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Growth Hormone Secretagogues Why bodybuilding peptides CJC-1295 plus ghrp is effective




In the 1980's three classes of compounds where studied to determine their effect on growth hormone release. These three compounds were:

Growth Hormone Releasing Hormone (natural hormone)
Growth Hormone Releasing Peptides (synthetic molecules often termed "GH-Secretagogues")
removed by basskiller due to the nature of the item in question -highly illegal and addictive
Individually each class of compound when administered in laboratory rats was found to induce growth hormone release. However when they were all combined growth hormone release dramatically increased.

Growth Hormone Releasing Hormone (GHRH) + Growth Hormone Releasing Peptide (GHRP) was found to induce a large synergistic secretion of growth hormone (GH).


When all three classes of compounds were examined it was discovered that each compound released GH by a mechanism different and distinct from that of the others. Furthermore it was found that these three modes of action accomplished growth hormone release in ways complementing and not interfering with each other.


Fortunately we are left with two tools with which we can maximize a synergistic release of growth hormone. These tools have no toxicity and promote desirable alterations in normal physiology.

Growth Hormone Releasing Hormone (GHRH) in the form of its long-lasting analog (CJC-1295) was discussed in the previous article. It is therefore left to this article to discuss Growth Hormone Releasing Peptides (GHRPs) and the human studies that demonstrate synergy between these two compounds (GHRP + GHRH).



Growth Hormone Releasing Peptides (GHRPs) - A Quick Look

What are they?

Growth Hormone Releasing Peptides (GHRPs) are synthetic forms of the natural hormone Ghrelin. These simple short-chained amino acid peptide strings possess most of the positive characteristics of Ghrelin (such as effecting GH secretion) and few of the negative properties (such as Ghrelin's lipogenic behavior (i.e. conversion of glucose to fatty acids)).

GHRPs belong to a broader class of compounds all of which share the common trait of being able to bind to the Growth Hormone Secretagogue Receptor (GHS-R) and effect GH release. These compounds include the synthetic peptides (GHRP-6, GHRP-1, GHRP-2, Hexarelin, Ipamorelin) and smaller synthetic non-peptide molecular compounds such as MK-0677 as well as the natural ligand Ghrelin. This broad class which includes all of the above but not Growth Hormone Releasing Hormone (GHRH) is termed Growth Hormone Secretagogues (GHSs).

These Growth Hormone Secretagogues (GHSs) exert their effect on increasing GH output in multiple ways.

First they INDIRECTLY increase growth hormone (GH) secretion by inducing Growth Hormone Releasing Hormone (GHRH) release from the hypothalamus in the brain. GHRH once released makes its way to the Growth Hormone Releasing Hormone Receptors (GHRH-R) in cells within the pituitary (a gland just below the brain) where it binds and exerts its direct influence in signaling GH release.

Second these GHS also make there way to those same pituitary cells where they themselves bind to a Growth Hormone Secretagogue Receptor (GHS-R) and exert a DIRECT influence in signaling GH release. This signaling uses a different mode of action distinct from that of GHRH. As a consequence both bound GHRH & bound GHS can exert their positive influence concurrently resulting in synergistic growth hormone (GH) release.

Third they INDIRECTLY increase GH secretion by reducing release of Somatostatin (the GH inhibiting hormone) from the hypothalamus and DIRECTLY by reducing the magnitude of Somatostatin's inhibiting action once it binds to its receptor on the pituitary cells.

In essence Growth Hormone Secretagogues (GHS) turn up the positive signal to release GHRH, turn down the negative signal to release the inhibiting hormone Somatostatin, speak directly to the growth hormone releasing pituitary cells themselves to encourage them to release GH and speak directly to the growth hormone releasing pituitary cells themselves to encourage them to ignore Somatostatin's message to stop releasing GH.




