THE SEQUENTIAL ADMINISTRATION OF GROWTH HORMONE-RELEASING HORMONE FOLLOWED 120 MINUTES LATER BY HEXARELIN, AS AN EFFECTIVE TEST TO ASSESS THE PITUITARY GH RESERVE IN MAN

OBJECTIVE GH deficiency, either in children or in adults, is a clinica lly relevant problem. The diagnosis is based on dynamic tests of GH se cretion, which are clear cut on a group basis but highly problematic f or individual diagnosis. The controversy surrounding the diagnosis of GH deficiency reflects the absence of a gold standard dynamic test. Th e synthetic hexapeptide hexarelin and GHRH stimulate GH secretion usin g different mechanisms. A sequential test has been devised using the a dministration of GHRH as first stimulus followed 120 minutes later by hexarelin. The two aims of the study were (a) to evaluate the interact ion of GHRH and hexarelin, and (b) to devise a sequential test of on r eserve. DESIGN The GH stimuli used were GHRH (1 mu g/kg i.v.) as a pit uitary stimulus, and hexarelin (1 mu g/kg i.v.) as a GH stimulus whose main action is hypothalamic. Each subject was tested twice in order t o serve as his own control. Three different studies, each with two dup licate tests, were performed on separate groups of individuals: (a) GH RH followed 120 minutes later by hexarelin and on the second day hexar elin followed 120 minutes later by GHRH; (b) GHRH followed 120 minutes later by GHRH and on the other day hexarelin followed 120 minutes lat er by hexarelin; (c) GH 0.5 IU i.v. followed 120 minutes later by GHRH and on the other day, the same dose of GH followed 120 minutes later by hexarelin. PATIENTS Eighteen normal volunteers (12 women, 6 men) af ter giving informed consent. MEASUREMENTS Plasma on levels were measur ed by time-resolved fluoroimmunoassay; each value shown is the mean +/ - SEM of n = 6. RESULTS GHRH followed 120 minutes later by hexarelin i nduced two episodes of GH secretion (expressed as mean on peak, mull). The GHRH-mediated on release showed a mean GH peak of 38.2 +/- 13.6 m U/l and after hexarelin 120 minutes later of 56.7 +/- 18.0 mU/l. The c ontrary sequence blocked the second stimulus, i.e. the hexarelin-stimu lated GH mean peak was 54.7 +/- 18.4, and the GH release 120 minutes l ater after GHRH was 4.8 +/- 1.9 (P < 0.05 vs GHRH used as first stimul us). In the two sequential tests using the same stimulus, the second G H peak was reduced. In fact, GHRH induced a CH mean peak of 63.8 +/- 2 1.1 mU/l as first stimulus, greater (P < 0.05) than when GHRH was admi nistered again 120 minutes later (22.0 +/- 5.9 mU/l). Similar results were obtained with hexarelin, with a first mean peak of 70.6 +/- 10.3 mU/l, and a second one 120 minutes later of 13.4 +/- 4.6 mU/l (P < 0.0 5). The blockade of the second stimulus was not due to the feed-back a ction of the on released by the first stimulus. In fact, the i.v. admi nistration of exogenous on induced a mean GH peak of 168.0 +/- 89.7 an d reduced the action of GHRH administered 120 minutes later (26.1 +/- 8.1). The previous administration of GH (mean peak 115.5 +/- 42.0) did not alter the action of hexarelin injected 120 minutes later, showing a mean peak of 71.9 +/- 11.2. The large variability in the stimulator y action of GHRH contrasted vividly with the reproducibility of hexare lin. Furthermore, individually analysed, only one of the 12 subjects t ested first with hexarelin, compared to 4 out of 12 tested with GHRH a s first stimulus, presented a blunted response (< 13 mU/l). After the sequential stimulus there were no false negatives. CONCLUSION The sequ ential administration of GHRH in normal subjects and of hexarelin 120 minutes later provides separate information regarding pituitary GH res erve, of both secretagogues without mutual interference. There were no t false negative results to the combined test. This sequentially delay ed test may be of some value in the clinical setting for assessing pit uitary GH reserve.