GS protein mutations and pituitary tumors: functional correlates and possible therapeutic implications.
In more than one third of growth hormone (GH)-secreting pituitary adenomas, a point mutation in the gene for the alpha-chain of the G stimulatory protein (gsp oncogene) causes the constitutive activation of the membrane adenylyl cyclase (AC) resulting in uncontrolled cyclic adenosine monophosphate (cAMP) elevation and GH hypersecretion. Tumors expressing gsp are characterized by high membrane AC activity, elevated intracellular cAMP content, and high rates of GH release in culture medium. The AC activity is not further stimulated by GH-releasing hormone (GHRH) and other specific and non-specific agents, while it is lowered by somatostatin, as the G inhibitory protein (Gi) is normally working. Acromegalic patients bearing adenomas with the gsp mutation do not present with any obvious clinical or epidemiological distinctive features. However, they have smaller tumors in relation to their circulating GH levels, suggesting that the gsp oncogene maintains a high rate of secretory activity in vivo. Most of these patients show paradoxical GH increases to thyrotropin-releasing hormone (TRH), but none to gonadotropin-releasing hormone (GnRH) or an oral glucose tolerance test (OGTT). As with the in vitro data, these patients are not very sensitive to GHRH administration, but are sensitive to the inhibitory action of somatostatin. In our experience, only three of six patients with non-gsp-mutated tumors had lowered serum GH levels during the administration of octreotide (100 micrograms thrice daily for 4 years), while all of six patients with gsp-mutated tumors had serum GH levels suppressed by octreotide treatment. Such a good GH suppressibility by somatostatin makes patients with gsp-mutated tumors the best candidates for medical treatment with somatostatin analogs.
Faglia
G
G
Institute of Endocrine Sciences, University of Milan, Italy.
Arosio
M
M
Spada
A
A
D000172:Acromegaly / Q000188:drug therapy / Q000601:surgery; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D015282:Octreotide / Q000627:therapeutic use; D009857:Oncogenes; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy
D019204:GTP-Binding Proteins; D015282:Octreotide