Oral GHS

Based on the effectiveness of GHRPs smaller non-peptide molecules were created in an effort to mimic the GH releasing effects of GHRPs with the desire to develop a compound with high oral bioavailability. As a result MK-0677 was eventually created as a non-peptide compound with sustained GH release and higher oral bioavailability. Unfortunately desensitization was found to occur fairly rapidly. In addition the dose for the orally administered MK-0677 is measured in several milligrams while the effective dose for the injectable GHRPs is measured in micrograms making GHRPs more cost effective. Research is ongoing on non-peptide GHSs, particularly with Ipamorelin derivatives so perhaps an oral GHS devoid of desensitization will eventually be developed.

My own thought is that these molecular compounds appear to be small enough to be used in a transdermal formula. Also it would be nice to have these orally/transdermally active compounds available to use on a limited basis perhaps making usage when traveling convenient.



Growth Hormone Releasing Peptides - A Longer Look

What are they?

In 1980 the first highly potent GH-Releasing peptide was developed and named GHRP-6. This peptide was found to illicit a strong GH release response and so became the first member of a class of growth hormone releasing peptides more broadly called GH secretagogues. Structurally GHRP-6 is composed of the amino acids L-Histidine, D-Tryptophan, L-Alanine, L-Tryptophan, D-Phenylalanine and L-Lysine. The "L" form of an amino acid is the naturally occurring form and often in the nomenclature the "L" is dropped. The "D" form does not occur in nature and is the isomeric form (i.e. mirror image) of the naturally occurring "L" form.

GHRP-6 is composed of both natural and isomeric forms of those aforementioned six amino acids. Its structure is represented as:

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2

Investigators subsequently modified the structure of GHRP-6 and identified more potent peptides. For example, activity was enhanced by replacing D-Trp with D-2-(2-napthyl)alanine and His with D-Alanine to create GHRP-2 whose structure is represented as:

D-Ala-D-2 Nal-Ala-Trp-D-Phe-Lys-NH2

In 1982, after a long search the natural hormone "Growth Hormone Releasing Hormone" (GHRH) was finally isolated and identified. As a result the interest in Growth Hormone Secretagogues (at that point limited to the three peptides) faded. Eventually researchers discovered that those GH-Releasing Peptides (specifically GHRP-6 & GHRP-2) followed a mode of action which bound them to and was mediated through receptors different from those for GHRH. In addition researches discovered that these GH-Releasing Peptides acted synergistically with the natural hormone Growth Hormone Releasing Hormone (GHRH) in vivo (in both laboratory animals & humans) to produce large releases of Growth Hormone.

Taken together these two discoveries made it clear that GHRPs were not simply surrogates of GHRH. GHRP-6 and its analogues were artificial activators of a separate newly discovered receptor termed the "Growth Hormone Secretagogue Receptor" (GHS-R). Eventually the natural hormone Ghrelin was discovered as the endogenous ligand that binds to the GHS-R. Together the natural hormone Ghrelin, and all the synthetic compounds (both peptides & smaller molecules) such as GHRP-6 were termed "Growth Hormone Secretagogues" (GHSs).

This nomenclature continues in the literature to this day however increasingly new terminology is used. For instance the "Ghrelin Receptor" is synonymous with "GHS-R" and "Ghrelin mimetics" are synonymous with all the synthetic compounds that are capable of binding to the GHS-R. This paper uses the more established nomenclature throughout.



Pituitary Actions of GHSs

All GHSs act directly on the pituitary. They do so by binding to and activating their specific receptor (GHS-R). Once this occurs GH secretion is commanded to rise. GHRH does the same thing. It acts directly on the pituitary and binds to and activates its specific receptor (GHRH-R). Once this occurs GH secretion is commanded to rise.

However GHSs and GHRH operate through a different "mode of action" or intracellular signaling system within the cell that eventually activates GH secretion. These modes of action are contrasted as follows.

