Reduced expression of the growth hormone and type 1 insulin-like growth factor receptors in human somatotroph tumours and an analysis of possible mutations of the growth hormone receptor.
OBJECTIVE
Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours.


METHODS
We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene.


RESULTS
No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P < 0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P < 0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P < 0.01).


CONCLUSIONS
Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.
Kola
Blerina
B
Departments of Endocrinology and Histopatholgy, St Bartholomew's Hospital and National Institute of Neurology and Neurosurgery, London, UK. A.B.Grossman@qmul.ac.uk
Korbonits
Márta
M
Diaz-Cano
Salvador
S
Kaltsas
Gregory
G
Morris
Damian G
DG
Jordan
Suzanne
S
Metherell
Lou
L
Powell
Michael
M
Czirják
Sándor
S
Arnaldi
Giorgio
G
Bustin
Stephen
S
Boscaro
Marco
M
Mantero
Franco
F
Grossman
Ashley B
AB
D000172:Acromegaly / Q000378:metabolism*; D000236:Adenoma / Q000737:chemistry* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D000368:Aged; D025461:Feedback, Physiological; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D013006:Growth Hormone / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000737:chemistry; D010911:Pituitary Neoplasms / Q000737:chemistry* / Q000378:metabolism; D015175:Prolactinoma / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis*; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D000324:Adrenocorticotropic Hormone; D005640:Follicle Stimulating Hormone; D013006:Growth Hormone; D017526:Receptor, IGF Type 1