GHRP-6 OR GHRP-2?-which one would you choose?

[muscledoc1]

And as far as dose/protocol for the GHRP-2,what is the best way to take?-advice apreciated,thanks.

 

[muscledoc1]

anyone????

 

[muscledoc1]

CANY GET AN OPINION FROM ANYBODY ON THIS BOARD????FUCK.

 

[angel]

I share your disgust Doc. No one but first time posters seem to use these off the wall peptides (and we know what that means) and there is never any feedback on results. Do they do any damn thing is my Q???
and I bet the answer is no. Well, perhaps they do make money for the sellers

 

[pesty4077]

And as far as dose/protocol for the GHRP-2,what is the best way to take?-advice apreciated,thanks.

Do a search on yahoo, and you will fnd good info, GHRP6 has promise. I just can't tell you anything myself. I was trying to paste it, but I don't know how.

 

[Phidias]

I share your disgust Doc. No one but first time posters seem to use these off the wall peptides (and we know what that means) and there is never any feedback on results. Do they do any damn thing is my Q???
and I bet the answer is no. Well, perhaps they do make money for the sellers

I love your reply, angel

In fact what are GHRP-6 & GHRP-2? Never heard of these holy grails

 

[muscledoc1]

I share your disgust Doc. No one but first time posters seem to use these off the wall peptides (and we know what that means) and there is never any feedback on results. Do they do any damn thing is my Q???
and I bet the answer is no. Well, perhaps they do make money for the sellers

Thanks brother,ive been on the boards longer than i have on this one,and for some reason it seems that people here(especialy the vets,and the ones that been here for a long time)-dont realy reply that much to someone that is not a "REGULAR"-on this board(i dont want to name people)-and i like this board for a lot of good info,but i dont know,it seems like i cant get any answers here..

 

[mad mardigan]

GHRP-6 does have some promise. GHRP-2 does as well, but alot less info available. Growth hormone releasing peptides are still pretty new and not many have used them. Some have reported big appetite increases with ghrp-6, and say that 2 is the same minus the appetite. Unfortunately, many that have used them equate the g-h-r-p with Go-home-really-pissed due to lack of results. These peptides are pretty inexpensive right now though, so why not try it out and let everyone know your results?

 

[muscledoc1]

GHRP-6 does have some promise. GHRP-2 does as well, but alot less info available. Growth hormone releasing peptides are still pretty new and not many have used them. Some have reported big appetite increases with ghrp-6, and say that 2 is the same minus the appetite. Unfortunately, many that have used them equate the g-h-r-p with Go-home-really-pissed due to lack of results. These peptides are pretty inexpensive right now though, so why not try it out and let everyone know your results?

Thanks,i apreciate your reply sir!!

 

[angel]

This board is a treasure to me and I was not putting down the information here. The sponsor/advertiser program is strong.

It is just that these youngsters on here get the idea this stuff actually works on people and they buy it and inject it and are putting a true unknown into their bloodstream.

I am 52 and have been around the block. I am a lab rat. This new stuff is a bit scary to me even though I have a foot in the grave (compared to the 18 yrs olds).

What I would try are some of the release peptides for weight loss. Not much harm can be easily done through those pathways and the science has been proven to work on humans.

You can have the rest till I hear some real feedback.

ANGEL

 

[dragonfire101]

Just do a Google or Pubmed search! There are studies and Sermorelin is a FDA approved GHRP.



**broken link removed** Talks about GHRP-2

**broken link removed**

 

[dragonfire101]

Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administration.

Frieboes RM, Murck H, Antonijevic IA, Steiger A.

Max Planck Institute of Psychiatry, Munich, Germany.

After repeated intravenous (i.v.) boluses of growth hormone-releasing peptide-6 (GHRP-6) we found recently increases of growth hormone (GH), corticotropin (ACTH) and cortisol levels and of the amount of stage 2 sleep. In clinical use, oral (p.o.), intranasal (i.n.) and sublingual (s.l.) routes of administration have advantages over i.v. administration. We compared the sleep-endocrine effects of 300 microg/kg of body weight (b.w.) GHRP-6 in enteric-coated capsules given p.o. at 21.00 h and of 30 microg/kg GHRP-6 i.n. or 30 microg/kg GHRP-6 sl. given at 22.45 h in normal young male controls with placebo conditions. After GHRP-6 p.o. secretion of GH, ACTH and cortisol remained unchanged. The only effect of GHRP-6 s.l. was a trend toward an increase in GH in the first half of the night. GHRP-6 i.n. prompted a significant increase in GH concentration during the total night and a trend toward an increase in ACTH secretion during the first half of the night, whereas cortisol secretion remained unchanged. Furthermore, after GHRP-6 i.n., sleep stage 2 increased in the second half of the night by trend, and spectral analysis of total night non-rapid eye movement (REM) sleep revealed a decrease of delta power by trend. In contrast sleep stage 2 decreased during the second half of the night after GHRP-6 p.o. Our data demonstrate that GHRP-6 is capable of modulating GH and ACTH secretion as well as sleep. However, the effects depend upon dosage, duration and route of administration.

Publication Types:
Clinical Trial

PMID: 10336729 [PubMed - indexed for MEDLINE]

Growth hormone-releasing peptides.

Ghigo E, Arvat E, Muccioli G, Camanni F.

Department of Internal Medicine, University of Turin, Italy.

Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, gluco corticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment. Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.

Publication Types:
Review

PMID: 9186261 [PubMed - indexed for MEDLINE]

Growth hormone releasing peptide (GHRP-6) stimulates phosphatidylinositol (PI) turnover in human pituitary somatotroph cells.

Lei T, Buchfelder M, Fahlbusch R, Adams EF.

Department of Neurosurgery, University of Erlangen-Nurnberg, Germany.

Growth hormone releasing peptide (GHRP-6) is a synthetic hexapeptide which specifically stimulates secretion of growth hormone (GH) by pituitary somatotrophs. The precise intracellular mechanism by which this is achieved has not been deciphered although it is known to involve protein kinase C (PKC) and Ca2+ but to be cAMP-independent. We have used cell cultures of human pituitary somatotrophinomas to demonstrate powerful effects of GHRP-6 on membrane phosphatidylinositol (PI) turnover, a second messenger system which leads to activation of PKC and mobilisation of intracellular Ca2+ reserves. Incubation of somatotrophinoma cells with GHRP-6 led to a dose-dependent stimulation of rate of PI turnover. GH secretion was increased in parallel. Effects were discernable after only 15 minutes incubation and rose to a maximum at 2 hours. PI turnover was stimulated by GHRP-6 in 8 of 8 tumours examined, effects ranging from 2.1 - 7.9 fold increases. Stimulation of GH secretion by GHRP-6 was independent of presence of gsp oncogenes, emphasising the cAMP-independent nature of its effects. These results provide evidence that the GH-stimulatory effects of GHRP-6 are achieved through activation of the PI second messenger system and thus support earlier findings that PKC and Ca2+ play central roles in mediating the effects of GHRP-6.

