 75.8%, as well as a reduc-tion in serum cortisol and plasma ACTH levels during this short-term treatment period. Consequently, pasireotide may be considered as a promising novel therapy for Cushing’s disease with both antisecretory and potential antiproliferative properties. It may also be that inhibiting ACTH release and subsequent cortisol levels via SSTR5 will restore SSTR2 expression and hence further aid ACTH inhibition.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.

Alexandraki&Grossman

ExpertOpin.Investig.Drugs(2008) 17(5) 671

3. Dopaminergicneuromodulators

Dopamine is the predominant catecholamine neurotransmitter in the human CNS [32], acting via its receptors (D1 – D5). The D2 receptor is expressed in the anterior and inter-mediate lobe of the pituitary gland [33,34], showing variable and heterogeneous expression in 89% of all types of pituitary tumours [35]. At present, dopamine agonists play a dominant role in the treatment of prolactinomas [36], but D2 receptor expression was also detected in 69% of silent or functioning ACTH-secreting pituitary tumours in one study [35], or in > 75% of such tumours in another study [37]. D2 receptor expression has been correlated with the inhibitory effect of dopamine agonists on ACTH secretion in vitro [37]. However, no specific binding of a dopamine agonist was demonstrated in some corticotroph pituitary tumours [36], and the D2 receptor was not demonstrated by 123I-epidepride and single-photon emission CT imaging in Cushing’s disease or Nelson’s syndrome [38].

The dopamine agonist bromocriptine suppressed ACTH secretion from cultured human pituitary tumour cells [39], and induced apoptosis in AtT-20 cells [40]. Dopaminergic modulation of ACTH secretion has been suggested to occur via regulation of hypothalamic CRH release in addition to direct inhibition of ACTH secretion by the corticotrophs [41-43]. In Cushing’s disease, bromocriptine treatment has shown variable results and its therapeutic potential is considered very limited [41,42,44-46]. In different studies the effectiveness of bromocriptine has varied between 0 and 50%, with normalisation of urinary and/or plasma cortisol in up to 40% of patients in various case reports and small series [41], but probably far less than 10% of unselected patients respond to this therapy [46]. Bromocriptine therapy has been also considered in cases of cyclical Cushing’s disease [47], and its beneficial effect has been suggested to characterise this peculiar disorder. To compound the complexity of its thera-peutic potential, there is also no agreement as to whether a single dose of bromocriptine predicts the long-term efficacy of the drug [46,48]. Notably, it had previously been speculated that a subset of ACTH-producing adenomas in Cushing’s disease of neuro-intermediate lobe origin could be characterised by bromocriptine responsiveness, hyper-prolactinaemia, and relative insensitivity to dexamethasone suppression, and these were thought to be under hypothalamic dopaminergic control [49]. However, this hypothesis was not confirmed by other investigators [50], and responsivity to bromocriptine has been associated with both corticotroph hyperplasia and a normal anterior pituitary gland [51].

Cabergoline has also been investigated and reported to inhibit ACTH secretion in vitro in cases with D2 receptor-positive cells [37]. After 3 months of therapy with cabergoline at doses of 2.5 – 3.5 mg/week, a decrease of > 50% in daily urinary-free cortisol level and a normalisation of cortisol production were observed in 60 and 40% of the patients, respectively. In addition, cabergoline has been successfully

used in a case of pituitary macroadenoma secreting aberrant ACTH [52], and in small series [53] has shown tumour shrinkage and a decrease in cortisol levels. On the other hand, a direct effect on peripheral cortisol secretion has not been identified [54]. The expression of the D2 receptor in 80% of corticotroph pituitary tumours and the effectiveness of cabergoline treatment in the normalisation of cortisol secretion in patients with Cushing’s disease justifies consid-eration of the use of cabergoline for controlling this disorder [37]. The authors believe that the value of dopamine agonists, specifically cabergoline [55,56] as well as their combination with SST receptor ligands such as pasireotide [2,57], should be better evaluated in terms of effectiveness and safety in lage scale trials.

4. Otherneuromodulatorycompoundsandligandsofdifferentnuclearhormonereceptors

Other compounds with neuromodulatory properties have been also investigated in Cushing’s disease, but there has been little evidence of consistent clinical benefit in the limited clinical trials and case reports reported so far.

