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

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 1-year old boy with a 8-year history of growth acceleration and acromegalic gigantism at presentation. 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 CH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (mu M) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high 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)alpha and of the phospholipase C-stimulating G protein alpha subunit G(q) alpha were found in the tumour. After bromocriptine, baseline AC activity 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 normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (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 expression 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 activation 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.