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.