4.1 CyproheptadineCyproheptadine is a histamine and serotonin antagonist with poor selectivity for receptor subtypes and also possessing anticholinergic activity [58]. It has been assumed that direct serotoninergic CNS control modulates hypothalamic factors that promote ACTH secretion [59], or that it exerts a direct inhibitory effect on CRH and vasopressin secretion from the hypothalamus [60,61]. In clinical studies, the response rate in patients treated with cyproheptadine or the similar meter-goline has been poor, as it has also been to the more selec-tive serotonin antagonists ritanserin and ketanserin [59,62-65]. However, more positive results have been reported in cases with resistant microadenoma [66] or in the presumed ‘hypothalamic’ Cushing’s disease (i.e., no evidence of adenoma on imaging, although this entity may not actually exist) [61]. It was predicted that up to 70% of patients with Cushing’s disease may respond to cyproheptadine treatment [62], but its variability in clinical effects and its sedative side effects, as well as the increase in appetite seen, limit its use [58,64]. It is the authors’ opinion that these compounds may have a direct effect on signalling pathways in the corticotroph independent of any effects on neurotransmitters, and that this form of therapy is too limited by its adverse effetcts to play any role in the modern management of Cushing’s disease.

4.2 SodiumvalproateSodium valproate (valproic acid) inhibits GABA aminotransferase. In patients with epilepsy it was shown to decrease ACTH levels [67,68], possibly inhibiting CRH and hence ACTH release. Placebo-controlled studies of the agent

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



did not support its use as monotherapy [69], although its combination with inhibitors of cortisol secretion appeared to be beneficial [70]. It is possible that it may alter cortisol metabolism, thereby only indirectly affecting ACTH release, and it does not seem to be of value in the therapy of corticotroph tumours.

4.3 RetinoicacidRetinoic acid is an effective compound in reducing ACTH plasma levels and tumour size in animal models [71,72], but no human clinical trials have been performed as yet. Interestingly, retinoic acid was proved to be potentially use-ful in rodent models decreasing corticotroph secretion and proliferation [71], as well as in a canine model of Cushing’s disease producing a significant decrease in ACTH and cortisol levels, amelioration of clinical signs and prolongation of survival, as well as pituitary tumour shrinkage without significant side effects [72]. The effects of retinoic acid in vitro seem to be paralleled by the in vivo effects [72]. AP-1 and Nur77/Nurr1 are positive transcriptional regulators of the ACTH gene in ACTH-secreting cells that are antago-nised by retinoic acid [71,73,74]. The stimulation of POMC by CRH, which is mediated by Nur77 and may also involve AP-1, was inhibited by retinoic acid, and a reduction of the CRH-stimulated POMC transcription was produced by mutation of the NurRE or AP-1-binding sites [71,73,75]. Endogenous production of ACTH was reduced by retinoic acid in AtT-20 tumour cells, but not in normal pituitary cells, suggesting that retinoic acid does not comprise part of the normal physiological feedback mechanism [71]. Genes that have been found to be differentially expressed in pituitary tumours might also be involved in the differential action of retinoic acid [74,76,77]. In addition, retinoic acid inhibits ACTH- and corticosterone-secreting cell proliferation and it is possible that in vivo other pathways independently of AP-1 or Nur77/Nurr1 contribute to this effect [71]. Other beneficial effects of retinoic acid include reduction of adrenal hyperplasia, by direct inhibition of adrenal cell proliferation, reversal of skin atrophy and immunostimulation [78].

4.4 PPAR-gagonistsPPAR-γ agonists (rosiglitazone and pioglitazone) have been suggested to be promising new agents specifically targeting pituitary tumours, based on in vitro and rodent models [79,80]. However, recent small-scale clinical trials have not shown any clear therapeutic effect in Cushing’s disease [81,82]. PPAR-γ belongs to the family of nuclear hormone receptors [83], and ligands for the nuclear receptor PPAR-γ had been shown to induce cell-cycle arrest and apoptosis in corticotropinoma cells, tumour growth arrest in vivo in a nude mouse model, and to inhibit ACTH and corticosterone secretion from tumour cells [80]. Previously, PPAR-γ expres-sion was described in both normal and adenomatous pituitary tissue [79,80,84,85]. A more recent study using more sensitive methodology revealed that PPAR-γ receptor is only

