OVEREXPRESSION OF THE GROWTH-HORMONE-RELEASING HORMONE GENE IN ACROMEGALY-ASSOCIATED PITUITARY-TUMORS - AN EVENT ASSOCIATED WITH NEOPLASTICPROGRESSION AND AGGRESSIVE-BEHAVIOR

The clinical behavior of growth hormone (GH)-producing pituitary tumor s is known to vary greatly; however, the events underlying this variab ility remain poorly understood, Herein we demonstrate that tumor overe xpression of the GH-releasing hormone (GHRH) gene is one prognosticall y informative event associated with the clinical aggressiveness of som atotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was d emonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern a nalysis and reverse transcriptase polymerase chain reaction, and prote in translation was confirmed by Western blotting, By comparison, trans cript accumulation was absent or negligibly low in 30 normal pituitary glands, GHRH transcripts were found to preferentially accumulate amon g clinically aggressive tumors, Specifically, GHRH mRNA signal intensi ty was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0 .71; P < 0.001), 2) linearly correlated with preoperative serum GH lev els (r = 0.56; P = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a mo del of postoperative remission likelihood was derived wherein remissio n was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test, In this ou tcome model, GHRH mRNA signal intensity proved to be the most importan t explanatory variable overall, eclipsing any and all conventional cli nicopathological predictors as the single most significant predictor o f postoperative remission; increases in GHRH mRNA signal were associat ed with marked declines in remission likelihood, The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at another institution. These data in dicate that overexpression of GHRH gene is an event associated with th e neoplastic progression and clinical aggressiveness of somatotroph ad enomas. More generally, these data merge essential elements of the hyp othalamic and pituitary hypotheses of pituitary tumorigenesis, providi ng for a more unified concept of neoplastic progression in the pituita ry.