Full text of DOI:10.1007/BF03351043

J. Endocrinol. Invest. 24: 430-437, 2001
Expression of somatostatin receptors on human pituitary
adenomas in vivo and ex vivo
S. Nielsen*, S. Mellemkjær*, L.M. Rasmussen**, T. Ledet***, N. Olsen****,
M. Bojsen-Møller*****, J. Astrup******, J. Weeke*, and J.O.L. Jørgensen*
*
Medical Department M; **Laboratory for Molecular Pathology; ***Research Laboratory for Biochemical
Pathology; ****Department of Nuclear Medicine; *****Department of Neuropathology; ******Department
of Neurosurgery, Aarhus Kommunehospital, Aarhus University Hospital, Aarhus, Denmark
ABSTRACT. The distribution and biologic activity of
somatostatin receptor subtypes (SSTR) in pituitary
adenomas is not clarified, especially regarding clin-
ically non-functioning adenomas (NFPA). We there-
fore characterized SSTR in human pituitary ade-
nomas by combining molecular biology and in vivo
scintigraphy. Co-expression of gonadotropin-re-
leasing hormone receptor (GnRH-R) mRNA was al-
so assessed to see whether this feature was asso-
ciated with adenoma subtype and SSTR status.
Pituitary tumor biopsies were obtained during
transsphenoidal adenomectomy from 21 patients
expressed in 18 cases, whereas SSTR4 was absent
in all but one. SSTR3 was frequently expressed in
NFPAs. Somatostatin receptor scintigraphy was
positive in most cases, and with a significantly high-
er uptake index in GH-producing adenomas all of
which expressed SSTR2 mRNA. The uptake index
appeared to be related to receptor density rather
than tumor volume. Expression of GnRH-R mRNA
was found in both NFPAs and GH-producing ade-
nomas and was not significantly associated with a
particular SSTR subtype population. In conclusion:
1) the distribution of SSTR is not significantly dif-
ferent between NFPA and GH-producing adeno-
mas; and 2) somatostatin receptor scintigraphy re-
veals a higher uptake in GH-producing adenomas
which is not significantly related to either SSTR dis-
tribution or tumor volume.
(
11 NFPA, 7 acromegalics, 2 prolactinomas, 1
Cushing’s disease). Expression of mRNA encoding
the 5 known SSTR subtypes and the GnRH-R was
determined by RT-PCR. Twelve patients also un-
derwent a pre-operative somatostatin receptor
scintigraphy. Most adenomas (no.=18) expressed
mRNA for more than one SSTR. SSTR2 mRNA was
(J. Endocrinol. Invest. 24: 430-437, 2001)
©
2001, Editrice Kurtis
INTRODUCTION
ever, well known that both the clinical response to
SS analogues as well as the outcome of in vivo re-
ceptor imaging display marked heterogeneity both
between and within different pituitary tumor types
(1-5). These differences are partly attributed to the
existence of at least 5 distinct SS receptor subtypes
(SSTR1-5), which exhibit differences regarding
amino acid sequence, affinity for SS analogues, and
SS is widely distributed throughout the central ner-
vous system and peripheral tissues. Hypothalamic
SS inhibits the secretion of hormones from the an-
terior pituitary, in particular GH and TSH, and also
exhibits anti-proliferative effects. Long-acting SS
analogues are currently used to control hormonal
hypersecretion and tumor growth in GH- and TSH-
secreting pituitary adenomas. Moreover, SS recep-
tor scintigraphy with radiolabeled octreotide de-
monstrates a high density of SS-binding sites in a
large proportion of pituitary adenomas. It is, how-
®
post-receptor signaling pathways (6). Octreotide
®
and lanreotide have high affinity for SSTR2 and
SSTR5, however, octreotide predominantly visual-
izes SSTR2. On the contrary, in vitro data suggest
that SSTR5 may be even more critical for the sup-
pression of anterior pituitary hormone release (6).
