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, GHRH hyperstimulation also results in dramatic increases in circulating GH and IGF-I. To determine whether GH/IGF-I modulates the development and growth rate of GHRH-induced pituitary tumors, pituitary growth and histology were evaluated in mice generated from cross-breeding metallothionein promoter-driven hGHRH transgenic mice with GH receptor binding protein (GHR) gene disrupted mice (GHR^−/−). Expression of the hGHRH transgene in 2-month-old GHR intact (GHR⁺) mice resulted in the doubling of pituitary weight that was largely attributed to an increase in the number of GH-immunopositive cells. Pituitary weight of GHR⁺ hGHRH mice did not significantly change between 2 and 6 months of age, whereas at 12 months, weights increased up to 100-fold those of GHR⁺ pituitaries, and 70% of the glands contained grossly visible adenomas. All adenomas stained positively for GH, whereas some showed scattered PRL staining. Pituitaries of GHR^−/− mice were half the size of those of GHR⁺ mice. Although reduced in size, the histological features of GHR^−/− mouse pituitaries were suggestive of somatotrope hyperplasia. Despite evidence of somatotrope hyperplasia, pituitaries from GHR^−/− mice 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 transgene in GHR^−/− mice did not significantly increase pituitary size between 2 and 6 months of age. However, at 12 months the majority of GHR^−/−, hGHRH pituitaries developed adenomas with mean pituitary weight and histological features similar to those of GHR⁺, hGHRH mice. These observations demonstrate that intact GH signaling is not required for GHRH tumor formation. Although the majority of GHR⁺, hGHRH and GHR^−/−, hGHRH pituitaries developed tumors by 12 months of age, a small subset remained morphologically indistinct from those at 2 months of age. These observations taken together with the fact that overt tumor formation is preceded by a static pituitary growth phase between 2 and 6 months, indicates that protective mechanisms are in place to maintain pituitary mass despite hGHRH hyperstimulation.