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Original Studies |
Mutations in Somatotroph Adenomas1
Laboratoire Interactions Cellulaires Neuroendocriniennes, UMR 6544 Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord (A.B., G.G., A.J.Z., I.M.-R., A.E., P.J.); and Service d’Endocrinologie (I.M.-R., P.J.), Laboratoire d’Anatomie-Pathologique et de Neuropathologie (D.F.-B.), and Service de Neurochirurgie (H.D.), Centre Hospitalo-Universitaire Timone, Marseille, France
Address all correspondence and requests for reprints to: Dr. Anne Barlier, Laboratoire ICNE, UMR 6544 CNRS, Université de la Méditerranée, Institut Fédératif Jean-Roche, Faculté de Médecine Nord, boulevard P. Dramard, 13916 Marseille Cedex 20, France. E-mail: barlier.a{at}jean-roche.univ.mrs.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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-subunit of G proteins. However, the impact of
the gsp mutations on the tumoral phenotype is not well
understood at present. This study aims to determine whether the
detection of this mutation could impact on the management of
acromegalic patients. We examined 30 acromegalic patients; 8 were
gsp positive, and 22 were gsp negative.
The gsp-positive adenomas appeared to secrete
significantly more when the ratio of basal GH level/tumor size was
considered. A better octreotide sensitivity of mutated adenomas was
clearly shown under in vivo (short and long term) and
in vitro conditions. During the acute octreotide test,
the GH nadir was significantly lower in the gsp-positive
adenomas (85% of maximal inhibition vs. 52%). Eighteen
patients were treated with octreotide (300 µg/day) for at least 3
months before surgery: the percent inhibition of GH hypersecretion was
higher in gsp-positive adenomas (76% vs.
47%). In cell culture, the octreotide-induced inhibition of GH release
was significantly higher in gsp-positive adenomas (71%
vs. 30%). Finally, during 2 yr of postoperative
follow-up, GH hypersecretion was controlled in all patients with
gsp mutation even in those in whom tumoral tissue
remained after surgery. On the contrary, in the
gsp-negative group, octreotide treatment was unable to
control hypersecretion in 4 patients bearing tumoral remnants. The
Gs mutation could, therefore, be a new marker to foresee
the susceptibility of the tumor to be controlled by somatostatin
analogs, which improves prognosis. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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-subunit of G proteins were initially reported by
Landis and collaborators in 1989 in four somatotroph tumors
characterized by markedly high cAMP levels (1). These mutations are
localized at two critical sites concerning the intrinsic guanosine
triphosphatase activity of the protein, i.e. amino acid
residues 201 and 227, leading to a constitutive activation of the
adenylyl cyclase (2). The mutated protein has been named the
gsp oncogene (1).
Several groups tried to characterize the clinical and biological
tableau of the patients bearing somatotroph adenomas indexed either
under the gsp oncogene or high adenylate cyclase activity
(3, 4, 5, 6, 7, 8). A broader issue raised by these clinical studies has been to
determine whether the presence of the Gs
mutation could have some impact on the management of this category of
acromegalic patients according to their variable sensitivities to
somatostatin agonists (9). The results of these studies have been
conflicting. The reported frequencies of Gs
subunit mutations range from 4.4–43% (3, 10). The smaller tumor size
of adenomas with mutations found by the two initial studies (3, 4) was
not confirmed by others (5, 6). The basal GH level was reported to be
lower (3), higher (4), or not significantly different (5, 6, 7, 8) compared
to levels in patients bearing the wild-type adenoma. Finally, some
studies have suggested that tumors with the gsp oncogene (7, 8, 11) or with high adenylate cyclase activity (4) displayed a better
sensitivity to somatostatin.
In the present work we examine whether the identification of the
gsp oncogene could be used as a therapeutic and pronostic
clue in the postoperative outcome as well as in treatment with
somatostatin agonists. Thirty acromegalic patients, all treated with
surgery, were categorized into two groups according to the presence or
absence of the Gs mutation. Their endocrine
and tumoral characteristics were compared in terms of GH secretory
pattern, tumor mass, histological data, and sensitivity to octreotide.
