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CJC-1295 & GHRP-6 basic guide

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Introduction to the thread

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.
Synthetic GH versus Natural GH in IUs

An attempt has been made on my part and can be found at:

#8 - Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH (part I of II)

#9 - Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH (part II of II)
Rather than demonstrate absolute values this comparison articles should serve to demonstrate that the body can produce pharmacological levels of growth hormone.

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, Hexarelin) 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

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 & 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)

CJC-1295 is difficult to produce and expensive to make. As a result it could be cost-prohibitive to use extensively. Modified GRF(1-29) while less convenient is much less expensive to make and because it is a pure peptide the synthesis process is straightforward. It should sell at a fraction of the cost of CJC-1295.

What follows on this first page of the thread 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 a couple original very thorough articles are must reads. They are:

Post #4 - Basic Guide: CJC-1295

Post #5 - Basic Guide: Growth Hormone Secretagogues

Post #6 - Basic Guide: Growth Hormone Secretagogues (part II)
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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Basic Peptide Primer
Written by Datbtrue
What is a peptide?

Peptides (proteins) are present in every living cell and possess a variety of biochemical activities. Some peptides are synthesized in the ribosomes of a cell by translation of mRNA (messenger RNA) into hormones and signaling molecules for example. Other peptides are assembled (rather then synthesized) and become enzymes with a vast variety of functions. Peptides also make up the structure of receptors which await binding of hormones & signaling molecules.

A peptide is a molecule created by joining two or more amino acids. In general if the number of amino acids is less than fifty, these molecules are called peptides, while larger sequences are referred to as proteins.

So peptides can be thought of as tiny proteins. They are merely strings of amino acids.

Raw Constituents of Peptides (Amino Acids)

Amino acids are small molecules made up of atoms. As part of their structure they posses a grouping of a Nitrogen (N) atom bonded to two Hydrogen (H) atoms. This is called an amino group and written as (NH2). In addition their structure is also made up of a second grouping of a Carbon (C) atom bonded to two Oxygen (O) and one Hydrogen atom. This group is called a carboxyl group and is written as (COOH).




Between these two groupings are atoms and bonds unique to each amino acid. In other words all amino acids possess the two groupings (amino & carboxyl) as end-points between which are sandwiched a unique set of atoms.

Amino Acids

Inside the human body there are twenty standard amino acids used by cells in peptide biosynthesis (i.e. the cellular creation of peptides from amino acids). Our genetic code specifies how to synthesize peptides and proteins from these amino acids.

Amino acids are classified into two groups: essential amino acids and nonessential amino acids.

An essential amino acid is an indispensable amino acid which cannot be made by the body and must be supplied by food. These include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Another amino acid - histidine is considered semi-essential because the body does not always require dietary sources of it.

Nonessential amino acids are made by the body from the essential amino acids or the routine breakdown of proteins. The nonessential amino acids are arginine, alanine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, proline, serine, and tyrosine.

All twenty amino acids are equally important in maintaining a healthy body. They are the raw constituents of peptides and proteins.

The standard abbreviations for amino acids come in two forms: a one letter form and a three letter form. They are:

A - Ala - Alanine
C - Cys - Cysteine
D - Asp - Aspartic Acid
E - Glu - Glutamic Acid
F - Phe - Phenylalanine
G - Gly - Glycine
H - His - Histidine
I - Ile - Isoleucine
K - Lys - Lysine
L - Leu - Leucine
M - Met - Methionine
N - Asn - Asparagine
P - Pro - Proline
Q - Gln - Glutamine
R - Arg - Arginine
S - Ser - Serine
T - Thr - Threonine
V - Val - Valine
W - Trp - Tryptophan
Y - Tyr - Tyrosine


Amino acids exist in either D (dextro) or L (levo) form. Most of the amino acids found in nature (and all within human cells) are of the L-form. As a generality all amino acids except glycine have a mirror image of the L-form. This mirror image is called the D-form. It is common when referring to the L-form (naturally occurring form) to leave off the "L" designation whereas the "D" designation is always explicitly written.

D-amino acids are found naturally in bacterial cell walls and used in some synthetic peptides to make a peptide more stable or more resistant to degradation.

Amino Acid + Amino Acid = Peptide

The amino acids are joined together by what is known as a "peptide bond". A "peptide bond" is a linkage in which the nitrogen atom of one amino acid (from the amino group (NH2) binds to the carbon atom of another amino acid's carboxyl group (COOH).

During this binding process a molecule of water is released. This is called a condensation reaction.

The resulting CO-NH bond is called a peptide bond, and the resulting molecule is called an amide.

On the following image note that the COOH group gives up an Oxygen Hydrogen (OH) bond and the NH2 group gives up a Hydrogen (H). This forms H2O, which is a water molecule which is not part of the newly created peptide. NOTE: in the following image the C (carbon) symbol is missing as it is assumed so I indicate it with a blue square.




This reaction creating a peptide bond between two amino acids creates a peptide. We can call this peptide (made up of two amino acids) a dipeptide.

This process can be repeated using the twenty amino acids as raw material to create longer peptide chains. Sometimes peptide chains consisting of fifty to 100 amino acids are called polypeptides. Often a peptide chain beyond 100 amino acids is called a protein.

GHRP-6 is a peptide made up of just six amino acids. It's structure is often written as His-DTrp-Ala-Trp-DPhe-Lys-NH2

Note that the Carboxyl grouping (COOH) is assumed in the first position and is usually not written. The amino group (NH2) is wrtitten in the last position. The "meat" or the part that makes GHRP-6 distinct is the seqence in the middle of histadine bonded to the "D" form of Tryptophan bonded to Alanine bonded to Tryptophan bonded to the "D" form of Phenylalanine bonded to Lysine.

Pepdide bonds are formed by water (H2O) condensation (removing water). The converse is also true. A peptide bond can be broken down by hydrolysis (adding water).

