BLOCKED GROWTH HORMONE-RELEASING PEPTIDE (GHRP-6)-INDUCED GH SECRETION AND ABSENCE OF THE SYNERGIC ACTION OF GHRP-6 PLUS GH-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMOPITUITARY DISCONNECTION - EVIDENCE THATGHRP-6 MAIN ACTION IS EXERTED AT THE HYPOTHALAMIC LEVEL
V. Popovic et al., BLOCKED GROWTH HORMONE-RELEASING PEPTIDE (GHRP-6)-INDUCED GH SECRETION AND ABSENCE OF THE SYNERGIC ACTION OF GHRP-6 PLUS GH-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMOPITUITARY DISCONNECTION - EVIDENCE THATGHRP-6 MAIN ACTION IS EXERTED AT THE HYPOTHALAMIC LEVEL, The Journal of clinical endocrinology and metabolism, 80(3), 1995, pp. 942-947
GH-releasing peptide (GHRP-6; His-D Trp-Ala-Trp-D Phe-Lys-NH2) is a sy
nthetic compound that releases GH in a specific and dose-related manne
r through mechanisms and a point of action that are mostly unknown but
different from those of GHRH. In man, GHRP-6 is more efficacious than
GHRH, and a striking synergistic action on GH release is observed whe
n GHRP-6 and GHRH are administered simultaneously. Based on such a syn
ergistic action, it has been hypothesized that GHRP-6 acts through a d
ouble mechanism by actions exerted both at the pituitary and hypothala
mic levels. The aim of the present study was a-fold: 1) to further cha
racterize the mechanism of action and synergistic effects of GHRP-6; a
nd 2) to study its action in patients with hypothalamopituitary discon
nection. Twelve patients with different neuroendocrine pathologies lea
ding to a state of hypothalamopituitary disconnection (functional stal
k section) and 11 age- and sex-matched normal controls were studied. E
ach subject underwent 3 tests on separate occasions, being challenged
with GHRH (100 mu g, iv), GHRP-6 (90 mu g, iv), or GHRH plus GHRP-6. G
H was analyzed as the area under the curve (mean +/- SE, micrograms pe
r L/120 min). In normal subjects GH secretion was 483.7 +/- 99.2 after
GHRH, 1434.8 +/- 393.0 after GHRP-6, and 3771.5 +/- 399.6 after GHRH
plus GHRP-6; the level of GH secreted after GHRH plus GHRP-6 treatment
was significantly (P < 0.05) higher than after the arithmetic sum of
GH levels after both compounds administered separately. In the group o
f patients with hypothalamopituitary disconnection, the level of GH se
creted after GHRH was similar to that in controls (423.4 +/- 62.8); ho
wever, a complete blockade was observed after GHRP-6 (97.3 +/- 7.9), s
ignificantly (P < 0.05) lower than after GHRH as well as lower than th
e GHRP-6-induced GPI release in control subjects (P < 0.01). After GHR
H plus GHRP-6, the patients with hypothalamopituitary disconnection sh
owed severely reduced secretion (745.3 +/- 67.6; P < 0.01 vs, controls
), a value that was not significantly different from the arithmetic ad
dition of levels produced by both compounds administered separately. R
egarding the regulation of GH secretion, these results indicate that:
1) GHRP-6 acts at the pituitary, but its potency is minimal and lower
than GHRH; 2) the main action of GHRP-6 is exerted through hypothalami
c structures; 3) the synergistic action that GHRP-6 exerts over GHRH a
ction is exerted at the hypothalamic level; and 4) the divergent GH se
cretion after GHRH and GHRP-6 may be a useful clinical test in states
of hypothalamopituitary disconnection In conclusion, the main action o
f GHRP-6 for inducing GH secretion in man is exerted through hypothala
mic structures, although the intimate mechanism of action is still und
etermined.