Introduction to natural GH release and GHRH – GHRPs

What is growth hormone?

Synthetic Growth Hormone is an artificially created hormone “identical” to the major naturally produced (endogenous) isoform. It is often referred to by its molecular mass which is 22kDa (kilodaltons) and is made up of a sequence of 191 amino acids (primary structure) with a very specific folding pattern that comprise a three-dimensional structure (tertiary structure). This tertiary structure is subject to potential shape change through a process known as thermal denaturation. While many labs are capable of generating growth hormone (GH) with the proper primary structure not all will be capable of creating a tertiary structure identical to the major naturally occurring growth hormone. The tertiary structure can determine the strength with which the growth hormone molecule binds to a receptor which will in turn affect the “strength” of the intracellular signaling which mediates the events leading to protein transcription, metabolism, IGF-1 creation, etc. It is this inconsistency that accounts in part for the differences in effectiveness of various non-pharmaceutically produced synthetic growth hormone.

Naturally produced Growth Hormone is produced in the anterior pituitary and to a far lesser extent in peripheral tissue. It is made up of a blend of isoforms the majority of which is the 22kDa (191 amino acid) variety with which most are familiar. In addition an isoform that is missing the 15 amino acids that interact with the prolactin receptor is also produced. This form is known as 20kDa and although it binds differently to the growth hormone receptor it has been shown to be equally potent to 22kDa. It appears that 20kDa has lower diabetogenic activity then 22kDa. The pituitary releases a blend of these two isoforms with 20kDa averaging perhaps 10% of the total although this percentage increases post-exercise. Currently there is no synthetic produced for external administration for this isoform.

Growth hormone (GH) in the body is released in pulsatile fashion. It has been demonstrated that this pattern promotes growth. The pituitary is capable of rather quickly synthesizing very large amounts of growth hormone which it stores large amounts in both a finished and unfinished form. Adults rarely experience GH pulses (i.e. releases of pituitary stores) that completely deplete these stores. As we age we do not lose the ability to create and store large amounts of growth hormone. Rather we experience a diminished capacity to “instruct” their release. The volume of GH that is released can not be properly equated to the exogenous administration of synthetic GH for the reason that a set of behavioral characteristics accompany natural GH that differ from those of synthetic GH. Among those characteristics are concentrated pulsatile release which upon binding in mass to growth hormone receptors on the surface of cells initiate signaling cascades which mediate growth events by translocating signaling proteins to the nucleus of the cell where protein transcription and metabolic events occur.

These very important signaling pathways desensitize to Growth Hormone’s initiating effects and need to experience an absence of Growth Hormone in order to reset and be ready to act again. The presence of GH released in pulsatile fashion is graphed as a wave with the low or no growth hormone period graphed as a trough. Therefore attempting to find a natural GH to synthetic GH equivalency is not very productive because in the end what is probably import is:
- the quantity & quality of intracellular signaling events; and
- the degree to which GH stimulates autocrine/paracrine (locally produced/locally used) muscle IGF-1 & post-exercise its splice variant MGF.

Brief overview of natural GH release

The initiation of growth hormone release in the pituitary is dependent on a trilogy of hormones:
Somatostatin which is the inhibitory hormone and responsible in large part for the creation of pulsation;

Growth Hormone Releasing Hormone (GHRH) which is the stimulatory hormone responsible for initiating GH release; and

Ghrelin which is a modulating hormone and in essence optimizes the balance between the “on” hormone & the “off” hormone. Before Ghrelin was discovered the synthetic growth hormone releasing peptides (GHRPs) were created and are superior to Ghrelin in that they do not share Ghrelin’s lipogenic behavior. These GHRPs are GHRP-6, GHRP-2, Hexarelin and later Ipamorelin all of which behave in similar fashion.
In the aging adult these Ghrelin-mimetics or the GHRPs restore a more youthful ability to release GH from the pituitary as they turn down somatostatin’s negative influence which becomes stronger as we age and turn up growth hormone releasing hormone’s influence which becomes weaker as we age.

The exogenous administration of Growth Hormone Releasing Hormone (GHRH) creates a pulse of GH release which will be small if administered during a natural GH trough and higher if administered during a rising natural GH wave.

Growth Hormone Releasing Peptides (GHRP-6, GHRP-2, Ipamorelin) are capable of creating a larger pulse of GH on their own then GHRH and they do this with much more consistency and predictability without regard to whether a natural wave or trough of GH is currently taking place.

Synergy of GHRH + GHRP

ghrp-2-bottleIt is well documented and established that the concurrent administration of Growth Hormone Releasing Hormone (GHRH) and a Growth Hormone Releasing Peptide (GHRP-6, GHRP-2 or Ipamorelin) results in synergistic release of GH from pituitary stores. In other words if GHRH contributes a GH amount quantified as the number 2 and GHRPs contributed a GH amount quantified as the number 4 the total GH release is not additive (i.e. 2 + 4 = 6). Rather the whole is greater than the sum of the parts such that 2 + 4 = 10.