The Amino Acid Structures of Peptides discussed in this thread

Growth Hormone Releasing peptides (GHRPs) (GH pulse initiators):

- GHRP-6 (His-DTrp-Ala-Trp-DPhe-Lys-NH2)

- GHRP-2 (DAla-D-2-Nal-Ala-Trp-DPhe-Lys-NH2)

- Hexarelin (His-D-2-methyl-Trp-Ala-Trp-DPhe-Lys-NH2)

- Ipamorelin (Aib-His-D-2-Nal-DPhe-Lys-NH2) - Ref-1

NOTES:
Aib = Aminoisobutyryc acid
D-2-Nal = "D" form of 2’-naphthylalanine
Growth Hormone Releasing Hormone (GHRH) (amplifies the GHRP initiated pulse):

- Growth Hormone Releasing Hormone (GHRH) aka GRF(1-44) (Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2) = half-life "less then 10 minutes", perhaps as low as 5 minutes. - Ref-2


- GRF(1-29) aka Sermorelin (Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2) - the biologically active portion of the 44 amino acid GHRH = half-life "less then 10 minutes", perhaps as low as 5 minutes. - Ref-3


- Longer-lasting analogs of GRF(1-29):

-- replace the 2nd amino acid Alanine w/ D-Alanine only to modify GRF(1-29), D-Ala2 GRF(1-29) (Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2) = half-life "closer to 10 minutes" - Ref-4


-- replace the 2nd, 8th, 15th & 27th amino acids & get modified GRF(1-29) or CJC-1295 w/o the DAC (i.e. the part that will bind to albumin & make the half-life days) (Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2) = Half-life at least 30 minutes or so - Ref-5

-- CJC-1295 (Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-Lys-(Maleimidopropionyl)-NH2) = Half-life measured in days, - Ref-6
NOTES:
Lys = linker to the Drug Affinity Complex (aka (Maleimidopropionyl))
"Since GH is released in a pulsatile manner and a higher level of GH is observed between 15 and 30 min after subcutaneous administration of GH-RH analogues, hydrolysis by trypsin-like enzymes could not affect the result of stimulation." - Potent Trypsin-resistant hGH-RH Analogues, JAN IZDEBSKI, J. Peptide Sci. 10: 524–529 (2004)
The analog in the above quoted study resisted degradation for 30 minutes. The quote implies that if your analog can last 30 minutes it has tapped out the potential for a single pulse.

Since another pulse won't be generated for about 2.5 - 3 hours analogs that last more than 30 minutes up to 3 hours are not any more beneficial.

You would need an analog that kept growth hormone releasing hormone around beyond 3 hours to have it trigger a second pulse.

Otherwise dosing the 30 minute analog every 3 hours will maximize GH output OR you could just use an analog such as CJC-1295 which lasts for many days and will trigger several GH pulses a day for several days on a single dose.

References:

Ref-1 - "lack of effect on ACTH and cortisol plasma levels" - Ipamorelin, the first selective growth hormone secretagogue , K Raun, European Journal of Endocrinology, 1996 Vol 139, Issue 5, 552-561

Ref-2 - Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus, Frohman LA, J Clin Invest. 1986 78:906–913 and Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-3 - Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive product cleaved at the NH2 terminus, Frohman LA, J Clin Invest. 1986 78:906–913 and Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-4 - Incorporation of D-Ala2 in Growth Hormone-Releasing Hormone-( l-29)-NH2 Increases the Half-Life and Decreases Metabolic Clearance in Normal Men, STEVEN SOULE, Journal of Clinical Endocrinology and Metabolism 1994 Vol. 79, No. 4

Ref-5 - See: Posts within this thread

Ref-6 - See: Posts within this thread
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A Brief Summary of Dosing and Administration

Dosing GHRPs

The saturation dose in most studies on the GHRPs (GHRP-6, GHRP-2, Ipamorelin & Hexarelin) is defined as either 100mcg or 1mcg/kg.

What that means is that 100mcg will saturate the receptors fully, but if you add another 100mcg to that dose only 50% of that portion will be effective. If you add an additional 100mcg to that dose only about 25% will be effective. Perhaps a final 100mcg might add a little something to GH release but that is it.

So 100mcg is the saturation dose and you could add more up to 300 to 400mcg and get a little more effect.

A 500mcg dose will not be more effective then a 400mcg, perhaps not even more effective then 300mcg.

The additional problems are desensitization & cortisol/prolactin side-effects.

Ipamorelin is about as efficacious as GHRP-6 in causing GH release but even at higher dose (above 100mcg) it does not create prolactin or cortisol.

GHRP-6 at the saturation dose 100mcg does not really increase prolactin & cortisol but may do so slightly at higher doses. This rise is still within the normal range.

GHRP-2 is a little more efficacious then GHRP-6 at causing GH release but at the saturation dose or higher may produce a slight to moderate increase in prolactin & cortisol. This rise is still within the normal range although doses of 200 - 400mcg might make it the high end of the normal range.

Hexarelin is the most efficacious of all of the GHRPs at causing an increase in GH release. However it has the highest potential to also increase cortisol & prolactin. This rise will occur even at the 100mcg saturation dose. This rise will reach the higher levels of what is defined as normal.
Desensitization

GHRP-6 can be used at saturation dose (100mcg) three or four times a day without risk of desensitization.

GHRP-2 probably at saturation dose several times a day will not result in desensitization.

Hexarelin has been shown to bring about desensitization but in a long-term study the pituitary recovered its sensitivity so that there was not long-term loss of sensitivity at saturation dose. However dosing Hexarelin even at 100mcg three times a day will likely lead to some down regulation within 14 days.

If desensitization were to ever occur for any of these GHRPs simply stopping use for several days will remedy this effect.

Chronic use of GHRP-6 at 100mcg dosed several times a day every day will not cause pituitary problems, nor significant prolactin or cortisol problems, nor desensitize.