poorly expressed in human pituitary tissue. The authors were unable to detect any specific abnormality of PPAR-γ expression in corticotroph tumours, revealing poor immuno-cytochemical expression in both normal pituitary and pituitary adenomas with only weak cytoplasmic staining [86]. Futhermore, the antiproliferative effects of rosiglitazone were only seen at very high doses and were not blocked by a specific PPAR-γ antagonist [86]. Combining these results with the lack of a consistent effect on ACTH or cortisol levels in normal subjects [87] or patients with Cushing’s disease after short- or long-term administration [81,82,88], it has been suggested that the treatment of pituitary tumours with PPAR-γ agonists is unlikely to be worth pursuing, and any effects of rosiglitazone or pioglitazone are also unlikely to involve the PPAR-γ receptor [86].

5. Conclusions

The ideal medical therapy for Cushing’s disease is far from established. However, many in vitro and in vivo studies as well as clinical trials have concluded that some compounds are not of any benefit, whereas others have some emerging effects that need to be better clarified and investigated. In clinical practice, pasireotide and cabergoline seem the most promising so far. The new chimeric SST–dopamine agonist, dopastatin (Ipsen, Paris, France), developed to treat other types of pituitary tumour, might be also a useful alternative therapy, but there are few data available. Finally, retinoic acid analogues might be a novel field for investigation to treat this pituitary disorder.

6. Expertopinion

An effective medical therapy that targets the pituitary adenoma would be a valuable therapeutic option for the management of Cushing’s disease, but in the presently available therapeutic armamentarium there is no effective medical therapy that directly and reliably targets the ACTH-secreting pituitary adenoma, and thus the underlying cause of the disease. Based on the fact that an abnormal regulatory feedback of ACTH secretion is present in Cushing’s disease and characterises the disorder, studies at the molecular level have investigated abnormalities of the structure or expression of the glucocorticoid receptor, but without evidence of any abnormality [89,90]. On the other hand, it has been suggested by studies in animals that the elevated ACTH plasma concentration might itself inhibit the secretion of ACTH [91,92], independent of steroid feedback, and feedback at the hypothalamic level by ACTH has also been demonstrated in human subjects [93]. Subsequently, it was revealed that ACTH receptor (ACTH-R) was absent in ∼ 70% of the ACTH-secreting tumours studied, but was present in all normal human pituitary specimens [94]. Interestingly, in the ACTH-secreting tumours expressing the ACTH-R, morning plasma ACTH levels were

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



significantly lower compared with those not expressing the ACTH-R. However, it was not clear how ACTH-R signalling might influence ACTH levels, as no clear difference in POMC expression between ACTH-R-positive and -negative ACTH-secreting tumours has been shown. Additionally, cortisol itself may downregulate the ACTH-R. These encouraging preliminary data on abnormalities of molecular signalling in Cushing’s disease may shed light on the mysterious aetiology of those pituitary tumours leading to more effective medical therapies targeting the tumour itself. Although ACTH itself may not be therapeutically useful, an understanding of the deranged feedback may allow for designer drugs to interact with this process.

In addition, a lipophilic nonpeptide corticotropin-releasing hormone type 1 receptor antagonist antalarmin has been found to reduce plasma ACTH and cortisol levels in animal models studies [95]; however, not all studies have confirmed this finding [96]. Further investigation focusing on the specific receptors involved in ACTH production, secretion and release may prove to be of clinical significance.

Furthermore, there are encouraging developments such as the SST analogue pasireotide, which is undergoing Phase II trials, plus preliminary data on the dopamine agonist cabergoline. Perhaps the chimeric SST–dopamine ligand [57] dopastatin will also show therapeutic promise in Cushing’s disease, as well as other novel SSTR ligands [97]. It will also be of considerable interest to see whether retinoic acid analogues may be therapeutically useful, although at present no trial is underway.

