BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.
ACTH-Secreting Pituitary Adenoma ; Adrenocorticotropic Hormone ; Blotting, Western ; Cell Cycle ; Cell Line ; Cell Proliferation ; Corticotrophs ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression ; Oxytocin ; Phosphotransferases ; Pituitary Neoplasms ; Polymerase Chain Reaction ; Pro-Opiomelanocortin ; Proliferating Cell Nuclear Antigen ; Protein Kinases ; Reverse Transcription

OBJECTIVE: Silent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA).METHODS: Among 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared.RESULTS: Strong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05).CONCLUSION: Total surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.
ACTH-Secreting Pituitary Adenoma ; Adenoma ; Adrenocorticotropic Hormone ; Cavernous Sinus ; Corticotrophs ; Female ; Humans ; Hydrocortisone ; Hypopituitarism ; Immunohistochemistry ; Incidence ; Pituitary Neoplasms ; Radiotherapy ; Recurrence

No abstract available.
ACTH-Secreting Pituitary Adenoma/complications/diagnostic imaging/surgery ; Adenoma/complications/diagnostic imaging/surgery ; Adolescent ; Biomarkers/urine ; Biopsy ; *Circadian Rhythm ; Creatinine/*urine ; Cushing Syndrome/*diagnosis/*urine ; Female ; Humans ; Hydrocortisone/*urine ; Magnetic Resonance Imaging ; Predictive Value of Tests ; Tomography, X-Ray Computed ; Treatment Outcome ; Urinalysis

The present case involves a 56-year-old woman with Cushing's disease due to pituitary macroadenoma. The patient had suffered from central obesity, general weakness for 1 year. Her serum cortisol levels were elevated throughout the observation period and the dexamethasone test failed to suppress the cortisol secretion. Plasma adrenocorticotropic hormone (ACTH) levels were significantly elevated (386 pg/mL). Sellar magnetic resonance imaging revealed a 3.1-cm pituitary tumor occupying the sellar region with extension to parasellar area. The pituitary mass was removed by transsphenoidal surgery incompletely and was pathologically identified as compatible to ACTH-producing pituitary adenoma by immunohistochemistry. Thereafter, cabergoline (1 mg/wk) was administered for the remnant adenoma, which gradually reduced ACTH levels in 7 days before starting radiation therapy. This case demonstrates the efficacy of cabergoline to treat Cushing's disease caused by pituitary macroadenoma.
ACTH-Secreting Pituitary Adenoma ; Adenoma ; Adrenocorticotropic Hormone ; Cushing Syndrome ; Dexamethasone ; Female ; Humans ; Hydrocortisone ; Immunohistochemistry ; Magnetic Resonance Imaging ; Middle Aged ; Obesity, Abdominal ; Pituitary Neoplasms ; Plasma

BACKGROUNDAdrenocorticotrophin (ACTH)-secreting pituitary adenomas account for approximately 7% - 14% of all pituitary adenomas, but its pathogenesis is still enigmatic. This study aimed to explore mechanisms underlying the pathogenesis of ACTH-secreting pituitary adenomas.

METHODSWe used fiber-optic beadarray to examine gene expression in three ACTH-secreting adenomas compared with three normal pituitaries. Four differentially expressed genes from the three ACTH-secreting adenomas and three normal pituitaries were chosen randomly for validation by reverse transcriptase-real time quantitative polymerase chain reaction (RT-qPCR). We then analyzed the differentially expressed gene profile with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway.

RESULTSFiber-optic beadarray analysis showed that the expression of 28 genes and 8 expressed sequence tags (ESTs) were significantly increased and the expression of 412 genes and 31 ESTs were significantly decreased. Bioinformatic and pathway analysis showed that the genes HIGD1B, EPS8, HPGD, DAPK2, and IGFBP3 and the transforming growth factor (TGF)-β signaling pathway and extracellular matrix (ECM)-receptor interaction pathway may play important roles in tumorigenesis and progression of ACTH-secreting pituitary adenomas.

CONCLUSIONSOur data suggest that numerous aberrantly expressed genes and several pathways are involved in the pathogenesis of ACTH-secreting pituitary adenomas. Fiber-optic beadarray combined with pathway analysis of differential gene expression appears to be a valid method of investigating tumour pathogenesis.