After surgery, the cure and the therapeutic outcome of patients were
evaluated in both groups. The tissue culture of the tumors allowed
determination of the in vitro sensitivity of cells in both
categories. These data provide further information about the impact of
the Gs mutation upon the evolution of GH
secretory adenomas and their therapeutic outcome.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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The present study was approved by the ethics committee of the University of Aix-Marseilles (France) and was undertaken after informed consent was received from each patient and the other participants.
Thirty acromegalic patients, from 24–67 yr of age, were studied. The
endocrine status and the characterization of the tumors were performed
before any treatment. The basal GH and PRL plasma levels were expressed
as the mean of GH or PRL measurements obtained hourly for 6 h.
Eight patients presented GH-PRL-secreting adenomas with supranormal
basal levels of both hormones. The size and extent of each pituitary
tumor were evaluated by magnetic resonance imaging and are indicated in
Table 1
. The evaluation of somatostatin
sensitivity over the short term was performed by an acute test using a
single 100-µg sc injection of octreotide (Sandostatin, Novartis,
Basel, Switzerland). Blood samples were obtained every hour for 6
h to measure both GH and PRL plasma concentrations. Acromegalic
patients were considered to be good responders when the mean GH levels
between 1–6 h after the first acute administration decreased to less
than 5 µg/L. Before surgery, 18 patients had been treated daily with
sc injections (100 µg, 3 times daily) of octreotide for 3–7 months.
The baseline plasma GH level was determined, as described above, after
3 months of treatment to evaluate the response to the long term
octreotide treatment. Due to the absence of tumor shrinkage after
treatment, all of the 30 patients underwent transphenoidal surgery. In
the 18 patients treated with octreotide, the drug was withdrawn at
least 2 weeks before surgery. The mean follow-up period after surgery
was 22 ± 3 months (range, 2–71 months). The criteria employed
for evaluating the cure for acromegaly were as follows: basal serum GH
level (mean of 6 hourly samples) lower than 2.5 µg/L, normalization
of the insulin-like growth factor I (IGF-I) level, and normal GH
dynamics, i.e. reversal of the abnormal preoperative GH
response to TRH and decrease in GH to a concentration lower than 1
µg/L during the glucose tolerance test (75 g, orally).
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Materials and Methods |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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subunit mutations in
tumor complementary DNA (cDNA)
The 30 somatotroph adenomas were collected immediately after
transphenoidal ablation and frozen at -80 C. From each tumoral
fragment, the total ribonucleic acid (RNA) was extracted using the
guanidium isothiocyanate-phenol method (13). A reverse transcriptase
(RT) reaction was performed from 5 µg total RNA with 200 U
Superscript II ribonuclease H-free RT (Life Technologies, Grand Island,
NY). A negative control was performed for the first strand synthesis,
which contained all of the above reagents but no RNA sample. A cDNA
fragment of 346 bp encompassing codons 201 and 227 of the
Gs gene was amplified from each sample by the
use of PCR with G1 and G2 amplimers (G1,
5'-AGGCTCTGTGGGAGGATGAAG-3'; G2, 5'-AGGCGGTTGGTCTGG
TTGT-3'). Two microliters of the RT product were amplified for 30
cycles in appropriate buffer with 50 pmol of each primer and 5 U native
Pfu DNA polymerase (Stratagene, La Jolla, CA), a
proofreading DNA polymerase, in a total volume of 100 µL. The
amplification conditions were as follows: denaturation at 96 C for 1
min using a Perkin-Elmer apparatus (Perkin-Elmer/Cetus, Norwalk, CT),
annealing at 62 C for 1 min, and extension at 72 C for 2 min. Negative
controls were run in parallel with the test tissues, using the negative
control of the RT reaction as a template for amplification. The
efficiency of the PCR was controlled on agarose gel, and the PCR
products were purified by spin column chromatography with Sephacryl
S-300 resin (Microspin S-300 HR column, Pharmacia, Piscatway, NJ). The
purified PCR products were used in a direct sequencing reaction with a
set of 5'- and 3'-fluorescein-labeled amplimers, localized medialad to
the G1 and G2 primers (S1, 5'-TTCCTGGAGAAGATCGAGG-3';
S2, 5'-CGGATGACCATGTTGTAG-3'). Direct DNA sequencing of the
PCR products was performed with an automated DNA sequencing system (ALF
DNA sequencer, Pharmacia).
