OBJECTIVE Hexarelin is a synthetic six‐amino‐acid compound capable of releasing GH in animals and in man. Its mechanism of action is not understood and little is known about the GH response after repeated administration. The aim of this study was to determine the GH response to the administration of two intravenous boluses of hexarelin, growth hormone releasing hormone (GHRH) or hexarelin with GHRH.DESIGN Single boluses of hexarelin (1 μg/kg), GHRH‐(1–29)‐NH2(1 μg/kg) or hexarelin with GHRH‐(1–29)‐NH2were administered intravenously. Each study was performed on two further occasions, with a second bolus being administered 60 or 120 minutes after the first. A control study was performed giving saline intravenously. Studies were performed in a random order.SUBJECTS Six healthy adult males (25.4–34.1 years) were studied.MEASUREMENTS Serum GH was measured by radioimmunoassay. GH secretion rates were derived from the measured serum GH concentrations using the technique of deconvolution analysis.RESULTS The peak GH secretion rate following the first intravenous bolus of hexarelin was greater than that following the first bolus of GHRH‐(1–29)‐NH2(P < 0.001), and was greatest following the administration of hexarelin with GHRH‐(1–29)‐NH2(P < 0.001). The coadministration of the two secretagogues resulted in peak GH secretion rates significantly greater than the arithmetic sum of those following their isolated administration (P = 0.001), demonstrating synergism. Compared to saline, the administration of a second bolus of hexarelin, GHRH‐(1–29)‐NH2or both resulted in significant further GH secretion (P = 0.02,P = 0.002,P = 0.03, respectively).The administration of a second bolus of hexarelin or hexarelin with GHRH‐(1–29)‐NH2120 minutes after the first bolus resulted in lower peak GH secretion rates (P = 0.03). The reductions in peak GH secretion rates following the 60‐minute boluses were not statistically significant. The peak GH secretion rates following the first GHRH‐(1–29)‐NH2boluses were similar to those following the 60 and 120‐minute GHRH‐(1–29)‐NH2boluses (P = NS). Irrespective of the interval between the boluses of hexarelin with GHRH‐(1–29)‐NH2, the peak GH secretion rates following the second boluses were not significantly different from the arithmetic sum of those following the administration of the second boluses of hexarelin or GHRH‐(1–29)‐NH2, indicating loss of synergism on repeated administration.CONCLUSIONS This study shows that hexarelin is a potent GH secretagogue active after two successive doses; the magnitude of the GH response to the second dose was influenced by the dosing interval. Hexarelin and GHRH‐(1–29)‐NH2are synergistic, a property which is lost after repeated administration. These findings may help