Acromegaly is most often associated with a pituitary somatotroph adenoma. While multiple lines of evidence suggest an intrinsic somatic cell defect in adenoma formation, the role of hypothalamic hormones in pituitary tumorigenesis remains unclear. We describe the functional and morphological features of the pituitary of a patient with a long-standing ectopic GH-releasing hormone (GHRH)-producing tumor and acromegaly. This 28-yr-old woman with a documented 10-yr history of a disseminated bronchial carcinoid was evaluated for clinical features of acromegaly. Elevated serum GH (88 micrograms/L) was not suppressed after glucose ingestion and was paradoxically stimulated by TRH, but did not respond to GHRH or GnRH administration. Serum insulin-like growth factor-1 (730 micrograms/L; normal, < 333 micrograms/L), insulin-like growth factor-binding protein-3 (9.5 mg/L; normal, 2-4.2 mg/L), and GHRH (26.1 micrograms/L; normal, < 20 ng/L) were elevated. Magnetic resonance imaging revealed a diffusely enlarged pituitary gland. Octreotide treatment for 4 months resulted in suboptimal clinical and biochemical responses. Examination of the transsphenoidally resected pituitary by light microscopy revealed diffuse somatotroph hyperplasia, with intact reticulin network and preservation of the acinar architecture. Electron microscopy showed active somatotrophs interspersed with other cell types. In situ hybridization revealed very strong positivity for GH mRNA, whereas fewer cells contained GHRH and somatostatin mRNA signals. Dispersed pituitary cells secreted GH into culture medium. GH release was stimulated by GHRH and GHRH plus TRH, but not by TRH alone; GH was suppressed by octreotide in vitro. We conclude that sustained exposure to ectopic GHRH leads to somatotroph hyperplasia, but, at least in this case, was not sufficient for adenomatous transformation.