Hormone assays
The measurements of PRL and GH were performed using commercial kits (Immunotech, Marseilles, France; Medgenix Diagnosis, Fleurus, Belgium). Normal PRL values ranged from 1–24 µg/L in women and from 1–17 µg/L in men. After an ethanol-acid extraction, the plasma IGF-I assay was performed using the IGF-I RIA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA). Normal IGF-I values vary according to age and sex and were established by our laboratory.
Immunocytochemistry
Tumoral tissue was placed in 10% formalin and embedded in
paraffin. Serial 5-µm sections were processed for Herlant’s
tetrachrome and periodic acid-Schiff stainings. Immunocytochemistry was
carried out using monoclonal antibodies directed against human PRL
(1:200 dilution), glycoprotein -subunit (GSU; 1:1000), LHß
(1:1000), FSHß (1:1000), and TSHß (1:1000) from Immunotech
(Marseilles, France); and monoclonal anti-GH antibody and polyclonal
anti-ACTH from Amersham (Les Ulis, France) and Dakopatts (Versailles,
France), respectively. Detection was performed using the
avidin-biotin-peroxidase method (ABC kit, Vector Laboratory, Institut
Pasteur, Paris, France). Controls were performed by replacing the
primary antibody with irrelevant Igs. The intensity of cell labeling
was ranked as low, medium, and high, and the observations were made by
the same investigator.
Cell culture studies
After surgery, fragments of each tumor were dissociated by mechanical and enzymatic methods (14). Three to 5 x 105 cells were plated on wells previously coated with extracellular matrix from bovine endothelial corneal cells (14). Tumoral cells were cultured in DMEM supplemented with 5% FCS. Subsequently, the cells were washed and cultured during 24 h in serum-free medium, as previously described (14), with or without a maximal 10-8 mol/L concentration of octreotide. The effects of the drug were tested in quadruplicate. Culture media were then collected and stored frozen for GH and PRL measurements.
Statistics
The results are presented as the mean ± SEM.
Statistical significance was determined by Mann-Whitney and
Kruskal-Wallis tests and by a nonparametric two-factor ANOVA.
Qualitative data were analyzed by 
2 test with Yates’
correction. To measure the strength of association between pairs of
variables without specifying dependency, Spearman rank order
correlations were run. The hyperbolic plot of the mean percentages of
blood GH inhibition after injection of octreotide was found to be the
best fit between the observed values and their graphic representation
(15). P < 0.05 was considered significant in all
tests.
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Results |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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subunit mutationsEight of 30 somatotroph adenomas (27%) presented a point mutation at Arg201. In all of these cases, Arg was converted to Cys, reflecting a CGT to TGT mutation. Accordingly, the cohort of acromegalic patients was divided into two groups. Data for patients in the gsp-positive group (n = 8) were thus compared to those for subjects in the gsp-negative group (n = 22).
Clinical and biological data
Concerning the Gs mutation, age and sex
did not differ significantly (Table 1
). Tumor size, as measured by
maximal diameter on magnetic resonance images, also was not different
(Table 1). As shown in Table 1, the distribution of gsp
mutations among the three categories of tumors, (microadenomas,
macroadenomas with moderate suprasellar extension, and macroadenomas
with extrasellar extensions) was not significantly different. However,
macroadenomas larger than 30 mm (n = 5) corresponded exclusively
to the gsp-negative group (data not shown). Extrasellar
extensions were found more frequently in the wild-type tumor (68%
vs. 37.5%), although the difference did not reach
statistical significance.
