Giant-cell granulomatous hypophysitis: a distinct clinicopathological entity

✓ Idiopathic giant-cell granulomatous hypophysitis is a chronic inflammatory disorder of the pituitary gland. It presents clinically as a sellar mass lesion with pituitary insufficiency and/or hyperprolactinemia, and is radiologically indistinguishable from a pituitary tumor. In most of the previously reported cases the documentation of the disorder has been limited to autopsy tissue. Only a few cases documented by biopsy have been recorded. Four cases are presented here with radiological, endocrinological, and surgical findings. The appropriately documented cases collected from the literature and the present series are reviewed and the incidence, patterns of clinical and radiological presentation, and operative management of this disorder are discussed. This entity should be considered when evaluating patients with a pituitary mass and evidence of hypopituitarism and hyperprolactinemia.</jats:p

Alterations in ventricular size and intracranial pressure caused by sagittal sinus pathology in man

✓ Lumbar cerebrospinal fluid (CSF) pressure and ventricular size were determined in six patients with impairment of cerebral venous outflow caused by either sagittal sinus thrombosis or arteriovenous shunting into the sagittal sinus. None of the patients had enlargement of the ventricular system, but all six had elevated CSF pressure (mean, 30 mm Hg). At least two mechanisms sufficient to prevent ventricular enlargement and significant hydrocephalus are suggested by these cases: 1) intracranial pressure elevations that occur as a result of cerebral venous outflow impediment maintain a positive pressure gradient between the intracranial CSF and the sagittal sinus contents, thereby increasing bulk CSF outflow; 2) in adults, increased function of alternative CSF outflow pathways occurs secondary to sagittal sinus thrombosis across the arachnoid villi of other intracranial vascular structures and in the spine. These mechanisms may have general importance in the generation of hydrocephalus caused by other disease states in adults but not in children.</jats:p

Everolimus reduces human ACTH-secreting pituitary adenoma in vitro cell viability

Everolimus (RAD001), an immunosuppressant drug, has antineoplastic activity in human neoplasia, including endocrine tumors, due to its ability to inhibit the AKT down-stream signaling pathway. It has been demonstrated that AKT is overexpressed and up-regulated in pituitary tumor, including ACTH-producing pituitary tumors, that are still orphan of an effective medical therapy. We therefore investigated the effects of RAD001 on cell viability, apoptosis and mTOR phosphorilation in 10 human ACTH-producing pituitary tumors in primary culture. Cells were treated with 10 nM–1 μM RAD001, 50 nM IGF1, and/or 10 nM SOM230 (a somatostatin receptor multiligand). After 48 h, cell viability was evaluated with a colorimetric method, apoptosis with caspase 3/7 assays and mTOR phosphorylation by a specific ELISA kit. RAD001 significantly and dose-dependently reduced cell viability in eight out of ten cultures (−15 to −25%; P<0.05), promoted apoptosis (+20 to +25%; P<0.05), reduced mTOR phosphorylation (−30 to −42%; P<0.05). IGF1 significantly promoted cell viability (+40%; P<0.01), inhibited apoptosis (−34%; P<0.05) and induced mTOR phosphorylation (+35%; P<0.05), effects that were completely abolished by co-treatment with 100 nM and 1 μM RAD001. SOM230 slightly but significantly reduced cell viability (−12%; P<0.05) and strongly potentiated RAD001 inhibitory effects (−58%; P<0.01). Our data demonstrate that RAD001 inhibits cell viability in selected ACTH-secreting pituitary adenomas, by inducing caspase 3/7 activity with a mechanism involving IGF1 signaling, which is enhanced by SOM230. Our results suggest that RAD001 acts as a pro-apoptotic stimulus, inducing the extrinsic pathway, and might represent a possible medical treatment aiming at controlling pituitary adenoma growth in Cushing’s disease

Multiple somatostatin receptor subtypes activation reduces cell viability in non-functioning pituitary adenomas by inhibiting Vascular Endothelial Growth Factor secretion

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing Vascular Endothelial Growth Factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures, we assessed SRIF receptors (SSTR1-5) expression and the in vitro effects on VEGF secretion and on cell viability of SRIF and of the stable SRIF analogue pasireotide (SOM230) which activates SSTR1, 2, 3 and 5. Twenty-five NFA were examined by RT-PCR for expression of α-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasidreotide. All NFA samples expressed α-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the “responder” group, but not in the “non responder” group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked Forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NF

Dopamine receptor 2 activation reduces cells viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

none10Dopamine (DA) therapy of non-functioning pituitary adenomas (NFA) can result in tumor stabilization and shrinkage. However, this effect is not always apparent and the mechanism of action is still unknown. Previous evidence showed that DA inhibits pituitary Vascular Endothelial Growth Factor expression (VEGF), that, in turn, is related to pituitary tumor growth. Our study aimed at clarifying whether VEGF secretion modulation might mediate the effects of DA agonists and chimeric compounds interacting with both DA receptor 2 (DR2) and somatostatin receptor (SSTR) 2 and 5 on cell proliferation in human NFA primary cultures. We assessed DR2, SSTR2 and SSTR5 expression, both at mRNA and protein level, as well as the in vitro effects on VEGF secretion and on cell viability of a selective DR2 agonist, cabergoline (Cab), and of the chimeric compound BIM-23A760, which interacts with DR2, SSTR2 and 5. Nine NFA were examined by RT-PCR and by microscopy immunofluorescence for expression of α-subunit, DR2, SSTR2 and 5. Primary cultures were tested with Cab and with BIM-23A760. All NFA samples expressed α-sub, while DR2 and SSTR2 were expressed in 5 and SSTR5 in 2 samples. In DR2 expressing tumors, Cab (but not BIM-23A760) significantly reduced cell viability (−18%; P<0.05) and VEGF secretion (−15%; P<0.05). These effects were counteracted by treatment with the DA antagonist sulpiride. In addition, the antiproliferative effects of Cab were completely blocked by co-treatment with VEGF. Our data demonstrate that Cab, but not the chimeric SSTR/DR compound, via DR2 can inhibit cell viability by reducing VEGF secretion in a selected group of NFA, providing support for the employment of DA agonists in medical therapy of NFA expressing DR2. Moreover, these data further support the hypothesis that pituitary VEGF expression is under dopaminergic control and underline the importance of an accurate biomolecular analysis of pituitay adenomas.noneMaria Chiara Zatelli; Federico Tagliati; Andrea Luchin; Maria Rosaria Ambrosio; Vincenzo Cimino; Marta Bondanelli; Massimo Scanarini; Giulio Maira; Laura De Marinis; Ettore degli UbertiZatelli, Maria Chiara; Tagliati, Federico; Luchin, Andrea; Ambrosio, Maria Rosaria; Vincenzo, Cimino; Bondanelli, Marta; Massimo, Scanarini; Giulio, Maira; Laura De, Marinis; DEGLI UBERTI, Ettor