Somatostatin and dopamine receptors as targets for medical

12 Pages·2009·0.25 MB·English

RevEndocrMetabDisord(2009)10:91–102
DOI10.1007/s11154-008-9082-4
Somatostatin and dopamine receptors as targets for medical
’
treatment of Cushing s Syndrome
C. de Bruin&R. A. Feelders&S. W. J. Lamberts&
L. J. Hofland
Publishedonline:19July2008
#TheAuthor(s)2008
Abstract Somatostatin (SS) and dopamine (DA) receptors effectively. A recent study showed that D receptors are
2
are widely expressed in neuroendocrine tumours that cause alsosignificantlyexpressedinthemajorityofEASandthat
Cushing’s Syndrome (CS). Increasing knowledge of spe- cabergolinemay decrease cortisol levelsin subsets ofthese
cific subtype expression within these tumours and the patients.Inboth normaladrenaltissue aswellasinadrenal
ability to target these receptor subtypes with high-affinity adenomas and carcinomas that cause CS, sst and DA
compounds,hasdriventhesearchfornewSS-orDA-based receptor expression has been demonstrated. Although
medicaltherapiesforthevariousformsofCS.InCushing’s selected cases of adrenal CS may benefit from sst or DA-
disease, corticotroph adenomas mainly express dopamine targeted treatment, its total contribution to the treatment of
receptorsubtype2(D )andsomatostatinreceptorsubtype5 these patients is likely to be low as surgery is effective in
2
(sst ), whereas sst is expressed at lower levels. Activation most cases.
5 2
of these receptors can inhibit ACTH-release in primary
cultured corticotroph adenomas and compounds that target Keywords Corticotrophadenoma.Cushing’sdisease.
either sst (pasireotide, or SOM230) or D (cabergoline) ACTH.Cortisol.Pituitary.Adrenal
5 2
have shown significant efficacy in subsets of patients in
recent clinical studies. Combination therapy, either by
administration of both types of compounds separately or 1 Introduction
by treatment with novel somatostatin–dopamine chimeric
molecules (e.g. BIM-23A760), appears to be a promising Cushing’s syndrome (CS) is a severe endocrine condition,
approach in this respect. In selected cases of Ectopic in which chronic systemic hypercortisolism leads to a
ACTH-producing Syndrome (EAS), the sst -preferring variety of signs and symptoms such as centripetal obesity,
2
compound octreotide is able to reduce cortisol levels peripheral muscle wasting, hypertension, diabetes mellitus,
osteoporosis and psychiatric disturbances [1]. In untreated
Disclosurestatement:Theauthorsofthismanuscripthavenothingto cases, morbidity and mortality rates are significantly
disclose. elevated compared to those in normal subjects [2]. Around
: : :
C.deBruin(*) R.A.Feelders S.W.J.Lamberts 70% of endogenous cases of CS are due to a pituitary
L.J.Hofland ACTH-producing basophilic adenoma (Cushing’s disease,
DepartmentofInternalMedicine,ErasmusMedicalCenter,
CD), around 15% are due to an adrenal cortisol-producing
roomEe569‘sGravendijkwal230,
benign or malignant tumour and the remaining cases are
3015,CERotterdam,TheNetherlands
e-mail:[email protected] generally due to ectopic ACTH-secretion from a neuro-
endocrine tumour elsewhere in the body [3]. First-line
R.A.Feelders
e-mail:[email protected] treatmentofCushing’ssyndrome,regardlessofitsorigin,is
usually surgery with the attempt to radically remove the
S.W.J.Lamberts
e-mail:[email protected] ACTH- or cortisol-producing tumour.
However,notallcasesofCSarewellmanagedbysurgery
L.J.Hofland
e-mail:[email protected] alone. For patients with CD it is known that long-term
92 RevEndocrMetabDisord(2009)10:91–102
remissionratesaftertranssphenoidaladenomectomydecrease modulatoryagentsthatcaninhibitACTH-hypersecretionat
to 50–80% with longer follow-up time [4]. A second the level of the pituitary. Important new insights in SS and
transsphenoidal surgery in patients with a recurrence of CD DA receptor physiology, combined with the recent avail-
is known to have significantly lower success rates than the abilityofmoreselectiveSSandDA-agonists,haveemerged
primary surgery [5, 6]. Other treatment options for patients andarethetopicofthecurrentreview.
with persistent or recurrent CD include conventional
radiotherapy or gamma knife surgery. Both are effective at
reducing ACTH hypersecretion in the majority of patients, 2 Somatostatin and dopamine receptors
but have a slow onset of action, with an average time until
remission of 9–24 months [7]. In addition, radiotherapy is 2.1 Somatostatin and dopamine receptors
accompanied by a significant risk of inducing secondary
pituitary dysfunction, cranial nerve damage or secondary Somatostatin (SS) is a 14 amino acid-long cyclic peptide
brain tumours [7–9]. As a definitive cure, patients with CD that is widely distributed throughout the human body. Its
can undergo bilateral adrenalectomy, but this does have functions vary from increasing gastro-intestinal motility to
important implications in terms of lifelong dependence on neurotransmission within the central nervous system,
adrenal hormone replacement therapy and risk of future mediating immune responses and inhibition of hormone
Addison crises, while there is risk of the development of release [15, 16]. SS exerts its functions by binding to all
Nelson’s syndrome. five somatostatin receptor subtypes (sst1–5), which belong
Similarly, in some patients with the ectopic ACTH- tothefamilyofG-protein coupledreceptors (GPCRs)[17].
producing syndrome (EAS), the primary neuro-endocrine Dopamine (DA) is a catecholamine with an equally wide
tumour cannot be localized despite extensive radiological range of functions including neurotransmission, control of
and nuclear imaging, whereas in other EAS patients, vascular tone, renal function and hormone secretion [18].