The distribution of SSTR expression in human pitu-
itary adenomas has not yielded uniform results (7-
Key words: Pituitary adenomas, somatostatin receptors, GnRH receptors.
Correspondence: Dr. Steen Nielsen, Medical Department M (Diabetes
and Endocrinology), Aarhus Kommunehospital, DK-8000 Aarhus C,
Denmark.
1
3). It is, however, apparent that the majority of tu-
mors expresses SSTR2 mRNA, whereas SSTR4 ex-
pression has only been reported in one study (10).
The degree of expression of SSTR1, SSTR3, and
E-mail: stn@adfm.au.dk.
Accepted November 15, 2000.
430

S. Nielsen, S. Mellemkjær, L.M. Rasmussen, et al.
SSTR5 appears to be more heterogeneous, espe-
cially in clinically non-functioning pituitary adeno-
mas (NFPAs). Regarding NFPAs, the differences
may reflect that this diagnostic entity comprises
several subtypes (14-16). The suppression by SS of
the secretion of gonadotropins and α-subunit is not
seen in all NFPAs (1, 17). Moreover, functional SSTR
protein has been documented by SS receptor
scintigraphy in some NFPAs, but the outcomes of
scintigraphy and SSTR expression have so far only
been directly compared in a small study in which
no association between the outcome of SS recep-
tor scintigraphy and SSTR distribution could be
documented (2). From a clinical point of view, more
insight into the composition and function of SSTR in
well-characterized pituitary adenomas may provide
a basis for designing SS analogues with distinct re-
ceptor affinities for treatment of not only GH-secre-
ting tumors, but also other pituitary diseases.
all tumors ex vivo, together with pre-operative in
vivo SS receptor scintigraphy. In addition, we asses-
sed mRNA expression of GnRH receptors in an at-
tempt to further characterize NFPA and evaluate
whether this feature was associated with a specific
SSTR composition.
SUBJECTS AND METHODS
Patients (Table 1)
Twenty-one patients with pituitary adenomas were
included in the study. All patients were character-
ized by a pre-operative routine endocrinological
examination. Tissue samples from the 21 patients
were obtained for reverse transcriptase polymerase
chain reaction (RT-PCR) analysis, whereas immuno-
histochemical analysis was performed on tissue
samples from 18 patients. Twelve patients under-
went a pre-operative SS receptor scintigraphy, and
a TRH-test with determination of TRH stimulated
α-subunit levels were performed in 14 individuals.
The diagnosis of a NFPA was based on the pres-
In this prospective study of acromegalic and NFPA
patients undergoing transsphenoidal adenomecto-
my we investigated mRNA expression of SSTR1-5 in
Table 1 - Characterization of subjects.
Pt. nr.
Sex
F
Age
60
27
67
35
35
61
51
61
49
51
36
26
40
65
63
49
47
30
36
27
35
Diagnosis
Treatment (prior to surgery)
3
5
7
9
NFPA
NFPA
Thyroxine
F
Insulin (T1DM)
F
NFPA
Estradiol, norethistrone
F
NFPA
Hydrocortisone
1
1
1
1
1
1
1
1
2
4
8
1
1
2
6
2
1
2
3
4
5
6
7
8
M
M
F
NFPA
Hydrocortisone, testosterone
NFPA
Hydrocortisone, testosterone, thyroxine
NFPA
-
M
M
M
F
NFPA
Hydrocortisone, testosterone
NFPA
-
NFPA
-
NFPA
Hydrocortisone
F
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Prolactinoma
Prolactinoma
Cushing’s disease
Hydrocortisone, thyroxine, desmopressin
M
M
M
F
-
-
Octreotide, lisinopril (hypertension)
0
1
1
Antihypertensive drugs
M
M
F
-
Hydrocortisone
-
0
9
F
Bromocriptine
-
F
F: female; M: male; NFPA: non-functioning pituitary adenomas; T1DM: type 1 diabetes mellitus.
