Surgical Management of Hypercortisolism from ACTH-Secreting Pituitary Adenomas

Abstract The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cδ (PRKCD) is a direct target of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing's disease.

Download Full-text

Endoscopic endonasal transsphenoidal approach for pituitary adenomas: technical aspects and report of casuistic

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2010000400024 ◽

2010 ◽

Vol 68 (4) ◽

pp. 608-612 ◽

Cited By ~ 16

Author(s):

Américo Rubens Leite dos Santos ◽

Roberto Monteiro Fonseca Neto ◽

José Carlos Esteves Veiga ◽

José Viana Jr ◽

Nilza Maria Scaliassi ◽

...

Keyword(s):

Pituitary Adenomas ◽

Pituitary Tumors ◽

Hormonal Control ◽

Subtotal Resection ◽

Endoscopic Endonasal ◽

Technical Aspects ◽

Transphenoidal Approach ◽

Acth Secreting ◽

Csf Leaks

OBJECTIVE: Analyse technical aspects, effectiveness and morbidity of the endoscopic endonasal transphenoidal approach for pituitary adenomas. METHOD: From January 2005 to September 2008, 30 consecutive patients underwent endoscopic endonasal resection of pituitary adenomas with a follow up from 3 to 36 months. Their medical charts were retrospectively analysed. RESULTS: There were 18 women and 12 men, mean age 44 years (range 17-65 yr). Among the 30 patients, 23 had macroadenomas and 7 microadenomas. Twelve patients had non-functioning tumors, 9 had ACTH-secreting tumors, 8 had GH-secreting tumors and 1 prolactinoma. Complete resection and hormonal control was achieved in all microadenomas. Macroadenomas were completely removed in 6 patients, subtotal resection in 6 and partial resection in 11. Three patients had diabetes insipidus and 5 had CSF leaks treated with lumbar drainage. CONCLUSION: The endonasal endoscopic approach for pituitary tumors is effective and has low morbidity.

Download Full-text

ACTH Secreting Pituitary Adenomas

Cushing’s Syndrome ◽

10.1007/978-1-4615-1103-8_7 ◽

2002 ◽

pp. 127-183

Author(s):

Marie-Laure Raffin-Sanson ◽

Yves de Keyzer ◽

Xavier Bertagna

Keyword(s):

Pituitary Adenomas ◽

Acth Secreting

Download Full-text

Clinical and Surgical Management of Giant Pituitary Adenomas

Surgery in and around the Brain Stem and the Third Ventricle ◽

10.1007/978-3-642-71240-1_48 ◽

1986 ◽

pp. 375-382 ◽

Cited By ~ 1

Author(s):

A. Basso ◽

M. Vitale ◽

C. Yampolsky ◽

A. Chervin ◽

A. Kreutel ◽

...

Keyword(s):

Surgical Management ◽

Pituitary Adenomas ◽

Giant Pituitary Adenomas

Download Full-text

Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

Neuroendocrinology ◽

10.1159/000500688 ◽

2019 ◽

Vol 110 (1-2) ◽

pp. 119-129 ◽

Cited By ~ 2

Author(s):

Antonella Sesta ◽

Maria Francesca Cassarino ◽

Mariarosa Terreni ◽

Alberto G. Ambrogio ◽

Laura Libera ◽

...

Keyword(s):

Protein Degradation ◽

Pituitary Adenomas ◽

Expression Profiles ◽

Primary Cultures ◽

Acth Secretion ◽

Specific Protease ◽

Ubiquitin Proteasome ◽

Ubiquitin Specific Protease ◽

Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

Download Full-text

Bevacizumab in Aggressive Pituitary Adenomas – Experience with 3 Patients

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1260-3975 ◽

2020 ◽

Author(s):

Katharina Osterhage ◽

Roman Rotermund ◽

Michael Droste ◽

Judith Dierlamm ◽

Wolfgang Saeger ◽

...

Keyword(s):

Pituitary Adenomas ◽

Transsphenoidal Surgery ◽

Pituitary Tumors ◽

Considerable Effect ◽

General Statement ◽

Patient Deterioration ◽

Short Period ◽

Acth Secreting ◽

Design And Methods ◽

Current Stage

Abstract Objective To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies. Design and Methods Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated. Results Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively. Conclusion The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.

Download Full-text