 

[dragonfire101]

**broken link removed**

Review of GHRP above LINK or below pasted


CMLS, Cell. Mol. Life Sci. 54 (1998) 1316–1329
1420-682X:98:121316-14 $ 1.500.20:0
© Birkha¨user Verlag, Basel, 1998
Review
Growth hormone-releasing peptide (GHRP)
C. Y. Bowers
Tulane University Medical School, 1430 Tulane Avenue, New Orleans (Louisiana 70112, USA),
Fax 1 504 587 4282, e-mail: [email protected]
Received 7 April 1998; received after revision 7 August 1998; accepted 7 September 1998
Abstract. Growth hormone-releasing peptides and non- ually accumulating to support that GHRP reflects the
peptides (GHRPs, GHRP-GHS) are a new chemical class GH-releasing action of a new natural hypothalamic
of GH secretagogues with a chemistry that ranges from hormone yet to be isolated and identified. Despite the
small synthetic peptides to peptidomimetics. They release de novo origin of GHRP, a major reason for the
GH in animals and humans by a unique dual and persistent investigation is because of the possible practicomplementary
action on the hypothalamus and pitu- cal diagnostic and therapeutic value in humans as well
itary. Although the present GHRPs are of unnatural as the potential theoretical value of new insight into the
origin, evidence by a number of investigators is grad- physiological regulation of GH secretion.
Key words. Growth hormone; GHRP; GHRH; SRIF; pituitary; hypothalamus; U-factor.
Introduction
Growth hormone-releasing peptide (GHRP) evolved
from a process recently designated by Michael Conn as
‘reverse pharmacology’ [1]. This aptly indicates the artificial
origin of GHRP and underscores the amazement and
surprise that the unnatural is gradually and persistently
evolving into the natural. Although the synthetic GHRPs
being developed were thought to mimic the GH-releasing
action of a new natural hypothalamic hormone, it was
apparent from the uncoded D-amino acid residues of the
unnatural synthetic GHRPs that the amino acid sequence
of the presumed natural hormone would be different.
Synthetic GHRPs, which have been developed by several
different groups, can be considered as small peptides and
peptidomimetics. Although they are all GH secretagogues,
in this overview they have been designated as
either GHRPs or GHRP-GH secretagogues (GHRPGHS)
in order to generically include the overall group
and to distinguish this class of GH secretagogues from
the many other types of GH secretagogues that exist.
Despite the unexpected wide range in chemistry of the
various GHRP-GHSs, most of the present evidence
supports that they all act via the same receptor and by
the same hypothalamic-pituitary endocrine and molecular
mechanism. Nevertheless, findings that are implied by
the different chemistries of the GHRP-GHSs include the
possibility of receptor subtypes as well as the possibility
of more than one intracellular signal transduction pathway.
As might be expected, the GHRP saga has been circuitous,
and many talented investigators have been responsible
for what has occurred. Because of the briefness
of this summary, most of the GHRP studies of other
investigators will only briefly be reviewed.
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1317
Historical background
In 1976, a series of synthetic enkephalin opiate analogues
were studied because the enkephalins were natural small
peptides of the brain and because opiates were known to
release GH. Thus in some way these natural opiate
peptides could have been related to the elusive putative
natural growth hormone-releasing hormone (GHRH).
Even though opiates usually were considered to release
GH via a direct hypothalamic rather than a pituitary
action, and were not thought to be GHRH itself, the
possibility was considered that these natural peptides
might release GH by a dual hypothalamic and pituitary
action. For this reason Met and Leu enkephalin as well
as their analogues were studied for a direct pituitary
action in vitro. Noteworthy was that the pentapeptide
TyrDTrpGlyPheMetNH2 (DTrp2), which was related to
the native Met enkephalin TyrGlyGlyPheMetCOOH,
was found to release GH in vitro, but its potency was low
(3–20 mg:ml medium) [2, 3]. However, some select in
vitro findings which indicate the importance of this
pentapeptide are the following. After many years of
unsuccessful attempts to isolate the putative natural
GHRH, a small synthetic molecule with a known amino
acid sequence was now available to demonstrate the
release of GH by a direct pituitary action. DTrp2 had no
opiate activity and was specific in action in that it did not
release thyrotropin stimulating hormone (TSH), luteinizing
hormone (LH), follicle stimulating hormone (FSH),
prolactin (PRL) or adrenocorticotropin hormone
(ACTH). Although somewhat unexpected, DTrp2 did
not release GH in vivo. Since it had the presumed direct
pituitary action of the putative natural GHRH, it was
considered to mimic the action of GHRH and to be a
small peptide with activity that could be improved upon
by the same structure-activity approach that we utilized
between 1969 and 1976 in the development of thyrotropin
releasing hormone (TRH) and luteinizing hormone
releasing hormone (LHRH) analogues [4, 5].
Between 1978 and 1980 theoretical conformational studies
performed by Momany were incorporated, and many
GHRP analogues were synthesized. Eventually these new
analogues had both in vitro and in vivo activity. As
recorded in table 1, during this time period four chemical
classes of tetra- and pentapeptide GHRPs were developed,
that is, DTrp2, DTrp3, DTrp2,3 and DTrp2LTrp4 [3,
6, 7]. The GHRPs developed before 1980 were only active
in vitro. A chemical hallmark of these small synthetic
GHRPs is the presence, position, number and stereochemistry
of the Trp residues. The first three classes
evolved empirically by varying the amino acid composition
and modifying the stereochemistry, sequence and
length of the peptide and by determining the GH-releasing
activity of the peptide in vitro. By the combined
empirical-theoretical approach, the first in vitro and in
vivo active hexapeptide, HisDTrpAlaTrpDPheLysNH2
(GHRP-6), evolved from the DTrp2LTrp4 class of
GHRPs [8, 9].
Biological actions
About the same time the isolation of natural GHRH was
accomplished in 1982, the following series of bioactive
results of GHRP-6 were reported. ‘GHRP-6 significantly
released GH in vitro from the pituitary of immature
