Etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose

To gain more insight on the pathogenesis of somatotroph pituitary adenomas, recent studies have focused on a subgroup of patients with acromegaly displaying a paradoxical growth hormone (GH) response during oral glucose tolerance test (OGTT). The paradoxical rise of GH after oral glucose intake occurs in about one-third of acromegaly patients and has been pathogenetically linked, by analogy to glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome, to the ectopic expression of GIP receptor (GIPR) in somatotroph adenoma cells. GIPR-expressing adenomas are negative for activating GNAS gene mutations and display distinct cytogenetic and DNA methylation profiles, highlighting their unique molecular pathogenesis. Acromegaly patients with a paradoxical GH response pattern seem to display higher insulin-like growth factor-1 (IGF-1) concentrations and harbour smaller adenomas that are more often of the densely granulated phenotype. They seem also to show a better response to somatostatin receptor ligands. In addition, persistent paradoxical GH response after surgery may be a biological marker of the residual disease postoperatively. Targeted therapy to antagonize GIP receptor on GIPR-expressing somatotroph adenomas could be a new treatment approach for acromegaly patients with a paradoxical pattern of GH response to OGTT.

Automated summary

Recent studies have focused on somatotroph pituitary adenomas in acromegaly patients showing a paradoxical GH response during OGTT, which has been linked to the ectopic expression of GIP receptor in adenoma cells. These adenomas are negative for activating GNAS gene mutations and have unique cytogenetic and DNA methylation profiles. Patients with paradoxical GH response pattern have higher IGF-1 levels and smaller adenomas, often densely granulated, and may respond better to somatostatin receptor ligands. Targeted therapy against GIP receptor on these adenomas could be a new treatment approach for these patients.