tumour resection can be irradical [10, 11]. Both types of AlsoforDAreceptors, fivesubtypesareknown(D1–5)that
EAS patients will benefit from bilateral adrenalectomy but belong to the GPCR family, which are further classified
with the same disadvantages as described above for CD. into D -like (D , D ) and D -like (D , D , D ). D -like
1 1 5 2 2 3 4 1
Also, some patients with CS due to a malignant adrenal receptors generally mediate stimulatory functions, whereas
tumour have advanced disease at the time of presentation mostD -likereceptorsareassociatedwithinhibition. Upon
2
and in these cases complete removal of the cortisol- bindingofSSorDAtotheirrespectivereceptorsexpressed
producing adrenal tumour will not be possible. on the plasma membrane of target cells, multiple cellular
For the above reasons there is a clear rationale behind effector systems can be activated, which include inhibition
thesearch for an effectivemedicaltherapyfor all causes of of Ca2+-influx, inhibition of adenylyl cyclase activity or
CS. A great number of drugs that act at the level of the stimulationofphosphotyrosinephosphatases[17,18].Both
pituitary, the adrenals or the glucocorticoid receptor itself, sst and DA receptors are abundantly expressed in the
have been evaluated in the past decades with generally human neuro-endocrine system and in the tumours that are
modest and variable results [12]. Most compounds either derivedfromit[19,20].MostoftheinvivofunctionsofSS
showlimitedefficacyorareassociatedwithserioustoxicity and DA (D -like) receptors are inhibitory and, therefore,
2
andadverseevents.Forinstance,thesteroidogenicinhibitor targeting these receptors with their natural agonists or
ketoconazole has been shown to effectively decrease syntheticallyderivedanalogshasprovidedopportunitiesfor
cortisol levels in about 50% of patients [13], but often medical therapy of various neuro-endocrine disorders.
causesconsiderablegastro-intestinalsideeffectsandcarries
a serious risk of medication-induced hepatitis, which limits 2.2 SS analogs and DA agonists
its use as a long-term monotherapy in CD patients [14].
Similarly, metyrapone can be effective in reducing cortisol Soon after its discovery in 1972, somatostatin was known
levels in patients with CS, but can cause hypertension and tobeamajorregulatorofGHreleasefromthepituitaryand
hypokalemia. Blockade of the glucocorticoid receptor with was therefore of interest for the potential treatment of
mifepristone (RU-486) can improve symptoms of CS, but acromegaly [21]. One of the characteristics of native SS,
the absence of a suitable biochemical parameter to however, is its very short half-life in the circulation, which
monitor treatment efficacy makes dose titration difficult isapproximately3min[22].Forthatreason,theproduction
and this can result in severe adrenal insufficiency in some ofsyntheticSSanalogswithasignificantlylongerhalf-life,
patients. was a major step forward in the treatment of this disorder.
Inrecentyears,however,researchintomedicaltherapies The first stable SS-analog produced was Octreotide (SMS
forCShasalsofocussedontheuseofbothsomatostatin(SS) 201–995), which has a half life of approximately 120 min
and dopamine (DA) agonists. These are regarded as neuro- aftersubcutaneousadministrationandwasshowntoreduce
RevEndocrMetabDisord(2009)10:91–102 93
GH and IGF-1 levels in approximately two thirds of neuro-endocrine disorders in which D expression plays
2
acromegalic patients [23, 24]. an imminent role.
Another important step in the development of SS
analogs was the discovery of the 5 somatostatin receptor 2.3 Chimeric somatostatin–dopamine compounds
subtypes in the 1990s. These findings clarified indirectly
that the two available SS-analogs at the time, Octreotide The fact that many neuro-endocrine cells co-express both
and its long-acting form Lanreotide, bind preferentially to sst and DA receptors, has driven the hypothesis that these
the sst , but only modestly to sst or any of the other receptors may work synergistically. In 2000, Rocheville et
2 5
subtypes. Native SS, on the other hand, binds with high al. [29] published an important paper on the functional
affinity to all of its receptors (sst1–5). In the subsequent heterodimerization of sst5 and D2 receptors in stably
years, evidence grew that not all neuro-endocrine tumours transfected CHO-K1 cells, which resulted in overall
expressed receptor subtypes in a similar manner. Whereas enhanced biological potency. Based on these observations,
growth-hormone producing adenomas generally expressed newchimericmoleculeshavebeensynthesizedthatcontain
high levels of sst , other adenomas, such as corticotroph structural elements of both SS and DA compounds and
2
adenomas expressed considerably lower levels of sst (see therefore bind with high affinity to both sst and DA
2
Fig.1).Theconceptthatdifferentneuro-endocrinetumours receptor subtypes. By binding to the two different recep-
with important differences in sst expression profiles would tors, these hybrid molecules may draw the receptors
require specific sst-targeting analogs, sparked the interest together in a spatial manner. This can lead to enhanced
for the development of new types of SS-analogs that potency of the chimeric compound, compared to activation
displayed high affinity for one or more SS receptor by two separate DA or SS analogs [30].
subtypes, see Table 1. One example of such a compound
is BIM-23244, which is a bispecific SS-analog with high
affinity for both sst and sst . In GH-producing adenomas 3 Cushing’s disease (CD)
2 5
thatwereonlypartially responsivetoOctreotide,thisnovel
bispecific compound suppressed GH-production in vitro 3.1 Somatostatin analogs in Cushing’s disease
significantly more effective than Octreotide, probably
through co-activation of sst receptors [25]. Another 3.1.1 Sst expression in normal corticotroph cells
5
example is Pasireotide (SOM230), which is a multi-ligand
SS-analog with high binding affinity for the sst , sst , sst WhereastheroleofhypothalamicSSasaprincipalregulator
1 2 3
and sst with IC values of 9.3, 1.0, 1.5 and 0.16 nM, ofpituitaryGH-releasehasbeenfirmlyestablished[31], the
5 50
respectively, see Table 1 [26]. Its binding profile, which effect of SS on ACTH release by the anterior pituitary
includes high sst -affinity, makes it a promising new drug gland has been less clear. Rat pituitary corticotrophs are
5
in the treatment of a number of neuro-endocrine tumours, known to express multiple sst, including sst and sst [32–
2 5
including CD (see below). 34], but treatment of cultured rat corticotrophs with SS-14
Dopamine agonists are an important class of drugs with does not result in inhibition of ACTH-release [35, 36]. On
a broad range of therapeutic indications, including neuro- the other hand, when rat pituitary cells are cultured in
logical disorders (Parkinson’s disease), cardiovascular glucocorticoid-free media, SS-14 is able to decrease
dysfunction and neuro-endocrine disorders. They can be ACTH-release [37]. In agreement with these findings,
classified into either non-ergot (e.g. quinagolide) or ergot- infusion of SS-14 or Octreotide does not alter ACTH-
derived (e.g. bromocriptine, cabergoline, pergolide). release in normal subjects [38–41], whereas both of these
Bromocriptine has been known for many years to effec- compounds can acutely decrease plasma ACTH levels in
tively inhibit prolactin (PRL) release in the majority of conditions of hypocortisolemia such as untreated Addison
prolactinomas [27]. With increasing knowledge on DA disease [42]. These observations suggest that the presence
receptors, it also became evident that selectivity of of glucocorticoids reduces the inhibitory effects of native
dopaminergic compounds for DA receptor subtypes was somatostatin and traditional SS analogs on ACTH release.