431

Pituitary somatostatin and GnRH receptors
ence of a pituitary macroadenoma as assessed by
either magnetic resonance imaging (MRI) or com-
puted tomography (CT) in the absence of clinical
and biochemical signs of hormonal hypersecretion.
Prolactin levels were either normal or only moder-
ately elevated (<50 μg/l). Normal to low levels of
FSH and LH were found in all patients.
The diagnosis of acromegaly was based on clinical
symptoms and signs together with significantly in-
creased serum IGF-I levels (mean±SE: 980±150
μg/l, range 402-1662 μg/l) and sustained elevations
in basal GH concentrations obtained from frequent
serum sampling over a 5-h period with the patient
in a supine position (mean±SE: 6.20±2.15 μg/l,
range: 1.67-18.23 μg/l).
The 2 patients with prolactinomas had prolactin
serum concentration of 221 and 880 μg/l (normal
range: 1-18 μg/l), respectively, and both patients
initially presented with amenorrhea. In the single
case of Cushing’s syndrome the diagnosis was
based on clinical symptoms and markedly elevat-
ed excretion of cortisol: 2668, 2995 and 3024
nmol/24 h on 3 separate days. Furthermore, a sig-
nificant ACTH response to CRH was demonstrated
during a CRH test.
Taq DNA polymerase/20 μl and 500 pmol of each
specific primer. The following primers were used:
SSTR1: 5’-GGAACTCTATGGTCATCTAC-3’ and 5’-
GCTGAGCACAGTCAGACAGT-3’ (3), SSTR2: 5’-
TGACAGTCATGAGCATCGAC-3’ and 5’-GCAAA-
GACAGATCATGGTGA-3’ (3), SSTR3: 5’-TCATCT-
GCCTCTGCTACCTG-3’ and 5’-GAGCCCAAAGA-
AGGCAGGCT-3’ (3), SSTR4: 5’-ATCTTCGCAGA-
CACCA GACC-3’ and 5’-ATCAAGGCTGGTCAC-
GACGA-3’ (3), SSTR5: 5’-CGTCTTCATCATCTACAC-
GG-3’ and 5’-GGCCAGGTTGACGATGTTGA-3’ (3),
GnRH-R: 5’-CAGCAAAGTCGGACAGTC and 5’-
AGTTGTAGTTCGTGGGGG (16) and finally GAPDH:
5’-GCCAAAAGGGTCATCATCTC-3’ and 5’-GTA-
GAGGCAGGGATGATGTTC-3’. Amplification of
DNA was performed with two initial cycles at 95 C for
60 sec followed by 60 sec at temperature of anneal-
ing which was specific for each primer and 60 sec at
73 C; this was followed by a number of cycles at 94 C
for 45 sec, followed by 45 sec at the temperature of
annealing and 45 sec at 73 C, and in the final cycle
the samples were incubated for 2 min at 73 C. The
temperature of annealing was 60 C in the case of
SSTR1-4, 65 C in the case of SSTR5, and finally 50 C
in the case of GAPDH and the GnRH-R. The amplifi-
cation of DNA was carried out in 30 cycles in the case
of GAPDH, 30 cycles for GnRH receptor and finally
38 cycles for SSTR1-5. The PCR product was sepa-
rated by gel electrophoresis in a 2% agarose gel con-
taining ethidium bromide. To ensure that an appro-
priate sensitivity level was used, the number of PCR
cycles was chosen after optimization experiments us-
ing a pool of cDNA containing reverse transcribed
RNA from several tumor types. This cDNA pool was
subjected to different number of cycles between 30
and 40. The number of cycles which gave rise to a
weak band was chosen for evaluation of all samples.
The PCR products were visualized in ultraviolet light
RT-PCR
The tissue samples were collected at the time of
transsphenoidal adenomectomy, immediately
frozen in liquid nitrogen and kept at -80 C until an-
alyzed.
