Prolactin Adenomas Research Articles

1235 Using Supervised Machine Learning to Validate a Novel Scoring System for the Prediction of Disease Remission of Functional Adenomas Following Transsphenoidal Resection

INTRODUCTION: Functional pituitary adenomas are common primary central nervous system tumors with potent systemic endocrinological effects. Postoperatively, remission rates range from 65-98%. METHODS: 392 adult patients who underwent primary resection of a functional pituitary adenoma at the three Mayo Clinic between 2006-2022 were retrospectively reviewed. Multivariate logistic regression was performed to identify variables predictive of disease remission. Variables found statistically significant on multivariate analysis were incorporated into our proposed pituitary-SCHEME score. Machine learning models were implemented to compare the accuracy of the pituitary-SCHEME score against the multivariate models. After training (314 patients) and cross-validation of the machine learning models, an independent testing set of 78 patients was performed. SPSS V27 and R4.2.1 were used for statistical analyses. RESULTS: 261 (66.6%) patients achieved post-operative biochemical remission. On multivariate analysis gross-total resection and Knosp-Grade 0,I,II adenomas were predictive of disease remission following resection, while macroadenomas (adenoma > 10mm), male sex, mammosomatotroph and Mixed Growth-Hormone + Prolactin adenomas were predictive of continued disease. In machine learning models, without Pituitary-SCHEME score, the K-Nearest Neighbors (KNN) model achieved the highest accuracy at 75.6% followed by Naive Bayes model. An increase in model sensitivity was achieved with inclusion of Pituitary-SCHEME score with the Linear-Discriminant-Analysis (LDA) model achieving the highest accuracy at 86.9%, followed by the Classification and Regression Trees (CART) model. The random forest model had the largest AUC-ROC among models with and without pituitary-SCHEME score. Model prediction accuracy (with vs. without pituitary-SCHEME score) were found to be statistically different based on Wilcoxon rank sum testing (p < 0.0001). CONCLUSIONS: The novel pituitary-SCHEME score, which incorporates perioperative and endocrinological measures, has promise as a clinical tool to predict patient outcomes following surgical resection of functional adenomas.

PITUITARY STONE ADENOMA ASSOCIATED WITH SEVERE HYPERPROLACTINEMIA CASE REPORT

A 35-year-old patient consulting for erectile dysfunction, with a progressive visual acuity loss. Biological assessment revealed hyperprolactinemia at 4315 ng/ml and low testosteronemia at 6.8 nmol/l. Skull X-ray showed an enlarged sellaturcica with voluminous intra- and suprasellar calcifications. A cranial CT scan revealed an intra- and suprasellar calcified mass. Transphenoidal surgery was performed. The tumor was partially removed and the piece was made of calcified grayish granular tissue. Histological examination showed adenomatous cells with large granular calcification lesions. Immunohistochemistry confirmed prolactin adenoma. Cabergoline treatment was effective on the calcified tissue remaining after surgery.

Type 2 Diabetes Revealing a Mixed GH (Acromegaly) and Prolactin Adenoma: A Case Report of the Internal Medicine Department of the Gabriel Touré University Hospital, Bamako, Mali

Type 2 Diabetes Revealing a Mixed GH (Acromegaly) and Prolactin Adenoma: A Case Report of the Internal Medicine Department of the Gabriel Touré University Hospital, Bamako, Mali

Type 2 Diabetes Revealing a Mixed GH (Acromegaly) and Prolactin Adenoma: A Case Report of the Internal Medicine Department of the Gabriel Touré University Hospital, Bamako, Mali

