Ghrelin-induced GH secretion in normal subjects is partially resistant to homologous desensitization by GH-releasing peptide-6

Objective: GH secretagogues and GH-releasing hormone (GHRH) exert a complex cross-talk at the somatotrope cell, and undertake homologous and heterologous desensitization. On the other hand, the discovery of ghrelin as a new factor implicated in the regulation of GH secretion makes a thorough assessment of its properties and cell biology processes mandatory. In order to implement this, three different testing schedules were devised using the administration, on the same day, of two GH stimuli administered in sequential order 120 min apart. The two aims of the study were (a) to evaluate the relative potency of ghrelin in comparison with other GH stimulants and (b) to assess the presence of homologous or heterologous desensitization between these compounds. Design: The different testing days performed in random order were (a) on one day, saline was administered at time 0 min and ghrelin at time 120 min, (b) on another testing day, GHRH was administered at 0 min followed by ghrelin at 120 min and (c) on the last testing day, GH-releasing peptide-6 (GHRP-6) and ghrelin were injected at 0 and 120 min respectively. Ghrelin, GHRH and GHRP-6 were always administered at 1 mug/kg i.v., and plasma GH was measured. Patients: Six normal subjects participated in the study after providing informed consent, and each was assessed on three different testing days, at least 1 week apart. Results: Saline did not modify peak GH (means+/-s.E.) values (1.5 +/- 0.6 mug/l), and ghrelin administered 120min later induced a significant GH rise (39.9+/-2.8mug/l). On a different testing day, GHRH induced a GH peak (9.4+/-2.8mug/l) lower than that of ghrelin injected 120min later (26.8+/- 4.7 mug/l). On the last testing day, GHRP-6 at time 0 induced a GH peak of 18.4+/-5.9 mug/l and ghrelin 120min later a peak of 19.8 +/-2.9 mug/l. The ghrelin-mediated GH secretion after GHRP-6 was significantly lower than the GH elicited by ghrelin when the preceding administration was saline. This demonstrated that ghrelin was partially affected by GHRP-6 and was not affected by GHRH. Conclusions: Calculated at equal mass doses or in molecular terms, ghrelin appears to be a more potent stimulus than GHRP-6 and GHRH. Ghrelin was completely insensitive to the previous administration of GHRH as well as relatively resistant to the homologous desensitization exerted by GHRP-6.