Pituitary (2017) 20:100–108

DOI 10.1007/s11102-017-0791-0

Somatostatin receptor ligands in the treatment of acromegaly

Monica R. Gadelha1,2 · Luiz Eduardo Wildemberg1,2 · Marcello D. Bronstein3 ·
Federico Gatto4 · Diego Ferone4,5 

Published online: 7 February 2017

© Springer Science+Business Media New York 2017

Abstract  First-generation somatostatin receptors ligands somatotropinomas. In patients resistant to first-generation

(SRL) are the mainstay in the medical treatment of acro-
megaly, however the percentage of patients controlled
with these drugs significantly varies in the different stud-
ies. Many factors are involved in the resistance to SRL. In
this review, we update the physiology of somatostatin and
its receptors (sst), the use of SRL in the treatment of acro-
megaly and the factors involved in the response to these
drugs. The SRL act through interaction with the sst, which
up to now have been characterized as five subtypes. The
first-generation SRL, octreotide and lanreotide, are con-
sidered sst2 specific and have biochemical response rates
varying from 20 to 70%. Tumor volume reduction can be
found in 36–75% of patients. Several factors may deter-
mine the response to these drugs, such as sst, AIP, E-cad-
herin, ZAC1, filamin A and β-arrestin expression in the
SRL, alternative medical treatment options include: SRL
high dose regimens, SRL in combination with cabergoline
or pegvisomant, or the use of pasireotide. Pasireotide is a
next-generation SRL with a broader pattern of interaction
with sst. In the light of the recent increase of treatment
options in acromegaly and the deeper knowledge of the
determinants of response to the current first-line therapy, a
shift from a trial-and-error treatment to a personalized one
could be possible.
Keywords  Somatostatin receptor ligands · Acromegaly ·
Somatostatin receptors · Octreotide · Lanreotide ·
Pasireotide
Introduction

* Monica R. Gadelha Transsphenoidal surgery is considered the first treatment

mgadelha@hucff.ufrj.br option in a large proportion of patients with acromegaly,
1 since it provides immediate reduction of GH levels with
Neuroendocrinology Research Center/Endocrinology
Section, Medical School and Hospital Universitário low complication rates [1]. However, even in reference
Clementino Fraga Filho, Universidade Federal do Rio de centers, disease cure cannot be achieved in up to 50% of
Janeiro, Rua Prof. Rodolpho Paulo Rocco, 9th floor, Ilha do patients harboring macroadenomas [2–4]. Therefore, a
Fundão, Rio de Janeiro 21941‑913, Brazil
considerable number of patients will require medical adju-
2
Neuroendocrinology Section and Molecular Genetics vant therapy. First-generation somatostatin receptor ligands
Laboratory, Secretaria Estadual de Saúde do Rio de
(SRL) are considered the mainstay in the medical manage-
Janeiro, Instituto Estadual do Cérebro Paulo Niemeyer,
Rio de Janeiro, Brazil ment of acromegaly [1].
3 With this review, we aim to update the somatostatin
Neuroendocrine Unit, Division of Endocrinology
and Metabolism, Hospital das Clinicas, University of Sao (somatotroph release inhibiting factor, SRIF) and its recep-
Paulo Medical School, São Paulo, Brazil tors (somatostatin receptors, sst) physiology, the use of
4
Endocrinology Unit, Department of Internal Medicine SRL for the treatment of acromegaly, and the determinants
and Medical Specialties and Center of Excellence of the response to these drugs.
for Biomedical Research, University of Genoa, Genoa, Italy
5
IRCCS AOU San Martino-IST Genoa, Genoa, Italy

13
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Pituitary (2017) 20:100–108 101
Somatostatin, somatostatin receptors
and somatostatin receptor ligands
In physiological conditions, the inhibitory control of GH
secretion by the anterior pituitary is primarily mediated by
the hypothalamic hormone SRIF [5]. SRIF, a cyclic peptide
present in mammals in two biologically active isoforms,
exerts its inhibitory effects on hormone secretion, cell
growth and differentiation via its specific membrane recep-
tors (sst) [5]. The sst belong to the seven transmembrane
segment receptor superfamily and functionally couple to G
proteins [6].