Introduction: Pituitary adenomas are benign, well-differentiated tumours that usually grow slowly over several years and are developed monoclonally from anteropituitary endocrine cells. We report a case of mixed GH and prolactin adenoma diagnosed in the Internal Medicine Department of the Gabriel Touré University Hospital, Bamako, Mali. Observation: The patient was a 36-year-old man with a 4-year history of type 2 diabetes mellitus who had consulted a specialist for headache, polyuro-polydipsic syndrome, decreased libido and erectile dysfunction. On clinical examination, a tumour syndrome was noted with headache and visual blur. The biology revealed a GH hypersecretion syndrome (IGF1) which was elevated to 561.9 µg/ml (VN=116-353) and prolactin elevated to 463.3 µIU/ml (VN: 24-324) and diabetes. Pituitary MRI revealed a pituitary macroadenoma. Our patient was treated with Dostinex 0.5mg/week with a gradual increase in dose and insulin. He was also referred to neurosurgery, where he is awaiting removal of the adenoma after glycaemic control and hormone normalisation. The evolution was marked by the disappearance of headaches, improvement in vision, GH and prolactin hypersecretion syndrome and glycaemic control. Conclusion: In sub-Saharan Africa, the problems posed by pituitary adenomatous pathologies are complex, due to the limited biological and morphological investigation facilities and the rarity of specialised surgical facilities.

Metabolic Disorders During Prolactinomas.

The metabolic profile during prolactinoma may be subject to significant changes. We aimed to describe the different metabolic aspects in patients monitored for prolactinoma and to study the correlations between the size of the prolactinoma and the metabolic parameters. We conducted a retrospective, descriptive, and analytical study of 77 cases of prolactinomas collected and monitored at the endocrinology and diabetology department of the Hedi Chaker Hospital in Sfax between 2000 and 2017. Our patients were divided into three groups according to the size of their prolactinomas. Statistical correlations were sought between tumor size and clinical and biological parameters. The mean age of our patients was 38.3 ± 14.2 years. They were divided into 51 women (66.2%) and 26 men (33.7%). Pituitary tumor syndrome was the most common circumstance of discovery in our population (62.3%). The clinical examination revealed an average waist circumference of 95.71 cm. Android fat distribution was observed in 25 women (49%) and 12 men (46.1%). A statistically significant positive correlation was objectified between waist circumference and tumor size (r = 0.29 and P = 0.019). The average body mass index was 28.08 kg/m2. Obesity was noted in 56 cases (72.7%). Glucose tolerance disorders and hypertriglyceridemia were also more evident each time prolactinoma size increased in contrast to the level of high-density lipoprotein cholesterol which decreased with adenoma size. Our study highlighted the metabolic and hormonal repercussions of prolactinomas. Metabolic syndrome was more common in patients with larger prolactinoma. These results should guide the initial assessment and therapeutic management of prolactin adenomas.

Resistant prolactinomas: a case series of 26 patients.

Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993-2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13-62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5-5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1-296.7] vs. 73.1 [22.6-170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27-11.27] vs 5.27 (2.9-26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7-21.6] vs 1.1 [0.44-3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.

Case Report A Rare Case of Plurihormonal Pituitary Adenoma Associating Cushing's Disease and Silent Prolactinoma

Plurihormonal pituitary adenomas are rare conditions that secrete two or more pituitary hormones. The association of prolactin with other hormones is described but associated with ACTH is uncommon. We report a rare case of mixed adenoma associating Cushing’s disease and silent prolactin adenoma in 21 years old male patient. This case highlights an unusual plurihormonal pituitary adenoma case with a rare association between ACTH and prolactin. It pathogeny is less clearly define.

Cystic appearance on magnetic resonance imaging in bihormonal growth hormone and prolactin tumors in acromegaly.

To investigate demographic, imaging and laboratory characteristics, and treatment outcomes of acromegaly patients who have bihormonal (BA) growth hormone (GH) and prolactin (PRL) immunoreactive adenomas compared to patients who have densely granulated GH adenomas (DGA) and sparsely granulated GH adenomas (SGA). Retrospective review of single-center surgically treated acromegaly patients; pathology was analyzed by asingle neuropathologist using 2017 WHO criteria. Preoperative magnetic resonance imaging was assessed to evaluate tumor size, cystic component, invasion and T2 signal intensity. Seventy-seven patients; 19 BA (9 mammosomatotroph and 10 mixed GH and PRL adenomas) were compared with 30 DGA, and 28 SGA. Patients with BA were older than SGA (49.6 vs 38.5years, p = 0.035), had a higher IGF-1 index (3.3 vs 2.3, p = 0.040) and tumors were less frequently invasive (15.8% vs 57.1%, p = 0.005). BA more frequently had a cystic component on MRI than both SGA and DGA (52.6% vs 14.3%, and 22%, p = 0.005 and 0.033, respectively). When all histological types were combined, biochemical remission postoperatively was more common in non-cystic than cystic tumors (50% vs 22.5%, p = 0.042). Somatostatin receptor ligand response rate was 66.7%, 90.9% and 37.5% in BA, DGA and SGA patients, respectively (p = 0.053). Imaging characteristics are an increasingly important adenoma behavior determinant. An adenoma cystic component may suggest that a GH adenoma is a BA. Cystic tumors exhibited lower rates of surgical remission in this series; therefore, optimized individual patient treatment is needed, as patients could be candidates for primary medical treatment.

