Synergistic actions of growth hormones


Results of earlier biological studies between 1982 and 1986 revealed a complementary and synergistic action of GHRP and GHRH on GH release when administered together to rats, cows and monkeys. Although this synergism supported the independent action of these 2 peptides, the marked inhibition of the in vivo GHRP GH response by GHRH antiserum emphasized that the in vivo GH response to GHRP greatly depended on endogenous GHRH and that GHRH may even be the mediator of the action of GHRP on GH release. Subsequent studies of Pandya et al. in normal young men further supported this conclusion since they demonstrated that a GHRH antagonist markedly inhibited the GH response to GHRP. In order to understand the GHRP-GHRH interrelationship it is necessary to emphasize that GHRP can release GH independently of GHRH. GHRP acts directly on the pituitary to release GH in the absence of GHRH and GHRP+GHRH additively augments GH release in vitro and synergistically m vivo indicating the 2 peptides have an independent action on GH release. Furthermore, in contrast to GHRH, GHRP releases a large amount of GH in vivo in rats with only a small concomitant rise of pituitary cAMP which demonstrates that endogenous GHRH is not the primary mediator of GH release induced by GHRP. When GHRH increases GH release in vivo, it concomitantly and markedly raises pituitary cAMP levels.

The in vitro demonstration that GHRH but not GHRP acts via the intracellular adenyl cyclase pathway and specific high affinity binding of GHRP sites in crude pituitary and hypothalamic peripheral cell membranes are other findings which underscore the differences between GHRP and GHRH. These results forecast the important accomplishment of the cloning of the G protein 7 transmembrane coupled receptor of GHRP. Subsequently, direct in vitro evidence has been obtained by Adams and Wu that GHRP acts via the phospholipase-C pathway, however, crosstalk does occur between the GHRP and GHRH pathways. Results show more direct evidence for the existence of the putative GHRPlike hormone in porcine hypothalami. Recorded are results of a highly purified fraction from porcine hypothalami, which is devoid of GHRH, that releases GH in vitro in the rat pituitary dispersed cell culture. When the fraction was added together with 3 different antagonists, 2 GHRP and one GHRH, only the GHRP and not the GHRH antagonist inhibited the GH release induced by this fraction. These results also demonstrate that the unnatural synthetic and the putative natural GHRP GH secretagogue activity parallel each other. Furthermore, in contrast to GHRH, this fraction did not increase pituitary cAMP. From mass spectrometiy results of Don Hunt, a small peptide and some of its amino acids have been identified in highly purified but still impure fractions that appear to reflect the activity of a natural GHRP-like hormone. In addition, we have utilized the empirical approach to synthesize the putative GHRP-like hormone de novo.

Some of the amino acids found in the highly purified porcine active fractions as well as those in the unnatural synthetic GHRPs were incorporated into these de novo peptides. Tlius far, small synthetic GHRPs consisting of only L-amino acids have been synthesized with moderate activity that could possibly be related in part to the putative natural GHRP-like hormone. Further isolation studies are currently on-going. The difference in the in vitro-in vivo results appears to be due to an additional in vivo action(s) that GHRP has on the hypothalamus and at times either indirectly or directly on the attenuation of the pituitary action of SRIF. In earlier studies, Thomer described GHRP as a functional SRIF antagonist. Some evidence for the latter was reported in rats and in humans by Massoud especially the effects of the combined GHRP and GHRH. Although the GHRP hypothalamic action has not been completely elucidated, strong indirect evidence has been obtained in humans to indicate that a new unappreciated action(s) is induced by GHRP. In part from the novel effects on GH release in humans, GHRP has been envisioned to act on the hypothalamus to release the putative hypothalamic U-factor (unknown factor). U-factor plus GHRH and at times GHRP or the putative GHRP-like hormone presumably act on the pituitary to release GH.

A basic point of general significance is that the endocrine mechanisms involved in the GH releasing action of GHRP are probably dosage dependent. Another general point is that one reason the GH releasing action of GHRP is somewhat confusing and difficult to understand is because GHRP has two anatomical sites of action and the hypothalamic actions are still incompletely understood.

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