female rats at 1 ng:ml incubation medium. The control
GH value in ng:ml9SEM was 167114 while the
stimulated values were 9559272 (B.01) at 1 ng, 16039
305 at 3 ng, 22449172 (B.001) at 10 ng and 21989358
(B.001) at 30 ng. When this peptide was administered
to unanesthetized 21 day old female rats, acute release of
GH (ng:ml serum) by 1, 10 and 100 mg was 1294
(B.02), 151956 (B.02) and 381961 (B.001), respectively,
the control value was 190.6. Additionally the
peptide significantly (B.001) augmented the body
weight gain of 16 day old female rats by a net increase
of 17.5 and 10% after 9 and 25 days of treatment with
30 and 100 mg once or twice daily. At the end of this
treatment period the peptide also was found to release
GH acutely after administration of 30 mg. Other results
of this GHRP include the following. The GHRP-6 did
not release LH, FSH, TSH or PRL in vitro or in vivo
(rat). Somatropin releasing inhibiting factor (SRIF) 1-14
and 1-28 inhibited the GHRP stimulatedGHrelease (rat)
in vivo and in vitro with SRIF 1-28 being more potent,
especially in vivo. GH levels rose acutely 10–25 fold at
2–10 min in rhesus monkeys, lambs, and calves. Also on
repeated administration of low and high dosages of
GHRP to immature rats, it was possible to demonstrate
an equivocal potentiation and an unequivocal down
regulation of the GH response’ [10].
In 1984, we reported that despite the GHRH-like activity
of GHRP, our data suggested that the GHRP action on
Table 1. Classes of GHRPs active only in vitro (1976–1980).
1 TyrDTrp2GlyPheMetNH2 (DTrp2)
2 TyrAlaDTrp3PheMetNH2 (DTrp3)
3 TyrDTrp2DTrp3PheNH2 (DTrp2, 3)
4 TyrDTrp2AlaTrp4DPheNH2 (DTrp2LTrp4)
Table 2. GHRP-GHRH relationship on GH release.
GHRP-GHRH Supported by the results of
relationship
A. Independent antagonists and cAMP in vitro
Dependent GHRH antiserum in vivo
B. Additive GHRPGHRH GH response in vitro
Synergistic GHRPGHRH GH response in vivo
C. Permissive pituitary cAMP in vivo
1318 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
GH release involved a different somatotroph receptor
from that of GHRH [9]. Between 1982 and 1984, interactions
between GHRP, GHRH-29:40:44 and the kappa
opiate agonist MRZ-2549 were studied in the rat. Repeated
GHRP injections desensitized the peptide’s GH
release without altering the GH release induced by
GHRH. In addition, the maximal GH response to
GHRH could be increased by simultaneous GHRP
injection. 2549 had a synergistic effect on both the
GHRH and GHRP responses. The GH response of both
2549 and GHRP could readily be desensitized. Desensitization
by 2549 did not decrease the GHRP or GHRHGH
release. In vitro results supported the in vivo results
in that more GH was released in vitro by GHRP and
GHRH together than the peptides alone, and during
periods of homologous desensitization by GHRP,
GHRH was fully active. 2549 was not active in vitro, and
thus its in vivo GH-releasing activity is due to an
extrapituitary site of action. Collectively the results indicated
these three different types of GH secretagogues
released GH by different but overlapping and complementary
mechanisms. From these results it was concluded
‘that indirect evidence suggested that the pituitary
somatotroph has multiple agonist receptors. It is possible
that several endogenous ligands with GH releasing activity
have yet to be identified [11].
Additionally, in 1984, it was postulated that GHRP may
reflect the activity of another natural hypothalamic
hormone involved in the regulation of GH release [9].
Subsequently, a considerable number of findings by
many investigators have continued to support this
possibility.
The classical neuroendocrine concept and approach utilized
in the establishment of the known hypothalamic
hypophysiotropic hormones, that is, TRH, LHRH,
GHRH, had to be modified in order to assess and
elucidate the full spectrum of actions of GHRP on GH
release, because GHRP appeared to act in a complementary
way on both the hypothalamus and pituitary to
release GH, whereas the classical hypophysiotropic hormones
have a direct positive pituitary effect and a
negative hypothalamic effect. Until recently, only a very
limited number of in vitro studies have been performed
directly on the hypothalamus; however, evaluation of the
hypothalamic action of GHRP has been assessed more
directly in vivo by administration of GHRP intracerebroventricularly
and by direct GHRP administration
into localized areas of the hypothalamus. In addition,
GHRH and SRIF have been measured in hypophyseal
portal blood after administration of GHRP. Between
1989 and 1992, three studies revealed specific highaffinity
binding sites for GHRP in the pituitary and also
the hypothalamus [12–14].
The relationship between the actions of GHRP and
GHRH in vitro and in vivo is outlined in table 2. Most
Figure 1. GH responses to GHRP-6 after saline and GHRH
antagonist (400 mg:kg) treatment, n9 [19]. Reprinted with permission
from: Pandya N, Demott-Friberg R., Bowers C. Y.,
Barkan A. L. and Jaffe C. A. (1998) Growth hormone (GH)-releasing
peptide-6 requires endogenous hypothalamic GH-releasing
hormone for maximal GH stimulation. J. Clin. Endocrinol.
Metab. 83: 1186–1189, © 1998 The Endocrine Society, Bethesda,
MD.
results reported over the last several years have indicated
the existence of a more unique relationship between
GHRP and GHRH than between GHRP and SRIF
[15–18]. In earlier studies, the pituitary was considered
to be the predominant anatomical site of action of
GHRP, but gradually more emphasis has been on the
hypothalamus. Even though the hypothalamus is currently
considered to be the more predominant anatomical
site of action(s), this action is still incompletely understood,
whereas the GHRP pituitary action on the phosphoinositol-
protein kinase C intracellular pathway is
well established and different from the activation of the
adenyl cyclase-protein kinase A pathway of GHRH.
A basic important in vivo issue still unresolved is to what
degree endogenous GHRH, which may be increased by
the hypothalamic action of GHRP, is the direct or major
mediator of GH release. Collectively, our in vivo results
in animals and humans on the hypothalamic action of
GHRP indirectly indicate that at low doses of GHRP
endogenous GHRH release is not increased. Nevertheless,
the data also indicate that endogenous GHRH plays
an essential but only a permissive or passive role in the
