The study of Clark and Robinson reported in 1989, very possibly forecasts the sensitization-desensitization action of continuous GHRP infusion in humans. Although the mechanism(s) was not elucidated in this study, continuous infusion of GHRP into conscious rats allowed a GH response each time pulses of GHRH were administered. In these rats, continuous GHRP infusion presumably desensitized the GHRP GH response but sensitized the GHRH action on GH release indicating there is only partial desensitization of the action of GHRP on GH release. The hypothetical hypothalamic U-factor proposed has been further substantiated by the results of the studies recorded. In these studies, in contrast to the studies recorded previously, unequal dosages of GHRP and GHRH were administered together. A low dose of 0.03 ag/kg GHRP-2 was administered with a maximal dose of 1 ig/kg GHRH to normal young men and women. Whether GHRP-2 and GHRH are administered together in equal or unequal dosages, GH is released synergistically. When the unequal dosage combination of the 2 peptides was administered in the study recorded in, it is notable that GHRP-2 augmented the release of GH even at a very low dosage of --2 jig to the subject.
Since this is a subthreshold GH releasing dosage, and the combined in vitro action of GHRP and GHRH is additive rather than synergistic, the results are considered to support that GHRP acts on the hypothalamus rather than the pituitary to mediate the synergistic release of GH. To explain this novel finding, the putative hypothalamic U-factor has been hypothesized to be released by an action of GHRP on the hypothalamus and to be secreted together with GHRH to release GH synergistically via the combined pituitary action of U-factor and GHRH. The excess exogenous GHRH administered eliminates the possibility that low dose GHRP induces a synergistic GH response because it releases endogenous GHRH from the hypothalamus. Also, for reasons previously stated, it is very unlikely that a GHRP effect on SRIF release or action mediates the GHRP synergistic GH response especially at such a low dosage of GHRP. Because of these low dose GHRP results and the indirect evidence in sheep, guinea pigs and rat indicating the limited transport of CHRP into the hypothalamus after peripheral administration due to the blood-brain barrier, we postulated that low dose GHRP acts outside the blood-brain barrier on the median eminence of the hypothalamus to induce this synergistic effect. The presumed hypothalamic action of GHRP at this low dose is considered to possibly reflect a basic physiological action of the putative GHRP-like hormone. In the results of the clinical study the GH response to a high dose of 10 Mg/kg GHRP-2 sc was compared to a 1 fig/kg dose of GHRP-2 i.v. which is the standard route and usual dose of GHRP-2 administration clinically. It is apparent that the very high dose of GHRP-2 alone releases an inordinate amount of GH.
This GH response is equivalent to the large amount of GH synergistically released by the combined 1 |ig/kg dosage of GHRP + GHRH and leads to the hypothesis that the same GH releasing mechanisms may be involved by these two approaches. High dose GHRP is considered to increase the endogenous release of GHRH from the hypothalamus which in turn acts together with U-factor and GHRP on the pituitary to induce a synergistic release of GH. Thus GHRP presumably acts on the hypothalamus to release GHRH but this seems to be dose dependent. In addition, since attenuation of the pituitary inhibitory action of SRIF on GH release may occur, this may be another one of the mechanisms by which the high dose as well as the combined peptides release such a large amount of GH. Results in the last study reveal possible new insight into the pathophysiology responsible for decreased GH secretion in some normal older subjects. Reasons usually proposed for this decreased GH secretion have been decreased secretion of endogenous GHRH or increased secretion of SRIF. It is now proposed that in some elderly subjects the decreased secretion of GH is due to neither decreased GHRH nor excess SRIF secretion but rather is due to a decreased secretion of the putative hypothalamic GHRP-like hormone. The results recorded are from the following study.
Twenty normal older subjects were randomly selected and the acute GH responses determined to i.v. bolus 1 fig/kg GHRH or GHRP-2, 0.1 micro g/kg GHRP-2 as well as 0.1 Mg/kg GHRP-2 + 1 micro g/kg GHRH. The mean peak GH responses of these 20 subjects have been divided into 3 groups according to the degree of the GH response to the combined low dose GHRP-2 and high dose GHRH, i.e., mild (39 micro ig/L), moderate (24 ig/L) and severe (2 ig/L). The most meaningful findings were obtained in the moderately impaired GH response group. In this group, the GH response to GHRH was markedly decreased possibly due to a decreased pituitary GH content secondary to a decreased secretion of endogenous GHRH or a pituitary insensitivity to the pituitary action of GHRH possibly indicating an excess secretion of SRIF. In regard to these 2 mechanisms, the greater GH response to 1 |ig/kg GHRP-2 reveals that a decreased pituitary content of GH is not the reason for the impaired GH response to 1 |.ig/kg GHRH. Additionally dramatic is that a low dose of GHRP-2 administered together with 1 micro g/kg GHRH reverses this impaired GH response to GHRH. As discussed previously, low dose GHRP-2 would be unlikely to be acting to augment the action of high dose GHRH by interfering with SRIF release or action. Furthermore, the relatively high GH response to 1 jg/kg GHRP alone is an indication endogenous GHRH is being secreted in these subjects because the GHRH antagonist studies of Pandy demonstrated that in normal young men without endogenous GHRH secretion, the GH releasing action of GHRP is markedly decreased.
The excess exogenous GHRH administered and the insensitivity of the pituitary to exogenous GHRH are both reasons to conclude that any release of endogenous GHRH by GHRP-2 would have an inconsequential effect on GH release. Release of endogenous GHRH via the hypothalamic action of GHRP or the direct pituitary action of low dose GHRP simply could not be the mechanism to explain how low dose GHRP reverses the impaired pituitary GH releasing action of GHRH. Rather it is hypothesized to be the result of U-factor released via the hypothalamic action of low dose GHRP. Whether a deficiency of the putative GHRP-like hormone plays a role in the mildly and severely impaired GH response groups is more difficult to project because of the smaller number of subjects studied as well as the borderline decreased values of the mildly impaired group and the extreme decreased GH values of the severely impaired group. These studies are currently being expanded to increase the number of subjects in each group in an effort to further prove or disprove the hypothesis that the decreased secretion of GH in some normal older men and women is the result of a deficiency of the putative hypothalamic GHRP-like hormone. In conclusion, the novel and unique effects of GHRP on GH release observed in humans appear to be immediately relevant to understanding and to distinguishing the actions of GHRP. The special GH releasing actions of GHRP with and without GHRH appear to be valuable for proposing conceptual pharmacological and physiological models of the actions of the unnatural synthetic GHRPs as well as the putative natural GHRP-Uke hormone on GH secretion.
It has not been possible to simulate the unusual GH releasing effects of GHRP observed in vivo by in vitro studies in which GHRP, GHRH and SRIF have been assessed in many different combinations and dosages and under various experimental conditions. Some of the in vivo results support the conclusion that GHRP activates new previously unappreciated mechanisms involved in the release of GH. The GH releasing action of GHRP is varied, dosage dependent as well as overlapping and complementary to the actions of GHRH and/or antagonistic to the actions of SRIF. The broad range of actions of GHRP on GH release appear to evolve from the dual complementary action on the hypothalamus and pituitary. Since evidence increasingly supports that a putative GHRP-Uke hormone probably does exist, our conceptual model of the physiological role of this hormone is as a modulator of the action of GHRH on the pulsatile secretion of GH. GHRH is viewed as the initiator of the GH pulses and the putative GHRP-like hormone the modulator by influencing the peak as well as the size and shape of the GH pulses.
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1. Clinical evaluation in humans
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