Synergy of GHRH + GHRP
It 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 Hexarelin) 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 Hexarelin) 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 GHRP is 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 &. 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)(serimorelin) 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). However this is not accurate. CJC-1295 results in continual GH bleed. Although natural pulsation still occurs CJC-1295 does nothing to increase those pulses. Instead it raises base levels of GH and creates a more feminized pattern of release. This not desirable.
Modified GRF(1-29)however when combined with a GHRP brings about a substantial pulse which has desirable effects.
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 Ghrelins 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 Somatostatins 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 Somatostatins message to stop releasing GH.
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.