Growth Hormone Pituitary Adenoma Research Articles

Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma.

Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP3) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.

Prognostic Models in Growth-Hormone- and Prolactin-Secreting Pituitary Neuroendocrine Tumors: A Systematic Review.

Growth-hormone (GH)- and prolactin (PRL)-secreting PitNETs (pituitary neuroendocrine tumors) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Proliferation markers alone have a questionable degree of prediction, so we try to identify validated prognostic models as accurately as possible. (1) Background: The data available so far show that the use of staging and clinical-pathological classification of PitNETs, along with imaging, are useful in predicting the evolution of these tumors. So far, there is no consensus for certain markers that could predict tumor evolution. The application of the WHO (World Health Organisation) classification in practice needs to be further evaluated and validated. (2) Methods: We performed the CRD42023401959 protocol in Prospero with a systematic literature search in PubMed and Web of Science databases and included original full-text articles (randomized control trials and clinical trials) from the last 10 years, published in English, and the search used the following keywords: (i) pituitary adenoma AND (prognosis OR outcome OR prediction), (ii) growth hormone pituitary adenoma AND (prognosis OR outcome OR prediction), (iii) prolactin pituitary adenoma AND (prognosis OR outcome OR prediction); (iv) mammosomatotroph adenoma AND (prognosis OR outcome OR prediction). (3) Results: Two researchers extracted the articles of interest and if any disagreements occurred in the selection process, these were settled by a third reviewer. The articles were then assessed using the ROBIS bias assessment and 75 articles were included. (4) Conclusions: the clinical-pathological classification along with factors such as GH, IGF-1, prolactin levels both preoperatively and postoperatively offer valuable information.

The Role of Soluble α-klotho Protein in Acromegaly

Soluble α-klotho (sαKl) is an isoform of the α-klotho protein that regulates calcium metabolism but also has anti-aging, anti-apoptotic, and tumor suppressor effects. The assumption that sαKl could inhibit the insulin-like growth factor 1 (IGF-1) signaling pathway has increased the interest of its research in acromegaly - a pathology characterized by an excess of growth hormone (GH) and IGF-1. This review aimed to identify the role of sαKl in acromegaly. Most studies have identified higher concentrations of sαKl in acromegaly versus non-GH pituitary adenomas (PAs) or healthy subjects. Also, the sαKl level was higher in active acromegaly versus controlled or cured disease. Moreover, sαKl positively correlated with GH, IGF-1, and GH-secreting PA size. The increased level of sαKl seems to be due to the autonomous secretion of GH, considering their drastic decrease after transsphenoidal surgery. The data regarding the relationship between sαKl, age, and gender in acromegaly are inconsistent. The latest research noted a correlation between sαKl and various parameters for monitoring the quality of life in acromegaly. In conclusion, sαKl could reflect the disease activity. Furthermore, sαKl would represent an alternative for monitoring acromegalic patients with discrepancies between IGF-1 and GH.

Growth hormone secreting pituitary adenomas show distinct extrasellar extension patterns compared to nonfunctional pituitary adenomas.

Patterns of extension of pituitary adenomas (PA) may vary according to PA subtype. Understanding extrasellar extension patterns in growth hormone PAs (GHPA) vis-a-vis nonfunctional PAs (NFPAs) may provide insights into the biology of GHPA and future treatment avenues. Preoperative MR imaging (MRI) in 179 consecutive patients treated surgically for NFPA (n = 139) and GHPA (n = 40) were analyzed to determine patterns of extrasellar growth. Extension was divided into two principal directions: cranio-caudal (measured by infrasellar/suprasellar extension), and lateral cavernous sinus invasion (CSI) determined by Knosp grading score of 3-4. Suprasellar extension was defined as tumor extension superior to the tuberculum sellae- dorsum sellae line, and inferior extension as invasion through the sellar floor into the sphenoid sinus or clivus. Categorical analysis was performed using Fisher's exact test. GHPAs were overall more likely to remain purely intrasellar compared to NFPA (50% vs 26%, p < 0.001). GHPAs, however, were 7 times more likely to exhibit isolated infrasellar extension compared to NFPA (20% vs 2.8%, p = 0.001). Conversely, NFPAs were twice as likely to exhibit isolated suprasellar extension compared to GHPA (60% vs 28%, p < 0.001), as well as combined suprasellar/infrasellar extension (25% vs 3%, p = 0.011). There were no overall differences in CSI between the two subgroups. GHPA and NFPA demonstrate distinct extrasellar extension patterns on MRI. GHPAs show proclivity for inferior extension with bony invasion, whereas NFPAs are more likely to exhibit suprasellar extension through the diaphragmatic aperture. These distinctions may have implications into the biology and future treatment of PAs.