ACTH-Secreting Pituitary Adenoma ; etiology ; genetics ; Adenoma ; etiology ; genetics ; Adult ; Disease Progression ; Expressed Sequence Tags ; Extracellular Matrix Proteins ; physiology ; Female ; Fiber Optic Technology ; Gene Expression Profiling ; Humans ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; methods ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; physiology ; Transforming Growth Factor alpha ; physiology

OBJECTIVE: Microscopic and endoscopic transsphenoidal approach (TSA) are major surgical techniques in the treatment of pituitary adenoma. Endoscopic endonasal transsphenoidal approach (EETSA) has been increasingly used for pituitary adenomas, however, its surgical outcome particularly in functioning pituitary adenoma has been debated. Here, we investigated the endocrine outcome of the patients with growth hormone (GH) and adrenocorticotropic hormone (ACTH) secreting pituitary adenoma treated by EETSA. METHODS: We treated 80 patients with pituitary adenoma by EETSA since 2004, of which 12 patients were affected by functioning pituitary adenomas (9 GH, 3 ACTH, 0 PRL; 9 macro, 3 micro). Surgical outcome of those patients treated by EETSA was compared with that of the 11 functioning pituitary adenoma patients (8 GH, 3 ACTH; 8 macro, 3 micro) who underwent sublabial microscopic TSA between 1997 and 2003. RESULTS: Imaging remission based on postoperative MRI was achieved in 8 (73%) and hormonal remission in 5 (45%) of 11 patients treated by sublabial microscopic TSA. Imaging remission was observed in 10 (83%, p=0.640) and hormonal remission in 10 (83%, p=0.081) of 12 patients by EETSA. CSF leakage was noticed in 2 (17%) of EETSA group and in 2 (18%) of sublabial microscopic TSA group. Panhypopituitarism was observed in 1 (9%) of EETSA group and in 3 (27%) of sublabial microscopic TSA group. CONCLUSION: EETSA appears to be an effective and safe method for the treatment of functioning pituitary adenomas.
ACTH-Secreting Pituitary Adenoma ; Adrenocorticotropic Hormone ; Endoscopy ; Growth Hormone ; Growth Hormone-Secreting Pituitary Adenoma ; Humans ; Hypopituitarism ; Pituitary Neoplasms

OBJECTIVETo evaluate the distribution and expression of peroxisome proliferator activated receptor gamma (PPAR-gamma) in human pituitary adenomas.

METHODSThirty eight consecutive surgically resected pituitary adenomas and 5 normal pituitary tissues were enrolled in the study. Immunohistochemistry was used to confirm the distribution of PPAR-gamma. Expression of PPAR-gamma was evaluated by Western blot.

RESULTSPPAR-gamma immunoreactivity was located in the nucleoli of pituitary adenoma cells. PPAR-gamma was expressed in all human pituitary adenomas and normal pituitary tissues. Its expression in pituitary adenomas was significantly higher than in normal pituitary tissues (P < 0.01), and its expression in ACTH-secreting adenomas was significantly higher than in any other type of pituitary adenomas (P < 0.05).

CONCLUSIONSPPAR-gamma may play an important role in the generation, growth, and invasion of human pituitary adenomas. It may become a novel therapeutic target for these tumors.

ACTH-Secreting Pituitary Adenoma ; metabolism ; Adult ; Female ; Humans ; Male ; Middle Aged ; PPAR gamma ; biosynthesis ; metabolism ; Pituitary Gland ; metabolism ; Pituitary Neoplasms ; metabolism

OBJECTIVE: We analyzed the clinical and endocrinological results of the transsphenoidal microsurgery for ACTH secreting pituitary adenomas. MATERIALS AND METHODS: From October 1995 to August 2000, 18 patients underwent transsphenoidal microsurgery for Cushing's disease. We analyzed the surgical results of 17 patients, one patient who was previously operated from other hospital was excluded. Age of the patients were 18 to 61 years old(mean 37.7), male to female ratio was 1: 3.3, and follow-up period was 3 to 50 months(mean 20.3). The selection of candidates for transsphenoidal exploration was based on endocrinologic criteria. Magnetic resonance imaging was the preferred radiologic test. Selective inferior petrosal sinus sampling of adrenocorticotropic hormone futher refined the diagnosis when endocrinologic and radiologic procedures were not definitive. RESULTS: Results of the preoperative endocrinological test were: level of serum ACTH 29.4 to 225ng/dL(mean 93.88ng/dL); serum cortisol 11.9 to 47.5ng/dL(mean 27.49ng/dL); 24-hour urine free cortisol 235 to 1019ng/day(mean 571.0ng/day). Inferior petrosal sinus sampling for ACTH was performed in 11 patients and all were confirmed by Cushing's disease and we could predict the laterality of the tumor in 9 of 11 patients. We performed transsphenoidal selective adenomectomy in 5 patients, adenomectomy and subtotal hypophysectomy in 2 patients, adenomectomy and partial hypophysectomy in 9 patients, and in the remaining one patient, hemihypophysectomy followed by total hypophysectomy due to remission failure. Fifteen of 17 patients(88.2%) showed endocrinological remission. Glucocorticoid replacement therapy was performed in all the patients who showed remission for 1 to 24 months(mean 5.9 months), and 6 patients received steroid over 6 months. CONCLUSION: We conclude that the direct demonstration of a tumor in the pituitary gland by MRI is the most important and definitive diagnostic tool and the location of a mass should be confirmed with increased level of ACTH by the inferior petrosal sinus sampling. Transsphenoidal microsurgery is effective treatment modality for Cushing's disease and the immediate postoperative evaluation of the surgical resection of the tumor is very important. The patients should show hypocortisolism, decreased, subnormal serum ACTH and cortisol levels and 24-hours urine free cortisol. We performed 18 transsphenoidal microsurgery for Cushing's disease in 17 patients and 15 patients(88.2%) showed endocrinological remission.
ACTH-Secreting Pituitary Adenoma ; Adrenocorticotropic Hormone ; Diagnosis ; Female ; Follow-Up Studies ; Humans ; Hydrocortisone ; Hypophysectomy ; Magnetic Resonance Imaging ; Male ; Microsurgery* ; Petrosal Sinus Sampling ; Pituitary Gland