release of GH induced by lower doses of GHRP rather
than being the direct mediator of this release [15–18]. In
contrast, at high doses, endogenous GHRH release
presumably is increased by GHRP, and thus endogenous
GHRH directly plays an active rather than a passive
role in the GH released by GHRP. The recent results
of Pandya et al. (fig. 1) demonstrate that a GHRH
antagonist markedly inhibited the GH response of
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1319
GHRP-6 in normal young men [19]. Because of the
differences in the in vitro and in vivo actions of GHRP
as well as the probable in vivo dose dependency of
endogneous GHRH, the in vivo GHRP actions and
Figure 4. Effect of GHRP-6, GHRP-1, GHRP-2 and GHRH in
normal young men. Values are mean9SEM. AUC, area under
the curve [17]. Reprinted with permission from: Bowers C. Y.
(1996) Xenobiotic growth hormone secretagogues. In: Growth
Hormone Secretagogues, pp. 9–28, Bercu B. and Walker R. (eds),
© 1998 Springer, New York.
Figure 2. Stimulation of arcuate neurons by GHRP. Specific
evidence for the direct hypothalamic action of GHRP in the
dw:dw rat (left panel) [23]. Reprinted with permission from:
Dickson S. L., Doutrelant-Viltart O. and Leng G. (1995) Growth
hormone (GH) deficient dw:dw rats and lit:lit mice show increased
fos expression in the hypothalamic arcuate nucleus following
systemic injection of GH-releasing peptide (GHRP-6). J.
Endocrinol. 146: 519–526, © 1998 The Endocrine Society,
Bethesda, MD. Evidence of increased c-fos mRNA after GHRP
treatment in the hypophysectomized (HPX) rat (right panel) [25].
Kamegai J., Hasegawa O., Minami S., Sugihara H. and Wakabayashi
I. (1996) The growth hormone releasing peptide KP-102
induces cfos expression in the arcuate nucleus. Mol. Brain Res. 39:
153–159, © 1998 Elsevier Science.
Figure 3. Effect of 200 mg:day bovine GH (hGH) treatment in
dw:dw female rats for 6 days. *PB0.05, ***PB0.001 vs. control
group. n5–6:group [31]. Reprinted with permission from: Bennett
P. A., Thomas G. B., Howard A. D., Van der Ploeg L. H. T.,
Smith R. G. and Robinson I. C. A. F. (1997) Expression and
regulation of the growth hormone secretagogue-receptor (GHS-R)
gene in normal and dwarf rats. Endocrinology 138: 4552–4557, ©
1998 The Endocrine Society, Bethesda, MD.
interrelationships with GHRH are confusing and convoluted.
In vitro data on the direct pituitary action of
GHRP and GHRH, alone and together, does not explain
a number of the observed in vivo GH-releasing
actions of these peptides.
A general point about the GHRPs concerns the importance
of distinguishing and considering the differences
between the pharmacological and putative physiological
actions. They are overlapping, but physiologically the
hypothalamic paracrine local secretion, distribution and
action of the putative GHRP hormone inside the bloodbrain
barrier would have special implications, as would
its presence, amount and timing of secretion into the
portal system. Pharmacologically the blood-brain barrier
also needs special consideration. This is because the
hypothalamic and pituitary actions of GHRP are complementary,
and low-dose GHRP administered peripherally
would be outside the blood-brain barrier and thus
perhaps only reach specific hypothalamic anatomical
sites.
More recently, demonstration of GHRP action on
anatomical sites of the hypothalamus involved in regulation
of GH secretion, in particular the arcuate neurons,
has been another important milestone [20–26].
Evidence obtained by Dickson et al. [23] and Kamegai
et al. [25] recorded in figure 2 demonstrates conclusively
a GHRP action on GHRH neurons but not SRIF
neurons. However, equally notable is that GHRP stimulates
only a small proportion (20%) of the GHRH
arcuate neurons and that most of the GHRP-stimulated
arcuate neurons are located in the non-GHRH ventral
1320 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
medial part of the nucleus. These neurons are still
incompletely identified in terms of type and function. So
far neuropeptide-Y (NPY)-containing arcuate neurons
have been identified as the most common neuron stimulated
by GHRP. Also, a subpopulation of GHRP-responsive
arcuate neurons are inhibited by the SRIF
analogue, octreotide, indicating an aspect of the
GHRP-SRIF relationship at the hypothalamic level in
need of further detailed study [26]. The finding that the
hypothalamic action of GHRP could be demonstrated
in hypophysectomized rats eliminated the possibility
that GH mediated these observed GHRP hypothalamic
actions [25]. GHRP stimulation of arcuate neurons of
the lit:lit mouse demonstrates that the GHRP action on
the hypothalamus is independent of a GHRH action
[23]. Because of a GHRH receptor mutation, this mutant
dwarf GH-deficient mouse is nonresponsive to
GHRH. A final pertinent result reflecting a hypothalamic
action of GHRP is the rise of GHRH in hypophyseal
portal blood after GHRP administration [27].
GHRP-GHS receptor
The Merck group’s accomplishments on GHRP-GHSs
under the direction of Roy Smith have been exceptional
at both the basic and clinical levels [28]. In 1996, they
accomplished the important milestone of cloning the
GHRP-GHS receptor [29]. It is a seven-transmembrane
G protein-coupled receptor expressed by a single highly
conserved gene in the human, chimpanzee, pig, cow, rat
and mouse. In 1998, results of Scott Feighner and his
Merck colleagues [30] demonstrated that single mutations
in transmembranes 2,3 and 5,6 affect binding and
activation of the GHRP-GH secretagogues. They proposed
a three-dimensional receptor model of the
spiropiperidine and benzolactam nonpeptide GHS and
the peptide GHRP-6. Mutating glutamic acid to glutamine
at position 124 in transmembrane 3 resulted in a
nonfunctional receptor for each of the three different
chemical types of GHRPs. Since each GHRP has an
essential positive charged N atom at the N terminus, the
nonfunctional receptor was explained by eliminating the
counter ion interaction between these three GH secretagogues
and the receptor. The transmembrane 2,5 and 6
mutations induced different effects on the binding and
activation of these three chemically different GHRPs.
This led to the interesting speculation that these three
GHRPs probably bind to the receptor site by different
orientations.
By using a riboprobe of the entire length of the receptor,