Long-term application of diethylstilbestrol upregulates expressions of µ - and m-calpains in pituitary intermediate lobe of female Wistar rats*

BACKGROUNDDuring formation of prolactin neoplasia, how cells and its structure in adenohypophysis affect prolactin cells should be further studied. Intermediate lobe can be regarded as a driving region to release prolactin (PRL) and may promote formation of prolactin neoplasia in pituitary anterior lobe. OBJECTIVETo observe the effect of diethylstilbestrol (DES) on the expressions of µ and m-calpains in pituitary intermediate lobe of female Wistar rats. DESIGNObservational contrast animal study. SETTINGBeijing Neurosurgical Institute. MATERIALSA total of 21 female Wistar rats, 3 weeks old weighing 70 – 80 g were housed with free access to tap water and standard pellet food. They were kept in a CL-grade condition, at (24±1)°C and a humidity of (55±5)%, and with a 12 hours day-night cycle. Caprine anti- µ - and m-calpains antibodies were provided by Santa Cruz Biotechnology, CA, USA; rabbit-anti-PRL antibodies by Dako, Denmark; rabbit-anti-ACTH antibody by Boster Company, Wuhan. METHODSThe experiment was carried out in Pathophysiological Department and Animal Laboratory, Beijing Neurosurgical Institute from August 2006 to January 2007. (1) Rats were randomly divided into groups with 7 in each group, including vehicle control group, in which rats were injected intraperitoneally with sun-flower seed oil (1 mL/kg, twice a week) for 16 weeks; DES group, where animals were administered with DES (5 mg/kg, twice a week) for 16 weeks; DES + vehicle control group, in which DES was administered for 12 weeks at the same dose with those in DES group, and then was discontinued and replaced by sun-flower seed oil (1 mL/kg, twice a week) for the following 4 weeks. (2) At 16 weeks later, pituitary tissue was dealt with HE staining and PRL immunohistochemical examination to observe evoke of tumor; meanwhile, immunohistochemical examination was used to observe expression of PRL of pituitary anterior lobe, expressions of µ - and m-calpains of pituitary intermediate lobe and distribution of adrenocorticotropin. MAIN OUTCOME MEASURES(1) Expression of PRL of pituitary anterior lobe, expressions of µ - and m-calpains of pituitary intermediate lobe and distribution of adrenocorticotropin. (2) Morphological observation of pituitary tissue. RESULTSAll 21 rats were involved in the final analysis. ? Results of immunohistochemical examination: Morphological changes of neoplasia in DES group were strongly positive to PRL, and this suggested that formation of prolactin adenoma was observed in pituitary tissue. As compared with vehicle control group, expression of adrenocorticotropic hormone (ACTH) was increased in both DES group and DES + vehicle control group. In addition, expressions of µ - and m-calpains in pituitary intermediate lobe were higher in DES group than that in vehicle control group. Otherwise, expressions of m-calpains in pituitary intermediate lobe was decreased in DES + vehicle control group, but expression of µ -calpains was still increased. (2) Morphological observation of pituitary tissue: Gland tubes were orderly arranged in rats in vehicle control group. Anterior pituitary gland in rats of DES group demonstrated an apparent disappearance of gland tubes and a relatively large-scaled vasculature formation, namely the vascular lake lined by tightly arranged endothelial cells. Local integrated tumor cell arrangements were also detected. In addition, the border between the IL and the anterior lobe was locally blurred. The definite tumor-like changes in pituitary tissues were confirmed in 6 of 7 female Wistar rats in DES group, and one spontaneous occurrence of tumor formation was found in vehicle control group. In DES + vehicle control group, DES withdrawal led to the subtile emergence of gland tube cavity, although tumor-like cells still existed in 4 of 7 rats, suggesting occurrence of the tumor regression due to the withdrawal of DES. CONCLUSIONA long-term application of DES can enhance the expressions of ubiquitours neutral cysteine protease in pituitary intermediate lobe and this suggests that both of them play a key role in release of hormone and formation of prolactin neoplasia through directly promoting PRL expression and release of neighboring pituitary intermediate lobe.