Preoperative basal serum GH and IGF-I levels were also not
significantly different. Plasma GH levels were correlated with adenoma
size (r = 0.47; P < 0.0059), which allows
correlation of secretion to tumor size. When the GH level/tumor
diameter ratio was considered, the adenomas with a
Gs mutation presented a higher secretory
activity (P < 0.04; Fig. 1). The PRL levels were higher in the
gsp-positive group (P < 0.03; Table 1).
Among the PRL- and GH-secreting adenomas, four of eight had the
Gs mutation.
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With respect to GH, the immunostaining ranking was not
significantly different in either group (P < 0.88).
With respect to PRL, despite the fact that gsp-positive
tumors secreted more PRL (Table 1), no difference was found between the
groups; positive PRL cells were found in 5 of 8 (62.5%) tumors with
mutation and in 12 of 22 (55%) tumors without mutation
(P < 0.67). The immunostaining ranking for
PRL-positive cells was also not different (P < 0.45).
Similarly, GSU-positive cells were found in the same proportion in
both categories. Four of 8 tumors with mutation and 7 of 22 (32%)
without mutation included cells positively immunostained for GSU
(P < 0.64), and the ranking did not differ
(P < 0.45).
Acute responses to octreotide
An acute octreotide test was performed before any treatment in 25
of 30 acromegalic patients, 7 with mutated tumors and 18 with wild
tumors. The mean percentages of octreotide-induced GH inhibition were
77 ± 6% and 59 ± 6% in gsp-positive and
gsp-negative groups, respectively. Octreotide responders
were present in both groups (5 of 7 gsp-positive
vs. 6 of 18 gsp-negative; Fig. 2, A and B). A hyperbolic plot of the
mean percent inhibitions of GH assessed from 1–6 h after a single
injection of octreotide is represented in Fig. 2C. The GH nadir of the
gsp-positive plot was lower (85 ± 4.6% of maximal
inhibition vs. 52 ± 8.4% for gsp-negative
tumors). The most discriminating time between the 2 groups was 5 h
after the injection of octreotide (P < 0.013). PRL
concentrations were measured in the same blood samples obtained during
the octreotide test. The injection of octreotide induced a slight
inhibition of PRL secretion, which was similar in patients bearing and
those not bearing the mutation (17 ± 9% for the mutated tumors
and 21 ± 5% for the wild tumors; P < 0.9).
Among the 8 patients with abnormally high basal PRL levels before
surgery, these levels remained supranormal after the injection of
octreotide in both categories.
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Eighteen patients were treated with octreotide before surgery. The
Gs mutation was found in seven of them. After
a treatment period of 3 months, basal GH levels were evaluated by the
mean of 6 hourly GH measurements. Sixteen patients had clinical
improvement; headache, paresthesia, and soft tissue swelling had
decreased. The two patients without marked improvement were mutation
free. The mean plasma GH value at the time of diagnosis in the
gsp-positive group was 64 ± 23 µg/L and fell to
8 ± 3 µg/L after 3 months of octreotide treatment. In the
gsp-negative group, the mean baseline GH value decreased
only from 51 ± 13 to 36 ± 16 µg/L. The mean GH inhibition
was 76 ± 6% in the mutation group vs. 47 ± 9%
in the wild-type group. The individual analysis (Fig. 3) showed a significant decrease in basal
GH levels in all mutated tumors; these levels were not modified in
three mutation-free adenomas. Three patients with mutated tumors and
three patients with wild-type tumors had plasma GH values below 5
µg/L. Their IGF-I values during treatment were 400, 383, and 203
µg/L for the patients bearing mutated tumors and 414, 347, and 300
µg/L for the patients bearing wild-type tumors (normal range for this
category of patients has been estimated to be between 100–300 µg/L).
The effective control of GH hypersecretion during long term octreotide
treatment was significantly better in the gsp-positive
group, as revealed by nonparametric two-factor ANOVA (P
< 0.001).