Predicting Subtype of Growth Hormone Pituitary Adenoma based on Magnetic Resonance Imaging Characteristics.

This study aimed to investigate the value of magnetic resonance (MR) characteristics in differentiating the subtypes of growth hormone pituitary adenomas. The clinical and MR imaging data of 70 patients with growth hormone pituitary adenoma confirmed by surgery and pathology were retrospectively analyzed. The tumors were divided into dense granular (DG; 36 cases) and sparse granular subtypes (SG; 34 cases). The tumors' MR features were analyzed, including the mean and maximum diameters, T2 signal intensity, T2 relative signal intensity (rSI), homogeneity, enhancement degree, and invasiveness (Knosp grade). Mann-Whitney U test and χ2 test were used to analyze MR characteristics between the 2 groups. The independent predictors and predictive probabilities of tumor subtypes were obtained via a logistic regression model, and the efficacy was compared by receiver operating characteristic curve. The mean and maximum diameters of growth hormone adenoma in DG and SG were 1.77 versus 2.45 and 1.95 versus 3.00 cm (median, P < 0.05), respectively. There was a significant difference between the 2 groups in T2 signal intensity and rSI (P values were 0.02 and 0.001, respectively). Most DG adenomas (86.1%) appeared as hypointense on T2 images, and 38.2% of SG adenomas were hyperintense. There was no significant difference in tumor homogeneity (P = 0.622). A significant difference was found in the Knosp grade between the 2 subtypes (P = 0.004). In addition, the enhancement degree of SG adenomas was significantly higher than that of DG adenomas (P = 0.001). Logistic regression analysis showed that high T2 rSI value and marked contrast enhancement were independent predictors of the 2 subtypes, and the odds ratios were 4.811 and 4.649, respectively. The multivariate logistic model obtained relatively high predicting efficacy, and the area under the curve, sensitivity, and specificity were 0.765, 0.882, and 0.500, respectively. There are significant differences in tumor size, T2 signal intensity, T2 rSI, enhancement degree, and invasiveness between DG and SG adenomas. The logistic model based on the marked contrast enhancement and high T2 rSI value has an important value in predicting the subtype of growth hormone adenoma.

Usefulness of the Texture Signatures Based on Multiparametric MRI in Predicting Growth Hormone Pituitary Adenoma Subtypes

ObjectiveTo explore the usefulness of texture signatures based on multiparametric magnetic resonance imaging (MRI) in predicting the subtypes of growth hormone (GH) pituitary adenoma (PA).MethodsForty-nine patients with GH-secreting PA confirmed by the pathological analysis were included in this retrospective study. Texture parameters based on T1-, T2-, and contrast-enhanced T1-weighted images (T1C) were extracted and compared for differences between densely granulated (DG) and sparsely granulated (SG) somatotroph adenoma by using two segmentation methods [region of interest 1 (ROI1), excluding the cystic/necrotic portion, and ROI2, containing the whole tumor]. Receiver operating characteristic (ROC) curve analysis was performed to determine the differentiating efficacy.ResultsAmong 49 included patients, 24 were DG and 25 were SG adenomas. Nine optimal texture features with significant differences between two groups were obtained from ROI1. Based on the ROC analyses, T1WI signatures from ROI1 achieved the highest diagnostic efficacy with an AUC of 0.918, the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.7, 72.0, 100.0, 100.0, and 77.4%, respectively, for differentiating DG from SG. Comparing with the T1WI signature, the T1C signature obtained relatively high efficacy with an AUC of 0.893. When combining the texture features of T1WI and T1C, the radiomics signature also had a good performance in differentiating the two groups with an AUC of 0.908. In addition, the performance got in all the signatures from ROI2 was lower than those in the corresponding signature from ROI1. ConclusionTexture signatures based on MR images may be useful biomarkers to differentiate subtypes of GH-secreting PA patients.

