Balance between somatostatin and D2 receptor expression drives TSH-secreting adenoma response to somatostatin analogues and dopastatins

Summary Context  First‐line therapy for thyrotropin‐secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst2‐preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximate...

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Published in:Clinical endocrinology (Oxford) 2012-03, Vol.76 (3), p.407-414
Main Authors: Gatto, Federico, Barbieri, Federica, Gatti, Monica, Wurth, Roberto, Schulz, Stefan, Ravetti, Jean-Louis, Zona, Gianluigi, Culler, Michael D., Saveanu, Alexandru, Giusti, Massimo, Minuto, Francesco, Hofland, Leo J., Ferone, Diego, Florio, Tullio
Format: Article
Language:English
Subjects:
Adenoma - drug therapy
Adenoma - genetics
Adenoma - metabolism
Adult
Biological and medical sciences
Cabergoline
Cell Proliferation - drug effects
Dopamine
Dopamine - analogs & derivatives
Dopamine - pharmacology
Dopamine - therapeutic use
Dopamine Agonists - pharmacology
Dopamine Agonists - therapeutic use
Drug Synergism
Endocrinopathies
Ergolines - pharmacology
Ergolines - therapeutic use
Fundamental and applied biological sciences. Psychology
Gene Expression - drug effects
Humans
Immunohistochemistry
Male
Medical sciences
Octreotide - pharmacology
Octreotide - therapeutic use
Patients
Pituitary gland
Pituitary Neoplasms - drug therapy
Pituitary Neoplasms - genetics
Pituitary Neoplasms - metabolism
Protein Isoforms - genetics
Protein Isoforms - metabolism
Receptors, Dopamine D2 - genetics
Receptors, Dopamine D2 - metabolism
Receptors, Somatostatin - genetics
Receptors, Somatostatin - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Somatostatin - analogs & derivatives
Somatostatin - pharmacology
Somatostatin - therapeutic use
Thyrotropin - blood
Thyrotropin - metabolism
Thyroxine - blood
Treatment Outcome
Triiodothyronine - blood
Tumor Cells, Cultured
Vertebrates: endocrinology
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Summary:Summary Context  First‐line therapy for thyrotropin‐secreting pituitary adenomas (TSHomas) is neurosurgery, while medical treatment rests mainly on somatostatin analogues. Clinically available sst2‐preferring analogues, octreotide and lanreotide, induce normalization of hormone levels in approximately 90% of patients and tumour shrinkage in 45%. Objective  We evaluated somatostatin 1, 2, 3 and 5 and dopamine D2 receptor expression in tumour samples from three TSHomas, and the relationships between receptor expression, in vitro antiproliferative response and clinical data, including octreotide test and three months of therapy with octreotide long‐acting repeatable (LAR). TSHoma cell proliferation was tested in vitro using octreotide, cabergoline and two chimeric compounds, BIM‐23A760 and BIM‐23A387. Results  All patients showed significant TSH lowering to acute octreotide test, but a hormonal response to long‐term treatment was observed in only two patients, showing a high sst5/sst2 ratio. Patient 2, characterized by high expression of sst2 and sst1 and a relative lower expression of sst5, experienced tachyphylaxis after prolonged octreotide treatment. In vitro, the somatostatin/dopamine receptor agonist BIM‐23A760 caused the highest antiproliferative effect among those tested. Combined treatment with octreotide and cabergoline displayed an additive effect of magnitude comparable to that of the other chimeric compound (BIM‐23A387). Octreotide resistance was confirmed in cells isolated from the nonresponder patient, although it could be overcome by treatment with the chimeric compounds. Conclusions  A high sst5/sst2 ratio might be predictive of a positive outcome to long‐term treatment with somatostatin analogues in TSHomas. Moreover, combined somatostatin and D2 receptor targeting might be considered as a potential tool to improve the response rate in octreotide‐resistant tumours.
ISSN:0300-0664
1365-2265
DOI:10.1111/j.1365-2265.2011.04200.x