GHRH

Now Sermorelin, GHRH (1-44) and GRF(1-29) all are basically GHRH and have a short half-life in plasma because of quick cleavage between the 2nd & 3rd amino acid. This is no worry naturally because this hormone is secreted from the hypothalamus and travels a short distance to the underlying anterior pituitary and is not really subject to enzymatic cleavage. The release from the hypothalamus and binding to somatotrophs (pituitary cells) happens quickly.

However when injected into the body it must circulate before finding its way to the pituitary and so within 3 minutes it is already being degraded.

That is why GHRH in the above forms must be dosed high to get an effect.

GHRH analogs

All GHRH analogs swap Alanine at the 2nd position for D-Alanine which makes the peptide resistant to quick cleavage at that position. This means analogs will be more effective when injected at smaller dosing.

The analog tetra or 4 substituted GRF(1-29) sometimes called CJC w/o the DAC or referred to by me as modified GRF(1-29) has other amino acid modifications. They are a glutamine (Gln or Q) at the 8-position, alanine (Ala or A) at the 15-position, and a leucine (Leu or L) at the 27-position.

The alanine at the 8th position enhances bioavailability but the other two amino substitutions are made to enhance the manufacturing process (i.e. create manufacturing stability).

For use in vivo, in humans, the GHRH analog known as CJC w/o the DAC or tetra (4) substituted GRF(1-29) or modified GRF(1-29) is a very effective peptide with a half-life probably 30+ minutes.

That is long enough to be completely effective.

The saturation dose is also defined as 100mcg.

Problem w/ Using any GHRH alone

The problem with using a GHRH even the stronger analogs is that they are only highly effective when somatostatin is low (the GH inhibiting hormone). So if you unluckily administer in a trough (or when a GH pulse is not naturally occurring) you will add very little GH release. If however you luckily administer during a rising wave or GH pulse (somatostatin will not be active at this point) you will add to GH release.

Solution is GHRP + GHRH analog

The solution is simple and highly effective. You administer a GHRH analog with a GHRP. The GHRP creates a pulse of GH. It does this through several mechanisms. One mechanism is the reduction of somatostatin release from the hypothalamus, another is a reduction of somatostatin influence at the pituitary, still another is increased release of GHRH from the brain and finally GHRPs act on the same pituitary cells (somatotrophs) as do GHRHs but use a different mechanism to increase cAMP formation which will further cause GH release from somatotroph stores.

GHRH also has a way of reciprocally reinforcing GHRPs action.

The result is a synergistic GH release.

The GH is not additive it is synergistic. By that I mean:

If GHRH by itself will cause a GH release valued at 2
and GHRP itself will cause a GH release valued at 5

Together the GH is not 7 (5+2) it turns out to say 16!
A solid protocol

A solid protocol would be to use a GHRP + a GHRH analog pre-bed (to support the nightime pulse) and once or twice throughout the day.

For anti-aging, deep restful restorative sleep, the once at night dosing is all you need. For an adult aged 40+ it is enough to restore GH to youthful levels.

However for bodybuilding or fatloss or injury repair multiple dosings can be effective.

The GHRH analog can be used at 100mcg and as high as you want without problems.

The GHRP-6 can always be used at 100mcg w/o problems but a dose of 200mcg will probably be fine as well.

Again desensitization is something to keep an eye on particularly with the highest doses of GHRP-2 and all doses of Hexarelin.

So 100 - 200mcg of GHRP-6 + 100 - 500mcg+ of a GHRH analog taken together will be effective.
This may be dosed several times a day to be highly effective.

A solid approach is a bit more conservative at 100mcg of GHRP-6 + 100mcg of a GHRH analog dosed either once, twice, three or four times a day.
When dosing multiple times a day at least 3 hours should separate the administrations.

The difference is once a day dosing pre-bed will give a youthful restorative amount of GH while multiple dosing and or higher levels will give higher GH & IGF-1 levels when coupled with diet & exercise will lead to muscle gain & fatloss.

Dose w/o food

Administration should ideally be done on either an empty stomach or with only protein in the stomach. Fats & carbs blunt GH release. So administer the peptides and wait about 20 minutes (no more then 30 but no less then 15 minutes) to eat. AT that point the GH pulse has about hit the peak and you can eat what you want.
 
cjc

Restoring Growth Hormone
"It has been argued that the age-dependent decline in coïtus steroid, Growth Hormone, and IGF-I production is nature’s way of protecting us from cancer and heart disease, but a far more likely scenario is that once we reach our reproductive capacity, nature begins programming us for death."- Roy G. Smith, Ph.D. Director, Huffington Center on Aging; Professor, Department of Molecular & Cellular Biology; former Vice President for Basic Research at Merck Research Laboratories, Merck & Co
Such programming begins as the second decade of life draws to a close, the negative consequences of which become more noticeable with each passing year.

We begin to experience a steady decline in immune function. (1,2) Our bodies increase production of glucocorticoids (catabolic hormones) and cytokines (inflammatory) which negatively impact metabolism, bone density, strength, exercise tolerance, cognitive function, and mood. (3,4–8)

The hormones of coïtus, dehydroepiandrosterone (DHEA), Growth Hormone (GH), and Insulin-like Growth Factor (IGF-1) are positively correlated with the health and well-being of the body in general and the specific functioning of metabolism, the cardiovascular system, the musculature skeletal system, cognitive function & the immune system. However these hormonal levels naturally decline as we age and as a consequence those systems necessary to maintain optimal health decline as well. (1-4,9)

"Hence, if we wish to maintain quality of life during aging we must oppose nature." - Roy G. Smith, Ph.D.
A progressive decline in lean body mass, atrophy of its component organs & reduction in their function and increased deposition of adipose tissue mass characteristic of the aging human body result partially from the body's diminished secretion of growth hormone. (10-13) These negative changes resulting from growth hormone deficiency have been shown to be reversible by replacement doses of growth hormone. (14-21)

Growth Hormone is a vital anabolic hormone whose positive stimulatory effects on protein synthesis (particularly in the liver, muscle, bone, cartlidge, spleen, kidney, skin, thymus, and red blood cells) and on lipolysis (the breakdown of fat stored in fat cells) contributes greatly to growth, repair & well-being. (10)

Growth Hormone (GH) secretion is primarily regulated by the release of two peptides, Growth Hormone-Releasing Hormone (GHRH) and Somatostatin. The hypothalamus region of the brain releases these hormones in response to signals from the central nervous system. GHRH once released makes its way to the receptors on the somatotrope cells of the pituitary gland below the brain where it stimulates Growth Hormone release.