Possibilities of endoscopic endonasal transsphenoidal surgery in treatment of growth-hormone pituitary adenomas

Pituitary adenomas are one of the most common primary central nervous system tumours and have an estimated prevalence of 17%. Management of hormone-secreting pituitary adenomas involves a multidisciplinary approach that can incorporate surgical, medical, and/or radiation therapies. Acromegaly is a rare, chronic disorder that mostly results from growth hormone (GH)-secreting pituitary adenoma. We analyzed the outcomes of surgical treatment for growth hormone (GH) pituitary adenomas based on 28 cases and determine factors that lead to biochemical remission.

SAT-276 Co-Secreting TSH and Growth Hormone Pituitary Adenoma

Introduction: Secreting pituitary adenoma is exceedingly rare. Less than 15 cases having been reported. Its clinical presentation and diagnosis is challenging. We report a case of pituitary macroadenoma, with features of acromegaly and hyperthyroidism. Case report: A 75 years’ old man presented with new onset atrial fibrillation. He had high FT4 with normal TSH. His ultrasound scan of the neck showed a solitary nodule. He had ablation twice and was started on bisoprolol and anticoagulant. He had MRI scan for headaches and this showed a pituitary macroadenoma. He had high IGF-1. His oral glucose tolerance showed failure of GH suppression. His FT4 was persistently high with normal TSH and he had high a subunits. This suggested the diagnosis of TSH and GH secreting pituitary adenoma. Discussion: TSH-secreting pituitary adenomas are rare and not uncommonly, they co-secrete other pituitary hormones including growth hormones. Somatotrophs and lactotrops share common transcription factors with thyrotrophs. TSH-secreting adenomas are benign but 60% of them are locally invasive. TSH-secreting pituitary adenomas typically present with either symptoms of tumor growth like headache or visual field disturbance or symptoms of hyperthyroidism. Thyroid nodules are common in patients with TSHomas. In patients with TSH-secreting pituitary adenomas, majority will need only surgery and radiation. The medical treatment used to normalize TSH and FT4 levels is somatostatin analogs. This is effective in about 90% of patients with TSH secreting pituitary adenomas TSHoma should be differentiated from resistance to thyroid (RTH). The main difference between TSHoma and RTH is the presence of signs and symptoms of hyperthyroidism in patients with TSHoma, absence of a family history, normal thyroid hormone levels in family members, and the presence of an elevated glycoprotein α-subunit in patients with pituitary tumor. Reference: H Adams and D Adams. A case of a co-secreting TSH and growth hormone pituitary adenoma presenting with a thyroid nodule. EDM case reports 2018 Hatem.eid1@nhs.net

BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.

BackgroundNonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA.MethodsThe expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes.ResultsImmunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis.ConclusionIn this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.

Co-secreting TSH and growth hormone pituitary adenoma

Co-secreting TSH and growth hormone pituitary adenoma

A case of a co-secreting TSH and growth hormone pituitary adenoma presenting with a thyroid nodule.

SummaryCo-secreting TSH and growth hormone pituitary adenomas are rare. We present a case of a 55-year-old woman who presented with symptoms of neck fullness. Ultrasound revealed multiple thyroid nodules and examination revealed several clinical features of acromegaly. She was found to have a co-secreting TSH and growth hormone pituitary macroadenoma. She underwent surgical resection followed by gamma knife radiation, which resulted in complete remission of her TSH and GH-secreting adenoma.Learning points:TSH-secreting pituitary adenomas are rare and about one-third co-secrete other hormones.Thyroid nodules are common in acromegaly and can be the presenting sign of a growth hormone-secreting pituitary adenoma.In the workup of acromegaly, assessment of other pituitary hormones is essential, even in the absence of symptoms of other pituitary hormone dysfunction.Complete remission of co-secreting GH and TSH pituitary macroadenomas is possible with surgery and radiation alone.

Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience

Study and comparison of characteristics of silent growth hormone adenomas (SGHA), silent corticotroph adenomas (SCA), and silent gonadotroph adenomas (SGA) in a single institution cohort of surgically treated pituitary adenomas. Retrospective analysis of SGHA surgically resected over 10 years: SGHA was defined as no clinical or biochemical evidence of acromegaly and positive GH immunostaining. Of 814 pituitary surgeries; 2.1% (n = 17) were SGHA, 4.5% (n = 37) SCA, and 18.9% (n = 70/371; 2011-2016) SGA. Mean age at SGHA diagnosis was 43 years, with a large female predominance (82%). Mean tumor size and cavernous/sphenoid sinus invasiveness for SGHA, SCA, and SGA were 1.5 ± 1.0 cm and 25%, 2.5 ± 1.2 cm and 43%, 2.9 ± 2.0 cm and 41%, respectively (tumor size p = 0.009, SGHA vs. SGA, and invasion p; not-significant). During mean follow-up of 3.9 years, two patients (11%) developed elevated insulin-like growth factor-1 and five patients (29%) required a second surgery for tumor recurrence. Rate of surgical reintervention was similar to SCA (31%), but higher than SGA (10%) (p = 0.035, SGHA vs. SGA), and 18% underwent radiation therapy, similar to SCA (19%, p; not-significant) but higher than SGA (2.9%, p = 0.018). This is the largest single center study characterizing SGHA behavior with SGA and SCA control groups in a cohort of surgically resected pituitary adenomas. SGHA present mostly in young females, and should be closely followed due to their higher likelihood of recurrence and potential of progression to clinical acromegaly. We propose that a complete hormonal staining panel be routinely performed for all pituitary adenomas.

Pure Androgen–Producing Adrenal Tumor: Clinical Features And Pathogenesis

Pure androgen-secreting adrenal tumors (PASATs) are extremely rare, most reports involving only a single case. This study examined 9 cases of PASAT, with an attempt to characterize its clinical features and to explore the pathogenesis. Clinical data of 9 patients with PASAT were retrospectively reviewed. Immunostaining was conducted, and the aryl hydrocarbon receptor-interacting protein gene (AIP) was amplified and directly sequenced. The onset age of the patients ranged from 3.5 to 64 years. All 8 female patients had virilization, whereas the 7-year-old male patient presented with sexual precocity. Serum testosterone levels were elevated (4.1 to 52.3 nmol/L). Adrenal masses were detected and removed in all patients and histologically diagnosed as adrenocortical adenoma or carcinoma. Two patients had both PASATs and growth hormone (GH)-secreting pituitary adenomas (GH pituitary adenoma). Immunohistochemistry revealed nuclear immunoreactivity for p53 in 3 of 7 patients and nuclear immunoreactivity for cyclin D1 in 2 of 7 patients. Immunostaining of β-catenin showed nuclear, cytoplasmic, and membrane immunoreactivity (2 of 7 patients) or merely cytoplasmic immunoreactivity (1 of 7 patients). The adrenocortical carcinoma showed positive staining for both p53 and cyclin D1 and a high Ki-67 index of 60%. Mutations p.Lys177Argfs*19 and p.Asp287Val in the AIP gene were identified in PASATs of the 2 patients with concomitant presence of GH pituitary adenoma. Clinical features of PASATs vary with gender and age of the patients. Abnormal p53 and β-catenin expression might be involved in the tumorigenesis of these tumors. AIP mutations might be responsible for the concomitant presence of PASATs and GH pituitary adenoma. ACA = adrenocortical adenoma ACC = adrenocortical carcinoma AIP = aryl hydrocarbon receptor-interacting protein DHEAS = dehydroepiandrosterone sulfate; GH growth hormone PASAT = pure androgen-secreting adrenal tumor.