of great importance for their overall efficacy and safety
profile. In comparison with bromocriptine, cabergoline has 3.1.2 In vitro studies with SS-analogs in corticotroph cell
a longer plasma half-life, binds with a higher affinity to lines and adenomas
the D receptor, is better tolerated by patients and can
2
induce normalization in patients with hyperprolactinemia The only available ACTH producing cell line from
that are proven to be resistant to bromocriptine therapy corticotrophoriginisthemurineAtT20cellline.Anumber
[28]. The fulfilment of these criteria makes cabergoline ofstudieshaveindicatedthatinthesecellssst and sst are
2 5
a promising drug for the treatment of a number of principallyinvolvedinregulationofACTHreleaseandthat
94 RevEndocrMetabDisord(2009)10:91–102
Fig. 1 Overview of sst expres-
Somatotroph adenomas Corticotroph adenomas
sioninsevenGH-producing
(somatotroph)andsixACTH-
producing(corticotroph)human 400 sst1 400 sst1
pituitaryadenomas.Notethe
differenceinscaleofthey-axis 300 300
betweensst1–3andsst5. rt
Somatotrophadenomashave p
abundantexpressionofbothsst2 /h1200 200
andsst5(leftcolumn),whereas st
corticotrophadenomasexpress s100 100
sst atsimilarlevelsbuthavea
5
significantlylowerexpressionof
nd nd nd nd nd nd nd nd nd nd
sst (rightcolumn).Valuesare 0 0
2 1 2 3 4 5 6 7 1 2 3 4 5 6
expressedascopynumbers
relativetothatofthereference sst sst
genehprt.N.d.Notdetectable 400 2 400 2
(Adaptedfrom[51,115])
300 300
t
r
p
h
/2200 200
t
s
s
100 100
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6
400 sst3 400 sst3
300 300
t
r
p
h200 200
/3
t
s
s
100 100
nd nd nd nd nd nd nd nd
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6
sst5 3000 sst5
3000
2000
2000 1500
1500
t
r
p
h
/51000 1000
t
s
s
500 500
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6
Adenoma no. Adenoma no.
selective agonists that target these subtypes effectively Octreotide, but not Pasireotide, lost most of its ACTH
inhibit ACTH secretion [43–47]. More recently it was inhibiting potential after glucocorticoid pre-treatment [48].
foundthatespeciallysst playedacrucialroleinregulating These data are in line with the original observations that
5
ACTH release in these cells and that sst -targeting glucocorticoids downregulate the total number of SS
5
agonistsweremoreeffectivethansst -agonistsininhibiting binding sites in cultured pituitary cells [49]. Evidence for
2
ACTH release [48]. Interestingly, pre-incubation with abrogation of sst -mediated effects by glucocorticoids
2
dexamethasone decreased the expression of sst in these has also been provided by Stalla et al. [50]. They found
2
cells, but not of sst , and in line with these findings that Octreotide decreased ACTH levels in corticotroph
5
RevEndocrMetabDisord(2009)10:91–102 95
Table1 Bindingaffinities(IC )ofSS-analogsandDA-agonistsmentionedinthisreview
50
Compound sst sst sst sst sst D D D
1 2 3 4 5 2Short 2Long 4
SS-analogs
Somatostatin(SS-14) 0.93 0.15 0.56 1.50 0.29
Octreotide 280 0.38 7.10 >1,000 6.30
Pasireotide(SOM230) 9.3 1.0 1.5 >1,000 0.16
BIM-23244 >1000 0.3 133 >1,000 0.7
Dopamineagonists
Dopamine 350 320 100
Bromocriptine 4.5 3.9 >1000
Cabergoline 0.53 0.41 81
Dopastatinchimeras
BIM-23A760 622 0.03 160 >1,000 42 15a
References:SS-bindingdata[26,112],DA-bindingdata[113],BIM-analogbindingdata[25,114]
aIC forD receptor(bothshortandlongisoform)
50 2
adenomas in vitro, but not in CD patients in vivo. How- 3.1.3 Clinical studies with SS-analogs in CD
ever, when these corticotroph adenoma cells in vitro were
pre-treated with the glucocorticoid hydrocortisone, the EarlystudiesshowedthatinpatientswithCD,Octreotideis
ACTH inhibiting effects of Octreotide were abolished in not able to effectively reduce ACTH secretion and hence
one of the cultures. Given the generalized state of hyper- cortisol levels [50, 54, 55]. In contrast, several smaller
cortisolisminCDpatientsandtherelativeresistanceofsst to studies and case reports found that patients with Nelson
5
glucocorticoid-induced down-regulation compared to sst , syndrome, i.e. an expanding ACTH-producing pituitary
2
SS-analogs with high sst affinity are of great interest in the adenoma after bilateral adrenalectomy, did respond to
5
development of new medical therapies for CD. Octreotide with reductions in ACTH [54, 56–58]. This
In 2005 and 2006, two studies were published that inde- differenceisreadilyexplainedbythedifferencesinaverage
pendently investigated sst expression in human corticotroph circulating cortisol levels in both disease states and the
adenoma tissues, obtained at the time of transsphenoidal effects of glucocorticoid-induced down-regulation of sst
2
surgery. In the first study, Hofland et al. [51] showed by receptors, as mentioned earlier [59].