GHRH when it binds to its receptor (GHRH-R) on the cellular membrane of a somatotrope cell activates the cAMP–PKA (cAMP-dependent protein kinase) pathway (in essence a secondary messenger), and by a poorly understood mechanism causes a persistent rise in intracellular Calcium (Ca2+) ions by opening Ca2+ channels (simply ports on the cell membrane that open and close to either permit or deny entry) on the cellular membrane and letting into the cell Ca2+ from the outside. The rise in calcium concentration within the cell signals in conjunction with other signaling processes the instruction to the somatotrope cell to release Growth Hormone.

It should be noted that Somatostatin (the GH inhibiting hormone) once bound to its receptor brings about a decrease in GH in part by inhibiting cAMP formation. As a consequence of limiting this messenger the signaling cascade is weakened resulting in less Calcium (Ca2+) ions entering the cell and thus inhibition of GH release.

GHSs however do not rely on cAMP as a messenger. GHSs once bound to their respective receptor initiate a process that leads to an inhibition of Potassium (K+) ion channels. This action results in a sustained depolarization of the cellular membrane. The result is identical to that affected by GHRH, namely the Calcium ion level rises via voltage-activated channels leading to the signal to secrete GH. But the mode of action relies on the use of depolarization of the cellular membrane and inhibiting Potassium ion channels rather then GHRH's cAMP-mediated opening of Calcium ion channels.

In addition to allowing Ca2+ into the cell, GHSs may also cause a rise in intracellular Ca2+ by redistribution from internal stores of Ca2+ within the cell. This process is mediated by the generation of inositol trisphosphate whose main functions are to mobilize Ca2+ from storage organelles and to regulate cell proliferation.

This brief description is an over simplification. The important point is that GHRH and GHS act through their own receptors and distinct intermediate pathways.

This is not the only difference. Although the image herein depicts one pituitary somatotrope with both types of receptors activated (GHRH-R & GHS-R) this may not give a completely accurate picture. GHRH and GHS appear to act on different somatotrope subpopulations. GHRP has been shown to increase the number of somatotropes releasing GH, without altering the amount of hormone released by each individual cell. On the other hand, GHRH stimulates both the number of cells secreting GH and the amount of GH secreted per cell.

From these limited discoveries we can begin to understand how GHRH and GHSs compliment each other's GH releasing actions rather then duplicate one another.

It should be noted that Somatostatin (the GH inhibiting hormone) has been shown primarily to decrease the number of cells secreting GH without affecting the amount of GH secreted per cell.

To sum up in very general terms GHS increases, while Somatostatin decreases, the number of active GH secreting somatotropes, probably because these two factors act by depolarizing and hyperpolarizing cells, respectively (i.e. GHSs turns the cell into a Calcium ion sponge & Somatostatin turns the cell into a squeegee, squeezing out and repelling Calcium ions).

On the other hand GHRH does both, but acts primarily by stimulating the amount of secreted GH within the active somatotropes.




Hypothalamic Actions of GHS

In vitro (in a laboratory dish) the amount of GH release from GHRH and GHSs is additive. GHSs cause a rise of 2...GHRH causes a rise of 1...put them together and the GH rise is merely the sum 3.

But something different happens when you put these two compounds into living breathing mammals. In vivo (in body) the GH rise that occurs from the combination of GHRH and GHSs is more then the sum of their individual contributions. There is substantial synergy such that 1 + 2 = 6.

This occurs as a result of GHSs actions within the Hypothalamus (region of the brain) rather then its direct pituitary actions. There are GHS receptors (GHS-R) in the hypothalamus; perhaps even subtype receptors. When GHSs bind to these receptors they behave like a hypothalamic neurohormone and as such exhibit a dual action.

They stimulate endogenous GHRH release and concurrently suppress endogenous Somatostatin release. How they do this is a complex process with much still unknown. Basically they incite electrical activation of arcuate neurons (within the hypothalamus). About seventy-five percent of the cells excited by GHRP-6 project outside the blood brain barrier (hypothalamus) into the median eminence (boundary between hypothalamus & the portal system which connects to the pituitary which lies just below the brain) and are neurosecretory involved in the regulation of pituitary function.