PURPOSE: To evaluate the diagnostic value of radiologic studies in the Cushing's disease MATERIALS AND METHODS: We analyzed retrospectively the CT(n=19, dynamic CT was not perfomed), MR (n=23, dynamic MR in 2 cases), and the results of inferior petrosal sinus sampling(IPSS)(n=13) in 25 patients(19 women, 6men, age range 16-58, mean 32.2) with pathologically-confirmed ACTH secreting pituitary adenoma. We analyzed the radiologic findings and determined how accurately each method could detect and lateralize the lesion within the pituitary gland. The results were compared with the surgical findings and with each other. RESULTS: Seven patients(28%) out of 25 had macroadenomas and the lesions were detected and correctly diagnosed by CT and MR in all. Eighteen patients(72%) had microadenoma. In patients with microadenoma the sensitivity was 38.5%(5/13) in CT, 64.7%(11/17) in MR, 90.9%(10/11) in IPSS. In two patients with dynamic MR, in whom the conventional Gd-enhanced MR showed false negative results, the lesions were detected as low signal intensity mass and correctly lateralized. Considering the results of both MR and IPSS, the sensitivity increased up to 94.1%(17/18). CONCLUSION: Considering the invasiveness of IPSS, Gd-enhanced MR, preferably dynamic, seems to be an imaging modality of choice in Cushing's disease. Combined use of IPSS in selected patients further increases the accuracy of diagnosis and lateralization.
ACTH-Secreting Pituitary Adenoma ; Diagnosis ; Female ; Humans ; Pituitary Gland ; Retrospective Studies

The records of 31 patients diagnosed as having Cushing's disease surgically treated via transsphenoidal approach at our instituion between March, 1984, and April, 1994, were retrospectively reviewed in order to determine the most ideal method in diagnosing and the treatment outcome of ACTH-producing pituitary adenomas. Preoperative diagnosis was made after evaluating the patients with endocrinological studies including inferior petrosal sinus(IPS) sampling, and high-resolution computerized tomography(CT) and/or high-field magnetic resonance(MR) imaging. The sensitivity of IPS sampling technique used in microadenoma cases was 85.7% and of evaluating with CT and MR imaging, 529% and 61.9%, respectively. Of the 31 cases, 22 were microadenomas, 6 macroadenomas, 1 hyperplasia, and 2 histopathologically identified as being not a tumor. Microsurgical procedures included 19 selective adenomectomy(SA), 7 hemihypophysectomy(HH), 2 partial adenomectomy(PA), and 3 multiple biopsies(BX). The surgical remission rates of SA group and H group were 89.5%(17 out of 22) and 71.4%(5 out of 7), respectively. PA and BX groups showed no remission. Out of 7 patients who underwent radiation therapy after showing no remission postoperatively, 5 demonstrated remission, giving an overall remission rate of 87.1%. It is concluded that IPS sampling and high-field MR imaging(including dynamic MR imaging) procedures are the most ideal methods in evaluating and diagnosing patients with Cushing's disease. Selective adenomectomy via transsphenoidal microsurgery is the most effective treatment modality, but such therapeutic intervention should be used with discretion. The best operative results are obtained in cases in which the margin of the adenoma is clearly visualized grossly, and the frozen bipsy of the resected margin is negative for tumor cells.
ACTH-Secreting Pituitary Adenoma* ; Adenoma ; Diagnosis ; Humans ; Hyperplasia ; Magnetic Resonance Imaging ; Microsurgery ; Retrospective Studies ; Treatment Outcome*