quantitative PCR that sst was highly expressed in 6/6 Since then, few clinical studies have been reported that
5
adenomas, whereas sst were expressed at much lower examined SS-analog therapy in CD, until some important
1,2,3,4
levels. In concordance with this, functional studies in five new insights developed. It was foremost the discovery that
additional adenomas demonstrated overall superior ACTH sst was highly expressed in the majority of human
5
inhibition by Pasireotide (10 nM) compared to Octreotide corticotroph adenomas, which made the novel multi-ligand
(10 nM) after 72 h. SS-analog Pasireotide an interesting compound to evaluate
In the second study, Batista et al. reported on a series of inpatientswithCD,duetoitssubnanomolarsst -affinity.A
5
13corticotrophadenomasderivedfrombothadult(n=7)and phase II multi-center clinical study was performed in 21
pediatric (n=6) CD patients [52]. In this study, quantitative patients with de novo or recurrent CD [60]. Patients were
PCR demonstrated the expression of subtypes 1, 2, 4 and 5 treated with SOM230 600 μg twice daily over a 15-day
in these adenomas, while at immunohistochemistry expres- period.Primaryendpointwasnormalizationof24-hurinary
sion of all subtypes was found. Both of these methods free cortisol (UFC) levels. Preliminary results of this study
showedthehighestexpressionofthesst subtype.Sixofthe showedthatoutof21includedpatients,four(19%)obtained
5
adenomaswereculturedinvitroandtreatedwithPasireotide. complete UFC normalization and another five (24%) had a
In 6/6 adenomas Pasireotide significantly decreased cellular significant decrease in UFC. Overall, Pasireotide was well
proliferationrates(range10–70%)asmeasuredbyuptakeof toleratedinthe2×600μgdose,exceptforsomemildgastro-
fluorescent vital stain and in 5/6 a significant decrease in intestinal side effects such as nausea, abdominal pain and
ACTHproductionwasobserved(range23–56%)atdosesof loosestoolsordiarrhoea.AmajorsideeffectofPasireotide,
1 to 10 nM after 48–96 h. Furthermore, a dissociation was however,whichwasalreadyknownfrompreviousstudiesin
seeninsomeoftheadenomasbetweentheanti-secretoryand acromegalic patients, was an overall increase in blood
anti-proliferative effectsofPasireotide,similarlytowhathas glucose levels. Worsening of glycaemic control was ob-
been described previously for GH-producing adenomas in served in almost all participating patients in this study, but
response to SS-analog treatment [53]. wasoftenatransienteffect.Insomecases,however,theuse
96 RevEndocrMetabDisord(2009)10:91–102
of subcutaneous insulin administration was required and in adenomas arising from the intermediate lobe may have
onecasethestudydrugwaswithdrawn. different characteristics than those arising from the anterior
Based on the current data, Pasireotide appears to be a lobe, although much controversy exists around this subject
potent cortisol-lowering drug in almost half of CD patients [67, 68].
and is well tolerated. A major advantage of Pasireotide
compared to Octreotide is its longer plasma half-life in the 3.2.2 In vitro studies with DA agonists in corticotroph cell
circulation, approximately 12 versus 2 h [61]. Pasireotide lines and adenomas
treatment does carry the risk of significant hyperglycemia,
however, in a substantial number of patients. A new Two reports have been published on the use of dopamine
challenge would be to identify subgroups of CD patients agonistsinthemurinecorticotrophcelllineAtT20,butthese
who are likely to benefit from sst -mediated (Pasireotide) have produced conflicting results. Farrell et al. found that
5
therapyandatthesametimedonotsufferexcessivelyfrom treatment with the dopamine agonist bromocriptine did not
increases in blood glucose levels. reducePOMCmRNAexpressioninthesecells,whereasYin
Anotherpotentialproblemmightbeanydirect effectsof et al. did show that bromocriptine inhibited proliferation of
Pasireotide therapy on GH and IGF-1evels in CD patients. thesecellswithinductionofapoptosis[69,70].Theobserved
It is well known that Pasireotide, via sst receptor difference may be due to the fact that in the second study
5
activation, directly decreases GH release and hence IGF-1 treatmentwithbromocriptinewassignificantlylongerthanin
levelsinpatientswithacromegaly.Whetherthisalsooccurs the first study (72 vs. 24 h, respectively).
in normal subjects without GH/IGF-1 axis overactivation, In 2004, Pivonello et al. [71] investigated DA receptor
has not been reported. Normal somatotrophs, however, expression in a series of 20 human corticotroph adenomas.
express sst in significant numbers and in normal rats, They showed that the majority (80%) of these adenomas
5
primates and dogs Pasireotide has been shown to signifi- express the D receptor as demonstrated by immunohisto-
2
cantly decrease GH and IGF-1 levels [62]. In patients with chemistry (IHC), receptor-ligand binding and RT-PCR. Of
CD, sustained hypercortisolism by itself causes a state of these D -positive adenomas, approximately 40% expressed
2
relative growth-hormone deficiency and therefore these the D long isoform, 20% D short and 40% expressed
2 2
patients may be at greater risk to become GH-deficient. bothisoforms.D wasexpressedin20%ofcases,whereas
4
Current and future clinical studies with Pasireotide in CD D , D and D expression was not observed. Functional
1 3 5
patientsshouldthereforeincludecarefulinvestigationofthe studiesinvitrocorrelatedverywellwiththeD expression
2
effects on the GH/IGF-1 axis. data: adenomas high in D expression responded well to
2
either bromocriptine or cabergoline therapy with inhibi-
3.2 Dopamine agonists in Cushing’s disease tion of ACTH release by 43% to 60%, whereas D -
2
negative adenomas failed to respond. The D - expression
2
3.2.1 DA receptor expression in normal corticotrophs data reported in this study are similar to those described
by an earlier paper, where 11/16 (69%) of corticotroph
Inhumans,nofirmdataexistwhetherornotACTHreleaseis adenomas, both functional and silent, expressed D
2
directly regulated by DA receptors in normal corticotroph receptors as demonstrated by in situ hybridisation and
cells. In rats it is known that the intermediate lobe in the immunohistochemistry [72].