The activation of these neurons by GHRP-6 is extremely long lasting (longer than 1 hour) and reaches the peak rapidly (within 5 to 10 minutes). Non-peptide GHSs respond slower perhaps for the reason that they penetrate the blood brain barrier slower than GHRP-6.

GHRP-6s excitation of neuronal activity beyond those neurons that regulate GHRH & Somatostatin (i.e. the remaining 25%) may account for some of the impact GHRPs have on non-GH releasing activity.

The important point is to recognize that GHSs have an impact on GHRH release and Somatostatin suppression at the hypothalamus which appears to be responsible for the now well-recognized synergistic effect on GH release from concurrent administration of GHRH & GHRPs in vivo.

Furthermore it should now be firmly understood that GH release is regulated by the following trinity - GHRH, Somatostatin and GHSs.


GHS Potency (i.e. efficacy) & Dosing in Humans
When administered at clinical research dosages, all GHSs (both peptides and non-peptides) release significantly larger amounts of GH (i.e. are more efficacious) than GHRH. This is not to be confused with the term potency which takes into account the molecular weight of a compound and thus measures GH output on a "per mol" basis. By this measure GHRH is more potent.

However if the desire is to administer these compounds and effect GH release then the only relevant standard is absolute amount of GH release and in that regard GHSs release more GH than GHRH. The following standards determined through clinical study will specifically clarify this concept.

In humans the maximal i.v. dose for GHRH has been found to be 1 mcg per kg of bodyweight. That is a level that saturates the receptors and beyond which there is no further benefit, until that dosage has dissipated.

In humans the maximal i.v. dose for GHSs such as hexarelin has been found to be 2 to 3 mcg per kg of bodyweight. In normal humans (i.e. those without disease or clinical malady) GH release is increased as the GHS dose increases up to the aforementioned maximal dose. Even very small amounts have been shown to have positive effects.

Unlike GHRH, GHSs are resistant to well-known inhibitors of GH secretion. Studies demonstrate that hexarelin-mediated GH secretion is reduced but not blocked by a rise in circulating free fatty acids or by a glucose load, nor by an infusion of Somatostatin nor drugs that enhance hypothalamic Somatostatin secretion.

GHRH is influenced by metabolic and hormonal factors that consequently make GHRH a very unpredictable GH stimulator, with large variations between individuals and a diversity of peaking times.

In contrast GHSs are not greatly influenced by metabolic and hormonal factors, the absence of which makes GHSs a very predictable GH stimulator. GHSs are potent and efficacious, their actions synchronized and reproducible, with no non-responders.

GHSs have been repeatedly demonstrated in studies to be very strong GH releasers in healthy young males. In addition GHSs have been shown in studies to be very strong GH releasers in females at all stages of the menstrual cycle. This again is important to note because GHSs are not greatly affected by changes in various hormone levels, be they thyroid hormone, estrogen, etc.

There may be an age-related reduction in the GH-releasing capability of GHSs. The studies have not yet been able to come to a consensus. However, the synergistic effect of GHRH and GHS on GH secretion is not reduced as humans age throughout the entire lifespan. This holds true even for the very old (Those in their 90's).

There are no reported side-effects with GHS usage. However both the peptidyl and non-peptidyl compounds have been found to induce slight increases (still within what is deemed the normal range) in prolactin and in adrenocorticotrophin(ACTH)/cortisol, and in a few studies dehydroepiandrosterone (DHEA). Low to moderate dose (1 mcg/kg) administration of GHRP-6 has been found to result in very large GH release with no significant effects on cortisol or prolactin. Of the peptides, Hexarelin appears to induce the highest level of these hormones (prolactin & cortisol). Ipamorelin a newer GHS has no effect on these hormones no matter what the dose.