Up to date, five human sst subtypes have been cloned
and characterized [6], with the transcript of the sst2 gene
presenting two splice variants (­ sst2A and s­ st2B) [7]. In addi-
tion, two truncated isoforms of sst5 have been described,
with four (sst5TMD4) and five (sst5TMD5) transmembrane
domains, respectively [8].
Since endogenous SRIF is not useful in clinical practice
due to its unique pharmacokinetic characteristics with a
very short half-life [9], synthetic SRL have been designed.
The first compounds developed were octreotide [10] and
lanreotide [11], both considered sst2 preferential ligands,
with a weak to moderate affinity for sst3 and sst5 [12].
However, since these drugs mainly target sst2, and the dif-
ferent sst subtypes are heterogeneously expressed in the
pituitary tumors, including somatotropinomas, researchers
aimed to generate compounds with a wider binding profile
for sst.
In this context, pasireotide, a stable cyclohexa-
peptide showing high binding affinity for multiple sst
(sst5 > sst2 > sst3 > sst1) [13], is currently the only sst pan-
ligand approved for clinical use in acromegaly. However,
despite the search for a compound able to mimic native
SRIF, recent studies have demonstrated that pasireotide dis-
plays different functional properties compared to both SRIF
and first-generation SRL when binding sst, and particularly
to sst2 [14]. SRIF and SRL binding affinities for the sst can
be found in Table 1.
Table 1  Binding affinity Characteristic Ligand
of endogenous somatostatin
(SRIF-14), octreotide Binding ­affinitya SRIF-14
(OCT), lanreotide (LAN) (EC50, nmol/l)
and pasireotide (PAS) to the
OCT
different human somatostatin
receptor subtypes LAN
PAS
hsst human somatostatin receptor subtypes, EC50 half-maximal effective concentration
a
 Binding affinitiy expressed as the mean ± SEM EC50 value in nmol/l [13]
Somatostatin receptor signalling pathways
SRIF/SRL binding to sst subtypes activates a number of
second messenger pathways [15]. The inhibitory effect on
hormone secretion is mainly mediated through the inhibi-
tion of C­ a2+ and activation of ­K+ channels, resulting in
the decrease of intracellular ­Ca2+ concentration (through
sst1, sst2 and sst5 activation), and the inhibition of ade-
nylyl cyclase, which lowers intracellular cAMP levels
(exerted by the activation of all different sst) [16]. Note-
worthy, in GH-secreting pituitary adenomas, differently
from other pituitary adenoma histotypes, the cAMP path-
way exert a positive effect on cell growth, thus represent-
ing an additional target for the control of cell prolifera-
tion [17].
However, stimulation of other second messengers, such
as phosphotyrosine phosphatases (PTPs), plays a pivotal
role in SRIF/SRL-mediated control of cell growth and
seems to be activated by the ligand-binding to all differ-
ent sst subtypes [18]. Briefly, in pituitary adenomas, SRIF/
SRL may exert their anti-proliferative action by inhibit-
ing the phosphatidylinositol 3-kinase (PI3K)/AKT signal-
ling pathway, mainly via sst2, or throughout the modula-
tion (inhibition/activation) of the mitogen-activated protein
(MAP) kinase pathway, targeting sst1, sst2 and sst5 recep-
tors. These events ultimately lead to the upregulation of the
cyclin kinase inhibitors p21cip1/waf1 and p27kip1 and the
tumor suppressor gene ZAC1 [19, 20]. Interestingly, recent
findings suggest the existence of a SRL–AIP–ZAC1 path-
way [15]. Indeed, SRL have been demonstrated to regu-
late AIP (aryl hydrocarbon receptor-interacting protein), a
protein involved in the tumorigenesis of somatotropinomas
and their responsiveness to SRL, which in turn can stimu-
late the expression of ZAC1 [21].