pituitaryisundertonicinhibitorycontrolfromdopaminergic
neurons from the hypothalamus [63–65]. The predominant 3.2.3 Clinical studies with DA agonists in CD
cell type in the intermediate lobe is the melanotroph, which
producespro-opiomelanocortin(POMC).Intheintermediate The DA agonist bromocriptine has been widely evaluated
lobe POMC is processed into α-melanocyte stimulating for its potential use in human corticotroph adenomas.
hormone (α-MSH) and corticotropin-like intermediate lobe Overall, results of these studies have been variable.
peptide(CLIP).ThisisdifferentfromthePOMC-processing Although initial reductions in ACTH levels are evident in
inanteriorcorticotrophcells,whichmainlyresultsinACTH. almost half of CD patients in response to bromocriptine
Thetonicinhibitionbyhypothalamicdopamineisthoughtto administration, these reductions are often minor and
beexertedthroughD receptors.Thisisdemonstratedbythe sustained responses to bromocriptine therapy occur only
2
fact that D -deficient mice develop intermediate lobe in a small percentage of patients [73]. Some studies have
2
hypertrophy with increased POMC expression, elevated suggested that corticotroph adenomas arising from the
ACTH and corticosterone levels, resulting in adrenal gland intermediate lobe may be more likely to respond to
hypertrophy [66]. In humans, the intermediate lobe in the bromocriptine [74].
pituitary is a rudimentary structure, but is still thought to Comparedtobromocriptine,cabergolinebindswitheven
contain important biological functions. Human corticotroph higher specificity and affinity to D -receptors and has a
2
RevEndocrMetabDisord(2009)10:91–102 97
longer duration of action [28]. Over the past decade, pergolide and cabergoline. Two important papers were
various case reports have demonstrated that ACTH- published in early 2007, which reported significantly
producing adenomas can be highly responsive to cabergo- increased risks (RR, 4.6–7.3) of valvular regurgitation in
linetherapy,bothinpatientswithCDaswellasinNelson’s patients with idiopathic Parkinson’s disease that had
syndrome [71, 75–83], see Table 2. In some of these cases received chronic treatment with either one of these drugs
shrinkage of the corticotroph adenoma was observed on [84, 85]. Other studies have recently confirmed these data
MRI [75–78, 82]. In the previously mentioned study by [86]. The pathogenetic mechanism behind this deleterious
Pivonello et al., 20 patients with CD were treated with sideeffectisthoughttobethebindingofEDDAto5-HT B
2
cabergoline at a dose of 1–3 mg/week for 3 months [71]. receptorsexpressedintheendocardialtissueofheartvalves
This resulted in a significant decrease in urinary free [85].
cortisol (UFC) in 60% of patients and even complete Thesefindingshaveledtoanumberofimportantactions,
UFCnormalizationin40%ofthem.Interestingly,therewas including the withdrawal of pergolide from the US market.
averygoodcorrelationbetweentheinvitrofindings onD Theimpactofthesestudiesonthe(future)useofcabergoline
2
receptor expression and the responses to cabergoline in patients with CD cannot be fully determined yet, as one
therapy in vivo. All D -expressing adenomas showed importantissueneedstobeemphasized.Themaximumdose
2
decreased cortisol levels in vivo in response to cabergoline of cabergoline prescribed inCD isaround 0.65 mg per day
therapy, whereas D -negative cases did not. Preliminary (4.5 mg/week), whereas the patients with Parkinson’s
2
data from another research group showed similar in vivo disease in the study by Zanettini et al. [85] received an
response rates after 20 months of cabergoline therapy [82]. average daily dose of 3.6 mg/day. In the other study by
In this study 3/8 CD patients (37.5%) had a complete Schade et al. [84], an important risk difference was found
normalization of 24 h UFC, 3/8 (37.5%) had a partial between patients taking >3 mg cabergoline daily for more
response (UFC≤1.25×ULN), whereas the remaining two than 6 months (RR 50.3, 95% CI 6.6–381.4) compared to
patients did not respond. In both studies, cabergoline those who took less than 3 mgdaily(RR 2.6;95% CI 0.5–
therapy was generally well tolerated. Despite the con- 12.8). Therefore, these observations in Parkinson’s disease
vincing results from both studies, the duration of treatment patientscannotbedirectlyextrapolatedtowardslower-dose
isstillrelativelyshort.Foragenuineassessmentoftheutility cabergoline therapy in CD. Monitoring of cardiac function
of the drug cabergoline as a medical treatment for CD, inCDpatientsonlong-termcabergolinetherapydoesseem
studies onitsefficacy andsafetywhenusedonalong-term to be a prerequisite, however.
basis in larger groups of patients are much needed. These
studies are currently ongoing and some preliminary results 3.2.4 Combined treatment with SS and DA agonists in CD
indicatesustainedefficacyafter1–2yearsoffollow-up[83].