it appears the receptor is mainly distributed within
the central nervous system (CNS). Besides the selective
localization of these receptors on the somatotroph cell
of the pituitary, also exciting and relevant to the CNS
action of GHRP are studies on the location and regulation
of the GHRP-GHS-R (GH-secretagogue receptor)
within the CNS. In addition to possible other anatomical
sites of the brain, the transcripts of the GHRPGHS-
R have been found to be prominently expressed in
the arcuate and ventromedial nucleus (VMN) as well as
the hippocampus, indicating that these are probably
major sites of GHRP action [31, 32]. Most notable are
the studies of Bennett and Robinson et al. (fig. 3) which
reveal the following series of important findings. The
receptors at the above three prominent anatomical sites
appear to be regulated by GH, because at each site the
receptor is increased by GH deficiency and decreased by
GH excess. Also, in the arcuate nucleus, GH decreased
Figure 5. Time response curve of GHRP-2 after i.v., s.c., oral and nasal administration in normal young men. Values are mean9SEM.
AUC, area under the curve; IGF-I (mg:l); BMI, body mass index.
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1321
Figure 6. GH, PRL and cortisol levels in normal young men after
1 mg:kg s.c. (left panel) and 300 mg:kg oral GHRP-2 (right panel).
Values are mean9SEM.
pituitaries and human pituitary tumour cells. Also, structure-
activity studies have revealed many specific chemical
requirements of the GHRP-GHS on pituitary action [17].
These results strongly support the pituitary as another
one of the anatomical sites of action, and it should be
included in the physiological and pharmacological conceptual
models on the action of the putative GHRP-like
hormone and the various GHRP-GHSs [16, 18].
Clinical effects
The following series of clinical results have been selected
in order to portray the scope of the effects of GHRP on
GH release in humans and, by implication, are reasons
for believing GHRP may be important clinically [38, 39].
In addition, they may reveal new basic knowledge about
the regulation and secretion of GH. Our first GHRP
(GHRP-6) studies in humans were performed in collaboration
with Michael Thorner in 1988 [40]. At the same
time, Ilson et al. [41] also reported clinical results of
GHRP-6 in normal young men.
Results of the GH responses induced by GHRP-6, -1, -2
are shown in figure 4. All three GHRPs induced more
GH release than GHRH at an intravenous (i.v.) bolus
dose of 1 mg:kg. The greater GH release implies that new
mechanisms are involved in the action of GHRP, an
the transcripts for GHRP-GHS-R as well as GHRH in
parallel, but GH has a nonparallel effect on GHRPGHS-
R and NPY transcripts in that the former was
decreased whereas the latter was increased. Continuous
GHRP-6 administration did not alter expression of the
GHRP-GHS-R in the arcuate or VMN. In the VMN, the
GHRP-GHS-R transcripts are higher in the female than
the male rat. Even though the GHRP-GHS-R is prominent
in the VMN, GHRP does not stimulate c-fos in the
VMN, which is in contrast to c-fos stimulation in the
arcuate nucleus.
Using different techniques, other groups have demonstrated
GHRPs in various peripheral tissues, including
the heart. Ong et al. [33] reported evidence for a pituitary
subtype GHRP-R.
Already the receptor has been identified in pathological
tissue. The GHRP-GHS-R has been detected in human
pituitary tumours, that is, somatotropinomas and prolactinomas
but not functionless pituitary tumours, and
the tumours with these receptors are responsive to the
action of GHRP [34, 35]. Similarly, the rat pituitary cell
line GH3 expresses the GHRP-GHS-R [34]. More recently,
messenger RNA (mRNA) for the GHRP-GHS-R
has been reported to be expressed in human foetal
pituitary at 18 and 31 weeks of age, and also it has been
shown to be functionally responsive to GHRP in vitro
[36].
Because of the current focus and recent exciting results
on the hypothalamic action of GHRP, it is necessary to
reemphasize that the pituitary action of GHRP needs to
be included in a conceptual model of how GHRP acts to
release GH [37]. It is relevant GHRP specifically releases
GH by a direct pituitary action via a specific receptor and
intracellular pathway in multiple animal species as well
as in humans. As stated above, functional GHRP receptors
have been demonstrated recently in human foetal
Figure 7. Effect of 36-h infusion of saline and GHRP-6 in normal
young men. Acute i.v. injections of TRH (50 mg), GHRH (1 mg:kg)
and GHRP-6 (1 mg:kg) were given at the times designated by the
arrows [43]. Reprinted with permission from: Jaffe C. A., Ho J.,
Demott-Friberg R., Bowers C. Y. and Barkan A. L. (1993) Effects
of a prolonged growth hormone (GH)-releasing peptide infusion on
pulsatile GH secretion in normal men. J. Clin. Endocrinol. Metab.
77: 1641–1647, © 1998 The Endocrine Society, Bethesda, MD.
1322 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
Figure 8. Effect of low subthreshold dose of GHRP-2 (0.03
mg:kg) alone and with high-dose GHRH (1 mg:kg) on the synergistic
release of GH in nine normal young men. Values are the
mean9SEM. AUC, area under the curve; IGF-I (mg:l); BMI,
body mass index.
Figure 9. Effect of 10 mg:kg s.c. GHRP-2 vs. 1.0 mg:kg i.v. and
11 mg:kg GHRP-2GHRH i.v. in the same seven normal
young men. Values are the mean9SEM. AUC, area under the
curve; IGF-I (mg:l); BMI, body mass index.
implication that has subsequently been substantiated.
Recorded in figure 5 are data which support that a
valuable clinical feature of GHRP is the release of GH
by all routes of administration. GHRP-2 released GH
in normal young men after i.v., subcutaneous (s.c.),
intranasal and oral administration. In the first clinical
study of GHRP-6 in normal young men, a small but
definite rise of cortisol and PRL was induced [40]. As
recorded in figure 6, similar results were obtained when
1 mg:kg s.c. or 300 mg:kg oral GHRP-2 was administered
to normal young men.
We, as well as other investigators, have demonstrated
that repeated frequent administration of GHRP
markedly inhibits the GH response in rats and humans.
Figure 10. GH response to GHRP-2, GHRH and GHRP-2GHRH in normal younger and older men. Values are the mean9SEM.
AUC, area under the curve; IGF-I, 303932 mg:l (younger) and 159915 (older); BMI (body mass index)2590.6 (younger) and