Thus, with only few agents available to directly inhibit ACTH release at present, and because Cushing’s disease is the most frequent cause of endogenous hypercortisolaemia, therapy targeting the adrenal remains the mainstay of therapy. Steroidogenesis inhibitors decrease cortisol levels by direct activity at one or more enzymatic steps, but they do not restore normal hypothalamic–pituitary–adrenal axis secretory dynamics, as they do not target the underlying tumour [2,44,98,99]. All these drugs require escalation after an initial low dose to minimise their side effects, whereas frequent monitoring is required to achieve an acceptable clinical and biochemical profile. The inhibition can be complete requiring ‘block-and-replacement’ scheme, or partial. In either case, patients should be well instructed about adrenal insufficiency symptoms or the recurrence of hypercortisolism symptoms. In addition, there may be requirements to increase the dose over time to maintain the desirable cortisol levels, as corticotroph tumours have a

higher than normal set-point for cortisol-negative feedback and ACTH secretion may increase in parallel with the fall in cortisol. Ketoconazole and metyrapone are the most frequently used drugs, and appear more effective and better tolerated than aminoglutethimide. Worldwide experience with both ketoconazole and metyrapone, either alone or in combination, suggests that these agents are the most effective primary treatment for Cushing’s disease. However, the presence of hirsutism frequently precludes metyrapone therapy in women, whereas gynaecomastia or hypogonadism requires caution with the use of ketoconazole therapy in men, and the drug may be hepatotoxic; gastrointestinal symptoms may occur by both compounds in both sexes. The other adrenal inhibitors are now rarely needed; however, etomidate remains an important option when intravenous administration is the only way of treating severely ill patients. In particular, problems associated with the use of mitotane (difficulty in monitoring and adverse effects) determine that its use is confined to the minority of patients who are not responsive or intolerant to ketoconazole and/or metyrapone. On the other hand, it is our opinion that there is little place for aminoglutethimide in the contemporary therapy of Cushing’s disease, whereas trilostane has never been widely used. Interestingly, ketoconazole in combination with pasireotide might be a promising option because they proved to have an additive inhibitory effect on ACTH and apoptosis on mouse corticotroph AtT-20 tumour cells, an effect that was not observed in the combination with octreotide. The authors speculated that ketoconazole treatment resulted in an increase in SSTR3 mRNA with subsequent enhancement of SOM230 activity [100]. Finally, mifepristone has been used in limited cases, but further evaluation of its safety and follow-up methodologies might render this agent a more attractive option; clinical trials in the ectopic ACTH syndrome are underway at present. Nonetheless, if patients remain intolerant or incompletely responsive to medical therapy, it is extremely important to remember that bilateral laparoscopic adrenalectomy will cause immediate remission of hypercortisolaemia when all else fails.

Declarationofinterest

AB Grossman has received lecture fees from and been on the advisory board of Novartis. KI Alexandraki declares no conflicts of interest. No payment was received for preparation of this manuscript.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



BibliographyPapers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

1. Makras P, Toloumis G, Papadogias D, et al. The diagnosis and differential diagnosis of endogenous Cushing’s syndrome. Hormones (Athens) 2006;5:231-50

2. Biller BMK, Grossman AB, Stewart PM, et al. Treatment of ACTH-dependent Cushing’s Syndrome: A Consensus Statement. J Clin Endocrinol Metab 2008;In press

• RecentconsensusregardingthetreatmentofCushing’sdisease.

3. Cozzi R, Montini M, Attanasio R, et al. Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J Clin Endocrinol Metab 2006;91:1397-403

4. Modlin IM, Latich I, Kidd M, et al. Therapeutic options for gastrointestinal carcinoids. Clin Gastroenterol Hepatol 2006;4:526-47

5. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 1999;20:157-98

6. Nielsen S, Mellemkjaer S, Rasmussen LM, et al. Expression of somatostatin receptors on human pituitary adenomas in vivo and ex vivo. J Endocrinol Invest 2001;24:430-7

7. Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab 2006;91:4482-8

• Astudydemonstratingtheantiproliferativeandantisecretoryroleofpasireotidein vitroinhumancorticotrophpituitaryadenomascelllines.

8. van der Hoek J, Waaijers M, van Koetsveld PM, 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

• Thisstudyshowedthedifferentpropertiesandregulationofsomatostatinreceptorsubtypes5and2incorticotrophpituitaryadenomascelllinesin vitro.

9. Hofland LJ, van der Hoek J, Feelders R, 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

• AnotherstudyfromtheRotterdam groupdemonstratingin vitrothedifferentialeffectsofoctreotideandpasireotideincorticotrophpituitaryadenomacelllines.

