The effect of GHRH on somatotrope hyperplasia and tumor formation in the presence and absence of GH signaling

Excessive GHRH stimulation leads to somatotrope hyperplasia and, ultimately , pituitary adenoma formation in the metallothionein promoter-driven human GHRH (hGHRH) transgenic mouse. This pituitary phenotype is similar to that observed in humans with ectopic production of GHRH. In both mice and man, G HRH hyperstimulation also results in dramatic increases in circulating GH a nd IGF-I. To determine whether GH/IGF-I modulates the development and growt h rate of GHRH-induced pituitary tumors, pituitary growth and histology wer e evaluated in mice generated from cross-breeding metallothionein promoter- driven hGHRH transgenic mice with GH receptor binding protein (GHR) gene di srupted mice (GHR(-/-)). Expression of the hGHRH transgene in 2-month-old G HR intact (GHR(+)) mice resulted in the doubling of pituitary weight that w as largely attributed to an increase in the number of GH-immunopositive cel ls. Pituitary weight of GHR(+) hGHRH mice did not significantly change betw een 2 and 6 months of age, whereas at 12 months, weights increased up to 10 0-fold those of GHR(+) pituitaries, and 70% of the glands contained grossly visible adenomas. All adenomas stained positively for GH, whereas some sho wed scattered PRL staining. Pituitaries of GHR(-/-) mice were half the size of those of GHR(+) mice. Although reduced in size, the histological featur es of GHR(-/-) mouse pituitaries were suggestive of somatotrope hyperplasia . Despite evidence of somatotrope hyperplasia, pituitaries from GHR(-/-) mi ce as old as 28 months of age were similar in size to those of 2-month-old mice and did not show signs of adenoma formation. Expression of the hGHRH t ransgene in GHR(-/-) mice did not significantly increase pituitary size bet ween 2 and 6 months of age. However, at 12 months the majority of GHR(-/-), hGHRH pituitaries developed adenomas with mean pituitary weight and histol ogical features similar to those of GHR(+), hGHRH mice. These observations demonstrate that intact GH signaling is not required for GHRH tumor formati on. Although the majority of GHR(+), hGHRH and GHR(-/-), hGHRH pituitaries developed tumors by 12 months of age, a small subset remained morphological ly indistinct from those at 2 months of age. These observations taken toget her with the fact that overt tumor formation is preceded by a static pituit ary growth phase between 2 and 6 months, indicates that protective mechanis ms are in place to maintain pituitary mass despite hGHRH hyperstimulation.