In the 1980's three classes of compounds where studied to determine their effect on growth hormone release. These three compounds were:

Why you need both GHRH analog (CJC-1295) and GHRP

GHS Down Regulation

A single dose of a GHS in vivo brings about an immediate down-regulation of responsiveness to subsequent administration. This desensitization appears to abate and sensitivity fully restored within a few hours.

However continual infusion of large amounts of GHS brings about a substantial initial release of GH, followed, after several hours, by long-term down-regulation of GH secretion.

The only published comparison of the results of differing modes of GHS delivery (twice daily injections vs. continuous infusion) in vivo demonstrated a dramatic dissipation of anabolism following infusions of high-dose GHS. However a pronounced anabolic effect was maintained with the same dose of GHS administered by intermittent injection.



From the results of this study, it is evident that with GHSs the optimal dosing pattern is administration by injection with sufficient intervals between dosing so as to maintain sensitivity.

The effectiveness is greatly diminished, perhaps to the point of having no benefit if GHSs duration of action becomes prolonged and sustained. GHSs unlike GHRH are best used to amplify those very import GH pulses while GHRH is effective at raising the total level of GH.

If we understand desensitization than we will easily understand why the oral GHS, MK-0677 in recent studies failed to demonstrate a "maintained acceleration of statural growth in children with GH-deficiency". MK-0677 was developed to be a long lasting orally active analogue of GHRP-6. MK-0677 is to GHRP-6 what CJC-1295 is to GHRH (i.e. long-lasting).

The problem is that while long-lasting analogues of GHRH do not result in desensitization and pronounced down-regulation, long-lasting analogues of GHRP-6 do desensitize and consequently lose effectiveness.

CJC-1295 brings about persistent and chronically elevated levels of GH while GHRP-6 if injected a couple of times a day amplifies the very important GH pulses. The two compounds greatly compliment each other. In the previous article on GHRH & CJC-1295 we discussed the importance of pulsation which has been shown to be necessary for growth. The other important component of anabolism is chronic GH elevation.

Continuously elevated levels of GH increase IGF-I levels more than intermittent increases in GH. The intermittent nature of GH release brought on by GHSs' mode of action does create a rise in IGF-I levels but the anabolic effect may not be pronounced.

It has been repeatedly demonstrated and is now recognized that in children the growth response to injections of IGF-I is far less than the growth response to injections of GH. This is in accordance with most animal studies, which demonstrate that treatment with IGF-I does "not produce the full anabolic and growth-promoting effects of GH treatment".

Protocols that elevate GH while maintaining and amplifying the pulses seem to be effective at producing anabolism. The combination of CJC-1295 and GHRP-6 do just that.





GHRH (and analogs) + GHSs = a lot of synergistic growth hormone release

There is not a lot of deviation in the published studies on the effect of these peptides and the saturation dose needed to bring about the effect in normal people (who often act as a control group).

We need only to examine the results of the normal test subjects from three oft-cited studies that established the relevant protocol.

In the first study "Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome", Alfonso Leal-Cerro..., Clinical Endocrinology 1994, 41 (5) , 649–654, three different peptide/peptide combinations were used.

GHRH was administered alone at 100mcg. This resulted in area under the curve (AUC) measured for 120 minutes of GH secretion of 1420 * 330.

GHRP-6 was administered alone at 100mcg. This resulted in area under the curve (AUC) measured for 120 minutes of GH secretion of 2278 * 290.

GHRH plus GHRP-6 was administered together at 100mcg each. This resulted in area under the curve (AUC) measured for 120 minutes of GH secretion of 7332 * 592.

As a single dose these results show that GHRP-6 is about twice as effective as GHRH.

The synergy between GHRH & GHRP-6 is clearly evident as co-administration resulted in twice the benefit of the additive values of single doses of the two peptides.

The second study is the one that established the saturation dose for these peptides often used in other studies. "Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone ", CY Bowers..., J. Clin. Endocrinol. Metab., Apr 1990; 70: 975-982.