10. Richardson UI, Schonbrunn A. Inhibition of adrenocorticotropin secretion by somatostatin in pituitary cells in culture. Endocrinology 1981;108:281-90

11. Heisler S, Reisine TD, Hook VY, Axelrod J. Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. Proc Natl Acad Sci USA 1982;79:6502-6

12. Strowski MZ, Dashkevicz MP, Parmar RM, et al. Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells. Neuroendocrinology 2002;75:339-46

13. 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

14. Invitti C, de Martin M, Brunani A, et al. Treatment of Cushing’s syndrome with the long-acting somatostatin analogue SMS 201-995 (sandostatin). Clin Endocrinol (Oxf ) 1990;32:275-81

15. Ambrosi B, Bochicchio D, Fadin C, et al. 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

16. Stalla GK, Brockmeier SJ, Renner U, et al. Octreotide exerts different effects in vivo and in vitro in Cushing’s disease. Eur J Endocrinol 1994;130:125-31

17. Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology 2004;80(Suppl 1):47-50

18. Sharma K, Patel YC, Srikant CB. C-terminal region of human somatostatin receptor 5 is required

for induction of Rb and G1 cell cycle arrest. Mol Endocrinol 1999;13:82-90

19. Grozinsky-Glasberg S, Franchi G, Teng M, et al. Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuroendocrine tumor cell line. Neuroendocrinol 2007 Nov 16 (Epub ahead of print)

• Adetailedanalyisisofthemodeof actionofoctreotideinaneuroendocrinetumourcellline.

20. Viollet C, Vaillend C, Videau C, et al. Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice. Eur J Neurosci 2000;12:3761-70

21. Park S, Kamegai J, Kineman RD. Role of glucocorticoids in the regulation of pituitary somatostatin receptor subtype (sst1-sst5) mRNA levels: evidence for direct and somatostatin-mediated effects. Neuroendocrinol 2003;78:163-75

22. 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

23. Invitti C, Pecori Giraldi F, et al. Effect of sandostatin on CRF-stimulated secretion of ACTH, beta-lipotropin and beta-endorphin. Horm Metab Res 1991;23:233-5

24. Stafford PJ, Kopelman PG, Davidson K, et al. The pituitary-adrenal response to CRF-41 is unaltered by intravenous somatostatin in normal subjects. Clin Endocrinol (Oxf ) 1989;30:661-6

25. Fehm HL, Voigt KH, Lang R, et al. Somatostatin: a potent inhibitor of ACTH-hypersecretion in adrenal insufficiency. Klin Wochenschr 1976;54:173-5

26. Julesz J, Laczi F, Janáky T, László F. Effects of somatostatin and bromocryptine on the plasma ACTH level in bilaterally adrenalectomized patients with Cushing’s disease. Endokrinologie 1980;76:68-72

27. Kelestimur F, Utas C, Ozbakir O, et al. The effects of octreotide in a patient with Nelson’s syndrome. Postgrad Med J 1996;72:53-4

28. Kraus J, Wöltje M, Höllt V. Regulation of mouse somatostatin receptor type 2 gene expression by glucocorticoids. FEBS Lett 1999;459:200-4

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



29. Silva AP, Bethmann K, Raulf F, Schmid HA. Regulation of ghrelin secretion by somatostatin analogs in rats. Eur J Endocrinol 2005;152:887-94

30. Ruan W, Fahlbusch F, Clemmons DR, et al. SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3? Mol Endocrinol 2006;20:426-36

31. Boscaro M, Petersenn S, Atkinson AB, et al. Pasireotide (SOM230), the novel multi-ligand somatostatin analogue, is a promising medical therapy for patients with Cushing’s disease: preliminary safety and efficacy results of a phase II study. ENDO 2006: The Endocrine Society 88th Annual Meeting; 27 June 2006, Boston, USA. 2006; Abstract OR 9-1

• Thesearetheresultsfromthefirst clinicaltrialofpasireotideinpatients withCushing’sdisease.