Total RNA was extracted from the tissue samples
®
with Trizol (GIBCO BRL). The amount and the qua-
lity of the RNA was assessed by measurement of
the optical density at 260 and 280 nm.
From each sample 1 μg of RNA was used for re-
verse transcription in 30 μl of buffer with final con-
centrations of 50 mM Tris, pH 8.3, 75 mM KCl, 3
®
mM MgCl , 0.5 mM dATP, 0.5 mM dTTP, 0.5 mM
using equipment from BioRad . As an arbitrary cut-
2
dCTP, 0.5 mMdGTP, 30 pmol random hexamers/30
μl and 200 U MMLV reverse transcriptase. The sam-
ples were incubated for 75 min at 37 C followed by
incubation for 15 min at 95 C. A similar procedure
was performed in a duplicate sample but without
the addition of the MMLV-RT. This non-reverse tran-
scribed material served as a negative control for
the PCR procedures. As a positive control expres-
sion of mRNA encoding the house-keeping enzyme
GAPDH was determined by a similar RT-PCR pro-
cedure.
off level a clearly visible band was considered as a
sign of gene transcription. The results of the gel
electrophoresis were determined by an indepen-
dent investigator who was unaware of the clinical
characteristics of the patients.
All PCR-reactions gave rise to DNA fragments with
the expected size.
Somatostatin receptor scintigraphy
111 MBq of 111In-pentetreotide (Octreoscan, Mal-
lincrodt) was given as an intravenous injection. The
profile of the cranium was imaged after 21 h using
a Siemens Orbiter gamma camera equipped with
a medium-energy, parallel-hole collimator and in-
terfaced to a Picker Odyssey VP Computer. The
pulse height analyzer windows were centered over
For the polymerase chain reaction 2 μl of the reverse
transcription product was used in 20 μl of solution
which contained final concentrations of 20 mM Tris,
pH 8.4, 50 mM KCl, 1.5 mM MgCl2, 0.5 mM dATP,
0.5 mM dTTP, 0.5 mM dCTP, 0.5 mM dGTP, 2.5 U
432

S. Nielsen, S. Mellemkjær, L.M. Rasmussen, et al.
Immunohistochemistry and α-subunit
1
71 keV and 245 keV with window widths of 20%
measurements
and 15%. The acquisition was performed with a
hardware zoom of x 1.5, a matrix of 128 x 128 and
total counts of 300.000 (18, 19). On the profile view,
circular regions of interest (ROIs) were placed on
the pituitary area and on the hemispheric brain. The
pituitary ROI was small (9 pixels) and centered
around the pixel with highest activity. The hemi-
spheric ROI (212 pixels) was placed over the pos-
terior part of the cerebrum. The uptake index was
calculated as the ratio of the pituitary mean activi-
ty to the hemispheric mean activity (19, 20). An up-
take indexꢀ2.5 was considered positive.
Adenoma tissue from all patients was fixed in phos-
phate buffered formalin for 24 h at room tempera-
ture, paraffin embedded and cut in 5 μm thick
slices. All sections were boiled for 10 min in a mi-
crowave oven. Endogenic peroxidase was blocked
by incubation for 30 min with methanol containing
0.9% H O . The antigens were visualized using a
2
2
classical immuhistochemical technique in which all
the primary polyclonal and the only monoclonal (α-
subunit) antibodies were applied in a concentration
between 1/400 and 1/1000. The secondary anti-
Table 2 - Expression of mRNA encoding all 5 somatostatin receptor subtypes (SSTR) and the GnRH receptor (GnRH-R).
Non-functioning pituitary adenomas
Patient no.
SSTR1
SSTR2
SSTR3
+
SSTR4
SSTR5
+
GnRH-R
3
5
7
9
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
12
13
14
15
16
17
18
+
+
+
+
+
+
+
+
+
+
Acromegaly
Patient no.