Endoscopic Endonasal versus Microsurgical Transsphenoidal Approach for Growth Hormone–Secreting Pituitary Adenomas—Systematic Review and Meta-Analysis

The pituitary adenoma causing acromegaly is typically resected through a transsphenoidal approach and visualized with an operating microscope or endoscope. We undertook a systematic review and meta-analysis examining the clinical efficacy of endoscopic and microsurgical approaches. Relevant studies using either endoscopic or microscopic transsphenoidal approaches for growth hormone pituitary adenomas were identified until February 2016. Data were extracted and analyzed according to predefined clinical end points. We identified 31 studies, in which 950 patients underwent endoscopic transsphenoidal resection and 2137 patients underwent microsurgical transsphenoidal resection. Patients undergoing microsurgery were less likely to present with hypothyroidism (10.7% vs. 19.1%, P= 0.033, 462 vs. 156 patients) and less likely to have macroadenomas (66.9% vs. 83.8%, P ≤ 0.001, 1484 vs. 884 patients); adenomas with cavernous sinus invasion (21.3% vs. 44.4%, P= 0.036, 592 vs. 558 patients); and a lower mean tumor volume (17.84 vs. 20.54 mm3, P= 0.012, 158 vs. 248 patients). Patients treated via the endoscopic approach were more likely to achieve remission for noninvasive macroadenomas (83.8% vs. 66.9%, P ≤ 0.001, 115 vs. 365 patients). Sinusitis (15.6% vs. 2.6%, P < 0.001, 241 vs. 295 patients) and intraoperative cerebrospinal fluid leak (21.6% vs. 1.0%, P= 0.022, 697 vs. 127 patients) were more common in patients treated endoscopically, and meningitis (0.7% vs. 1.7%, P= 0.027, 511 vs. 1513 patients) was more common in patients undergoing a microsurgical approach. Our study shows the clinical utility of the endoscopic approach and demonstrates potential benefits including increased remission rates with noninvasive macroadenomas and a lower rate of meningitis.

Editorial: Systems Biological Aspects of Pituitary Tumors.

The Editorial on the Research Topic Systems Biological Aspects of Pituitary Tumors Pituitary adenomas are a category of neoplasms with a high degree of heterogeneity that occur in the central regulatory organ pituitary, which plays important roles in the hypothalamus–pituitary-targeted organ axis systems that impact on important physiological functions of human body (1–3). Rapidly developed omics and systems biology (4–6) impact on treatment of pituitary adenomas and gradually change the paradigms from the traditional single-factor strategy to a multi-parameter systematic strategy. A pituitary adenoma is a complex, chronic, and whole-body disease that alters the genome, transcriptome, proteome, and metabolome and involves multiple factors, processes, and consequences (7–9). Pituitary adenomas gradually change in the model of predictive screening, diagnosis, and prognostic assessment of pituitary adenomas that previously only depended on changes of serum single-hormone change and pituitary imaging, and in the therapeutic model of cancer from general radiotherapy and chemotherapy to a personalized strategy (8, 9). This present issue focuses on systems biological aspects of pituitary adenomas, which contains four topics. (i) The first topic addressed vitamin D status and calcium–phosphate homeostasis in acromegaly patients (Halupczok-Żyla et al.). Vitamin D deficiency and alteration in calcium–phosphate balance are associated with a wide spectrum of diseases, such as cancer, diabetes, cardiovascular disease, and respiratory disease. Data demonstrate that acromegaly patients are at the higher risk of vitamin D deficiency and have a tendency to a lower level of calcium and higher level of inorganic phosphate. Data suggest the importance of inorganic calcium–phosphate homeostasis in the pathogenesis of acromegaly patients (growth hormone pituitary adenomas) from the systemic view point. (ii) The second topic addressed the alteration in the chemokine network in pituitary adenomas from a systemic view (Grizzi et al.). Chemokines are a category of inflammatory mediators that exert their roles through typical and atypical chemokine receptor signaling pathways. An alteration of chemokines and receptors is associated with cancer and inflammatory diseases. The chemokine network is proposed as the target of biomarker and new therapeutic approach for pituitary adenomas. (iii) The third topic addressed the proteomic variations in pituitary adenomas (Zhan and Wang). Proteomics is the key component of functional genomics and systems biology. Much progress has been achieved in pituitary adenoma proteomics to expand and enrich the systems biology analysis of pituitary adenomas. This topic emphasized the significance of variations in proteome and protein molecular networks for personalized and precise studies of pituitary adenomas. (iv) The fourth topic focused on molecular network variations in different subtypes of non-functional pituitary adenomas (Zhan and Long). That topic emphasized the integrative molecular networks derived from multiple omics data at the genome, transcriptome, proteome, peptidome, and metabolome levels, and on their variations in different subtypes of non-functional pituitary adenomas. These studies will benefit discovery of effective and reliable biomarkers and therapeutic targets for personalized and precise studies of highly heterogeneous non-functional pituitary adenomas. It is clear that the systems biological aspects of pituitary adenomas cover a very wide range from systemic concepts to analytic methods; from genome, transcriptome, proteome, and metabolome to interactome; from single omics to integrative omics; from panel analysis to molecular network analysis; from genetic feature to phenotype; and from common features to individual characteristics, to investigate the diversity of pituitary adenomas that include functional and non-functional pituitary adenomas and their subtypes (10–15). It must be clearly mentioned that this issue contains only a limited fraction of the very important systems biological aspects of pituitary adenomas. This research topic serves as a modest spur to induce researchers who study systems biology strategies to come forward with its valuable contributions to research and clinical practice of pituitary adenomas. From the point of view of systematic strategies in pituitary adenomas, it is necessary for future studies to systematically investigate variations in the genome, transcriptome, proteome, peptidome, and metabolome in pituitary adenoma tissue and body-fluids (cerebrospinal fluid, CSF; serum/plasma), and especially for different subtypes of pituitary adenomas (7, 9). Systems biology approaches will be used to integrate all experimental data and all clinical information of an individual and to propose corresponding molecular networks specific to a pituitary adenoma in order to achieve efficient prediction screening, early stage diagnosis, prognostic assessment, and individualized and precise prevention and therapy (16, 17). Future issues will collect different levels of omics studies, especially the integrative omics studies together with genetics and clinical information with developed advanced computational biology approaches.