32. Missale C, Nash SR, Robinson SW, et al. Dopamine receptors: from structure to function. Physiol Rev 1998;78:189-225

33. Caron MG, Beaulieu M, Raymond V, et al. Dopaminergic receptors in the anterior pituitary gland. Correlation of [3H]dihydroergocryptine binding with the dopaminergic control of prolactin release. J Biol Chem 1978;253:2244-53

34. Munemura M, Cote TE, Tsuruta K, et al. The dopamine receptor in the intermediate lobe of the rat pituitary gland: pharmacological characterization. Endocrinology 1980;107:1676-83

35. Stefaneanu L, Kovacs K, Horvath E, et al. Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine 2001;14:329-36

36. Cronin MJ, Cheung CY, Wilson CB, et al. [3H]Spiperone binding to human anterior pituitaries and pituitary adenomas secreting prolactin, growth hormone, and adrenocorticotropic hormone. J Clin Endocrinol Metab 1980;50:387-91

37. Pivonello R, Ferone D, de Herder WW, et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J Clin Endocrinol Metab 2004;89:2452-62

• Theseauthorsinvestigatedthedopamineagonistcabergolineincorticotrophpituitarytumoursinrelationtodopaminereceptorexpression.

38. Pirker W, Riedl M, Luger A, et al. Dopamine D2 receptor imaging in pituitary adenomas using iodine-123-epidepride and SPECT. J Nucl Med 1996;37:1931-7

39. Adams EF, Ashby MJ, Brown SM, et al. Bromocriptine suppresses ACTH secretion from human pituitary tumour cells in culture by a dopaminergic mechanism. Clin Endocrinol (Oxf ) 1981;15:479-84

40. Yin D, Kondo S, Takeuchi J, Morimura T. Induction of apoptosis in murine ACTH-secreting pituitary adenoma cells by bromocriptine. FEBS Lett 1994;339:73-5

41. Miller JW, Crapo L. The medical treatment of Cushing’s syndrome. Endocr Rev 1993;14:443-58

42. Sonino N, Boscaro M. Medical therapy for Cushing’s disease. Endocrinol Metab Clin North Am 1999;28:211-22

43. Ishibashi M, Yamaji T. Direct effects of catecholamines, thyrotropin-releasing hormone, and somatostatin on growth hormone and prolactin secretion from adenomatous and nonadenomatous human pituitary cells in culture. J Clin Invest 1984;73:66-78

44. Nieman LK. Medical therapy of Cushing’s disease. Pituitary 2002;5:77-82

45. Bevan JS, Webster J, Burke CW, Scanlon MF. Dopamine agonists and pituitary tumor shrinkage. Endocr Rev 1992;13:220-40

46. Kawamura M, Nakano T, Miki H, et al. Bromocriptine-responsive Cushing’s disease; clinical and biochemical remission accompanied by amelioration of impaired ocular movement. Intern Med 2007;46:1117-22

47. Adachi M, Takayanagi R, Yanase T, et al. Cyclic Cushing’s disease in long-term remission with a daily low dose of bromocriptine. Intern Med 1996;35:207-11

48. Boscaro M, Benato M, Mantero F. Effect of bromocriptine in pituitary-dependent Cushing’s syndrome. Clin Endocrinol (Oxf ) 1983;19:485-91

49. 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

50. McNicol AM, Teasdale GM, Beastall GH. A study of corticotroph

adenomas in Cushing’s disease: no evidence of intermediate lobe origin. Clin Endocrinol (Oxf ) 1986;24:715-22

51. 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

52. Miyoshi T, Otsuka F, Takeda M, et al. Effect of cabergoline treatment on Cushing’s disease caused by aberrant adrenocorticotropin-secreting macroadenoma. J Endocrinol Invest 2004;27:1055-9

53. Illouz F, Dubois-Ginouves S, Laboureau S, et al. Use of cabergoline in persisting Cushing’s disease. Ann Endocrinol (Paris) 2006;67:353-6

54. Pivonello R, Ferone D, De Herder WW, et al. Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors. J Clin Endocrinol Metab 2004;89:4493-502

55. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 2007;356:39-46

56. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29-38

57. Gruszka A, Ren SG, Dong J, et al. Regulation of growth hormone and prolactin gene expression and secretion by chimeric somatostatin-dopamine molecules. Endocrinology 2007;148:6107-14

• Oneofthefewstudiesofthenewchimericsomatostatin-dopaminemolecule.