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After surgery, the mean follow-up period was not different in the
2 groups (P < 0.9). According to our criteria of
successful surgical outcome, 15 of 30 patients were considered cured
after surgery, 5 with mutated tumors and 10 with wild-type tumors
(Table 2). Incompletely removed adenomas
were treated by external radiation and/or medical treatment according
to the tumoral extension and the somatostatin sensitivity. Eight
patients (26%) received radiotherapy. Interestingly, all of these
belonged to the gsp-negative group. Seven patients received
somatostatin agonist treatment. This treatment allowed efficient
control the GH hypersecretion in the three gsp-positive
patients, but in none of the four gsp-negative patients.
After surgical removal, the three observed recurrences in our series
were all mutation free. These patients showed increasing GH levels
associated with further tumor growth, necessitating a second surgery.
These data suggested that the most aggressive tumors, poorly controlled
by the multiple therapeutic procedures, belonged to the
mutation-free group.
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The in vitro effect of octreotide (10-8
mol/L for 24 h) on GH secretion was examined in 7
gsp-positive and 18 gsp-negative somatotroph
adenomas. A positive correlation was observed between the
octreotide-induced inhibition of GH secretion in vivo and
that in vitro (r = 0.67; P < 0.0028;
Fig. 4). The octreotide-induced
inhibition of GH secretion was significantly higher in
gsp-positive adenomas (P < 0.006; Fig. 5). The maximal inhibitory effect on GH
release varied from 40–90% in gsp-positive tumors and from
10–60% in gsp-negative tumors, and the mean percentages of
GH inhibition were 71 ± 5% and 30 ± 6%, respectively. The
more sensitive tumors (n = 2; maximal inhibition of GH secretion,
>80%) were mutated, whereas the 6 resistant tumors (maximal
inhibition of GH secretion, <20%) were consistently of the wild
type.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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-subunit of the G protein is
somatic in origin, with the presence of both a mutant and a normal
s allele. In human somatotroph adenomas, the wild-type
allele is weakly, or not at all, expressed. The analysis of genomic DNA
revealed an equal amount of mutant and wild s sequences,
whereas a greater amount of the mutated form was found in cDNA (1, 16).
Consequently, in the present study, we preferred to use cDNA to detect
the mutation. Gs mutations have been found in
27% of our series of somatotroph adenomas; the same percentage is
found when all previous studies are considered together (Table 3). In fact, the prevalence rate varied
largely from 4.4–43% (3, 5, 6, 7, 8, 10, 17, 18, 19), without explanatory
factors for this large divergence (8). The low incidence of
Gs mutations in some populations is not
congruent with its key role in the tumorigenesis of adenomas expressing
the mutated protein.
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protein as well as the oncogenic
Gs have been shown to induce activation of
cAMP-dependent pathways (20, 21). Increased levels of activated CREB
(cAMP recognition element-binding protein), which is the terminal step
in the cAMP-dependent pathways, have been found in the whole series of
15 human GH-secreting adenomas, whereas only 4 cases contained the
gsp oncogene (20). The wild-type Gs
has been found to be more expressed in at least 2 somatotroph adenomas
compared to 2 nonfunctioning adenomas (20). The quantitative expression
of Gs in different types of pituitary adenomas
remains to be analyzed. These facts preclude at present comparison of
the studies that take the high adenylyl cyclase activity as a mutation
indicator to those founded on the actual detection of the mutation.
Consequently, in what follows we compared only the studies concerning
tumors bearing a positively detected Gs
mutation.
Our gsp-positive patients presented with smaller and less
invasive tumors. The difference did not reach statistical significance,
probably because of the low number of patients. Nevertheless, the
smaller size of tumors bearing the Gs
mutations was confirmed by the better rate of their postoperative cure.