Moreover, apoptosis has been highlighted as another
possible anti-tumoral effect of SRIF/SRL, mediated through
their binding to sst3 and sst2, via a NF-kB–JNK–caspase
pathway [19]. Figure 1 shows a simplified representation of
the sst signalling pathways.
hsst1 hsst2 hsst3 hsst4 hsst5
0.93 ± 0.12 0.15 ± 0.02 0.56 ± 0.17 1.5 ± 0.4 0.29 ± 0.04
280 ± 80 0.38 ± 0.08 7.1 ± 1.4 >1000 6.3 ± 1.0
180 ± 20 0.54 ± 0.08 14 ± 9 230 ± 40 17 ± 5
9.3 ± 0.1 1.0 ± 0.1 1.5 ± 0.3 >100 0.16 ± 0.01
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102
Fig. 1  Simplified representation of somatostatin receptor signaling in
GH-secreting pituitary adenomas. AC adenylyl cyclase, cAMP ciclyc
AMP, PTPase phosphotyrosine phosphatase, RAF RAF kineses, MEK
MAP kinase kinases, ERK extracellular signal-regulated kinase, PI3K
phosphoinositide 3-kinase, JNK c-Jun N-terminal kinase, AIP aryl
hydrocarbon receptor-interacting protein; p21 and p27, cyclin kinase
inhibitors; Zac1 tumor suppressor gene. Adapted from ref. 16–20,35
Somatostatin receptor expression and modulation
The presence of sst in GH-secreting pituitary adenomas has
been already demonstrated more than thirty years ago [22].
Sst2 is the subtype more commonly expressed, identified in
more than 95% of adenomas, followed by sst5, present in
about 85% of cases. Sst1 and sst3 are expressed in about
40% of tumors, while sst4 is almost undetectable [23, 24].
Different studies, aimed to evaluate the quantitative
expression of sst, show that sst5 is the more abundantly
expressed subtype at mRNA level, followed by sst2, sst3
and sst1 [25, 26]. However, the evaluation of protein
expression, performed by immunohistochemistry with vali-
dated monoclonal antibodies, shows that sst2 seems more
abundant than sst5 [27, 28].
In this light, the high (although heterogeneous) expres-
sion of sst2 and sst5 represent the physiopathological
rationale for the successful clinical application of first gen-
eration SRL in the medical management of GH-secreting
pituitary adenomas [29].
Interestingly, recent studies demonstrate that SRL pre-
surgical treatment result in a lower sst2 protein expression
in the tumour samples (mainly at membrane level), com-
pared to medically-naïve adenomas [28, 30]. However, this
finding has not been confirmed at mRNA level, thus sug-
gesting a phenomenon of receptor internalization rather
than a true sst2 down-regulation [28]. This latter observa-
tion is in line with the clinical finding of a general lack of
13
Pituitary (2017) 20:100–108
tachyphylaxis to SRL therapy in acromegaly patients, even
after many years of treatment [29].
Histopathological and molecular determinants
of somatostatin receptor ligand responsiveness
in acromegaly
It has been widely demonstrated that sst2 expression is
positively correlated (both at mRNA and protein level) with
the in  vitro and in  vivo GH suppression following SRL
treatment [31–33]. In this light, sparsely granulated pitui-
tary adenomas, showing a lower sst2 expression compared
to the densely granulated ones, have been demonstrated to
have a worse response to medical therapy with SRL [34].
Noteworthy, sparse granulation pattern of tumor cells
have been correlated with the adenoma hyperintensity on
T2-weighted magnetic resonance imaging (MRI) sequences
[35]. Furthermore, recent studies have shown that soma-
totropinoma T2-weighted hyperintensity correlates with
a lower hormone reduction and less tumor shrinkage in
response to SRL treatment [36]. However, the efficacy
of SRL seems not to be correlated with the expression of
other sst than sst2 (including sst5). Interestingly, this find-
ing has been confirmed investigating the in vitro anti-secre-
tory effect of the sst panligand pasireotide on GH-secreting
adenoma cells [32].
Moreover, a number of studies have demonstrated that
the expression of sst on cell membrane is a dynamic pro-
cess, because the different receptors undergo a complex
trafficking regulated by a specific cell machinery, involv-
ing desensitization, internalization as well as recycling/
degradation [37]. In this context, the expression of different
proteins, such as filamin A and β-arrestins, have been dem-
onstrated to affect the receptor’s function [26, 38]. In par-
ticular, lower β-arrestin levels are correlated with a better
biochemical response to first generation SRL treatment in
GH-secreting adenomas, both in vitro and in vivo [26, 39].