β-catenin knockdown inhibits pituitary adenoma cell proliferation and invasion via interfering with AKT and gelatinases expression

Pituitary adenomas are among the most prevalent forms of intrinsic brain tumors. Although most pituitary adenomas are benign, some of them may become invasive and cause significant mass effect and hormonal dysfunction. We have previously shown that β-catenin is overexpressed in human pituitary adenomas and its level correlates to tumor grades. In the present study, we further investigated the role of β-catenin in pituitary adenoma cell proliferation and invasion in vitro. Stable β-catenin knockdown pituitary adenoma cell line was created by transfecting mouse growth hormone pituitary adenoma GT1.1 cells with β-catenin shRNA plasmid. Cell proliferation and invasion were assessed using CCK-8 kit and transwell assay, respectively. Our data demonstrated that knockdown of β-catenin with shRNA significantly inhibited the proliferation and invasion of GT1.1 cells. In β-catenin shRNA transfected cells, the expression of AKT, STAT3, cyclin D1 and CDK4 were significantly suppressed, which accounted for the observed growth retardation following β-catenin shRNA transfection. Moreover, β-catenin shRNA transfection led to a drastic reduction in MMP-2/9 secretion into the conditioned media, which might be responsible for the reduced invasiveness of β-catenin shRNA-transfected pituitary adenoma cells. These results indicate that β-catenin may regulate the expression of AKT, STAT3, cyclin D1, CDK4 and MMP-2/9 to promote pituitary adenoma cell proliferation and invasion.

Effect of interfering RNA targeting pituitary specific transcription factor-1 on biological behaviors in rat growth hormone pituitary adenoma cells