Such a smaller size of the gsp-positive tumors was found
previously in other morphological studies (3, 8). This raises the
question of the role played by the mutated Gs
subunit in cell proliferation in human somatotroph adenomas; such a
role has been clearly demonstrated in pituitary cell lines transfected
with mutated Gs protein (22, 23). As
previously shown in primary culture of rat hypophysis or in transgenic
mice (24, 25), a continuous stimulation of adenylyl cyclase signaling
pathways by the gsp oncogene should induce somatotroph cells
to increase hormonal secretion. It is controversial whether human
adenomas bearing the gsp oncogene display a higher basal GH
level (3, 5, 6, 7, 8). We showed that the serum GH level is strongly related
to the size of the tumor, in agreement with a previous study (26). We
found consistent, but not significant, higher basal GH levels in tumors
presenting the gsp mutation. However, GH secretion became
significantly higher in mutated adenomas when the ratio of basal GH
level/tumor diameter was considered. Such a relationship between tumor
size and secretion may explain the false decrease in GH secretion
observed in 1 study (3) and the failure to find higher GH secretion in
others (5, 6, 7, 8). The differences in the secretion of GH as well as PRL
were not immunocytochemically discernible, as the percentages of GH-
and PRL-immunoreactive cells were not different in the two groups, as
pointed out by Harris (5). Unbiased quantitative studies are necessary
to clarify this point. Three studies examined the octreotide
sensibility of tumors bearing positively detected
Gs mutations. They suggested that in this
category of adenomas there could be a more marked octreotide inhibitory
response of GH secretion than in the mutation-free tumors. The main
point of the present study is to clearly show the better octreotide
responsiveness of gsp-positive tumors in three experimental
conditions: short term in vivo, long term in
vivo, and in vitro. Yang et al. (8) showed
that the percentage of GH inhibition was significantly higher in
gsp-positive tumors during the in vivo acute
octreotide test (95% vs. 81%; P <
0.0035). Nevertheless, this test is not reliable enough to predict the
efficacy of the chronic administration of the drug (27). In our study,
a clearly better octreotide sensitivity was shown in patients bearing
the mutation after 3 months of treatment. After 4 days of octreotide
administration (100 µg, sc, 3 times daily), Faglia et al.
(11) found that all 6 of the octreotide responders had the mutations
compared to 3 of 6 in the mutation-free group. Some acromegalic
patients with McCune-Albright syndrome (due to postzygotic mutation of
the Gs subunit) are also good responders to
octreotide therapy (28, 29). The better octreotide responsiveness found
in vivo was confirmed by our in vitro study, and
we found a significant correlation between these 2 experimental
conditions, confirming the previous study by Kelijman et al.
(30). In cell culture, Adams et al. found 8 of 8
octreotide-responsive tumors in gsp-positive adenomas
compared to 8 of 13 in gsp-negative adenomas (7). If all of
the mutated tumors are good octreotide responders, the lack of the
gsp oncogene does not allow us to conclude any octreotide
resistance, as some gsp-negative adenomas are true
somatostatin-sensitive microadenomas. Nevertheless, in our series, the
largest invasive and octreotide-resistant macroadenomas are all
mutation free.
It has been shown (31) that the degree of responsiveness to
octreotide could be correlated with the expression of somatostatin
receptors (SSTR). It is, therefore, tempting to speculate that SSTR
could be highly expressed in gsp-positive tumors. In the
AtT-20 pituitary cell line, forskolin induced a 4-fold stimulation of
one of SSTR subtype 2 transcripts, suggesting a regulation of its
expression by the cAMP-dependent pathways (32). Moreover, it could be
possible that the gsp oncogenic protein induces postreceptor
modifications of G proteins that disrupt the balance between the
different -subunits and the ß
-complex. Such a better
sensitivity to somatostatin analogs may reduce or even reverse the
function of the mutated, constantly activated
Gs and in this way influence the therapeutic
outcome of the patients. In our experience, among the 8 patients
presenting gsp mutations and followed for 22 months, 5
(62%) were considered cured by surgery, and 3 were efficiently
controlled by somatostatin analogs after partial surgical removal of
the tumor. On the contrary, only 10 of 22 (45%)
gsp-negative patients were considered cured after surgery.
None of the gsp-negative patients bearing active tumor
remnants were efficiently controlled by the long term administration of
somatostatin agonists alone, and 3 of them had a further tumor growth
burst even during treatment with somatostatin agonists.