Noteworthy, pasireotide results in a lower internalization of
sst2 compared to octreotide, through a significantly lower
β-arrestin recruitment [40].
Besides sst2 expression alone, the heterogeneous expres-
sion of different ssts on pituitary adenoma cells may rep-
resent another factor affecting SRL efficacy [24, 37]. In
this context, the role of sst5 expression in GH-secreting
adenoma is still debated. Indeed, some authors have shown
that sst5 co-expression with sst2 may enhance sst2-acti-
vated pathways after selective ligand activation [41]. This
finding may represent the result of the receptors’ interac-
tion (heterodimerization) observed on cell membrane [41].
Moreover, other studies have demonstrated that sst5 can
play a clear role in reducing GH secretion in somatotro-
pinoma cells [42] and that a sst2-sst5 bispecific analogue
Pituitary (2017) 20:100–108 103
can achieve better control of GH hypersecretion in a larger
number of cases, compared to octreotide [43].
However, a low sst2/sst5 ratio is clearly associated with
a poor response to first-generation SRL therapy in acro-
megaly [44], and the presence of the sst5 truncated isoform
sst5TMD4 correlates with a worse response to SRL [45].
Moreover, besides sst expression, trafficking and inter-
actions, peculiar GH-secreting adenoma molecular pheno-
types (e.g. low E-cadherin or RKIP expression, low AIP
and ZAC1 levels) have been demonstrated to be associated
with reduced response to SRL treatment [15, 24]. In par-
ticular, mutations of the AIP gene (mainly associated to
familial cases of acromegaly) or low wild-type AIP expres-
sion correlate to a poor response of somatotropinomas to
first-generation SRL [46, 47]. Noteworthy, the impact of
most of these peculiar adenoma features on the efficacy of
pasireotide has not been elucidated in detail so far. How-
ever, recent data from Iacovazzo and colleagues show that,
in a small group of somatotropinomas resistant to first-gen-
eration SRL (n = 11), tumors with low AIP expression and
sparsely granulated adenomas may benefit from pasireotide
treatment [48]. Moreover, in the same subgroup of patients,
the authors observed that the biochemical responsiveness to
pasireotide was correlated with a higher sst5 expression on
tumor cells [48].
Finally, a peculiar gene mutation identified almost 30
years ago [49] has been positively correlated with a better
response to SRL treatment in acromegaly patients. Indeed,
GH-secreting adenomas carrying a mutation of the α sub-
unit of the Gs protein coupled to GHRH receptor (GSP
mutation), which results in a constitutive activation of the
adenylyl cyclase, have been demonstrated to be more sensi-
tive to first-generation SRL therapy [50].
Somatostatin receptor ligands in the treatment
of acromegaly
The sst2 preferential ligands, octreotide and lanreotide, are
first-generation SRL, while the panligand pasireotide repre-
sents the next-generation SRL [51]. Octreotide and pasire-
otide can be found in the subcutaneous and intramuscular
(octreotide LAR and pasireotide LAR) formulations, while
lanreotide have both intramuscular (lanreotide SR) and
deep subcutaneous (lanreotide autogel) preparations.
First‑generation somatostatin receptor ligands
Medical treatment of acromegaly is usually indicated
after unsuccessful surgery or for those patients who are
poor surgical candidates. In these cases, first-generation
SRL are used in the majority of patients. Other drug
options are cabergoline and pegvisomant, which will not
be addressed in this review [1]. Interestingly, the first
study describing long-term treatment of acromegaly with
SRL, published more than 30 years ago, reported a rapid
amelioration of patients’ clinical signs and symptoms and
near normalization of GH and IGF-1 levels in all four
patients treated with subcutaneous formulation of octreo-
tide [52].
During this long lasting history, the reported SRL con-
trol rates vary widely, from 20% up to 70% [53–55]. An
earlier meta-analysis evaluating the effects of long-acting
SRL in the treatment of acromegaly included 1526 patients
(612 treated with octreotide LAR and 914 with lanreotide
SR). Normal GH (<2.5 µg/L) and IGF-1 values were found
in 57 and 67% of patients treated with octreotide LAR and
in 48 and 47% of those treated with lanreotide SR. It is
important to mention that 791 (52%) of patients were pre-
selected for SRL responsiveness before entering the study,
which could have overestimated the effect of these drugs on
the biochemical control of the disease [54].