SSTR1
SSTR2
SSTR3
+
SSTR4
SSTR5
+
GnRH-R
1
2
4
8
+
+
+
+
+
+
+
+
+
+
+
+
+
+
10
11
21
+
+
+
Prolactinomas
Patient no.
6
SSTR1
SSTR2
+
SSTR3
+
SSTR4
SSTR5
+
GnRH-R
+
+
+
20
Cushing’s disease
Patient no.
SSTR1
SSTR2
SSTR3
+
SSTR4
+
SSTR5
GnRH-R
19
433

Pituitary somatostatin and GnRH receptors
body containing horseradish-peroxidase was used
in a dilution of 1/100. The color was developed by
diaminobenzidine and the nuclei were stained with
hematoxylin. Antibodies against the following com-
ponents were used: ACTH, GH, prolactin, FSH, LH,
TSH, α-subunit and SS.
were expressed in 8, 15 and 7 tumors, respective-
ly. SSTR4 mRNA was only detected in one tumor,
which was the only ACTH-secreting tumor in the
present study.
mRNA encoding the GnRH receptor was detected
in 9 of 21 adenomas. More than half of the NFPAs
(6 out of 11) expressed GnRH-R mRNA, but there
was no statistical difference in the frequency of
GnRH-R mRNA expression between the NFPAs and
the rest of the tumors (p=0.26). No statistically sig-
nificant association was detected between expres-
sion of GnRH-R mRNA and SSTR mRNA subtypes.
Serum levels of α-subunit were assessed by a mo-
®
noclonal antibody radioimmunoassay (Biomerica ).
The patients were admitted to the endocrine re-
search laboratory at 09:00 h and a cannula was in-
serted in an antecubital vein. Blood samples for as-
sessment of serum levels of α-subunit were drawn
at -90, -75, -60, -45, -30, -15, 0, 15, 30, 45, 60, 75
and 90 min, and 400 μg TRH was given intra-
venously at 0 min. The peak value of α-subunit af-
ter administration of TRH was compared to the av-
erage α-subunit concentration in the samples taken
prior to TRH administration.
Somatostatin receptor scintigraphy (Table 3)
A pathological uptake index was found in 9 of 12
patients of whom 5 harbored a GH-producing pi-
tuitary adenomas, and 4 harbored NFPAs. In 2 pa-
tients with an NFPA and the patient with the ACTH-
producing adenoma a normal uptake index was
found. The mean uptake index among patients with
GH producing adenomas was significantly higher
compared to NFPAs [mean±SE: 4.58±0.63 (range:
3.60-7.00) vs 3.37±0.71 (range: 2.32-6.87), respec-
tively (p<0.05)].
Statistics
Non-parametric data were compared by Wilcoxon’s
signed rank test for paired samples while non-
paired data were compared by Mann-Whitney’s U
test. Proportions were compared by the Chi-square
test. A p-value less than 0.05 was considered sta-
tistically significant.
No distinct association was apparent between the
pattern of SSTR mRNA expression and the outcome
of SS receptor scintigraphy. Nevertheless, SSTR2
mRNA was demonstrated in 8 out of 9 with a patho-
logical uptake index.
RESULTS
Immunohistochemistry and α-subunit
measurements (Table 1)
MRI showed a suprasellar tumor extension in 8 of
12 cases. Neither the volume nor the width of the
All preparations showed adenoma tissue only.
Staining for prolactin was found in both prolacti-
nomas and 2 of 4 somatotroph adenomas, as well
as one NFPA. Immunostaining for LH was more fre-
quently positive among NFPAs than in the rest of
the tumors in this series (p<0.05), whereas the fre-
quency of the positive immunostaining for FSH,
TSH and α-subunit did not differ significantly bet-
ween the groups. In NFPAs staining for TSH was
positive in 6 of 9 cases and staining for α-subunit
was positive in 5 of 9 cases. Furthermore, α-sub-
unit was found in 4 of 5 somatotroph adenomas,
and in one corticotroph adenoma. The peak value
of α-subunit increased significantly after injection
of TRH (basal: median: 116.25 mIU/ml; TRH-stimu-
lated peak: median 464 mIU/ml, p=0.002).
tumor was significantly associated with the uptake
index (volume: r=0.469, p=0.124; width: r=0.381,
p=0.222) as assessed by linear regression.