Oneimportantissuethatrecentlyhasdominatedthefield Due to the reported presence of both sst and DA receptors
of medical therapy with DA-agonists has been the possible in human corticotroph adenomas and the fact that both
association between valvular heart disease and long-term receptor types can inhibit ACTH production in vitro, the
therapy with the ergot-derived dopamine agonists (EDDA) conceptofacombinationtherapywithbothSS-analogsand
Table2 OverviewstudiesoncabergolineuseinACTH-producingpituitaryadenomas(CDandNelson)
Year Firstauthor(ref) No.of Type Macro- Dose Duration Shrinkage Remarks
patients adenoma (mg/wk) (months) observed
1999 Pivonello[75] 1 Nelson no 1–2 12 yes NormalizationACTH
2001 Petrossians[76] 1 SilentCD yes 1.75 24 yes Restoredcranialnervefunction
2004 Miyoshi[77] 1 CD yes 0.25–0.5 6 yes DecreasedACTH
2004 Casulari[78] 1 Nelson yes 1.0 48 yes NormalizationACTH
2004 Pivonello[71] 20 CD 5/20 1–3 3 n.e. 40%full+20%partialUFCresponse
2006 Shraga-Slutzky[79] 1 Nelson yes 1.5–2 72 no DecreasedACTH(−90%)
2006 Illouz[80] 3 CD no 1–3 1–9 no NormalizationUFCin2/3patients
2007 Garcia[81] 1 Nelson no 2 42 n.e. DecreasedACTH
2007 Godbout[82] 8 CD n.m. 0.75–3.0 20–28 yes 38%full+38%partialUFCresponse
2007 Pivonello[83] 15 CD n.m. 1–7 3–24 n.e. Sustainedremissionin10/15
patientsafter12–24months
n.e.Notevaluated,n.m.notmentioned
98 RevEndocrMetabDisord(2009)10:91–102
DA-agonists in CD seems to be a feasible approach [87]. lesions on 111In-pentereotide scan (Octreoscan), whereas
These studies could be performed by co-treatment with most patients with CD do not [95]. The observation that
individual SS-analogs and DA-agonists (pasireotide+ many of the EAS producing neuro-endocrine tumours
cabergoline) or perhaps, in the near future, by administra- have functional sst receptors, despite the chronic hyper-
2
tion of SS-DA-chimeric compounds such as BIM-23A760, cortisolism they are exposed to, could be explained by
which displays high affinity for sst , D and to a lesser aberrantglucocorticoidreceptorsignallinginthesetumour
2 2
extentsst (seeTable1).Iffunctionalheterodimerizationof cells. This has been investigated extensively by a number
5
these receptor subtypes occurs in vivo, as has already been ofresearchgroupsoverthepasttwentyyears.Itwasfound
shown to occur in vitro by different groups, this type of that many of the cell lines, derived from EAS producing
treatment could result in greatly enhanced efficacy of these small-cell lung carcinomas, carry gross mutations in the
compounds[29].Also, ascorticotrophadenomascan differ genetic sequence of the glucocorticoid receptor (GR) [96,
considerably in the total number of sst and D receptors 97].ThesecanbelocatedeitherintheDNA-bindingorthe
2
they express [51, 52, 71], targeting of multiple receptors ligand-binding domain, but can also involve a number of
could increase the overall response rate in this group as a transcription factors. The loss of function of the GR has
whole, compared to the use of individual SS or DA importantimpactonPOMCproductioninthesecells.Any
agonists. This has already been shown for GH-producing form of negative feedback is generally lost in these cells,
adenomas, where BIM-23A760 had overall superior effi- leadingtoexcessiveanduninhibitedproductionofPOMC
cacy compared to individual sst , sst or D -targeting and ultimately, the full clinical spectrum of Cushing’s
2 5 2
agonists in terms of in vitro GH inhibition [88, 89]. As it Syndrome. Another result of aberrant GR functioning,
is known that also in CD only subsets of patients have may be that glucocorticoid-induced down-regulation of
respondedtoeither cabergolineorpasireotidemonotherapy somatostatinreceptorsubtype2(sst )doesnotoccurinthese
2
in vivo, it may well be that similar phenomena occur in tumours,asopposedtopituitary-derivedcorticotrophadeno-
corticotroph adenomas and that combination therapy can mas. This could well explain the relatively high degree of
increase overall response rates. Until now, no studies have positive Octreoscans and reported efficacy of Octreotide in
been published that have investigated this hypothesis. this group of neuro-endocrine tumours [98, 99].
Theoretically, co-treatment with sst and DA agonists One main concern with the use of SS analogs in EAS,
may have other advantages as well. As stated before, the however, appears to be the long-term control of hyper-
inefficacy of sst -preferring compounds in CD, is probably cortisolism. Although initial responses to Octreotide are
2
due todown-regulation ofsst -expression by high levelsof frequent, these are not always sustained and treatment
2
circulating glucocorticoids [48, 50, 51]. Inversely, if escapes are commonly encountered, due to a number of
combined treatment with these analogs is effective and possible mechanisms of tachyphylaxis [100].
thuslowerscortisollevelsinthesepatients,thiscouldresult
in a return of sst expression. The latter would result in 4.2 Dopamine agonists
2
enhanced efficacy of SS-analogs with sst -affinity and
2
hence strongly increase pharmacotherapeutical options in Farrelletal.[69]showedin1992thatthedopamineagonist
these patients [59, 90]. bromocriptine could effectively inhibit POMC mRNA and
ACTH precursor secretion in a small cell lung cancer cell
line (CORL103), that is known to cause EAS. After these
4 Ectopic ACTH-producing syndrome (EAS) initial observations, to our knowledge no (clinical) studies
have been performed that investigated the potential use of
4.1 Somatostatin analogs DAcompoundsinEAS,untilarecentstudybyPivonelloet
al. [101]. In this study, six patients with EAS-causing
For some decades it has been known that neuro- carcinoid tumours (four lung, one thymic, one pancreatic)
endocrine tumours that cause ectopic ACTH-producing underwent surgery. Five out of these 6 resected EAS
syndrome (EAS), such as bronchial carcinoids or small tumours expressed D , as determined by IHC. Three
2
cell lung cancer (SCLC), often express functional SS patients had persistent EAS after surgery and were treated
receptors. A number of smaller studies and case reports with cabergoline at 3.5 mg/week for 6 months. All three
have been published on the use of Octreotide in patients patients had measurable D mRNA and two out of three
2
with EAS. Interestingly, Octreotide was efficacious in had D mRNA expression on RT-PCR. Two patients had
4
lowering cortisol levels in a significant number of these complete normalization of UFC after 3 months of cabergo-
patients, as opposed to the studies performed in patients linetreatment,althoughoneofthemhadatreatmentescape
with CD [91–94]. This discrepancy is further confirmed afterwards. Of note, the long-term responder had the
by the fact that many patients with EAS have positive strongest overall D expression, including the D short
2 2
RevEndocrMetabDisord(2009)10:91–102 99
isoform, and was also D -receptor positive. In other adenomas and carcinomas, some of which cause CS [110,
4
pituitary tumours this expression profile has been asso- 111]. D and D receptor subtypes were found in the
2 4
ciated with a good response to cabergoline therapy [71, cortisol-producing adrenal adenomas and carcinomas by
102].Despitethesmallsizeofthisstudy,itisprobablethat RT-PCR. The adenomas expressed both D isoforms (short
2
at least a subgroup of EAS patients could benefit from D - and long), whereas the carcinomas only expressed the D -
2 2
targeted treatment, but obviously these results need to be longisoform.FunctionalstudiesshowedthattheD -agonist
2
confirmed in larger series. cabergoline was able to modulate ACTH- and angiotensin
II-stimulated aldosterone release [111].