Most recent data, especially from prospective con-
trolled studies, show control rates varying from 20 to 40%
[56–59]. After 48 weeks of treatment with octreotide LAR,
25% of 68 patients had GH < 2.5  µg/L and normal IGF-1
[59], while the same endpoints were reached in 43% of 108
patients treated with lanreotide autogel for 52 weeks [58].
Real life studies conducted in reference centers indicate a
control rate around 40% [60]. Noteworthy, octreotide LAR
and lanreotide autogel seem to be equally effective in the
biochemical control of acromegaly [61].
Nevertheless, a large recent meta-analysis evaluating the
effects of long-acting SRL in the treatment of acromegaly,
including 4446 patients, reported the normalization of GH
levels in 56% and IGF-1 in 55% of patients, respectively
[53]. In this study, pre-selection of patients was not found
to yield better GH and IGF-1 responses, while prior SRL
therapy and study duration came out as a significant effi-
cacy determinants [53]. However, a composite GH and
IGF-1 normalization response rates was not described, and
most studies did not consider the current criteria for GH
normalization (less than 1 µg/L).
These drugs also have antiproliferative effects, with
tumor reduction being found in the majority of patients.
Two prospective studies showed that, out of 68 patients
treated with octreotide LAR for 48 weeks, 75% showed
a tumor volume reduction >20% [59], and after treat-
ment with lanreotide autogel for 12 weeks, 54.1% out of
90 patients had tumor shrinkage higher than 20% [62].
However, this aspect has been also evaluated in two large
meta-analysis [63, 64]. Out of 424 patients who under-
went primary treatment with SRL, 36.6% experienced
tumor reduction [64]. On the other hand, considering both
first-line and adjuvant therapy, octreotide induced tumor
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104
shrinkage in 53% of 1685 patients, with a mean percentage
reduction in tumor size of 37.4% [63].
The first-generation SRL are well tolerated, with mild
and usually transient side effects. The majority of these
are gastrointestinal related, mainly nausea, diarrhea and
abdominal pain or distension. Hair loss, cholelitiasis and
bradycardia may also occur [56, 59]. The effects of these
drugs over glucose metabolism is unpredictable, with glu-
cose increase occurring in up to 42% of patients, however
some patients may present improvement of hyperglycemia
following GH and IGF-1 reduction [65].
A strong definition of resistance to SRL is still lacking.
It may be defined as a failure to achieve biochemical con-
trol criteria (GH < 1.0 µg/L and a normal age-adjusted IGF-
1) and tumor volume increase or absence of >20% decrease
after at least 12  months of treatment [29]. Resistance to
SRL can be considered as total or partial, however these
concepts are also not clearly defined. Total resistance may
be defined as a failure to decrease IGF-1 levels more than
20%, which represent the intra-assay variability. In terms
of clinical relevance, partial resistance could be consid-
ered as a IGF-1 reduction higher than 50% from baseline,
without normalization [29]. In such cases, the management
should be individualized and current options include: sur-
gical debulking, increase of the dose of SRL, combina-
tion therapy, switching to pasireotide or pegvisomant, and
radiotherapy [29]. Since this review focus on SRL, we will
further describe the high dose schedules and the efficacy of
pasireotide.
High dose therapy
Octreotide LAR usual doses vary from 10 to 30 mg every
28  days (40  mg is approved in some countries). The effi-
cacy of reducing interval to 21  days or increasing dosage
to 60  mg was evaluated in a study with partial responder
patients (>50% GH reduction with conventional dos-
age). Four out of 11 patients normalized IGF-1 with dose
increase, without significant modification of the safety [66,
67].
Next‑generation somatostatin receptor ligand
Pasireotide LAR has been recently approved for the treat-
ment of acromegaly patients which are not cured by sur-
gery or for whom surgery is not an option (according to
the European Medicine Agency, patient should be inad-
equately controlled with another SRL) [51]. The efficacy
of pasireotide as first line medical treatment was evaluated
in comparison with octreotide LAR in a study including
358 patients randomly allocated for treatment with either
13
Pituitary (2017) 20:100–108
drugs. Pasireotide LAR was superior to octreotide LAR,
with control rates of 31.3 and 19.2% (p = 0.007) after
12  months, respectively. In this study, 80.8% of patients
treated with pasireotide presented tumor volume reduc-
tion >20% [56]. The efficacy of pasireotide was also evalu-
ated in 198 patients resistant to first-generation SRL. Of the
130 patients randomized to pasireotide LAR 40 or 60 mg,
15 and 20%, respectively, achieved complete biochemical
control after six months, whereas none of the 68 patients
that continued the previous treatment was controlled [68].