Somatostatin once released makes its way to the receptors on the somatotrope cells of the pituitary gland below the brain where it inhibits Growth Hormone release. (15)

The primary physiological action of somatostatin is to inhibit synthesis and release of GH. (16-19) The primary physiological action of Growth Hormone-Releasing Hormone (GHRH) is to stimulate synthesis and release of GH.

The end product of this cascade, Growth Hormone (GH) once secreted exerts its effect in the body as a whole both directly and indirectly through its initiation of Insulin-like Growth Factor (IGF-1) synthesis in the liver. IGF-1 in turn exerts its effect in the body and its rise in turn begins to inhibit any further GH release.



Growth Hormone (GH) is released periodically within the body in a controlled pulsating fashion. This periodic pattern plays an important role in transmitting the GH "growth, repair & well-being" message to tissue. A review of several studies involving GH replacement in GH-deficient animals reveals the biological significance of episodic secretion. These studies conclude that GH released in a pulsatile pattern is far more efficient in improving mammalian growth and repair than the method of GH administration by constant infusion.

In males GH pulses occur approximately every three (3) hours, a frequency that appears across most mammals. The secretion bursts are preceded and followed by almost undetectable levels of plasma GH.

In females however GH pulses occur more frequently and the base level of plasma GH remains higher than males who have fewer GH pulses but the amplitude of which are more pronounced.

GH pulse amplitudes are increased during slow wave sleep such that particularly in males, most GH secretion occurs at night. (22)

Growth Hormone secretion is highest during the growing years of youth and early adulthood. In humans the secretion rate starts to noticeably decrease during the third decade of life and strongly decreases during the fourth decade of life. As we age the daytime secretory pulses diminish first, while the sleep associated GH pulse persists and diminishes gradually.


Nudging Nature

Growth Hormone levels may be increased either by exogenically administering Growth Hormone or by administering Growth Hormone-Releasing Hormone which then endogenically stimulates the somatrope cells of the pituitary to secrete additional Growth Hormone. The primary advantage of GHRH is that GH ends up being released in physiological conformance to the body’s natural biorhythm. This biorhythm is pulsatile.

Studies have concluded that endogenous Growth Hormone Releasing Hormone (GHRH) is the principal regulator of pulsatile GH secretion in humans and that continuous GHRH infusion augments pulsatile GH release. Whereas exogenic administration of GH raises overall GH levels but has no effect on amplifying the pulses.

People of all ages naturally continue to possess the ability to secrete GH from stores within the pituitary. Most studies are in agreement on this point. One study in particular examined the effects of administration of GHRH & a Growth Hormone Releasing Peptide on all adult age groups from those in their 20's to those above 75 years of age. They observed substantial increases in GH release as a direct result of administration of GHRH & GHRP-6. This prompted them to conclude, "...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." (23)


Long-lasting GHRH analog CJC-1295

While the studies have demonstrated repeatedly that administration of GHRH does increase GH secretion and amplifies the release pulse there does remain a significant drawback. GHRH has a very short half life, measured in minutes with a fairly short clearance rate measured in hours. (24) While this is a sufficient amount of time to exert a positive effect on GH secretion, particularly if GHRH is administered multiple times a day, the result is less than optimal. (25,26)

It is for this reason that longer-lasting analogs of GHRH were researched and developed. (28) The most effective of which is CJC-1295.

Exposure of native GHRH to blood plasma results in rapid degradation. CJC-1295, a synthetic human GHRH analog avoids rapid degradation by possessing the ability to selectively and covalently bind to endogenous albumin after subcutaneous administration. Albumin possesses a half-life of 19 days in humans and so modified GHRH bound to albumin greatly extends its half-life and duration of action. (27)



In a recent (2006) study "Prolonged Stimulation of Growth Hormone (GH) and Insulin-Like Growth Factor I Secretion by CJC-1295, a Long-Acting Analog of GH-Releasing Hormone, in Healthy Adults", Sam L. Teichman, et al. Journal of Clinical Endocrinology & Metabolism 91(3):799-805, CJC-1295 was found to result in "sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30mcg/kg or 60 mcg/kg."

It has been demonstrated repeatedly in various studies that GHRH is effective at instigating GH release and longer acting analogs do increase the overall effectiveness. So it is no surprise that the results of this CJC-1295 study comport with what has been previously demonstrated.

What was unknown was what effect persistent elevation of GH by a long-lasting GHRH analog would have on the pulsatility of release. This was explored in a follow up study, "Pulsatile Secretion of Growth Hormone (GH) Persists during Continuous Stimulation by CJC-1295, a Long- Acting GH-Releasing Hormone Analog", Madalina Ionescu, et al. The Journal of Clinical Endocrinology & Metabolism 91(12):4792-4797.

That study found that pulsatility was not interfered with and was in fact preserved in all subjects both immediately after administration and continuing 7 days post-administration.

This is obviously a very beneficial characteristic to preserve. In fact episodic release appears to be imperative to growth and repair of tissue in mammals.

The study further found that while growth hormone secretion was increased by almost fifty percent there was no increase in pulse amplitude or frequency. All of the increase came from a substantial elevation of trough levels with preserved pulsatility.

One further note of interest is that study participants were all of young age with lower lean body masses which may indicate that GHRH in the form of CJC-1295 is an effective avenue for growth hormone release for those of young age.