58. Krieger DT, Amorosa L, Linick F. Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med 1975;293:893-6

59. Suda T, Tozawa F, Mouri T, et al. 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

60. van Waveren Hogervorst CO, Koppeschaar HP, Zelissen PM, et al. Cortisol secretory patterns in Cushing’s disease and response to cyproheptadine treatment. J Clin Endocrinol Metab 1996;81:652-5

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



61. Tomita A, Suzuki S, Hara I, et al. Follow-up study on treatment in 27 patients with Cushing’s disease: adrenalectomy, transsphenoidal adenomectomy and medical treatment. Endocrinol Jpn 1981;28:197-205

62. Ambrosi B, Gaggini M, Secchi F, Faglia G. Lack of effect of antiserotoninergic and/or dopaminergic treatment in patients with pituitary-dependent Cushing’s syndrome. Horm Metab Res 1979;11:318-9

63. Cavagnini F, Raggi U, Micossi P, et al. Effect of an antiserotoninergic drug, metergoline, on the ACTH and cortisol response to insulin hypoglycemia and lysine-vasopressin in man. J Clin Endocrinol Metab 1976;43:306-12

64. Sonino N, Fava GA, Fallo F, et al. Effect of the serotonin antagonists ritanserin and ketanserin in Cushing’s disease. Pituitary 2000;3:55-9

65. Tanakol R, Alagöl F, Azizlerli H, et al. Cyproheptadine treatment in Cushing’s disease. J Endocrinol Invest 1996;19:242-7

66. 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

67. Koppeschaar HP, Croughs RJ, Thijssen JH, Schwarz F. Sodium valproate and cyproheptadine may independently induce a remission in the same patient with Cushing’s disease. Acta Endocrinol (Copenh) 1983;104:160-3

68. Beckers A, Stevenaert A, Pirens G, et al. Cyclical Cushing’s disease and its successful control under sodium valproate. J Endocrinol Invest 1990;13:923-9

69. Colao A, Pivonello R, Tripodi FS, et al. Failure of long-term therapy with sodium valproate in Cushing’s disease. J Endocrinol Invest 1997;20:387-92

70. Nussey SS, Price P, Jenkins JS, et al. The combined use of sodium valproate and metyrapone in the treatment of Cushing’s syndrome. Clin Endocrinol (Oxf ) 1988;28:373-80

71. Páez-Pereda M, Kovalovsky D, Hopfner U, et al. Retinoic acid prevents experimental Cushing syndrome. J Clin Invest 2001;108:1123-31

72. Castillo V, Giacomini D, Páez-Pereda M, et al. Retinoic acid as a novel medical therapy for Cushing’s disease in dogs. Endocrinology 2006;147:4438-44

• Thisstudydemonstratedaclear beneficialroleforretinoicacidin canineCushing’sdisease.

73. Philips A, Lesage S, Gingras R, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 1997;17:5946-51

74. Tran P, Zhang XK, Salbert G, et al. COUP orphan receptors are negative regulators of retinoic acid response pathways. Mol Cell Biol 1992;12:4666-76

75. Boutillier AL, Monnier D, Lorang D, et al. Corticotropin-releasing hormone stimulates proopiomelanocortin transcription by cFos-dependent and -independent pathways: characterization of an AP1 site in exon 1. Mol Endocrinol 1995;9:745-55

76. Kliewer SA, Umesono K, Heyman RA, et al. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling. Proc Natl Acad Sci USA 1992;89:1448-52

77. Cooney AJ, Leng X, Tsai SY, et al. Multiple mechanisms of chicken ovalbumin upstream promoter transcription factor-dependent repression of transactivation by the vitamin D, thyroid hormone, and retinoic acid receptors. J Biol Chem 1993;268:4152-60

78. Schwartz E, Mezick JA, Gendimenico GJ, Kligman LH. In vivo prevention of corticosteroid-induced skin atrophy by tretinoin in the hairless mouse is accompanied by modulation of collagen, glycosaminoglycans, and fibronectin. J Invest Dermatol 1994;102:241-6

79. Heaney AP, Fernando M, Melmed S. PPAR-gamma receptor ligands: novel therapy for pituitary adenomas. J Clin Invest 2003;111:1381-8

80. 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

81. Ambrosi B, Dall’Asta C, Cannavo S, et al. Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing’s disease. Eur J Endocrinol 2004;151:173-8

