Ghrelin is more effective than GHRH in stimulating GH release in normal adult humans and monkeys in vivo. This robust effect of ghrelin has been largely attributed to regulation of hypothalamic input, whereas the direct effect of ghrelin on pituitary GH release has been minimized by the observation that ghrelin has only a modest impact on GH release, compared with GHRH, in cultures prepared from human fetal pituitaries and GH-producing adenomas, as well as pituitaries from nonprimate species. However, comparable in vitro studies have not been performed to test the direct effect of ghrelin on normal adult primates. Therefore, in the present study, primary pituitary cell cultures from female baboons ( Papio anubis) were used as a model system to test the direct effects of ghrelin on primate somatotrope function. In this model, both ghrelin and GHRH increased GH release in a dose-dependent fashion. Surprisingly, at maximal concentrations ( 10 nM), both ghrelin and GHRH elicited a robust increase in GH release ( 4 and 24 h, respectively), and both up-regulated GH secretagogue-receptor and GHRH-receptor mRNA levels ( 24 h). Combined treatment with ghrelin and GHRH resulted in an additive effect on GH release, suggesting that distinct intracellular signaling pathways are activated by each ligand, as confirmed by the use of specific inhibitors of intracellular signaling. Together, these results present the first evidence that a direct effect of ghrelin on somatotrope function may play a major role in stimulating GH release in primates.
