MANAGEMENT OF ENDOCRINE DISEASE: Etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose

Abstract

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 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 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 GH response to OGTT.

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

“…Therefore, GIPR activation is considered to be mimicking GHRHR stimulation by hypothalamic GHRH hormone [ 25 ]. Acromegaly patients with GIPR expression commonly react to oral glucose load with a paradoxical increase in GH level, which resembles the induction of hormone secretion in food-dependent Cushing’s syndrome [ 11 ]. DNA methylation profiling in GIPR -high versus GIPR -low somatotroph PitNETs showed a difference in genome-wide methylation pattern which is in line with our results, indicating that this group represents a separate molecular subtype [ 12 ].…”

“…Recently, a subset of somatotroph PitNETs with elevated expression of gastric inhibitory polypeptide receptor (GIPR) was identified [ 9 , 10 ]. In these tumors GIPR expression is considered to additionally stimulate cAMP pathway causing paradoxical GH response to glucose intake [ 11 ]. These tumors were suggested to constitute a separate molecular subgroup as they differ in epigenetic profile and high GIPR expression is mutually exclusive with GNAS mutations [ 12 ].…”

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

“…They clearly show that in transcriptomic group 1 there are patients with GNASwt, DG tumors (mainly pure somatroph PitNETs but also tumors that are positive for both GH and LH) with low frequency of invasive growth. These tumors are positive for both NR5A1 (SF-1) and GIPR expression and probably include the patients with paradoxical GH response to glucose intake, according to previous studies (Hage et al, 2021). These patients are the least frequent and they account for approximately 20% of patients suffering from acromegaly.…”

“…Therefore, GIPR activation is considered to be mimicking GHRHR stimulation by hypothalamic GHRH hormone (Regazzo et al , 2020). Acromegaly patients with GIPR expression commonly react to oral glucose load with a paradoxical increase in GH level, which resembles the induction of hormone secretion in food-dependent Cushing's syndrome (Hage et al , 2021). DNA methylation profiling in GIPR -high versus GIPR -low somatotroph PitNETs showed a difference in genome-wide methylation pattern which is in line with our results indicating that this group represents a separate molecular subtype (Hage et al , 2019).…”

“…Recently, a subset of somatotroph PitNETs with elevated expression of gastric inhibitory polypeptide receptor (GIPR) was identified (Regazzo et al , 2017; Occhi et al , 2011). In these tumors GIPR expression is considered to additionally stimulate cAMP pathway causing paradoxical GH response to glucose intake (Hage et al , 2021). These tumors were suggested to constitute a separate molecular subgroup as they differ in epigenetic profile and GIPR high expression is mutually exclusive with GNAS mutations (Hage et al , 2019).…”