The results of the study charted above show that administration of single doses of CJC-1295 remained in high concentration for 7 days with measurable concentration for 14 subsequent days. (29)

As seen in the chart below this resulted in substantial increases in mean serum GH levels in all dosing groups, which were dose incremental and persisted for up to 7 days.



As seen in the chart below this chronic elevation in CJC-1295 levels resulted in substantial increases in mean serum IGF-1 levels in all dosing groups, which were dose incremental and persisted for up to 7 days.



The results from a toxicology study wherein 50mcg/kg of CJC-1295 was administered subcutaneously to monkeys for a period of six months found no ill effects and no indication of presence of neutralizing antibodies. They concluded that the Drug Affinity Complex (DAC) a technology that enables covalent binding (conjugation) of a drug to albumin produced no evidence of immunogenic or immunotoxic effects in monkeys. (30)

In summary, although the added Drug Affinity Complex adds complexity and increases the expense of CJC-1295 peptide synthesis, it does add tremendously to both the dosing convenience and the biological activity of GHRH without any identifiable adverse toxicity.

References:

1 - Hadden JW, Malec PH, Coto J, Hadden EM 1992 Thymic involution in aging. Prospects for correction. Ann NY Acad Sci 673: 231–239

2 - Mackall CL, Gress RE 1997 Thymic aging and T-cell regeneration. Immunol Rev 160:91–102

3 - Ershler WB, Keller ET 2000 Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270

4 - van Eekelen JA, Rots NY, Sutanto W, de Kloet ER 1992 The effect of aging on stress responsiveness and central corticosteroid receptors in the brown Norway rat. Neurobiol Aging 13:159–170

5 - Martignoni E, Costa A, Sinforiani E, Liuzzi A, Chiodini P, MauriM, Bono G, Nappi G 1992 The brain as a target for adrenocortical steroids: cognitive implications. Psychoneuroendocrinology 17: 343–354

6 - Liu J, Mori A 1999 Stress, aging, and brain oxidative damage. Neurochem Res 24:1479–1497

7 - Sapolsky R, Armanini M, Packan D, TombaughG1987 Stress and glucocorticoids in aging. Endocrinol Metab Clin North Am 16:965– 980

8 - Heffelfinger AK, Newcomer JW 2001 Glucocorticoid effects on memory function over the human life span. Dev Psychopathol 13:491–513

9 - Murialdo G, Barreca A, Nobili F, Rollero A, Timossi G, Gianelli MV, Copello F, Rodriguez G, Polleri A 2001 Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia. J Endocrinol Invest 24:139–146

10 - Rudman D. Growth hormone, body composition, and aging. J Am Geriatr Soc 1985; 33:800-7.

11 - Meites J. Neuroendocrine biomarkers of aging in the rat. Exp Gerontol 1988; 23:349-58.

12 - Finkelstein JW, Boyar RM, Roffwarg HP, Kream J, Hellman L. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972; 35:665-70.

13 - Rudman D, K*tner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest 1981; 67:1361-9.

14 - van Buul-Offers S, Van den Brande JL. The growth of different organs of normal and dwarfed Snell mice, before and during growth hormone therapy. Acta Endocrinol 1981; 96:46-58.

15 - Parra A, Argote RM, Garcia G, Cervantes C, Alatorre S, Perez-Pasten E. Body composition in hypopituitary dwarfs before and during human growth hormone therapy. Metabolism 1979; 28:851-7.

16 - van der Werff ten Bosch JJ, Bot A. Effects of human pituitary growth hormone on body composition. Neth J Med 1987; 30:220-7.

17 - Crist DM, Peake GT, Mackinnon LT, Sibbitt WL Jr, Kraner JC. Exogenous growth hormone treatment alters body composition and increases natural killer cell activity in women with impaired endogenous growth hormone secretion. Metabolism 1987; 36:1115-7.

18 - Jorgensen JOL, Pedersen SA, Thuesen L, et al Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1989; 1:1221-5.

19 - Crist DM, Peake GT, Egan PA, Waters DL. Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol 1988; 65:579-84.

20 - Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321:1797- 803.

21 - Jones AJS, O’Connor JV. Chemical characterization of methionyl human growth hormone. In: Hormone drugs: proceedings of the FDA–USP Workshop on Drug and Reference Standards for Insulins, Somatropins, and Thyroid- axis Hormones, Bethesda, Maryland, May 19–21, 1982.

22 - Holl RW, Hartman ML, Veldhuis JD, et al. Thirty-second sampling of plasma growth hormone in man: correlation with sleep stages. J Clin Endocrinol Metab 1991;72:854–61.

23 - Micic D, et al. 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. J Clin Endocrinol Metab. 1998 Jul;83(7):2569-72

24 - Frohman LA, Downs TR, Williams TC, Heimer EP, Pan YCE, and Felix AM. Rapid enzymatic degradation of growth hormone-releasing hormone by plasma in vitro and in vivo to a biologically inactive, N-terminally cleaved product. J Clin Invest 78: 906–913, 1986.

25 - Iordanova VK, Wen SY, Moreau IA, Smith SY, Frohman LA, and Castaigne JP. Every other day subcutaneous administration of CJC-1295, a drug affinity complex (DAC)-growth hormone releasing factor (GRF) analogue, increases body weight and bone mineral content in dogs (Abstract). 87th Annual Meeting of The Endocrine Society, 2005, p. P1–78.

26 - Jette L, Leger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, and Bridon DP. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology 146: 3052–3058, 2005.

27 - Peters JRT. All About Albumin. Biochemistry, Genetics and Medical Applications. San Diego, CA: Academic, 1996.

28 - Hoffman, Andrew R., et al. Efficacy of a Long-Acting Growth Hormone (GH) Preparation in Patients with Adult GH Deficiency. J Clin Endocrinol Metab 90(12):6431–6440

29 - Teichman SL, Neale A, Lawrence B, Cagnon C, Castaigne JP, and Frohman LA. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab 91: 799–805, 2006.

