Aim: Clinical acromegaly is characterized by high GH secretion in the presence of high circulating IGF-I levels. We therefore hypothesized that the physiological IGF-I-GH negative feedback loop may be reset in somatotroph adenomas, and we investigated the role of type 1 IGF receptor (IGF-R) and GH receptor (GHR) by quantifying mRNA expression in somatotroph tumours, and investigated the possible presence of mutations of the GHR gene.
Methods: Pituitary tumours (GH-, FSH-, PRL-, ACTH and non-functioning pituitary adenomas [NFPA]) and normal pituitary tissue were obtained at transsphenoidal surgery and autopsies respectively. 'Real-time' RT-PCR assay was used for the quantification of IGF-R and GHR mRNA and sequencing was performed on the cDNA of the GHR gene.
Results: IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary, NFPA, FSH and PRL-secreting tumours (p<0.001), but the levels were comparable in somatotroph and corticotroph tumours. The levels of GHR mRNA were also significantly lower in somatotroph tumours compared to normal pituitary (p<0.0013). GHR mRNA levels were similar in somatotroph and the other tumours. No mutations of the GHR mRNA were detected in 18 GH-secreting tumours. Four different polymorphisms of the GHR gene, two of which are unpublished to date, have been detected in the above samples.
Conclusions: The lower expression of the GHR and of the IGF-R in somatotroph tumours compared to normal pituitary suggests the possibility of an altered feedback of both GH and IGF-I in these tumours. Such decreased expression may be causal in the altered feedback, and hence may be at least part of the explanation of the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH. The finding of no mutations in 18 GH-secreting tumours suggests that decreased feedback inhibition of GH because of abnormal GHR is unlikely to be a common factor in the pathogenesis of these tumours.