4.3 Somatostatin–dopamine chimeras Taken together, despite the abundant expression of both
SS and DA receptors in both the normal and the abnormal
Another interesting development in EAS tumours is the humanadrenalgland,therearecurrentlynodatathatwould
evaluation of dopamine-somatostatin chimeric molecules. stronglysupporttheuseofSS-analogorDA-agonisttherapy
Ferone et al. [30] examined the effects of the chimeras inpatients withadrenal adenomas orcarcinomas that cause
BIM-23A370 and BIM-23A387 in the non-small cell lung CS. Given the high degree of surgical cure that can be
cancer cell line CALU-6. It was found that in these cells obtainedinmostofthesepatients,thecontributionofSSand
that natively express both sst and D receptors at high DA-agonisttherapyinthispatientgroupislikelytobelow.
2 2
levels, the chimeric compounds had a stronger direct
inhibitory effect on cell proliferation than the SS and DA-
selective compounds alone. These data clearly confirm the 6 Summary
hypothesis of heterodimerization between these two recep-
tors, as had been suggested before by other groups [29]. In all forms of Cushing’s syndrome (pituitary, ectopic and
A recent case report provides some further clinical adrenalCS)asubsetofpatientscannotbecuredbysurgery
evidence for this potential synergism between sst and DA alone and therefore requires effective adjuvant treatment.
receptors in EAS. In this case, a man with EAS due to a Medical therapy can offer important advantages over other
lung carcinoid tumour was treated medically after incom- secondary treatments such as radiotherapy and bilateral
plete surgical removal. Cortisol levels normalized only adrenalectomy, including a relatively rapid onset of action
temporarilywitheitherSS-analog(Lanreotide)ordopamine andthefact thatintegrity oftheHPA-axisismaintained. In
agonist (Cabergoline) therapy alone. However, when both CD,sst andD receptorsplayacrucialintheregulationof
5 2
drugsweregivensimultaneously,basedonco-expressionof ACTH-release from corticotroph adenoma cells both in
sst and D that was demonstrated by RT-PCR on the vitro and in vivo. Agents that selectively target these
5 2
resected tumour specimen, the patient came into complete receptorscan significantly reduce urinary cortisol excretion
and prolonged remission [103]. in subsets of patients. Combined treatment with these
agents could in theory result in increased overall response
rates, but these studies still need to be performed. In
5 Adrenal Cushing’s syndrome selected cases of ectopic ACTH-producing syndrome, D -
2
agonists are shown to be effective in reducing cortisol
ImmunohistochemicalandRT-PCRstudieshaveshownthat production,eitheraloneorincombinationwithSS-analogs.
all sst subtypes (1–5) are expressed in the majority of Tumours that cause adrenal CS do express SS and DA
normal adrenal cortices as well as in most cortisol- receptors, but there is only limited data on the efficacy of
producing adenomas [104–106]. Interestingly, immuno- agentsthattargetthesereceptorsneitherinvitronorinvivo.
staining occurred only in a minority (<30%) of these Their overall contribution to the management of these
adenoma cells. One of the studies described a remarkably patients is likely to be low.
high expression of sst in the adenomas [104], but this was
4
not found in another study [105]. To our knowledge, no
studies have been performed so far to evaluate SS-analog Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
therapy in cortisol-producing adenomas and carcinomas in
mits any noncommercial use, distribution, and reproduction in any
vitro.Intermsofclinicalstudies,octreotidedoesnotappear medium,providedtheoriginalauthor(s)andsourcearecredited.
to be effective in cases of adrenal carcinomas [107].
DA receptors (D andD -like)areabundantly expressed
1 2
innormalhumanadrenalcortex,wheretheyareinvolvedin References
the regulation of aldosterone release, but also in cortisol
and androgen production [108, 109]. Their presence has 1. Orth DN. Cushing’s syndrome. N Engl J Med 1995;332
been clearly established in different types of adrenal (12):791–803.
100 RevEndocrMetabDisord(2009)10:91–102
2. Lindholm J, et al. Incidence and late prognosis of cushing’s binding and a unique antisecretory profile. Eur J Endocrinol
syndrome: a population-based study. J Clin Endocrinol Metab 2002;146(5):707–16.
2001;86(1):117–23. 27. Molitch ME, et al. Bromocriptine as primary therapy for
3. Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367 prolactin-secreting macroadenomas: results of a prospective
(9522):1605–17. multicenterstudy.JClinEndocrinolMetab1985;60(4):698–705.
4. Atkinson AB, et al. Long-term remission rates after pituitary 28. ColaoA,LombardiG,AnnunziatoL.Cabergoline.ExpertOpin
surgery for Cushing’s disease: the need for long-term surveil- Pharmacother2000;1(3):555–74.
lance.ClinEndocrinol2005;63(5):549–59. 29. Rocheville M, et al. Receptors for dopamine and somatostatin:
5. Benveniste RJ, et al. Repeated transsphenoidal surgery to treat formationofhetero-oligomerswithenhancedfunctionalactivity.
recurrent or residual pituitary adenoma. J Neurosurg 2005;102 Science2000;288(5463):154–7.
(6):1004–12. 30. FeroneD,etal.Somatostatinanddopaminereceptorexpression
6. LocatelliM,VanceML,LawsER.Clinicalreview:thestrategyof in lung carcinoma cells and effects of chimeric somatostatin–
immediatereoperationfortranssphenoidalsurgeryforCushing’s dopamine molecules on cell proliferation. Am J Physiol
disease.JClinEndocrinolMetab2005;90(9):5478–82. EndocrinolMetab2005;289(6):E1044–1050.
7. Mahmoud-AhmedAS,SuhJH.RadiationtherapyforCushing’s 31. Brazeau P, et al. Hypothalamic polypeptide that inhibits the
disease:areview.Pituitary2002;5(3):175–80. secretion of immunoreactive pituitary growth hormone. Science
8. VanceML.Pituitaryradiotherapy.EndocrinolMetabClinNorth 1973;179(68):77–9.
Am2005;34(2):479–87.xi. 32. O’CarrollAM,KrempelsK.Widespreaddistributionofsomato-
9. Jagannathan J, et al. Gamma Knife surgery for Cushing’s statin receptor messenger ribonucleic acids in rat pituitary.
disease.JNeurosurg2007;106(6):980–7. Endocrinology1995;136(11):5224–7.