30 – Wen, S. et al. Immunogenicity AND Immunotoxicity Assessments of Two Drug Affinity Complexe Compounds in Cynomogus Monkeys. Toxicologist, Report 170, 2005.
 
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Basic Guide: Growth Hormone Secretagogues

Growth Hormone Secretagogues


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")
Opiates (Dermorphin & Benzomorphan)
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).

However when the Opiate was combined with GHRH & GHRP the synergy was huge amounting to a release of GH more than double that achieved by the GHRH/GHRP combo alone.



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.

Unfortunately opiates have several drawbacks. Not withstanding their illegality chronic use is both toxic and addicting with undesirable alterations in normal physiology.

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).

NOTE: The information presented in this section was drawn generally from Refs: 1-11



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.

NOTE: The information presented in this section was drawn generally from Ref: 12


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.

NOTE: The information presented in this section was drawn generally from Refs: All of the Bower's studies



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.

NOTE: The information presented in this section was drawn generally from Refs: 13-17



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.

NOTE: The information presented in this section was drawn generally from Refs: 13-5, 9, 18
 
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Why you need both GHRH analog (CJC-1295) and GHRP

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 graphed out above 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.

NOTE: The information presented in this section was drawn generally from Refs: 32-37



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.
 
Laatst bewerkt:
Growth Hormone Administration vs. CJC-1295/GHRP-6 + GHRH

Units of Measurement

Growth Hormone (GH) like other biologically active substances is measured in International Units (abbreviated as IU) which are based on the measured biological activity for that substance the establishment of which is determined by international agreement. International Units are specific to each substance and so one IU of one substance has no equivalence to one IU of another substance.

While it is fairly straightforward to compare the amount of GH among various dosing administrations (a two (2) iu dose is twice the amount of a four (4) iu dose) and it is easy to ask the manufacture the weight of each iu (Nutropin reveals that 1 iu of their GH is equal to 333 mcg while Lilly's Humatrope trials define 1 iu as 370 mcg (2.7iu per 1mg)) it is not so simple to compare Growth Hormone to other "Growth Hormone Releasing" compounds such as CJC-1295 and GHRP-6.

Practically all studies that use Growth Hormone (GH) or Growth Hormone Releasing Hormone (GHRH) or its analog CJC-1295 or Growth Hormone Releasing Peptides all take blood samples to measure the amount of GH present in blood plasma at various points in time. The unit of measurement is a standardized unit which can be used to make comparisons across different compounds.

The studies either report results as "nanograms (ng) per milliliter (ml)" or "micrograms (ug) per liter (L)". For the reason that ng = 1/1000 ug and ml = 1/1000 L, ng/ml will always equal ug/L. So no matter how the studies report results comparison is straightforward. In making the cross-comparisons contained herein for simplicity I have chosen to report results as ng/ml.

In addition the amount of hormone released into plasma (i.e. concentration) is based on units divided by time. This measurement is called area under the curve (AUC). However some studies will use the hour as the unit of time while others will use the minute. Therefore comparing AUCs between studies using different units of time requires a conversion to a common unit of time.

I will make the conversion herein in written form but be careful when you look at graphs.

Therefore this examination will look to several studies involving administration of the compounds of interest and compare the blood plasma levels of GH and peak concentration as a result of administration of each tested compound. The result of this cross-study examination will reveal the efficaciousness of various doses of GH, CJC-1295 and GHRH + GHRP-6 in increasing GH in blood plasma.


Studies used for comparison

Growth Hormone Administration

The primary study used herein is the Lilly Clinical trial using single dose administration of Humatrope in normal adults to assess pharmacokinetics. The doses used were .05 IU/kg (intravenously) and .27iu/kg (subcutaneously and intramuscular). In an 80kg adult that equates to 4iu and about 22iu. In our comparison we will only look at the 22iu subcutaneous and intramuscular dose.


CJC-1295 Administration

In "Prolonged Stimulation of Growth Hormone (GH) and Insulin-Like Growth Factor I Secretion by CJC-1295, a Long-Acting Analog of GH-Releasing Hormone, in Healthy Adults", Sam L. Teichman, et al. Journal of Clinical Endocrinology & Metabolism 91(3):799-805, sixty-six healthy normal men and women aged 21-61 were administered various doses of CJC-1295 (long-lasting GHRH analog). The CJC-1295 was administered in a single dose and again in some groups 7 days later and other groups 14 days later. For the reason that we are only examining a week's worth of data only the initial dose is of interest. Blood samples were collected before dosing and then at 15, 30, and 60 minutes and 2, 3, 4, 6, 8, 10, 12, and 24 hours afterdosing; and then every 8 hours on days 2–3, then daily on days 4, 5, 6, 7.

The doses administered were: 30mcg/kg; 60mcg/kg; 125mcg/kg; 250mcg/kg

GHRH + GHRP-6 Administration

While we are limited in our choice of GH administration studies and CJC-1295 studies (there are only two, the results of which are available to the public) we have many available studies measuring the effects of co-administration of GHRH and GHRPs.

So we will briefly look at the results from two studies to give us an idea of how much GH release is contributed by the enhanced pulse brought on by this synergistic combination.

They are, "Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome", Alfonso Leal-Cerro, et al., Clinical Endocrinology 1994, 41 (5) , 649–654

and

"Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone", Bowers, C.Y., et al. J. Clin. Endocrinol. Metab. 70, 975–982.


What's Normal?

Before we look at the studies lets take a brief look at how much growth hormone (GH) is secreted naturally.

The following very comprehensive study measured growth hormone output over twenty-four hours among healthy normal people of all ages.


Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship With Growth Hormone and Cortisol Levels in Healthy Men, Eve Van Cauter, PhD; Rachel Leproult, MS; Laurence Plat, MD, JAMA. 2000; 284:861-868

The youngest category, those under 25 years of age secrete about 2iu of GH per 24 hours, while those in older categories sectrete 1 iu or less.