2790.6 (older). Age2591.0 (younger) and 6692.0 (older) [18]. Reprinted with permission from: Bowers C. Y. (1998) GHRP
GHRH synergistic release of GH: scope and implication. In: Growth Hormone Secretagogues, pp. 1–25, Bercu B. and Walker R. (eds),
© 1998 Marcel Dekker Inc., New York.
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1323
As demonstrated in figure 7, the results of continuous
GHRP-6 administration to normal young men are particularly
noteworthy [42, 43]. A priori, it was projected
that the GH response to continuous GHRP administration
in humans, as observed in rats, would be desensitized.
As predicted, in the study of Jaffe et al., the GH
response to i.v. bolus GHRP-6 in normal young men
was markedly desensitized at the end of the continuous
infusion for 36 h, but the increase in the normal spontaneous
pulsatile secretion of GH during the entire
GHRP infusion period was not predicted. Despite the
desensitization of the GHRP-GH response, as indicated
by the decreased GH response to i.v. bolus GHRP at
the end of the GHRP infusion period, the amplitude
but not the frequency of the spontaneous GH pulses
continues to be increased, underscoring a unique physiological
type of action of GHRP on GH secretion.
Another noteworthy finding in this study was augmentation
of the GH response to i.v. bolus GHRH at the
end of the GHRP infusion period, at least during the
first two of the three repeated i.v. bolus injections of
GHRH. These results demonstrate that desensitization
and sensitization of the GHRP action can occur concomitantly.
However, desensitization of the GH response
to GHRP is partial, whereas at the same time
the GH response to GHRH continues to be sensitized
or augmented.
In principle, these results might have been predicted
from the study of Clark and Robinson reported in 1989
in which conscious rats were continuously infused with
GHRP-6 for 8 h and i.v. bolus GHRH administered
each hour [44]. Each GHRH bolus injection elicited GH
release during the GHRP infusion, but not without it,
indicating that GHRP sensitized the pituitary action of
GHRH on GH release. The actual mechanism involved
is still unclear, but it is now known that continuous
GHRP infusion and longer-acting GHRP-GHSs, that
is, the Merck peptidomimetic MK-0677, have been
found to enhance GH pulsatile secretion in normal
subjects. The many important GHRP-GHS results of
the Merck group have been reviewed by Smith et al. as
well as Patchett et al. [28, 45, 46]. These studies again
support that the longer-acting effect of the GHRP-GHS
does not completely desensitize the GH response.
Particularly noteworthy are the comparative effects of
the GH-releasing action of low- vs. high-dose GHRP,
because they reveal novel aspects of the GHRP action
[18, 39, 47]. Figure 8 shows the GH response to a very
low dose of GHRP-2, 0.03 mg:kg (2 mg:subject), alone
and together with a 1 mg:kg maximal dose of GHRH in
normal young men. Even at a subthreshold GH-releasing
dosage, GHRP-2 augmented the GHRH-GH response.
Conclusions from these results are as follows.
The lack of a GH response to 2 mg of GHRP supports
that the action of the subthreshold GH-releasing dose
of GHRP is on the hypothalamus rather than the
pituitary. Because of the low dose of GHRP-2 and the
blood-brain barrier, the anatomical site of action of the
low dose is postulated to be on the hypothalamic median
eminence. In addition, it is hypothesized that the
Figure 11. GH response to GHRP-2, GHRH and GHRP-2GHRH in normal younger and older women. Values are the
mean9SEM. AUC, area under the curve; IGF-I265922 mg:l (younger) and 114911 (older); BMI (body mass index)2590.5
(younger) and 2690.7 (older). Age2591.1 (younger) and 6792.0 (older) [18]. Reprinted with permission from: Bowers C. Y. (1998)
GHRPGHRH synergistic release of GH: scope and implication. In: Growth Hormone Secretagogues, pp. 1–25, Bercu B. and Walker
R. (eds), © 1998 Marcel Dekker Inc., New York.
1324 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
Table 3. On the pathophysiology of older men and women with decreased GH secretion.
Peptide i.v. bolus Dose mgkg Mild peak Moderate peak Severe peak
GH ngml GH ngml GH ngml
GHRH 1.0 14.792.7 4.290.2 3.391.2
GHRP-2 0.1 6.392.5 3.591.2 1.290.4
GHRP-2GHRH 0.11.0 38.696.5 24.094.2 7.190.9
GHRP-2 1.0 41.294.7 32.895.1 14.392.3
AUC GH mg:l · 4 h
GHRH 1.0 10119179 352946 263967
GHRP-2 0.1 376995 217954 103934
GHRP-2GHRH 0.11.0 21969402 14029272 391927
GHRP-2 1.0 24269344 18909327 7069117
IGF-I (mg:l) 151.0917.0 121.0911.0 117.0918.0
Age (years) 63.892.3 67.891.3 67.393.1
BMI 25.390.7 26.790.2 26.591.8
n 5 11 4
Values: mean9SEM. BMI, body mass index; AUC, area under the curve.
hypothalamic GHRP action is not due to release of
endogenous GHRH, because the excess exogenous
GHRH administration would obviate any effect of endogenous
GHRH that may be released by GHRP.
Other previous relevant findings are that the GHRPSRIF
in vitro and in vivo GH-releasing action in animals
and humans does not support that low-dose
GHRP involves an action on SRIF release from the
hypothalmaus or inhibition of the action of SRIF on
the pituitary to release GH. To explain these results in
humans, we have hypothesized that low-dose GHRP
releases U-factor (unknown factor) from the hypothalamus,
and that by a pituitary action U-factor augments
the GH-releasing action of GHRH. Also envisioned is
that U-factor may be involved in the action of the
putative GHRP-like hormone in the physiological regulation
of pulsatile secretion of GH.
Results in figure 9 reveal that a novel effect on GH
release also occurs when a large pharmacological dose
of GHRP is administered. In this study a high dose of
10 mg:kg s.c. released an inordinate amount of GH in
normal young men. In these same men the GH response
to i.v. bolus 1 mg:kg GHRP-2 as well as 1 mg:kg
GHRP-21 mg:kg GHRH was determined. Since the
GH response to 1 mg:kg GHRH alone is always much
lower than the GH response to 10 mg:kg GHRP-2 in
normal young men, it is not possible to explain the later
response by a hypothalamic action of GHRP on the
release of endogenous GHRH alone. Our interpretation
of these results is that endogenous GHRH as well as
U-factor is released via the hypothalamic action of
high-dose GHRP and that GHRP, GHRH and U-factor
act together on the pituitary to release GH synergistically.
