The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors

Ghrelin is a recently identified endogenous ligand of the GH secretagogue ( GHS) receptor. It was originally isolated from the stomach, but has also be en shown to be present in the rat hypothalamus. It is a 28-amino acid pepti de with an unusual octanoylated serine 3 at the N-terminal end of the molec ule, which is crucial for its biological activity. Synthetic GHSs stimulate GH release via both the hypothalamus and the pituitary, and the GHS recept or (GHS-R) has been shown by us and others to be present in the pituitary. We investigated whether ghrelin messenger ribonucleic acid (mRNA) and pepti de are present in the normal human hypothalamus and in normal and adenomato us human pituitary. RNA was extracted from pituitary tissue removed at autopsy and transsphenoi dal surgery(n = 62), and ghrelin and GHS-R type la and Ib mRNA levels were investigated using real-time RT-PCR. Both ghrelin and GHS-R mRNA were detec ted in all samples. Corticotroph tumors showed significantly less expressio n of ghrelin mRNA, whereas GHS-R mRNA levels were similar to those in norma l pituitary tissue. Gonadotroph tumors showed a particularly low level of e xpression of GKS-R mRNA. Immunohistochemistry, using a polyclonal antibody against the C-terminal end of the ghrelin molecule, revealed positive stain ing in the homolog of the arcuate nucleus in the human hypothalamus and in both normal and abnormal human pituitary. Pituitary tumor ghrelin peptide c ontent was demonstrated using two separate RIA reactions for the N-terminal and C-terminal ends of the molecule. Both forms were present in normal and abnormal pituitaries, with 5 +/- 2.5% octanoylated (active) ghrelin (mean +/- SD) present as a percentage of the total. We suggest that the presence of ghrelin mRNA and peptide in the pituitary implies that the locally synth esized hormone may have an autocrine/paracrine modulatory effect on pituita ry hormone release.