Note that Humatrope indicates that absolute bioavailability of an intramuscular or subcutaneous dose is about 66%. So perhaps 3iu of exogenously administered synthetic GH is a replacement dose equivalent to 2iu of indogenously secreted GH.
 
Laatst bewerkt:
Comparing GH administration to CJC-1295 administration

Total GH Release:

When CJC-1295 was administered at 30mcg/kg; 60mcg/kg; 125mcg/kg and 250mcg/kg the total GH levels (area under the curve (AUC)) were respectively:

AUC: 758, 969, 977, and 1370 ng/ml per hour




Keep in mind that for a 80kg adult the 30mcg/kg dosing amounts to 2.4mgs of CJC-1295 per week and the 60mcg/kg dosing amounts to 4.8mgs of CJC-1295.

So 2.4 mgs of CJC-1295 produced an AUC of 758 ng/ml per hour.

When synthetic Growth Hormone (Humatrope) was administered at the equivalent of 22iu (in someone weighing 80+ kg) the following GH levels (area under the curve (AUC)) were reached:

AUC Intramuscular: 495 +/- 106

AUC Subcutaneous: 585 +/- 90



Peak Concentration:

However the GH release pattern results in a much higher mean maximum concentration for the GH administration than the CJC-1295 administration.

The GH study resulted in peaks of 53 to 63 ng/ml.

The CJC-1295 study resulted in dose respected peaks of 6.6; 9.6; 9.9; 13.3 ng/ml.
 
Laatst bewerkt:
Comparing GH administration to GHRP + GHRH administration

Total GH Release:

The Alfonso Leal-Cerro study demonstrated the following GH release:

GHRH by itself dosed at 100mcg resulted in:
(AUC) 120 minutes = 1420 * 330 ng/ml when we convert that to AUC measued in hours we get about: 25 ng/ml

GHRP-6 by itself dosed at 100mcg resulted in:
(AUC) 120 minutes = 2278 * 290 ng/ml when we convert that to AUC measued in hours we get about: 40 ng/ml

GHRH + GHRP-6 dosed together at 100mcg each resulted in:
(AUC) 120 minutes = 7332 * 592 ng/ml when we convert that to AUC measued in hours we get about: 130 ng/ml
The Bowers study demonstrated that a small dose of GHRP (.1mcg/kg) added to a saturation dose of GHRH (1mcg/kg) resulted in the following GH release:

(AUC) 120 minutes = 10,065 ng/ml when we convert that to AUC measued in hours we get about: 170 ng/ml

In comparison to synthetic GH administration we find that:

22iu of synthetic GH results in 495 - 585 ng/ml
Saturation doses of GHRH & GHRP results in 130 - 170 ng/ml

These results indicate that 22iu is between 3.8 and 3.4 more efficacious then a single administration of GHRH & GHRP which means that a single dose of GHRH & GHRP has the potential to produce better then the equivalent of 5iu of GH in plasma.

A dosing protocol of GHRH + GHRP at saturation dose, administered 3 times per day has the potential to exceed the equivalent of 15iu.

Note though that using this methodology GHRP-6 at a saturation dose by itself may add the equivalent of 1.4 to 1.8 iu per administration... or 4.2 to 5.4 iu per day if administered three times.


Peak Concentration:

From the graphs it is easy to see that GHRH+GHRP results in short-term peaks of 80 to 130 ng/ml.

While the synthetic GH study resulted in less pronounced peaks of 53 to 63 ng/ml of longer duration.



Systemic IGF-1 levels

Simply stated the synthetic Growth Hormone when administered intramuscularly or subcutaneously in high enough dose results in a release profile that is not pulsatile. The release profile is an elevation and this elevation results in higher levels of systemic IGF-1 in circulation then either an intravenous administration of GH or administration of the pulsatile peptides.

While multiple daily dosings of GHRH/GHRP result in a significant rise in systemic IGF-1 (not graphed out here) they do not over time result in as substantial an elevation of circulating IGF-1 as synthetic GH administered non-intravenously.

To understand the difference in GH in plasma profile of synthetic GH administered by intravenous I provide a copy of the GH study graph identical to the clinical study graph posted above with the addition of the intravenous dosing of GH. As you can see intravenous dosing of GH results in what could be described as a pulse because GH is elevated very high and then clears quickly.



So what does a high dose of synthetic GH administered subcutaneously or intramuscularly (but not by IV) do to systemic levels of IGF-1?

To find out we must switch to a Japanese study which undertook such study.

In Pharmacokinetics and Metabolic Effects of High-Dose Growth Hormone Administration in Healthy Adult Men, Toshiaki Tanaka, et al., Endocrine Journal 1999, 46 (4), 605-612, fifteen healthy normal Japanese adult males aged from 20 to 27 years were administered various doses of recombinant GH (Norditropin). The GH was administered in a single dose at 9:00 a.m. after overnight fasting. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 9, 12 and 24 hours after the single injection.

The doses administered were: .075iu/kg; .15iu/kg and .30iu/kg
When the average weight of each test subject is accounted for the doses administered approximated: 5iu; 10iu and 20iu

In the higher dose category the study dosed every day for a week and collected blood samples each day.

IGF-1 levels were measured and can be graphed as follows:



From this graph a few quick things can clearly be understood:

IGF-1 creation is a slow ongoing process that increases every day that you administer GH until it plateaus after a week. This should tell you that there is no fear that anything will specifically interfere with GH's ability to instigate IGF-1 creation. All of the timing protocols which fear that insulin or "this and that" will interfere with IGF-1 creation are baseless and such "write-ups" that call for timing are flawed.
It is constant GH elevations that result in ever higher levels of systemic IGF-1 creation

What none of this tells us

This does not tell us what is happening locally. By locally I mean IGF-1 that is not made in the liver and circulated systemically. Local IGFs are made in small amounts and used exclusively in the tissue of their birth.

Local IGF-1 in muscle has been demonstrated to be responsible for muscle growth and only if muscle-made IGF-1 is lacking does systemic IGF-1 play a significant (although incomplete) role.

