Ghrelin: a step forward in the understanding of somatotroph cell function and growth regulation.

In 1977 C Y Bowers and coworkers developed a series of small peptides which stimulated in vitro the release of growth hormone (GH) from pituitary cells, although their potency was rather weak (1). Further studies based on conformational energy calculations in conjunction with peptide chemistry modifications and biological activity testing, led in 1984 to the development of several more potent peptides, including growth hormone-releasing peptide-6 (GHRP-6) (2). This hexapeptide was shown to be a potent releaser of GH both in vivo and in vitro in all tested animal species. Furthermore, this compound was shown to be active when administered by different routes such as i.v., i.p., i.m. and even by the oral route (3–4), thus becoming the standard reference compound for GH secretagogues (GHS). Unfortunately, this development was largely unnoticed by the scientific community at the time it was published, the reason being that in 1982, growth hormone-releasing hormone (GHRH) was characterized, and the work of most basic and clinical research centres was focused on assessing the role of GHRH in the regulation of somatotroph cell function, its mechanism of action as well as its diagnostic and therapeutic implications. In fact, it became dogma that GH secretion by the anterior pituitary gland was the net result of the antagonistic actions of two hypothalamic hormones – GHRH and somatostatin – which reach their receptors on the somatotroph cells via portal vessels. Thus, GHRH and somatostatin will be the final integrative pathway for the pertinent information reaching the hypothalamus. Different neurotransmitters and a vast array of metabolic and hormonal signals originated in peripheral tissues would influence GH secretion by regulating hypothalamic GHRH and somatostatin release and/or by modulating their effect directly on the somatotrophs. Nonetheless, it soon became apparent that the mechanism of action of GHRP-6 on GH secretion could not easily be explained according to the above mentioned model of GH secretion, and that GHRP-6 was not a surrogate of GHRH (3–6). The initial comparative analysis of the effects of GHRH and GHRP-6 on GH secretion suggested that their mechanism of action was both different and complementary. Thus, while GHRH is a much more potent releaser of GH in vitro than GHRP-6, the opposite happens in vivo. Evidence for different mechanisms of action also derived from studies using maximally or sub maximally effective doses of GHRH and GHRP-6, which showed that the GH secretory responses in vivo were potentiated rather than additive. Besides, homologous but not heterologous desensitization could be shown after repetitive administration of these peptides. Finally, different mechanisms of action were confirmed through the identification of different receptors and intracellular signalling for GHRH and GHRP-6 (7). Nevertheless, there were still some uncertainties regarding the physiological relevance of this system due to the failure to isolate the endogenous ligand for this receptor(s) for GHRP-6. Once it was clear that GHRP-6 was a potent regulator of GH secretion acting through a different mechanism of action than GHRH, most pharmaceutical companies involved in the GH field and several independent groups developed and tested different GHRP-6 analogues, also called GHS (Fig. 1), that were active orally, and had improved potency and bioavailibility. One of these developed compounds was MK-0677 that was used for the cloning of the only known GHS-receptor (7).