G(S) PROTEIN MUTATIONS AND PITUITARY-TUMORS - FUNCTIONAL CORRELATES AND POSSIBLE THERAPEUTIC IMPLICATIONS

In more than one third of growth hormone (GH)-secreting pituitary aden omas, a point mutation in the gene for the alpha-chain of the G stimul atory protein (gsp oncogene) causes the constitutive activation of the membrane adenylyl cyclase (AC) resulting in uncontrolled cyclic adeno sine monophosphate (cAMP) elevation and GH hypersecretion. Tumors expr essing gsp are characterized by high membrane AC activity, elevated in tracellular cAMP content, and high rates of GH release in culture medi um. 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 (G(i)) is normally worki ng. Acromegalic patients bearing adenomas with the gsp mutation do not present with any obvious clinical or epidemiological distinctive feat ures. However, they have smaller tumors in relation to their circulati ng GH levels, suggesting that the gsp oncogene maintains a high late o f secretory activity in vivo. Most of these patients show paradoxical GH increases to thyrotropin-releasing hormone (TRH). but none to gonad otropin-releasing hormone (GnRH) or an oral glucose tolerance test (OG TT). 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-g sp-mutated tumors had lowered serum GH levels during the administratio n of octreotide (100 mu g thrice daily for 4 years), while all of six patients with gsp-mutated tumors had serum GH levels suppressed by oct reotide treatment. Such a good GH suppressibility by somatostatin make s patients with gsp-mutated tumors the best candidates for medical tre atment with somatostatin analogs. Copyright (C) 1996 by W.B. Saunders Company