Gsp Mutations Research Articles

Clinical and prognostic significance of granulation patterns in somatotroph adenomas/tumors of the pituitary: a meta-analysis.

Sparsely granulated somatotroph adenoma/tumor (SGST) is thought to be more clinically aggressive than densely granulated somatotroph adenoma/tumor (DGST). However, the literature is not entirely consistent as to the disparate demographic and behavioral features of these subtypes. In this study, we conducted a meta-analysis to further clarify the demographic, clinicopathological, prognostic, and molecular characteristics of SGST versus DGST. We accessed two electronic databases to search for potential data. Pooled estimates of odds ratio (OR), mean difference (MD), and corresponding 95% confidence interval (CI) were calculated using the random-effect model. SGST was associated with younger patient age and lower male-to-female ratio (p < 0.001) compared to DGST. Clinically, SGST had larger tumor size and high rate of cavernous sinus and suprasellar extension (p < 0.001) than DGST. During postoperative follow-up, SGST was associated with a lower endocrinological remission rate (OR 0.60; 95% CI 0.40 to 0.90; p = 0.01) and a poorer response rate to SRL (OR 0.16; 95% CI 0.08-0.35; p < 0.001) in comparison to DGST. The prevalence of GSP mutations was significantly lower in SGST (OR 0.36; 95% CI 0.17 to 0.79; p = 0.01). SGST and DGST were demographically, clinicopathologically, and molecularly different from each other with the former associated with adverse treatment outcomes and poor response to medical therapy. There are still gaps in translational studies that could help us better understand the behavior of these tumors and identify potential targets in the treatment of sparsely granulated tumors.

Characterization of sporadic somatotropinomas with high GIP receptor expression

To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR-) GIPR. Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR- tumors. Twenty-eight out of 56 (50%) GIPR- tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR- tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors.

Gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

Simple SummaryAcromegaly treatment consists of surgical, medical, and radiation therapy. First-generation somatostatin receptor ligands are the mainstay of medical therapy, with approximately 40% disease control rate. Several parameters have been evaluated as predictors of response to these drugs, including mutations in the stimulatory G-protein α subunit (gsp mutation), which is still controversial. In this study, we aimed to evaluate in a large series of patients whether gsp mutation predicts long-term response to medical treatment and to characterize the gsp mutated population. The ability to predict response to medical therapy would help to choose a therapy that presents higher odds of controlling the disease, which ultimately would reduce treatment costs and disease morbi-mortality.Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

Activating genomic alterations in the Gs alpha gene (GNAS) in 274 694 tumors.

Activating point mutations in two codons (R201 and Q227) in the alpha subunit of the stimulatory GTP binding protein (GNAS) gene-coined gsp mutations-were originally reported in growth hormone secreting pituitary adenomas. In these tumor types, gsp activating mutations were associated with uncontrolled intracellular cAMP accumulation leading to cellular proliferation and tumor formation. Since the original description of gsp mutations in pituitary and later thyroid neoplasia, many more tumors were genotyped for these specific activating mutations. In this paradigm, GNAS is an oncogene that can be activated by other molecular mechanisms, such as DNA amplification and translocation. Herein, we describe the largest account to date of tumor types that harbor pathogenic GNAS genomic alterations (GAs) including the "classical" gsp activating point mutations, delineate some common features of these tumors, and speculate as to the possible mechanisms whereby GNAS activating GAs are associated with the various stages of tumorigenesis.

The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia.

Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune–Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1–3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08% (95% CI, 2.73, 15.42); p=0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2)=58%, p value for heterogeneity=0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93% (95% CI, 1.40, 12.46); p=0.01], albeit with no significant heterogeneity (I(2)=35%, p value for heterogeneity=0.16). The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogues: a meta-analysis

Objective Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved.

Treatment of acromegaly in the era of personalized and predictive medicine.

Acromegaly is a chronic disorder usually diagnosed late in the disease evolution. Such delayed diagnosis, together with the inability to achieve the treatment goals of normalizing biochemical disease markers and controlling tumour mass may result in substantial morbidity and mortality. Somatostatin analogues (SSA) are accepted as first-line medical therapy or as second-line therapy in patients undergoing unsuccessful surgery and are considered a cornerstone in the treatment of acromegaly. However, because a high percentage of patients experience SSA medical treatment failure, the identification of biomarkers associated with a successful or unsuccessful response to all classes of medical therapy would help in the choice of treatment and potentially allow for a quicker normalization of biochemical parameters. The current treatment algorithms for acromegaly are based upon a "trial-and-error" approach with additional treatment options provided when disease is not controlled. In many other diseases, therapeutic algorithms have been evolving towards personalized treatment with the medication that best matches individual disease characteristics, using biomarkers that identify therapeutic response. Additionally, a personalized approach to complementary treatment of comorbidities present in the acromegalic patient is also required. This review will discuss the development of a potential treatment algorithm for acromegaly addressing the biochemical control of the disease as well of its associated comorbidities, under a personalized approach based upon markers of prognostic and predictive significance, such as tumour size, MRI adenoma signal, GH value after acute octreotide test, granular adenoma pattern, Ki-67, somatostatin receptor phenotype, aryl hydrocarbon-interacting protein expression, gsp mutations, RAF kinase activity, E-cadherin and beta-arrestin-1.