In these same men, GHRP-2GHRH at 1
mg:kg releases the same inordinately large amount of
GH as 10 mg:kg GHRP-2. These results support the
hypothesis that a high dose of 10 mg:kg GHRP releases
endogenous GHRH. In part, the synergistic response
probably involves attenuation of the inhibitory pituitary
action of SRIF on GH release by the pituitary action of
the three peptides. In studies in humans by Massoud et
al. [48] combined GHRPGHRH was more effective
Figure 12. Synergism in short-statured children. Acute test to
GHRP-2, GHRH and GHRP-2GHRH (left panel) [55] and
GHRP-1, GHRH and GHRP-1GHRH (right panel) [53].
Reprinted with permission from: (left panel) Pihoker C., Middleton
R., Reynolds G. A., Bowers C. Y. and Badger T. M. (1995)
Diagnostic studies with intravenous and intranasal growth hormone
releasing peptide-2 in children of short stature. J. Clin.
Endocrinol. Metab. 80: 2987–2992, © 1998 The Endocrine Society,
Bethesda, MD, and (right panel) Mericq V., Cassorla F., Garcia
H., Avila A., Bowers C. Y. and Merriam G. (1995) Growth
hormone responses to growth hormone releasing peptide (GHRP)
and to growth hormone releasing hormone (GHRH) in growth
hormone deficient children (GHD). J. Clin. Endocrinol. Metab. 80:
1681–1684, © 1998 The Endocrine Society, Bethesda, MD.
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1325
Figure 13. Effect of GHRPs on height velocity in short-statured children. Height velocity ranged from 2.1 to 3.2 cm:year [49–51].
Reprinted with permission from: (left panel) Klinger B., Silbergeld A., Deghenghi R., Frenkel J. and Laron Z. (1996) Desensitization
from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormone releasing peptide
in short chidren. Eur. J. Endocrinol. 134: 716–719, © 1998 Society of the European Journal of Endocrinology. (Middle panel) Pihoker
C., Badger T. M., Reynolds G. A. and Bowers C. Y. (1997) Treatment effects of intranasal growth hormone releasing peptide-2 in children
with short stature. J. Endocrinol. 155: 79–86, © 1998 The Endocrine Society, Bethesda, MD. (Right panel) Mericq V., Salazar T., Avila
A., Inguez G., Bowers C. Y., Cassorla F. et al. (1998) Treatment with growth hormone releasing peptide accelerates growth of growth
hormone-deficient children. J. Clin. Endocrinol. Metab. 83: 2355–2360, © 1998 The Endocrine Society, Bethesda, MD.
in attenuating the effect of SRIF on GH release than
the peptides alone.
Results of the synergistic release of GH induced by i.v.
bolus 1 mg:kg GHRP-2GHRH in normal younger
and older men and women are recorded in figures 10
and 11, respectively. A synergistic GH response to the
two peptides together occurred in all subjects. In addition,
the GH responses to GHRP-2, GHRH and
GHRP-2GHRH were notably less in the older than
in the younger subjects.
The following are possible pathophysiological mechanisms
responsible for decreased GH secretion in normal
older subjects. In the past, the hypothesis has been that
there is a decrease of GHRH secretion or an increase of
SRIF secretion to account for decreased GH secretion.
We now propose that decreased secretion of the putative
GHRP-like hormone may be one reason GH secretion
is decreased in some older subjects. Also, it is
possible that this may be due to a mixture of the above
or none of the above.
To investigate the pathophysiology of the decreased
secretion of GH in normal elderly subjects and the
possibility of a putative GHRP-like hormone deficiency,
GH responses to i.v. bolus 1 mg:kg of GHRH or
GHRP-2, 0.1 mg:kg of GHRP-2 and 0.1 mg:kg of
GHRP-21 mg:kg of GHRH were determined. In this
study, the GH results of 20 normal older subjects were
categorized into three groups according to the degree of
the decreased peak GH response to GHRP-2GHRH,
that is, mild (5 subjects), moderate (11 subjects),
marked (4 subjects). As recorded in table 3 the peak
GH response of the combined peptides in the mildly
impaired group was 39 mg:l, whereas this value was only
2 mg:l in the markedly impaired group and 24 mg:l in the
moderately impaired GH response group. In regard to
new insight into the pathophysiology of decreased secretion
of GH in older subjects, the most meaningful
results were obtained from the moderately impaired GH
response group. This insight was derived from the results
of a very low peak GH response of 4 mg:l to the 1
mg:kg dose of GHRH as well as the reversal of this
decreased GH response by administrating the low dose
of GHRP-2 in combination with 1 mg:kg of GHRH.
The impaired pituitary response to 1 mg:kg of GHRH
implies a primary pituitary disorder, perhaps due to
decreased pituitary stores of GH secondary to decreased
endogenous GHRH secretion or possibly due to
excess SRIF secretion; however, the dramatic reversal
by 0.1 mg:kg of GHRP-2 administered together with 1
mg:kg of GHRH weighs strongly against either one of
these possibilities. Low-dose GHRP is envisioned to act
on the hypothalamus to release U-factor and together
1326 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
with GHRH reverse the impaired pituitary GH response
to GHRH. The results clearly demonstrate that
decreased pituitary GH stores are not the reason
GHRH is ineffective. Also, it is apparent that even if
low-dose GHRP-2 released GHRH by a hypothalamic
action, the impaired pituitary response to exogenous
GHRH reveals that any endogenous GHRH released
would be ineffective. Additionally, from data of our
Figure 14. Continuous infusion of GHRP-2 in critically ill patients, n20 [57, 58]. Reprinted with permission from: Van den Berghe
G., de Zegher F., Veldhuis J. D., Wouters P., Awouters M., Verbruggen W. et al. (1997) The somatotropic axis in critical illness: effect
of continuous GHRH and GHRP-2 infusion. J. Clin. Endocrinol. Metab. 82: 590–599 and Van den Berghe G., De Zegher F., Baxter
R. C., Veldhuis J. D., Wouters P., Schetz M. et al. (1998) Neuroendocrinology of prolonged critical illness: effects of exogenous
thyrotropin-releasing hormone and its combination with growth hormone-secretagogues. J. Clin. Endocrinol. Metab. 83: 309–319, ©
1998 The Endocrine Society, Bethesda, MD.
Figure 15. Sequential i.v. hexarelin-GHRH administration in normal women (n6); age2492, BMI2291 (left panel); anorexic
women (n14), age2091.4, BMI1590.4 (middle panel); and women with secondary amenorrhoea (n7), age2191,
BMI1790.6 (right panel) [60]. Reprinted with permission from: Popovic V., Micic D., Djurovic M., Obradovic S., Casanueva F. F.