Patients with true mixed growth hormone and prolactin-secreting pituitary adenoma: a case series of 12 patients

Objective: Mixed growth hormone (GH) and prolactin (PRL) secreting adenomas are the most common type of plurihormonal pituitary adenomas. We assessed the clinical presentations and impacts of transsphenoidal surgery (TS) on patients with mixed GH and PRL adenomas including surgical outcomes, complications, and prognosis.Method and patients: Twelve patients (7 males, 5 females) were operated in the neurosurgery department of Qilu hospital affiliated to Shandong University, Shandong, China. We analyzed hormone levels of preoperation, postoperation (within 24 h) and at 12-month follow-up and correlated levels with tumor volumes.Results: The remission rate was 66.7% (8/12), the recurrence rate was 16.7% (2/12), the cause-specific mortality was 0 and the overall mortality rate was 16.7% (2/12) due to stroke and myocardial infarction respectively. A significant drop was seen in GH, PRL, and Insulin-like-growth-factor-1 (IGF-1) levels between preoperation and postoperation with mean values from 52.6 to 9.9 ng/ml (p = 0.0015), from 321.6 to 190.9 ng/ml (p = 0.0026) and from 815.7 to 230.6 ng/ml (p = 0.0004), respectively. This drop was more significant between preoperation and follow-up with mean values from 52.6 to 3.0 ng/ml (p = 0.002), from 321.6 to 61.6 ng/ml (p < 0.0001), and from 815.7 to 195.0 ng/ml (p = 0.0001), respectively. However, there was no significant correlation between tumor volume and all of the hormone levels.Conclusions: Most mixed GH and PRL adenomas are aggressive with a high risk of recurrence and mortality.

Macroprolactinome géant : à propos d’un cas

The biologically active prolactin is in monomeric form. There are polymerized forms, also called big prolactin and forms linked to immunoglobulins G also called macroprolactin or big big prolactin. We report the case of a 45-year-old patient, operated for prolactin adenoma in 2012.The male macroprolactinoma is a tumor of late discovery, which makes interesting the study of these particularities in order to establish in the light of clinico-biological data and medical imaging therapeutic recommendations and adapted follow-up after consultation between neurosurgeon, endocrinologist and biologist.

Application of microprobe vascular Doppler in the operation of skull base lesions

Objective To investigate the effect of microprobe vascular Doppler (MVD) on the operation of skull base lesions. Methods From September 2017 to September 2018, 13 patients with skull base lesions at Neurosurgery Department of the first Affiliated Hospital of Soochow University were retrospectively analyzed. The 13 cases included 6 cases of meningioma in Sellar region, 2 cases of meningioma in petroclival region, 3 cases of pituitary adenoma of Knosp Ⅲ-Ⅳ grade, 1 case of chordoma in Sellar clival region, and 1 case of invasive growth of granulation tissue in intraorbital, skull base, sphenoid and ethmoid sinus after Aspergillus infection. The surgical methods included neuroendoscopic transnasal approach and microsurgical resection under craniotomy microscope. MVD was applied in all operations of this series. Medical imaging examination and follow-up were performed after operation. Results Among the 13 patients, total resection of meningioma in Sellar region was performed in 6 cases and subtotal resection in 2, total resection of Knosp grade Ⅲ-Ⅳ pituitary adenoma was conducted in 2 and subtotal resection in 1. Total resection was performed in 1 case of invasive growth of granulation tissue in intraorbital, skull base, sphenoid and ethmoid sinus after Aspergillus infection and 1 case of chordoma in Sellar base clival region. Uncorrected left eye vision was reported in the patient with Aspergillus infection post surgery. Postoperative symptoms of the other patients were improved. The prolactin level of 1 patient with prolactin adenoma was more than 204 ng/ml before operation. At 2 months post operation, the prolactin level was 105.66 ng/ml after oral bromocriptine combined with radiotherapy. The last reexamination was 11.3 ng/ml without hypophysis dysfunction. Six patients had varying degrees of electrolyte disorder after operation. Four patients had fever after operation and all returned to normal before discharge from hospital after treatment. All patients were followed up for (16.1±3.3) months(10-22 months), and there was no recurrence in imaging examination. Conclusion With the aid of MVD during the surgical resection of invasive growth lesions and large space occupying lesions in the skull base, the important blood vessels invaded, wrapped, pushed and displaced by the lesions can be monitored in real time, which might help avoid the disastrous consequences during and after operation and reduce the risk of surgery. Key words: Skull base neoplasms; Microsurgery; Natural orifice endoscopic surgery; Microprobe vascular Doppler