The safety profile of pasireotide is similar to first-gen-
eration SRL, except for the increase in the frequency and
degree of hyperglycemia. In the two studies comparing
pasireotide LAR with the first-generation SRL, hypergly-
cemia related adverse events were reported in 57.3–65%
of patients treated with pasireotide LAR and in 21.7–30%
with first-generation SRL [56, 68]. However, grade 3 or 4
events were reported in only 9% of patients treated with
pasireotide [56]. Hyperglycemia occurred early after drug
initiation, with fasting glucose levels increasing four weeks
after the first administration, remaining stable afterwards
and going back to pretreatment levels after drug withdrawal
[51, 68]. The mechanisms of pasireotide-mediated hyper-
glycemia are not completely understood so far. Most studies
investigating these mechanisms were carried out in healthy
individuals and studies addressing this issue in acromegaly
patients are still ongoing. However, the reduction of insu-
lin and incretin hormones secretion, without major changes
in insulin sensitivity, seems to contribute to the detrimen-
tal effect on glucose metabolism [69, 70]. Therefore, up to
date, therapies able to increase incretin levels/effect (either
using DDP-IV inhibitors or GLP-1 agonists) seem to be
the more effective strategy for the control of pasireotide-
induced hyperglycemia [51, 70]. Metabolic assessment
should be performed before pasireotide LAR is initiated
and glucose levels should be closed monitored during the
first 3 months of therapy and for four to six weeks after a
dose increase [71].
Conclusions
Due to the high sst expression on GH-secreting adenoma
cell membrane, SRL still represent the first line medical
treatment for acromegaly. Although a number of different
SRL (selective for a single receptor, bi-specific compounds,
panligands) have been tested in the last decades, octreotide
and lanreotide, together with the recently approved pasire-
otide, represent the only SRL available for the clinical man-
agement of acromegaly to date.
Results from different studies evaluating the efficacy of
the first-generation SRL are largely variable (from 20 to
70% of complete biochemical control), and evidences from
Pituitary (2017) 20:100–108 105
the most recent meta-analysis describe an average control
rate of GH or IGF-1 levels in about 55% of acromegaly
patients. Therefore, these data have raised the issue of SRL
resistance in acromegaly, and forced researchers and clini-
cians to face this challenge. In this context, the histopatho-
logical and molecular markers of response to SRL may
help changing the acromegaly treatment from a uniform,
trial-and-error therapy to a personalized approach based on
these markers. The “cocktail therapies” and the new drug,
pasireotide, represent the first response to this issue. As for
pasireotide, the results coming from real life experience in
acromegaly will be crucial to define the positioning of this
new SRL in the treatment algorithm of the disease.
Moreover, further research is strongly needed in order
to develop even more safe and effective compounds, fully
exploiting the huge amount of novel insights in the patho-
physiology of sst acquired in the recent years.
Compliance with ethical standards  12. Ben-Shlomo A, Melmed S (2008) Somatostatin agonists for
Conflict of interest  MRG has received unrestricted research grants
and lecture fees from Novartis, Ipsen and Pfizer, has participated on
advisory boards of Novartis and Ionis and is PI in clinical trials by
Novartis and Ipsen. LEW has no conflicts of interest to declare. MDB
is speaker for Ipsen and Novartis; member of Steering Committees of
Chiasma, Ipsen and Novartis; PI of clinical trials of Ipsen, Novartis
and Pfizer. FG is speaker for Novartis and participated on advisory
boards of Novartis, AMCo Ltd. and IONIS Pharmaceuticals. DF is
speaker, participated on advisory boards and received research grants
from Novartis and Ipsen.
Ethical approval  This article does not contain any studies with
human participants performed by any of the authors as it is a review.
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