and Dieguez C. (1997) Absence of desensitization by hexarelin to subsequent GH releasing hormone-mediated GH secretion in patients
with anorexia nervosa. Clin. Endocrinol. 46: 539–543, © 1998 The Endocrine Society, Bethesda, MD.
CMLS, Cell. Mol. Life Sci. Vol. 54, 1998 Review Article 1327
Figure 16. Effect of hexarelin and corticotropin releasing factor
(CRF) in patients with Cushing’s disease (n10) and adrenal
adenomas (n5) on ACTH and cortisol [60]. Reprinted with
permission from: Popovic V., Micic D., Djurovic M., Obradovic
S., Casanueva F. F. and Dieguez C. (1997) Absence of desensitization
by hexarelin to subsequent GH releasing hormone-mediated
GH secretion in patients with anorexia nervosa. Clin.
Endocrinol. 46: 539–543, © 1998 The Endocrine Society,
Bethesda, MD.
Pihoker et al. [55] and Mericq et al. [53] on diagnostic
studies are recorded in figure 12. As recorded in figure
13, GHRP studies of Laron et al. [49], Pihoker et al.
[50] and Mericq et al. [51] demonstrate the effects of
chronic GHRPs after intranasal or subcutaneous administration.
The GHRP effects on height velocity
(2.1–3.2 cm:year) are less than those induced with
recombinent human GH, but the GHRP approach is
yet to be optimized in terms of the particular GHRP
formulation, dosage, time and frequency of administration.
Furthermore, since the mechanism of action of
GHRP has increasingly become better understood,
more rational clinical approaches will be proposed in
the future. Current studies in children and elderly subjects
include chronic administration of GHRP-2 as well
as the Merck GHRP-GHS (MK-0677).
In a series of studies Van den Berghe et al. [56–58]
demonstrated that nightly GH secretion during prolonged
critical illness is characterized by a high number
of small secretory bursts superimposed on low basal
secretion in the presence of low-serum IGF-I levels.
Both basal and pulsatile GH secretion, as recorded in
figure 14 was increased moderately by continuous infusion
of GHRH, substantially by GHRP-2 and strikingly
by GHRP-2GHRH [57, 58]. GHRP-2 alone or together
with GHRH robustly raised serum IGF-I levels
within 24 h. It has been concluded that these observations
open perspectives for the GHRP-GHSs as potential
antagonists of the catabolic state in critical care
patients.
Other interesting studies have been performed by Cordido
et al. in obese subjects [59] and in women with
anorexia nervosa and secondary amenorrhoea by
Popovic et al. [60]. In the latter study, as shown in
figure 15, hexarelin and GHRH were administered sequentially
2 h apart. In normal women and women with
secondary amenorrhoea, hexarelin inhibited subsequent
GH responses to GHRH. Since hexarelin did not inhibit
GHRH-GH responses in women with anorexia
nervosa, it was suggested by these investigators that this
may be a new way to differentiate young women with
anorexia nervosa from those with secondary amenorrhoea.
Ghigo et al. have performed a considerable number of
unique GHRP studies with hexarelin [61]. As recorded
in the right panel of figure 16, hexarelin increased serum
ACTH and cortisol levels in patients with Cushing’s
disease, but not patients with Cushing’s syndrome due
to an adrenal adenoma [62]. As recorded in the left
panel, CRH had little or no effect in both types of
patients.
Summary
Proof of principle of the GHRP clinical approach appears
to be established, and now optimization of this
previous GHRP-2-SRIF in vitro and in vivo studies, a
low dose of GHRP would not be expected to attenuate
the pituitary inhibitory action of SRIF on GH release.
Another meaningful result is the relatively large amount
of GH release induced by 1 mg:kg of GHRP-2 alone.
Since in vivo GHRP requires endogenous GHRH secretion
in order to induce GH release, this particular result
indicates endogenous GHRH is being secreted but the
pituitary GHRH response of these older subjects is
impaired.
Collectively, these results indicate that in some normal
older subjects GH secretion is decreased not because of
decreased secretion of endogenous GHRH or an excess
secretion of SRIF, but rather it is postulated that this
may be due to a possible deficiency of the putative
GHRP-like hypothalamic hormone. Whether a deficiency
of the putative GHRP-like hormone might play a
role in the mild and severely impaired GH response
groups is more difficult to evaluate because of the
smaller number of observations and the more borderline
decreased values of the mild group. Studies to
prove or disprove this hypothesis are ongoing in our
clinical research centre.
Already three studies have demonstrated that chronic
administration of GHRP for 6 to 24 months to shortstatured
children with various degrees of GH deficiency
augments height velocity [49–51], and four studies have
been performed on the possible acute diagnostic use of
GHRP in short-statured children [52–55]. Results of
1328 C. Y. Bowers Growth hormone-releasing peptide (GHRP)
approach is needed. Of particular importance, especially
in normal older men and women with decreased GH
secretion, is that GHRP induces physiological secretion
of GH. Because the normal negative feedback GH
systems are still operative in these subjects, overtreatment
with GHRP would be minimized.
One reason for the sustained interest in GHRP by many
investigators is that it has both a theoretical and a
practical aspect. From the theoretical standpoint, results
are continuing to accumulate on the possible presence
and role of the putative GHRP-like hormone,
which may be involved in the physiological regulation
of GH secretion. From the practical standpoint, the
interest in GHRP has evolved mainly from effects in
humans. GHRP releases GH in humans regardless of
age or sex, and sometimes the effects on GH release
have been novel and imply that it may be of both
diagnostic and therapeutic value.
Acknowledgements. This work was supported in part by National
Institutes of Health grants AM-06164, DK40202 and PHS
RR05096-09 (GCRC). Special appreciation is expressed to Dr.
Granda-Ayala, to the technicians and the fellows of the endocrinology
and metabolism section of the department of
medicine, and to Robin Alexander for typing the manuscript.
Special thanks are expressed to Dr. Fred Wagner at BioNebraska
for supplying GHRH 1-44NH2.
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