Gspmutation in acromegaly and its influence on TRH-induced paradoxical GH response

We recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH. Sixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status. Twenty-six (38·8%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (73·1%). Among the paradoxical GH responders to TRH, 21 patients (42·9%) had a gsp mutation and 28 patients (57·1%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (80·8% and 68·3%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P = 0·045) and greater GH suppression by octreotide (88·7% vs 75·4% GH decrease, P = 0·003) than the gsp-negative group. Paradoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naïve patients with somatotroph adenomas

Somatotroph adenomas causing acromegaly are histologically classified into densely granulated (DG) and sparsely granulated (SG) subtypes with different morphology, clinical characteristics and treatment outcomes. Granulation pattern has been reported to co-segregate with a recurrent mutation at codon 49 in growth hormone receptor (GHR) and GSP oncogene. This study examines response to the octreotide suppression test (OST) in relation to granulation pattern and mutation in GHR and GSP. This is a retrospective, single-centre study of 52 patients with pathologically confirmed somatotroph adenoma who were naïve to medical therapy presenting between January 2001 and October 2010. Clinical, radiological and hormonal data at diagnosis were recorded. GHR and GSP were genotyped, granulation pattern determined and response to the OST measured. SG adenomas were larger (P=0.038), occurred in younger patients (P=0.029), were more common in females (P=0.026) and were more invasive (P<0.0001 and P=0.001), with diminished responses to the OST (P=0.007) compared with DG adenomas. GSP mutation was unrelated to granulation pattern but associated with smaller tumours (P=0.027), producing more GH (P=0.048) that responded better to the OST (P=0.022). Codon 49 of GHR was not mutated. Adenoma histological phenotype, not genotype, corresponds to clinical and biochemical characteristics and response to the OST. SG adenomas constitute a clinically more unfavourable subtype but are not associated with GHR mutations in our series. Ascertainment of the adenoma subtype may become an important consideration in the management of acromegaly.

A Rare Cause of Hypertestosteronemia in a 68‐Year‐Old Patient: A Leydig Cell Tumor Due to a Somatic GNAS (Guanine Nucleotide‐Binding Protein, Alpha‐Stimulating Activity Polypeptide 1)–Activating Mutation

Leydig cell tumors of the testis are the most common type of non-germ cell testicular tumors. In adult patients, gynecomastia, oligozoospermia, erectile dysfunction, and other signs of feminization can be present, whereas testosterone levels are frequently in the normal range or slightly reduced. We describe a patient with a history of impaired sexual function, as well as progressive enlargement of the left testis, without gynecomastia. Hormonal evaluation demonstrated very high testosterone, estrogen, and pan-alpha-inhibin levels. Magnetic resonance imaging revealed the presence of left testicular hypertrophy without evidence of testicular mass. After left orchiectomy, histologic examination confirmed the diagnosis of Leydig cell tumor, and steroid hormone levels normalized. A heterozygous missense somatic gsp mutation (R201C) was found in tumoral tissue, whereas no mutation was found in the surrounding normal tissue or in leukocyte DNA. This case provides evidence that somatic activating gsp mutation in Leydig cells may result in tumor development, leading to overexpression of the inhibin alpha subunit and hyperactivity of the testosterone biosynthetic pathway.

Clinical implications of growth hormone–secreting tumor subtypes

Growth hormone (GH) pituitary tumors are almost always benign adenomas, yet are associated with significant morbidity and mortality. Surgical and medical responses of GH tumors are often incomplete, and therefore predictors of residual or recurrent disease are needed. Clinical features, including patient gender, age or size of adenoma, have proven to be unreliable predictors of recurrence. Differing clinical behavior between the two GH tumor subtypes, sparsely granulated (SG) versus densely granulated (DG), has been reported, but has not been used routinely in clinical management. SG tumors are more common in younger patients (<50 years), and are usually larger tumors. SG tumors have been reported to be less responsive to somatostatin analogs (SSA) than DG tumors. The mechanisms underlying these potential differences in tumor behavior, however, are poorly defined. Subsets (up to 50 %) of DG adenomas harbor a gsp mutation that can activate cAMP that provides a theoretical intracellular target for somatostatin therapy. In contrast, some SG tumors have reduced somatostatin receptor expression and mutations in the extracellular domain of the GH receptor that may contribute to SSA resistance. While DG versus SG growth hormone adenomas are readily distinguished by immunohistochemistry, other less common GH adenoma variants still require electron microscopy (EM) for confident subclassification. Whether these less common variants possess unique clinical features is unknown. Research is needed to identify clinically relevant biomarkers of GH pituitary tumors that predict risk of recurrence and response to medical therapy.

Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly

Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas. To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment. Seventy-eight patients with active acromegaly were included. Long-term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E-cadherin and SSTR2a. Protein levels of E-cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas. DG adenomas and the transitional group had higher serum levels of IGF-1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long-term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E-cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG. Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

Effect of gsp oncogene on expression of GHSR - 1a and Ghrelin mRNA in human GH - secreting pituitary adenomas

Objective To investigate the relationship between the expression of growth hormone secretagogue receptor type 1a (GHSR- 1a) 、Ghrelin mRNA and gsp oncogene in human GH- secreting pituitary adenomas. Methods The gsp oncogene mutation in 43 cases of GH -secreting pituitary adenomas was detected by PCR - DNA direct sequencing analysis. The expression of GHSR - 1a、Ghrelin mRNA was determined by SYBR green real -time fluorescent quantitative PCR. Then the relationships between the expression of GHSR -1a、Ghrelin mRNA and gsp oncegene were studied with statistical methods. Results There was no significant difference in the expression of ghrelin mRNA between mutation - positive and mutation - negative adenomas. The expression of GHSR - 1a mRNA was significantly higher in gsp - positive adenomas than that in gsp - negative adenomas. There was significant direct correlation between the levels of ghrelin mRNA and GHSR mRNA expression in gsp - positive and gsp - negative adenomas. Conclusions Gsp oncogene may up - regulate the expression of GHSR - 1a mRNA and has no effect on the expression of ghrelin mRNA in human GH - secreting pituitary adenomas. In addition, ghrelin could elevate the expression of GHSR - 1a mRNA in GH - secreting pituitary adenomas with or without gsp mutations. Key words: Gsp oncogene; GHSR - 1a; Ghrelin

Absence of activating mutations of CXCR4 in pituitary tumours

Mutations of the gsp oncogene are responsible for 30-40% of GH-producing pituitary adenomas and 10% of nonfunctioning pituitary adenomas (NFPAs). However, the pathogenetic mechanism of the remaining pituitary tumours still remains to be identified. Recently, the interaction between the chemokine stromal cell-derived factor 1 and its receptor CXCR4 was found to play an important role in GH production and cell proliferation in various pituitary adenoma cell lines. As CXCR4 is a Gi-coupled chemokine receptor, its constitutive activating mutations may be involved in pituitary tumour formation by cyclic adenosine monophosphate (cAMP)-independent, ERK-related pathways. We investigated whether somatic activating-mutations of CXCR4 might be a possible tumourigenic mechanism for gsp-negative GH-secreting pituitary adenomas and NFPAs. Direct sequencing of polymerase chain reaction-amplified products for coding exons of CXCR4 were performed using genomic deoxyribonucleic acid samples from 37 GH-producing pituitary tumour tissues that were negative for the gsp mutation and 14 CXCR4 expressing NFPAs. Immunohistochemical analyses and double immunofluorescent staining of sectioned paraffin-embedded pituitary tissues revealed that CXCR4 is highly expressed in GH-producing pituitary adenomas and NFPAs. Direct sequencing showed that two synonymous mutations in exon 2 (87 C > T and 414 C > T) were detected in 4 out of 51 pituitary tumours. Our results indicate that an activating mutation of the CXCR4 may not be a common pathogenetic mechanism in GH-producing pituitary tumours and NFPAs.

Classification et physiopathologie des adénomes hypophysaires

Pituitary adenomas are benign tumors that can be classified according to the type of hormone they produce, immunocytochemical characteristics (which generally confirm the clinical classification) or, as proposed by WHO in 2004, specific differentiation markers of the various ligneages. The pathophysiology of pituitary adenomas is largely unknown. Although a clonal origin is very likely, no univocal molecular abnormality (except for gsp mutations, found in 40% of somatotropic adenomas) has yet been found. Studies of cell cycle proteins, growth factors and oncogenes are beginning to shed light on the complex underlying mechanisms.