While the GHRPs (GHRP-6, GHRP-2 and Ipamorelin) come in only one half-life form and are capable of generating a GH pulse that lasts a couple of hours re-administration of a GHRPis required to effect additional pulses.

Growth Hormone Releasing Hormone (GHRH) however is currently available in several forms which vary only by their half-lives. Naturally occurring GHRH is either a 40 or 44 amino acid peptide with the bioactive portion residing in the first 29 amino acids. This shortened peptide identical in behavior and half-life to that of GHRH is called Growth Hormone Releasing Factor and is abbreviated as GRF(1-29).

GRF(1-29) is produced and sold as a drug called Sermorelin. It has a short-half life measured in minutes. If you prefer analogies think of this as a Testosterone Suspension (i.e. unestered).

To increase the stability and half-life of GRF(1-29) four amino acid changes where made to its structure. These changes increase the half-life beyond 30 minutes which is more than sufficient to exert a sustained effect which will maximize a GH pulse. This form is often called tetrasubstituted GRF(1-29) (or modified) and unfortunately & confusingly mislabeled as CJC-1295. If you prefer analogies think of this as a Testosterone Propionate (i.e. short-estered).

Note that some may also refer to this as CJC-1295 without the DAC (Drug Affinity Complex).

Frequent dosing of either the aforementioned modified GRF(1-29) or regular GRF(1-29) is required and as previously indicated works synergistically with a GHRP.

In an attempt to create a more convenient long-lasting GHRH, a compound known as CJC-1295 was created. This compound is identical to the aforementioned modified GRF(1-29) with the addition of the amino acid Lysine which links to a non-peptide molecule known as a “Drug Affinity Complex (DAC)”. This complex allows GRF(1-29) to bind to albumin post-injection in plasma and extends its half-life to that of days. If you prefer analogies think of this as a Testosterone Cypionate (i.e. long-estered). Unfortunately CJC-1295 results in growth hormone bleed. This means that although pulsation remains base levels end up chronically elevated.

You do not want to use CJC-1295. You want to use Modified GRF(1-29).
Why? (Partial Explanation)
“Cell-to-cell communication is also likely to reflect the density and proximity of adjacent cells as GH responsiveness (but not sensitivity) to GHRH is enhanced at higher densities and basal GH release is greatest at low densities.”

“Cell-to-cell contact may therefore affect the cellular integrity of somatotrophs because GH synthesis or secretory granule storage may be better maintained in high density cell concentration then in low-density concentrations.” – Growth Hormone, Stephen Harvey
What happens is cells in the pituitary communicate. They self organize and create a firing network for coordinated growth hormone release. This communication creates a high density of GH releasing cells. They are in close proximity through their communicatory network. The cells have specific spatial relationships that may be modulated by peripheral endocrines. These include sex steroids, thyroid hormones, glucorticoids and even the pancreatic and gut hormones. Their spatial relationship is also effected by physiological state such as nutrient status, age and pregnancy.

As a quick example, corticotroph, thyrotrophs and folliculostellate cells are in close proximity to somatotrophs and communicate with them through gap junctions (almost like just reaching out and touching signaling). They have the potential to effect and be effected by their neighbors.

What happens when you have GHRH always around is you force these somatotrophs to release GH because they are sensitive to the GHRH binding to them and effecting release. By constantly occupying you are preventing them from coordinating with surrounding cell populations. You force these cells to act as low density subpopulations. Basal GH release is greatest when you can disperse the spatial relationship between somatotrophs and that is what an always on GHRH will do.
CJC-1295 as an always on GHRH will force upon somatotrophs loner behavior with a single constant chore. This reduces GH responsiveness as this only occurs when somatotrophs can communicate, self organize and maintain social relationships with the surrounding community. These types of social somatotrophs are better able to make and store GH then the loner cells.

So CJC-1295 seems to disperse somatotrophs and enslave them getting less from them then if it had just let them congregate in towns and cities.

Aging has an effect on the vitality of city centers as well and as we age these somatotroph population centers become less vigorous. By using a more physiological GHRH such as modified GRF(1-29) together with a modulator GHRP-2 we revitalize that inner city and allow our cells to be more social and thus more productive. If instead we choose to use CJC-1295 we not only fail to remedy the problem associated with age , but we may end up exacerbating it.

I conjecture that it also makes them better neighbors to corticotroph, thyrotrophs and folliculostellate cells as well.
What follows is:
A Basic Peptide Primer (which introduces the concept & structure of peptides)

A Brief Summary of Dosing and Administration (for someone that wants to know the “how to use” straight away)
If all of this is a bit unclear because a lot of new concepts are thrown at you the following original article should help:
Growth Hormone Secretagogues

I have only one pet-peeve and that is when someone refers to synthetic growth hormone as “real” growth hormone. The GH that your body produces is as real as it gets. It is what grew you from a fetus to a boy (girl) and from a boy (girl) to a man (woman). – DatBtrue

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