GLUT3 expression in cystic change induced by hypoxia in pituitary adenomas.

Tumor cells require large amounts of energy to sustain growth. Through the mediated transport of glucose transporters, the uptake and utilization of glucose by tumor cells are significantly enhanced in the hypoxic microenvironment. Pituitary adenomas are benign tumors with high-energy metabolisms. We aimed to investigate the role of expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1) in pituitary adenomas, including effects on size, cystic change and hormone type. Pituitary adenomas from 203 patients were collected from January 2013 to April 2017, and immunohistochemical analysis was used to detect the expression of GLUT3 and GLUT1 in tumor specimens. GLUT3-positive expression in the cystic change group was higher than that in the non-cystic change group (P = 0.018). Proportions of GLUT3-positive staining of microadenomas, macroadenomas, and giant adenomas were 22.7 (5/22), 50.4 (66/131) and 54.0% (27/50), respectively (P = 0.022). In cases of prolactin adenoma, GLUT3-positive staining was predominant in cell membranes (P = 0.000006), while in cases of follicle-stimulating hormone or luteotropic hormone adenoma, we found mainly paranuclear dot-like GLUT3 staining (P = 0.025). In other hormonal adenomas, GLUT3 was only partially expressed, and the intensity of cell membrane or paranuclear punctate staining was weak. In contrast to GLUT3, GLUT1 expression was not associated with pituitary adenomas. Thus, our results indicate that the expression of GLUT3 in pituitary adenomas is closely related to cystic change and hormonal type. This study is the first to report a unique paranuclear dot-like GLUT3 staining pattern in pituitary adenomas.

Reasons and results of endoscopic surgery for prolactinomas: 142 surgical cases.

We report herein a retrospective analysis of the results of 142 consecutive prolactinoma cases operated upon using an endoscopic endonasal trans-sphenoidal approach over a period of 6 years. Medical records of 142 cases were analysed with respect to indications for surgery, duration of hospital stay, early remission rates, failures and recurrence rates during a median follow-up of 36 months. On the basis of magnetic resonance imaging (MRI) data, 19 patients (13.4 %) had microadenoma, 113 (79.6 %) had macroadenoma, and the remaining 10 (7.0 %) had giant adenomas. Cavernous sinus invasion was identified in 25 patients by MRI and confirmed during surgery. Atypical adenoma was diagnosed in 16 patients. Sparsely granulated prolactin adenoma was identified in 99 patients (69.7 %). Our results demonstrate that male sex and higher preoperative prolactin levels are independent factors predicting persistent disease. The post-surgical complications are as follows: 2.8 % patients had meningitis, 2.1 % patients had postoperative cerebrospinal fluid leak and 2.1 % patients had panhypopituitarism. At the end of follow-up, 74.6 % patients went into remission. During follow-up period, five patients who had initial remission developed recurrence. Our series together with literature data suggest that an endoscopic endonasal trans-sphenoidal approach in the treatment of proloctinomas has a favourable rate of remission. According to the findings of this study, endoscopic endonasal trans-sphenoidal surgery might be an appropriate therapy choice for patients with prolactinoma who could not have been managed with recommended therapeutic modalities.