DISCUSSION
The present study was performed to further our un-
derstanding of SS receptors in human pituitary ade-
nomas by combining molecular biology and in vivo
scintigraphy. Our main finding was that SSTR2
mRNA is expressed in the vast majority of soma-
totroph pituitary adenomas and NFPAs, whereas
SSTR4 mRNA is absent in most cases. SS receptor
scintigraphy was positive in most cases, and with a
significantly higher uptake index in GH-producing
adenomas all of which expressed SSTR 2 mRNA.
Expression of GnRH-R mRNA was present in both
NFPAs and some GH-secreting adenomas and was
not associated with a specific pattern of SSTR.
Relatively few studies have evaluated the expression
of SS receptor subtypes in human pituitary adeno-
mas (7-10) and discrepancies remain regarding the
distribution. In agreement with 2 of the studies (7, 9)
we observed SSTR2 mRNA to be expressed in the
Somatostatin receptor and gonadotropin
releasing hormone receptor mRNA expression
(Table 2)
In most tumors (no.=18) expression of mRNA en-
coding multiple SSTR was demonstrated. SSTR2
was the most widely distributed (no.=18), whereas
SSTR1 mRNA, SSTR3 mRNA and SSTR5 mRNA
434

S. Nielsen, S. Mellemkjær, L.M. Rasmussen, et al.
Table 3 - Somatostatin receptor scintigraphy and somatostatin receptor subtypes (SSTR) mRNA expression.
Patient no.
Diagnosis
SSTR mRNA
3
Uptake index
MRI
D
1
2
+
+
+
4
5
H
W
5
5
9
NFPA
NFPA
+
+
2.79
2.68
2.32
3.12
2.40
6.87
4.64
3.81
7.00
3.86
3.60
1.92
6
5
+
+
+
+
20
31
28
31
33
12
20
42
20
11
3
12
22
28
21
29
17
20
18
20
11
3
18
34
28
23
34
14
25
24
18
11
3
1
1
1
1
4
8
1
1
2
1
2
3
7
8
NFPA
NFPA
NFPA
+
+
+
+
+
+
+
+
+
NFPA
+
+
+
+
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Acromegaly
Cushing
+
+
0
1
1
9
+
+
+
+
+
H, D and W: height, depth and width (mm) of the adenomas as measured by magnetic resonance imaging (MRI). Uptake indexꢀ2.5 is considered
positive.
vast majority of NFPAs and somatotroph pituitary
adenomas. Moreover, we have confirmed that SSTR4
mRNA is absent in NFPAs as well as somatotroph pi-
tuitary adenomas. Especially regarding the SSTR3
the previous studies disagree, since Greenman et al.
pressed in most pituitary adenomas and the RT-
PCR analysis reflects the distribution of SSTR in
these tumors.
It is generally believed that SS receptor imaging
mainly visualizes SSTR2 receptors (23), but our
study is the first to provide a direct comparison be-
tween the outcome of octreotide scintigraphy and
the distribution of pituitary SSTR in the same pa-
tient. As predicted SSTR2 mRNA was found in 8 of
9 tumors in which a pathological uptake index was
found. SSTR2 mRNA was, however, also expressed
in 2 NFPAs with a normal uptake index, which could
be explained by detection of a very low level of
SSTR2 receptors by the sensitive PCR method.
Surprisingly, a pathological uptake index was found
in a patient only expressing SSTR3 mRNA despite
the relatively low affinity of octreotide for SSTR3.
