MAMMOSOMATOTROPH ADENOMA CAUSING GIGANTISM IN AN 8-YEAR OLD BOY - A POSSIBLE PATHOGENETIC MECHANISM

The pathophysiology of mammosomatotroph adenomas remains unclear. We s tudied a mammosomatotroph adenoma removed from an 1-year old boy with a 8-year history of growth acceleration and acromegalic gigantism at p resentation. Elevated basal GH (mean 28 mu g/l) and PRL (mean 120 mu g /l) plasma levels were observed, as well as paradoxical responses of C H to L-dopa, TRH and oral glucose administration; PRL was reduced by L -dopa and slightly increased by TRH; GHRH stimulated release of both G H and PRL. Two operations were required to remove the very large tumou r and the patient was treated with bromocriptine before the second. Ho rmonal secretion by tumour explants in culture was evaluated under bas al conditions and after stimulation or inhibition. High levels of GH a nd PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caus ed a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hor mone release only at very high (mu M) concentrations. Intracellular ev ents were studied by determination of the guanosine triphosphate bindi ng (G) protein levels and adenylate cyclase (AC) activity in the tumou r tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very hi gh levels of the AC-stimulatory G protein alpha subunit G(s) alpha and very low amounts of the AC-inhibiting G protein alpha subunit G(13)al pha and of the phospholipase C-stimulating G protein alpha subunit G(q ) alpha were found in the tumour. After bromocriptine, baseline AC act ivity was normalized and could no longer be stimulated; G(s) alpha and G(13)alpha levels were unchanged while those of G(q) alpha were norma lized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analys is did not reveal any mutations in the hot spots of G protein alpha su bunits (alpha(s), alpha(12), alpha(o2), and alpha(11)) genes or in the H-ras and p53 genes. G(s) alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA ex pression of pit-1 decreased after bromocriptine treatment, that of G(s ) alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of G(s) alpha, resulting in chronic a ctivation of adenylate cyclase. Furthermore, our results suggest that the antisecretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.