82. 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

83. Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors:

a nuclear receptor signaling pathway in lipid physiology. Ann Rev Cell Dev Biol 1996;12:335-63

84. Bogazzi F, Russo D, Locci MT, et al. Peroxisome proliferator-activated receptor (PPAR)gamma is highly expressed in normal human pituitary gland. J Endocrinol Invest 2005;28:899-904

85. Winczyk K, Pawlikowski M. Immunohistochemical detection of PPARgamma receptors in the human pituitary adenomas: correlation with PCNA. Folia Histochem Cytobiol 2005;43:137-41

86. Emery MN, Leontiou C, Bonner SE, et al. PPAR-gamma expression in pituitary tumours and the functional activity of the glitazones: evidence that any anti-proliferative effect of the glitazones is independent of the PPAR-gamma receptor. Clin Endocrinol (Oxf ) 2006;65:389-95

• EvidenceispresentedthatanyapparentantiproliferativeeffectofrosiglitazoneinCushing’sdiseasemaynotoccurviathePPAR-gammaReceptor.

87. Catrina SB, Virtanen K, Hällsten K, et al. Effect of rosiglitazone on early-morning plasma cortisol levels. Neuro Endocrinol Lett 2005;26:763-4

88. Giraldi FP, Scaroni C, Arvat E, et al. Effect of protracted treatment with rosiglitazone, a PPARgamma agonist, in patients with Cushing’s disease. Clin Endocrinol (Oxf ) 2006;64:219-24

89. Dahia PL, Honegger J, Reincke M, et al. Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors. J Clin Endocrinol Metab 1997;82:1088-93

90. Antonini SR, Latronico AC, Elias LL, et al. Glucocorticoid receptor gene polymorphisms in ACTH-secreting pituitary tumours. Clin Endocrinol (Oxf ) 2002;57:657-62

91. Kitay JI, Holub DA, Jailer JW. Inhibition of pituitary ACTH release;an extra-adrenal action of exogenous ACTH. Endocrinology 1959;64:475-82

92. Hodges JR, Vernikos J. Circulating corticotrophin in normal and adrenalectomized rats after stress. Acta Endocrinol (Copenh) 1959;30:188-96

93. Suda T, Tomori N, Yajima F, et al. A short negative feedback mechanism regulating corticotropin-releasing hormone release. J Clin Endocrinol Metab 1987;64:909-13

94. Morris DG, Kola B, Borboli N, et al. Identification of adrenocorticotropin

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.



receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas. J Clin Endocrinol Metab 2003;88:6080-7

• ThisstudyshowedthepresenceoftheACTHreceptorexpressionincorticotrophsandtheirrelativelossinCushing’sdiseasetumours.

95. Habib KE, Weld KP, Rice KC, et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci USA 2000;97:6079-84

96. Holsboer F, Ising M. Central CRH system in depression and anxiety – Evidence from clinical studies with CRH1; receptor antagonists. Eur J Pharmacol 2008

97. Kronenberg HM, Melmed S, Polonsky KS, Larsen PR. Williams Textbook of Endocrinology. Canada: Saunders Elsevier, 2007; 222:Figure 8-53

98. Morris D, Grossman A. The medical management of Cushing’s syndrome. Ann NY Acad Sci 2002;970:119-33

99. Gross BA, Mindea SA, Pick AJ, et al. Medical management of Cushing disease. Neurosurg Focus 2007;23:E10

100. Feelders RA, van der Hock J, Waaijers M, et al. Medical treatment of Cushing’s disease: ketoconazole induces apoptosis of corticotroph tumor cells which is potentiated by the new somatostatin analogue SOM230. In: ENDO 2006: The Endocrine Society’s 88th Annual Meeting, 24 – 27 June 2006,

Boston, MA. 2006; P2-733 [Abstract]

AffiliationKrystallenia I Alexandraki & Ashley B Grossman†

†Author for correspondenceProfessor of Neuroendocrinology St. Bartholomew’s Hospital, Ashley Grossman FMedSci, London EC1A 7BE, UK Tel: +44 207 6018343; Fax: +44 207 6018505; E-mail: [email protected]

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Wat

erlo

o on

10/

31/1

4Fo

r pe

rson

al u

se o

nly.

pituitary-targeted medical therapy of cushing's disease

Documents