10. Ilias I, et al. Cushing’s syndrome due to ectopic corticotropin 33. Day R, et al. Expression of mRNA for somatostatin receptor
secretion: twenty years’ experience at the National Institutes of (sstr) types 2 and 5 in individual rat pituitary cells. A double
Health.JClinEndocrinolMetab2005;90(8):4955–62. labeling in situ hybridization analysis. Endocrinology 1995;136
11. Isidori AM, et al. The ectopic adrenocorticotropin syndrome: (11):5232–5.
clinical features, diagnosis, management, and long-term follow- 34. Mezey E, et al. Cell specific expression of the sst2A and sst5
up.JClinEndocrinolMetab2006;91(2):371–7. somatostatinreceptorsintheratanteriorpituitary.Endocrinology
12. MorrisD,GrossmanA.TheMedicalmanagementofCushing’s 1998;139(1):414–9.
syndrome.AnnNYAcadSci2002;970(1):119–33. 35. BrownMR,RivierC,ValeW.Centralnervoussystemregulation
13. Castinetti F, et al. Ketoconazole revisited: a preoperative or ofadrenocorticotropinsecretion:roleofsomatostatins.Endocri-
postoperative treatment in Cushing’s disease. Eur J Endocrinol nology1984;114(5):1546–9.
2008;158(1):91–9. 36. KraicerJ,GajewskiTC,MoorBC.Releaseofpro-opiomelanocortin-
14. Nieman LK. Medical therapy of Cushing’s disease. Pituitary derivedpeptidesfromtheparsintermediaandparsdistalisoftherat
2002;5(2):77–82. pituitary: effect of corticotrophin-releasing factor and somatostatin.
15. Barnett P. Somatostatin and somatostatin receptor physiology. Neuroendocrinology1985;41(5):363–73.
Endocrine2003;20(3):255–64. 37. Lamberts SW, et al. Studies on the conditions determining the
16. LambertsSW,KrenningEP,ReubiJC.Theroleofsomatostatin inhibitory effect of somatostatin on adrenocorticotropin, prolac-
anditsanalogsinthediagnosisandtreatmentoftumors.Endocr tin and thyrotropin release by cultured rat pituitary cells.
Rev1991;12(4):450–82. Neuroendocrinology1989;50(1):44–50.
17. Patel YC. Somatostatin and its receptor family. Front Neuro- 38. Stafford PJ, et al. The pituitary-adrenal response to CRF-41 is
endocrinol1999;20(3):157–98. unaltered by intravenous somatostatin in normal subjects. Clin
18. MissaleC,etal.Dopaminereceptors:fromstructuretofunction. Endocrinol(Oxf)1989;30(6):661–6.
PhysiolRev1998;78(1):189–225. 39. HallR,etal.Actionofgrowth-hormone-releaseinhibitoryhormone
19. Reubi JC, et al. Somatostatin receptors in human endocrine inhealthymenandinacromegaly.Lancet1973;2(7829):581–4.
tumors.CancerRes1987;47(2):551–8. 40. LightmanSL,FoxP,DunneMJ.TheeffectofSMS201–995,a
20. Pivonello R, Ferone D, Lombardi G, Colao A, Lamberts SW, long-actingsomatostatinanalogue,onanteriorpituitaryfunction
HoflandLJ.Novelinsightsindopaminereceptorphysiology.Eur in healthy male volunteers. Scand J Gastroenterol Suppl
JEndocrinol2007;156(Supplement1):S13–S21. 1986;119:84–95.
21. Giustina G, etal.Dose-response study ofthe inhibitingeffectof 41. InvittiC,etal.EffectofsandostatinonCRF-stimulatedsecretion
somatostatin ongrowthhormoneandinsulin secretioninnormal ofACTH,beta-lipotropinandbeta-endorphin.HormMetabRes
subjectsandacromegalicpatients.Metabolism1975;24(7):807–15. 1991;23(5):233–5.
22. LambertsSW.Theroleofsomatostatinintheregulationofanterior 42. Fehm HL, et al. Somatostatin: a potent inhibitor of ACTH-
pituitaryhormonesecretionandtheuseofitsanalogsinthetreatment hypersecretion in adrenal insufficiency. Klin Wochenschr
ofhumanpituitarytumors.EndocrRev1988;9(4):417–36. 1976;54(4):173–5.
23. Lamberts SW, et al. The somatostatin analog SMS 201–995 43. Cervia D, et al. Pharmacological characterisation of native
induces long-acting inhibition of growth hormone secretion somatostatin receptors in AtT-20 mouse tumour corticotrophs.
without rebound hypersecretion in acromegalic patients. J Clin BrJPharmacol2003;139(1):109–21.
EndocrinolMetab1985;60(6):1161–5. 44. RichardsonUI,SchonbrunnA.Inhibitionofadrenocorticotropin
24. LambertsSW,etal.Long-termtreatmentofacromegalywiththe secretion by somatostatin in pituitary cells in culture. Endocri-
somatostatin analogue SMS 201–995. N Engl J Med 1985;313 nology1981;108(1):281–90.
(25):1576–80. 45. Tallent M, et al. Somatostatin receptor subtypes SSTR2 and
25. SaveanuA,etal.Bim-23244,asomatostatinreceptorsubtype2- SSTR5 couple negatively to an L-type Ca2 + current in the
and 5-selective analog with enhanced efficacy in suppressing pituitarycelllineAtT-20.Neuroscience1996;71(4):1073–81.
growth hormone (GH) from octreotide-resistant human GH- 46. StrowskiMZ,etal.Somatostatinreceptorsubtypes2and5inhibit
secretingadenomas.JClinEndocrinolMetab2001;86(1):140–5. corticotropin-releasing hormone-stimulated adrenocorticotropin
26. Bruns C, et al. SOM230: a novel somatostatin peptidomimetic secretion from AtT-20 cells. Neuroendocrinology 2002;75(6):
withbroadsomatotropinreleaseinhibitingfactor(SRIF)receptor 339–46.