In that study GHRH at a dose of 1.0 microgram/kg was administered alone and then together with various doses of GHRP-6 (0.1, 0.3, and 1.0 microgram/kg). They found that the submaximal dosages of 0.1 and 0.3 microgram/kg GHRP-6 plus 1 microgram/kg GHRH did have the effect of stimulating GH release synergistically.

However the larger dose of 1 mcg/kg of GHRP-6 was found to be the saturation dose when used in combination w/ 1 mcg/kg of GHRH.

It is also noteworthy that serum prolactin and cortisol levels rose about 2-fold above base levels only at the 1 microgram/kg dose of GHRP-6 and not at the submaximal dosages.

The final study, "Preserved Growth Hormone (GH) Secretion in Aged and Very Old Subjects after Testing with the Combined Stimulus GH-Releasing Hormone plus GH-Releasing Hexapeptide-6", Micic D..., J Clin Endocrinol Metab. 1998 Jul;83(7):2569-72 is fascinating for several reasons.

By reference to citation it is noted that "GHRH plus GHRP-6 (both at saturating dose) is nowadays considered the most potent stimulus of GH secretion in man being able to restore the GH secretion in states associated with chronic blockade of somatotroph activity (as in obesity)...it elicits a near-normal GH discharge in obesity, in patients with hypothyroidism and in patients with type 2 diabetes mellitus."

This particular study examined the effects of combined administration of GHRH, immediately followed by GHRP-6 in a group of very old subjects (age higher than 75 yr), as compared with both normal adults (less than 40 yr) and aged subjects (age 46–65 yr). The dosing levels used were 90mcg of GHRH followed by 1mcg/kg of GHRP-6.

All the subjects had a positive GH secretory response to the combined administration with no differences observed between men and women. However the group comprising the very old had the highest level of GH release followed by the group comprising the aged subjects with the "less than 40 yr group" experiencing a substantial rise but not as high as the other two groups.

The study concluded that the lack of side-effects & safety of the protocol and the discovered lack of age-related decline in the "GHRH-GHRP-6-mediated GH release opens the possibility of using it as a therapeutical tool to revert some deleterious manifestations of aging in man."




In CONCLUSION, Growth Hormone (GH) is regulated by a trinity composed of Growth Hormone Releasing Hormone (GHRH), Growth Hormone Secretagogues (GHS) and Somatostatin. GHRH and GHSs individually have a positive impact on GH secretion. These two compounds operate through distinct modes of action which complement each other and when administered together result in synergistic GH secretion.

Growth Hormone Releasing Peptides (GHRPs), a subclass of GHSs are effective across all age groups in amplifying GH pulses. Pulsation is a necessary component of growth generation in mammals. GHRH when co-administered with GHRPs has the effect of further increasing the amplitude and "area under the curve" of a GH pulse. The result is a GH pulse many multiples more effective then that achieved by an unaided GH pulse.

In addition to pulsation, overall growth is better accomplished when total levels of GH are elevated without hindering pulsation. Elevated GH levels appear to be a necessary component of growth generation as well. One of the reasons this is so appears to be that chronically elevated GH levels result in more pronounced sustained levels of IGF-1 then that achieved through intermittent GH elevations.

Persistent levels of GHRH do not result in desensitization. Elevated levels of GHRH result in sustained GH release. A long-lasting version of GHRH, CJC-1295 has demonstrated the ability to sustain elevated GH levels in humans.

GHRP-6 is perhaps the most well studied of all GHSs. In physiological doses there are virtually no side effects. It has been demonstrated to be effective for all age groups.




Combined administration of CJC-1295 and GHRP-6 is a very effective, well studied method of increasing the total amount of GH secreted within the body. By adjusting the dosing of these compounds and accounting for such factors as age one may choose to achieve a "youthful" restoration, an above normal elevation or a substantially above normal elevation of both GH levels and pulsatile release.

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