The accumulation of radioactivity was estimated by
a scintigraphic index. No correlation between ei-
ther tumor-volume or tumor-width, and uptake in-
dex could be demonstrated. These observations
suggest that the uptake index primarily depends
on the type of the tumor and the density of func-
tioning receptors with a high affinity for the scinti-
graphic tracer (pentetreotide). The high uptake in
acromegaly may therefore also suggest a higher SS
receptor density in somatotroph adenomas com-
pared to NFPAs which has also been proposed in a
previous study (2).
(8) demonstrated the expression of SSTR3 mRNA in
all NFPAs and most somatotroph adenomas, where-
as Miller et al. reported this receptor subtype to be
absent in all NFPAs and most somatotroph adeno-
mas. We found the expression of SSTR3 to be a com-
mon feature in both of these tumor types. Ad-
ditionally, our study indicates that SSTR1 mRNA and
SSTR5 mRNA are expressed in some but not all
NFPAs and somatotroph adenomas. By contrast,
Greenman et al. (8) found SSTR5 mRNA to be ex-
pressed in most somatotroph adenomas and Jaquet
et al. (13) demonstrated the expression of SSTR5
mRNA in all 15 GH-secreting tumors included.
However, in the latter study SSTR5 mRNA expres-
sion was subject to considerable variation, and in
that context our data using an arbitrary cut-off level
in a qualitative assessment of mRNA expression sup-
port different levels of SSTR5 mRNA expression in
this particular adenoma type.
In this context it should be remembered that RT-
PCR analysis only reveals the presence of mRNA
and not the intact and functioning receptor itself.
However, the presence of SS receptors in pituitary
adenomas has previously been demonstrated by
means of autoradiographic methods (21, 22). Con-
sequently, it seems likely that SS receptors are ex-
The clinical value of a scintigraphic uptake index is
still a matter of debate (2, 24, 25). A so-called den-
435

Pituitary somatostatin and GnRH receptors
sity index (DI), based on the ratio between the up-
take index of the whole pituitary area and the vol-
ume of the tumor obtained by MRI, has been sug-
gest to provide a better predictive measure of the
efficacy of SS analogue treatment of pituitary ade-
nomas (25). In our study, however, a DI calculated
as the ratio between the uptake index and the
width of the adenoma did not give a better sepa-
ration between NFPA and somatotroph adenomas
than that of our uptake index (data not shown).
Expression of GnRH-R mRNA has mainly been docu-
mented in a small number of NFPAs (16, 26, 27). Our
finding of GnRH-R mRNA in 6 out of 11 NFPA ex-
tends and supports the previous reports. Several lines
of evidence suggesting that both hypothalamic- and
pituitary-derived GnRH may play a role in the regu-
lation of pituitary tumor cell growth (27), which makes
it potentially relevant to study the association be-
tween mRNA expression of GnRH-R mRNA and SSTR
in individual pituitary adenomas. We did not, how-
ever, find evidence of a unique pattern of co-expres-
sion of these receptors apart from the observation
that 8 out of 9 GnRH-R positive adenomas also ex-
pressed SSTR 2 mRNA. Future experimental studies
are needed to evaluate whether modulates the ac-
tion of GnRH on pituitary tumor cell biology.
In summary, our study confirms that SSTR2 mRNA is
expressed in most pituitary adenomas in contrast to
SSTR4, which was absent in all but one. Moreover
SSTR3 mRNA is frequently expressed in NFPAs and
in a substantial proportion of other pituitary adeno-
mas. SS receptor scintigraphy in vivo revealed a
pathological or significant uptake index in 75% of the
tumors, which appeared to be related to receptor
density rather than tumor volume. Future studies with
specific antagonists will undoubtedly teach us more
about the biology of pituitary adenomas.
Identification of somatostatin receptor subtypes and
an implication for the efficacy of somatostatin analogue
SMS 201-995 in treatment of human endocrine tumors.
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4
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