Local IGFs in muscle are increased by growth hormone and testosterone. It is conjectured that pulsatile GH (such as IV dosing) or the use of GHRH/GHRPs results in high levels of muscle IGFs w/o creating high levels of systemic circulating IGFs.

If this proves to be true then that would be an advantage because high systemic levels of IGF-1 are positively correlated w/ cancer and mortality.

More detailed discussions about these sorts of things take place deeper in this thread.
 
Laatst bewerkt:
protocol

But if the study is attempting to maximize the total amount of GH release over a 24 hour period I think they would want both GHRH chronically elevated and several GH pulses amplified.

CJC-1295 chronically elevates GHRH without desensitizing or creating a waning GH release profile. This raises the troughs of GH (i.e. GH remains elevated & consequently so does liver-synthesized IGF-1). Elevated levels of IGF-1 have been shown to contribute to growth.

GHRH + GHRPs administered together synergistically amplify a two hour pulse. Pulsation had been determined to be highly necessary for tissue growth. The studies do show that some GHRPs increasingly exert an effect up to about 400mcg (or 4mcg/kg). However adding more than 100mcg (1mcg/kg) of GHRH did not add to the synergy.

Optimally you could dose 100mcg of CJC-1295 w/ 100-400mcg of GHRP in the morning (on an empty stomach 25 minutes before eating); again in the afternoon/PWO; finally just before bed.

That protocol would create a weekly total of CJC-1295 of 2.1 mgs.

There is benefit to adding more CJC-1295 but this will only increase Base GH levels & IGF-1 levels not pulse amplitude. The CJC-1295 clinical trial demonstrated that the CJC-1295 dose (aprox. 2.1 mgs) could be doubled, tripled even quadrupled and exert ever increasing positive elevations of GH & IGF-1 levels.

It doesn't matter how/when you dose the extra CJC-1295 (i.e. you will dose 100mcg 3x per day w/ GHRP and the remaining CJC-1295 as is convenient).

You could administer the extra CJC-1295 w/ the daily CJC/GHRP doses or twice a week in two large doses.

As non-diseased aging adults our pituitary gland continues to possess the ability to secrete large amounts of GH (well above what is youthfully normal). Obviously there is a limit and this limit is arrived at in part by the negative feedback signals. Optimally dosing GHRH (analog CJC-1295) & GHRPs (GHRP-6, GHRP-2, Hexarelin, Ipamorelin) can likely achieve a GH releasing profile similar to and substitute for mid-high level exogenic dosing of Growth Hormone (GH).

It is probably less then optimal but you could do well just dosing CJC-1295 twice per week and hit GHRP-6 two (2) to three (3) times a day.

A single dose of CJC-1295 "decays" by about 10% a day. So that single dose will follow the "effectiveness" percentages indicated below over the week:
 
goede post Klaassie,

dat CJC zie je de laatste tijd steeds vaker in NL..misschien ook eens proberen haha
 
kost geen drol, maar je moet dr dan ook redelijk wat van nemen.
 
p
wat zijn dan gebruikelijke dosissen?



---------- Toegevoegd om 09:03 ---------- De post hierboven werd geplaatst om 09:02 ----------

[/COLOR]p
wat zijn dan gebruikelijke dosissen?

op us forums lees ik wel vaker dat de dosis 3x100 cjc en 3x100 ghrp6 per dag.
geeft heel goede resultaten.ik las ergens van een kerel waar zijn igf waarde met 280% was gestegen op 5 weken tijd.ze gebruiken er ook huperzine-a bij

hier zijn de resultaten van die kerel
I did get some good news today though. I did a baseline IGF-1 before I started the peptides and my level was 186 ug/L. The normal range on the test is 140 - 410. Today my level came back at 518 ug/L (after 5 weeks of the peptides)! Thats like a 275% increase!
 
Laatst bewerkt:
Nou ik ben nu precies zo bezig met het schema hoe het hierboven wordt omschreven is,het is heftig spul of de combinatie ervan.
Ben nu 1 week bezig zo, een pomp dat wil je niet weten.
heelemaal top gasten.
 
Nou ik ben nu precies zo bezig met het schema hoe het hierboven wordt omschreven is,het is heftig spul of de combinatie ervan.
Ben nu 1 week bezig zo, een pomp dat wil je niet weten.
heelemaal top gasten.

ook ik ben nu 1,5 week bezig en krijg zelfs al carpale tunnelsyndrome.ik slaap als een baby en dromen als een gek....heerlijk spul.
 
Waarom zou je elke dag 3x moeten injecteren als CJC 1295 zo een enorm lange halfwaarde tijd heeft? Of gaat daar puur om de GHRP? Anders zou je met CJC toch 2x per week 1mg kunnen doen en kom je ook aan de 2mg in de week?
 
hoe bewaar je GHRP-6 als je de vloeistof in de vial gedaan heb. ik zet het gewoon in de ijskast en de andere vials (waar nog geen vloeistof bij is) leg ik in de diepvriezer. is dat ok? vermits er 5mg in een vial zit en je tussen 300 en 600mcg per dag gebruikt doe je dus al minstens 9 dagen met een vial. heeft de GHRP dan niet veel van zijn kracht verloren. ik dacht ergens gelezen te hebben dat je het maar een paar dagen kan bijhouden eens de vloeistof erbij is. op trainingsgebied of in de spiegel merk is alleszins niets. ik neem het wel niet voor de training vermits ik 's middags tijdens de pauze ga trainen. wel een bepaald hongergevoel na de inspuiting en mijn kale plekken (allopecia arreata) op mijn hoofd zijn voorlopig ook nog niet teruggekomen. ik weet dat dit een kenmerk van groeihormoon kan zijn. ik ben nu een dag of twintig bezig.
 
ik zie dat nergens staan eigenlijk. mss haal je GHRH en CJC door elkaar ???
 
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