In conclusion, the Gs mutation could be a new
marker to foresee the capacity of the tumor to respond to the
somatostatin analogs. Because of the greater responsiveness to
octreotide, the gsp-positive tumor should have a better
prognosis, and patients could be better candidates for pharmacological
treatment. This proposal has to be confirmed by further studies
including a greater cohort of acromegalic patients assessed through
longer follow-up periods.
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Acknowledgments |
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Footnotes |
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Received November 10, 1997.
Revised January 16, 1998.
Accepted January 23, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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chain
of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 340:692–696.[CrossRef][Medline]
-subunit production in somatotroph adenomas
with and without Gs mutations. J Clin Endocrinol Metab. 75:918–923.[Abstract]
gene in growth hormone-secreting pituitary adenomas by the
polymerase chain reaction-direct sequencing method using
paraffin-embedded tissues. Acta Endocrinol (Copenh). 129:301–306. enhances activation of the adenylyl cyclase signal
transduction cascade. Mol Endocrinol. 11:1053–1061. (Q227L)
show enhanced hormone secretion and proliferation. Mol Cell Endocrinol. 127:41–47.[CrossRef][Medline]
-subunits stimulate Pit-1 promoter activity
via a protein kinase A-mediated pathway acting through deoxyribonucleic
acid binding sites both for Pit-1 and for adenosine 3',5'-monophosphate
response element-binding protein. Endocrinology. 137:1286–1291.[Abstract]
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A. Barlier, J.-F. Vanbellinghen, A. F. Daly, M. Silvy, M.-L. Jaffrain-Rea, J. Trouillas, G. Tamagno, L. Cazabat, V. Bours, T. Brue, et al. Mutations in the Aryl Hydrocarbon Receptor Interacting Protein Gene Are Not Highly Prevalent among Subjects with Sporadic Pituitary Adenomas J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1952 - 1955. [Abstract] [Full Text] [PDF]
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G M Besser, P Burman, and A F Daly Predictors and rates of treatment-resistant tumor growth in acromegaly Eur. J. Endocrinol., August 1, 2005; 153(2): 187 - 193. [Abstract] [Full Text] [PDF]
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 A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]
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S. O. Akintoye, C. Chebli, S. Booher, P. Feuillan, H. Kushner, D. Leroith, N. Cherman, P. Bianco, S. Wientroub, P. G. Robey, et al. Characterization of gsp-Mediated Growth Hormone Excess in the Context of McCune-Albright Syndrome J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5104 - 5112. [Abstract] [Full Text] [PDF]
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A. Barlier, I. Pellegrini-Bouiller, G. Gunz, A. J. Zamora, P. Jaquet, and A. Enjalbert Impact of gsp Oncogene on the Expression of Genes Coding for Gs{alpha}, Pit-1, Gi2{alpha}, and Somatostatin Receptor 2 in Human Somatotroph Adenomas: Involvement in Octreotide Sensitivity J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2759 - 2765. [Abstract] [Full Text]
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E. Ballaré, S. Mantovani, A. Lania, A. M. Di Blasio, L. Vallar, and A. Spada Activating Mutations of the Gs{alpha} Gene Are Associated with Low Levels of Gs{alpha} Protein in Growth Hormone-Secreting Tumors J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4386 - 4390. [Abstract] [Full Text]
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, Microadenomas and
intrasellar macroadenomas, including tumors with moderate suprasellar
extension. 
, Macroadenomas with extrasellar extensions. Significance
was determined by Mann-Whitney U test.
, Basal GH level. •,
Mean GH levels between 1–6 h after a single 100-µg sc injection of
octreotide. C, The mean percent GH inhibition after the injection of
octreotide in each group is represented by a hyperbolic plot.
Significance was determined by nonparametric ANOVA (Kruskal-Wallis).
) and gsp
negative (•)]. The in vivo octreotide sensitivity was
determined by the percent decrease in GH after acute octreotide
injection (see Fig. 2