ABSTRACT

Marta Korbonits, John A. Little, Peter J. Trainer, Michael Besser, and Ashley Grossman St. Bartholomew's Hospital, London, England

Mary L. Forsling United Medical and Dental Schools, St. Thomas's Campus, London, England

Alfredo Costa University of Pavia, Pavia, Italy

Giuseppe Tringali and Pierluigi Navarra Catholic University Medical School, Rome, Italy

I. BACKGROUND

Growth hormone secretagogues (GHSs), growth hormone-releasing peptides (GHRPs) and their pharmacological nonpeptidyl analogs, are small molecules with in vitro and in vivo growth hormone-releasing activity both in animal and human studies. Recently, a specific GHS receptor belonging to the G-proteincoupled receptor family has been cloned (1). The receptor is located in the pituitary and in the hypothalamus as well as in other tissues, and probably activates the protein kinase C (PKC) system; it also has a direct effect on in-

232 Korbonits et al.

A. The Effects of GHSs The GHSs have a direct effect on in vitro pituitary growth hormone (GH) release in both animal and human somatotrophs, but a variety of studies have indicated that they are much more potent in vivo and can also act on the hypothalamus, which action seems to be especially important in humans (5-10). All studies agree that GH-releasing hormone (GHRH) potentiates the effect of GHSs on GH release in vivo. In in vitro studies on pituitary cells, some data point to a potentiating effect, whereas others have found only an additive effect on GH release (11-15). The presence of endogenous GHRH is crucial for the effect of GHSs in humans, as established in several clinical studies in patients with pituitary stalk section (8-1 0). However, some animal studies were still able to demonstrate GH release after the transection of the pituitary stalk (16, 17). These discrepancies could be explained by the possibly more complex destruction of the hypothalamic-pituitary area in the patients studied. Furthermore, apart from possible species differences, the patient groups studied were obviously more heterogeneous in terms of age, cause of the pituitary-hypothalamic disconnection, and underlying diseases, than the group of experimental animals.