Combining Cadherin Expression with Molecular Markers Discriminates Invasiveness in Growth Hormone and Prolactin Pituitary Adenomas

Although growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas are considered benign, in many patients, tumour growth and/or invasion constitute a particular challenge. In other tumours, progression relies in part on dysfunction of intercellular adhesion mediated by the large family of cadherins. In the present study, we have explored the contribution of cadherins in GH and PRL adenoma pathogenesis, and evaluated whether this class of adherence molecules was related to tumour invasiveness. We have first established, by quantitative polymerase chain reaction and immunohistochemistry, the expression profile of classical cadherins in the normal human pituitary gland. We show that the cadherin repertoire is restricted and cell-type specific. Somatotrophs and lactotrophs express mainly E-cadherin and cadherin 18, whereas N-cadherin is present in the other endocrine cell types. This repertoire undergoes major differential modification in GH and PRL tumours: E-cadherin is significantly reduced in invasive GH adenomas, and this loss is associated with a cytoplasmic relocalisation of cadherin 18 and catenins. In invasive prolactinomas, E-cadherin distribution is altered and is accompanied by a mislocalisation of cadherin 18, β-catenin and p120 catenin. Strikingly, de novo expression of N-cadherin is present in a subset of adenomas and cells exhibit a mesenchymal phenotype exclusively in invasive tumours. Binary tree analysis, performed by combining the cadherin repertoire with the expression of a subset of known molecular markers, shows that cadherin/catenin complexes play a significant role in discrimination of tumour invasion.

Culture and identification of the tumor stem-like cells isolated from rat prolactinoma MMQ cell lines

Objectives To explore the in vitro culture condition of the tumor stem-like cells isolated from rat prolactinoma MMQ cell lines and to observe their characteristics of proliferation, differentiation, and formation of planted tumor. Methods MMQ cells were cultured with serum-free medium suspension of containing epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and the tumor stem cell spheres (briefly cell spheres) were obtained. Clone culture was conducted and its proliferative capacity was observed. Then flow cytometry was used to detect the CD133-positive cell ratio. Western blot was used to detect cell sphere CD133 and nestin expressions. Immunofluorescence technique was used to detect the expressions of cell sphere CD133, nestin, homing cell adhesion molecules (HCAM/CD44), octamer binding transcription factor 4 (OCT4), stem cell antigen 1 (SCA1), as well as their expressions of differentiated cell glial fibrillary acidic protein (GFAP), β-tublinIII, and S100 protein. Twenty-seven female nude mice were randomly divided into 3 groups: a cell sphere planting group, a MMQ cell sphere planting group, and a normal control group (n=9 in each group). Six weeks after subcutaneous plantation, the tumor volume and serum prolactin (PRL) levels were measured. The sections of tumor tissue were detected by the HE staining and immunohistochemistry. Results Under the condition of suspension culture of serum-free medium, only a few cells survived and formed cell spheres. After being blown away, cells could clone and proliferate into cell spheres. The proportion of CD133 positive cells was 1.10±0.17%. CD133, nestin, HCAM/CD44, OCT4, and SCA1 on the cell spheres showed positive expression. After the differentiation of cell spheres, the cells expressed GFAP, β-tublinIII, and S10 protein. The volume of tumor formation in the cell sphere planting group was 1262.2±279.1 mm3, and the MMQ cell sphere planting group was 495.9±158.9 mm3 (P<0.05). The serum PRL of the tumor-bearing nude rats in the cell sphere planting group (median, P25, P75) was 36.08 (34.23, 41.42) ng/ml, and the MMQ cell sphere planting group was 21.51 (20.39, 22.98) ng/ml respectively, and they both higher than 0.26 (1.03-0.15) ng/ml in the normal control group (P<0.05). The HE staining of tumor tissue showed the similar characteristics of the rat pituitary adenoma. Immunohistochemical staining showed that the PRL and nerve synaptophysin (Syn) expressions were positive. Conclusions In MMQ cell lines of rat pituitary prolactin adenoma, a small amount cells with tumor stem-like cell characteristics exist, and they can be cultured successfully In vitro. Key words: Prolactinoma; In vitro; In vivo; MMQ cell line; Tumor stem-like cells; Rats

Endoscopic endonasal transsphenoidal surgery of 1,166 pituitary adenomas.