Pituitary adenylate cyclase-activating polypeptide directly stimulates LH and FSH secretion by human pituitary gonadotrophinomas

The effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on LH and FSH secretion by human pituitary gonadotrophinomas in cell culture was studied. PACAP (1-38 peptide, 0.2-20 nmol/L) dose-dependently stimulated both LH and FSH secretion after 24 hours incubation. Of 11 tumours studied, PACAP (20 nmol/L) stimulated LH and/or FSH secretion by 1.7-4 fold in 9 cases. Two tumours did not respond to PACAP, although LHRH was stimulatory in these. None of the 11 tumours contained gsp mutations, excluding the possibility that these were the cause of the occassionally observed non-responsiveness to PACAP. A combination of PACAP (20 nmol/L) together with TRH (25 nmol/L) resulted in greater stimulatory effects on LH and FSH secretion than exerted by either peptide alone, but this was not observed with LHRH. In 3 tumours tested, PACAP stimulated cAMP production 2-3 fold by cultured human pituitary gonadotrophinomas but had no effect on rate of phosphatidylinositol (PI) turnover. These results indicate that PACAP can directly stimulate LH and FSH secretion by human pituitary gonadotrophs and that PACAP-receptors in gonadotrophin-secreting tumours are coupled with adenylate cyclase but not the PI second messenger system. We conclude that PACAP may play a role in controlling gonadotroph function in the human pituitary gland.

Recent advances in the molecular biology of growth-hormone secreting human pituitary tumours.

The application of DNA technology has led to significant progress in our understanding of the aetiology of GH-secreting pituitary tumours. X-chromosome inactivation and RFLP analysis has revealed that GH-secreting tumours are monoclonal in origin and thus arise as a consequence of a somatic mutation within a single cell. Using PCR and sequence analysis, such a mutation has been identified in 30-40% of tumours. This is the so-called gsp mutation in which the gene for the alpha s subunit of the Gs protein is converted to an oncogene the expression of which results in constitutive adenyl cyclase activity and thus excessive cAMP production. In our own studies, we demonstrate that it is unlikely that a defect within the promoter region of the GH gene will prove to be a cause of excessive GH secretion in acromegaly. In contrast, we have shown that the GH gene is hypomethylated in tumour derived DNA and this may account, at least in part, for abnormal GH gene expression.

Analyses of Factors Influencing the Acute Effect of Octreotide in Growth Hormone-secreting Adenomas

Somatostatin analogues such as octreotide are used to treat active acromegalic patients by reducing serum growth hormone (GH) levels. However, the acute effect of octreotide on GH secretion differs among patients. To elucidate factors influencing the acute effect of octreotide, we collected data from 56 patients with somatotroph adenoma from two institutions. We analyzed the correlation of the following factors with the acute effect of octreotide: immunohistochemical staining of somatostatin receptor subtype 2A (SSTR 2A), presence of gsp mutation, proliferative potentials analyzed by Ki-67 staining index (SI). We found that the acute effect of octreotide significantly correlated with two factors: Ki-67 SI and the plasma membrane-dominant staining pattern of SSTR 2A. Monovariate analysis revealed a statistically significant inverse relation of Ki-67 SI with the reduction of GH by octreotide. We assessed the contribution of each factor on the acute effect of octreotide by multivariate analysis. Significant multiple regression was confirmed with p value of 0.003. Post-test revealed that the plasma membrane-dominant staining pattern of SSTR 2A was significantly related to the reduction of GH by octreotide. These results show that the acute effect of octreotide is positively related to SSTR 2A staining on the plasma membrane.

Effective Combined Medical Treatment With Octreotide Long Acting Release (Sandostatin LAR) and Cabergoline for an Extremely Rare Pituitary Somatotroph Adenoma Producing Growth Hormone-Releasing Hormone

Combined medical treatment with long acting octreotide and cabergoline is now used with active patients with acromegaly and can reduce serum growth hormone (GH) and insulin-like growth factor-1 levels. In this article, we analyzed again the molecular aspects of the previously reported rare GH-releasing hormone (GHRH)-producing somatotroph adenoma, and introduce the effects of the combined medical treatment using octreotide LAR and cabergoline for GHRH-producing somatotroph adenoma. The present GHRH-producing somatotroph adenoma had a high Ki-67 staining index, weak, and cytoplasmic-dominant immunostaining of somatostatin receptor 2A, and no gsp mutation. This adenoma was predicted to be resistant to the medical therapy using octreotide LAR. In this extremely rare GHRH-producing pituitary somatotroph adenoma, octreotide LAR alone cannot reduce random GH and insulin-like growth factor-1 levels sufficiently, but combined medical therapy with octreotide LAR and cabergoline can reduce them into the normal range. We show that combined medical treatment with octreotide LAR and cabergoline was effective for a somatotroph adenoma that had a high proliferative potential, weak and cytoplasmic-dominant immunostaining of somatostatin receptor 2A, and no gsp mutation, and has active GH production and secretion regulated by locally generated GHRH from adenoma cell.