Objective To observe the effect of small interfering RNA (siRNA) silencing pituitary specific transcription factor 1 (Pit-1) gene expression on the biological behaviors in the rat pituitary growth hormone adenoma cells (GH3).Methods Pit-l-targeted siRNA was designed and synthesized,and transfected into GH3 cells with mixed with liposome.Western blotting and reverse transcription polymerase chain reaction (RT-PCR) were applied to detect the expression levels of Pit-1 protein and mRNA after siRNA-Pit-1 transfection.Cell proliferation was examined by using cell counting kit-8 (CCK-8) cell proliferation-toxicity test.Cell apoptosis was detected by using flow cytometry.In vitro invasion ability changes in GH3 cells were detected by Transwell cell array.Results siRNA significantly inhibited the expression of Pit-1 protein and mRNA.As compared with negative control group,cell proliferation ability was decreased with the absorbance (A) values being respectively decreased by 0.46 and 0.41 at 36 and 48 h,apoptosis rate was increased by 3.17％,6.36％ and 8.46％,and the number of cells penetrating the membrane was decreased by 38.43,46.54 and 38.13 at 24,36 and 48 h in siRNA group,respectively (P ＜ 0.05 for all).Conclusion Pit-1 siRNA can effectively inhibit proliferation,promote apoptosis and reduce invasiveness of GH3 cells. Key words: Pituitary adenoma; Pituitary specific transcription factor-1

Effect of pituitary-specific transcription factory small interfering RNA on biological behaviors of growth hormone pituitary adenoma GH3 cells in rats

Objective To observe the effects of pituitary-specific transcription factory (Pit-1)small interfering RNA (siRNA) on biological behaviors of growth hormone pituitary adenoma GH3 cells in rats.Methods Design and synthesis of the Pit-1 gene of siRNA,mixed with liposome transfection of GH3 cells.Using protein immunoblot assay (Western blotting),reverse transcription polymerase chain reaction (RT-PCR) assay for the determination,after siRNA translated 24 h,of Pit-1 protein and Pit-1 mRNA expression ; with cell counting kit-8 (CCK-8) cell proliferation-toxicity test in the detection of cell growth increment change; by flow cytometry for detection of apoptosis changes ; system preparation of Transwell cell determination of GH3 cells in vitro invasion ability changes.Results SiRNA significantly inhibited Pit-1 protein and the Pit-1 mRNA the expression level decreased by 58.18％ and 75.82％,respectively;CCK-8 method results showed that the siRNA group cell growth significantly lower than the negative control group; siRNA group increased apoptosis rate (9.250 00 ±0.996 95)％ compared with the negative control group (2.893 30±0.665 16)％ ;siRNA group through the Matrigel gum and cell membrane (92.91 ± 53.25)months,with the negative control group (7.50 ± 7.95) comparison invasion force significantly weakened,and the difference was statistically significant (P ＜0.05).Conclusion Pit-1 siRNA can effectively inhibit GH3 cell growth,promote their apoptosis,reduced invasiveness. Key words: Pituitary adenomas; Small interfering RNA; Biological behavior

Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS 201-995 before transsphenoidal surgery.

The purpose of this study was to determine whether the long-acting somatostatin analog SMS 201-995 (octreotide) shrinks growth hormone (GH)-secreting adenomas and improves the results of subsequent transsphenoidal surgery. Ten previously untreated active acromegalic patients (nine women and one man) with invasive tumors were treated with SMS 201-995 (100 micrograms subcutaneously every 8 hours) for 6 weeks prior to transsphenoidal surgery. The clinical activity, mean GH secretion, insulin-like growth factor (IGF)-I concentration, and tumor volume were measured under basal conditions and on Days 14, 28, and 42 of treatment. The SMS 201-995 improved the symptoms of acromegaly in all patients. Mean levels of both GH and IGF-I (+/- standard deviation) were significantly decreased by Day 14 (from 92.9 +/- 30.5 to 44.9 +/- 20.3 micrograms/liter and from 10.6 +/- 7.4 to 5.9 +/- 2.6 U/ml, respectively), after which there were only slight further decreases. Six (60%) of the 10 patients experienced tumor shrinkage ranging from 9% to 78% (mean 30%). When it occurred, tumor shrinkage was significant by Day 14 (7.9 +/- 6.3 to 6.5 +/- 5.1 cu cm) and no further shrinkage was achieved by longer administration. Transsphenoidal surgery reduced postoperative GH levels to less than 2 micrograms/liter and IGF-I to less than 1.5 U/ml in six patients (60%). This percentage of cure is higher than expected from the literature and the authors' previous experience. However, an investigation of the influence of this drug on several parameters, such as reduction of tumor size or GH and IGF-I concentrations, has failed to prove any relationship. Only pretreatment size of the tumor was of predictive value with respect to the surgical outcome.