AimTo report the results of a series of patients undergoing pure endoscopic endonasal pituitary surgery and to evaluate the efficacy and safety of this procedure.Materials and methodsThe data of 1,166 patients that underwent endoscopic endonasal transsphenoidal adenoma removal between December 2006 and June 2013 were retrospectively reviewed. Pre- and postoperative hormonal status (3 months after surgery) were analyzed and compared with the clinical parameters originally presented by the patients. The incidences of tumor removal, hormonal control, and tumor removal complications were retrospectively analyzed.ResultOut of 577 nonfunctioning adenomas, 180 were growth hormone (GH) secreting, 308 prolactin (PRL) secreting, 26 mixed GH/PRL adenomas, 68 adrenocorticotropin secreting, and 7 thyroid-stimulating hormone-secreting adenomas. The gross total removal of pituitary adenomas was achieved in 98 % of microadenomas, 92 % of macroadenomas, and 76 % of giant adenomas. Hormonal control was achieved in 47 (69 %) cases of ACTH adenomas, 119 (66 %) GH adenomas, 262 (85 %) PRL adenomas, and 6 (86 %) TSH adenomas. Postoperative complications were observed in 168 (14.4 %) patients. The most frequent complications were diabetes insipidus (7 %), epistaxis (1.7 %), hyposmia (1.5 %), anterior lobe insufficiency (1.3 %) ,and CSF leaks (0.6 %).ConclusionThe pure endoscopic approach is a safe, efficacious, and minimally invasive technique for the removal of pituitary adenomas. A higher gross total resection rate is vital for non-functional and functional adenomas. For patients with functional adenomas, while hormonal remission is unlikely to be achieved by surgery, the use of adjuvant therapy is advocated to obtain long-term hormonal control.

Clinical and diagnostic characteristics of hyperprolactinemia in childhood and adolescence

Pituitary adenoma is the most common cause of hyperprolactinemia, which is a rare endocrine disorder encountered in pediatric patient care. Epidemiological and clinical information about hyperprolactinemia in childhood and adolescence is limited. Clinical signs of hyperprolactinemia are very heterogeneous. In girls, disturbances in menstrual function and galactorrhea may be seen, whereas in boys, headache, visual disturbances, delayed pubertal development and hypogonadism are often present. Owing to the ease of ordering a serum prolactin measurement, an evidence-based, cost-effective approach to the management of this endocrine disorder is required. Before a diagnosis of hyperprolactinemia is made, drug use, renal insufficiency, hypothyroidism, and parasellar tumors should be excluded. The main objectives of treatment are normalization of prolactin level, adenoma shrinkage, and recovery from clinical signs related to hyperprolactinemia. In patients with microadenoma, invasive or non-invasive macroadenoma, and even in patients with visual field defects, dopamine agonists are the first-line treatment. Surgical treatment is indicated in patients who are unresponsive or intolerant to medical treatment or who have persistent neurological signs. Radiotherapy should be considered as a supportive treatment for patients in whom surgery fails or medical response is not achieved.

Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas

Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Correlation Between Histological Subtypes and MRI Findings in Clinically Nonfunctioning Pituitary Adenomas

Clinically nonfunctioning pituitary adenomas (CNFPAs) consist of several histological subtypes, including null cell adenoma (NCA), silent gonadotroph cell adenoma (SGA), silent corticotroph adenoma (SCA), and other silent adenomas (OSA) (i.e., GH, TSH, and prolactin adenomas). To detect possible correlations between MRI findings and the subtypes, we retrospectively studied 390 consecutive patients with CNFPA who underwent surgery between 2008 and 2010. They were classified into three groups: NCA/SGA (313 cases), SCA (39 cases), and OSA (36 cases); in addition there were two unusual cases of plurihormonal adenoma. Three MRI findings were less common in NCA/SGA than in the other groups (P < 0.0001): giant adenoma (>40 mm), marked cavernous sinus invasion (Knosp grade 4), and lobulated configuration of the suprasellar tumor. When these MRI findings were negative in patients older than 40 years old, 91.0% (212/233) were NCA/SGA. These MRI findings were frequently noted despite a low MIB-1 index in SCA. OSA showed a high MIB-1 index and a preponderance in younger patients. In conclusion, although SCA and OSA consisted of only 20% of CNFPAs, their frequency significantly increased when the tumor was large, invasive, and lobulated, and the patient was younger than 40 years old.