A short look at how we arrived at Ipamorelin

[Stacked]

Growth Hormone Releasers History Leading up to Ipamorelin

GHRH

There are two known hypothalamic hormones, Growth Hormone Releasing Hormone (GHRH) and somatostatin, that are key regulators of Growth Hormone (GH) release from somatotrophs (GH releasing cells) in the pituitary gland; GHRH stimulates GH secretion, and somatostatin inhibits GH secretion.

GHS

In addition to GHRH, a synthetic hexapeptide (6-amino-acid peptide), was created in the late 1970’s by the Bowers’ group and named GHRP-6 (growth hormone releasing peptide (made up of 6 amino acids) 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 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 called "Levo" of an amino acid is the naturally occurring form and often in the nomenclature the "L" is dropped. The "D" form called "Dextro" does not occur in nature and is the isomeric form (i.e. mirror image) of the "L" form.

The structure of GHRP-6 is represented as:

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2​

Investigators later modified the structure of GHRP-6 and identified other GH releasing peptides.

GHRP-1 was created and briefly tested as a peptide with a similar GH release profile. Its structure is represented as:

Ala-His-D2-Nal-Ala-Trp-D-Phe-Lys-NH2​

Investigators modified these structures and found that GH-releasing activity was enhanced by replacing D-Trp of GHRP-6 at the second position with D-2-(2-napthyl)alanine and His of GHRP-6 at the first position with D-alanine to create GHRP-2 whose structure is represented as:

D-Ala-D-2 Nal-Ala-Trp-D-Phe-Lys-NH2​

Through various studies over the years the mechanisms underlying GHRP-6’s actions as a GH releaser were examined. It was established that GHRP-6 acted directly on somatotrophs to cause GH release and to potentiate the effects of GHRH. In contrast to GHRH, which increases cAMP in somatotrophs, GHRP-6 alone had no effect on intracellular cAMP, but when combined with GHRH, the hexapeptide amplified the effects of GHRH on cAMP production. GHRP-6 was subsequently shown to "activate L-type Ca2+ channels, to depolarize the plasma membrane of somatotrophs by inhibiting K+ channels, and behave as a functional antagonist of somatostatin. In contrast to GHRH, which stimulates GH release through the kinase A pathway, GHRP-6 apparently transduced its signal through protein kinase C."

This is how all of the GHRPs work at the pituitary to effect GH release. They modulate GH-release in pulsatile fashion. So in addition to the key regulators GHRH and Somatosatatin we have a third system: "the GH-releasing peptide (GHRP) system".


GHRP-2, GHRP-1, GHRP-6, hexarelin, all elevate plasma GH in humans. All of these GH secretagogues potently release GH and in addition, prolactin (PRL) and cortisol. A molecular derivative of GHRP-6, known as MK-677 appears to effect cortisol indirectly by stimulating adrenocorticotrophin (ACTH). We could say that these GH secretagogues are a little sloppy or that they are not 100% specific effectors of GH release.

GHRH administration in studies in humans causes a slight increase in both ACTH and cortisol. So GHRH is not totally specific for GH release either.


Ipamorelin is a growth hormone releasing peptide that was created by eliminating the Ala-Trp bond found in the middle of GHRP-6, GHRP-2 and GHRP-1. The His-D2-Na at the second and third position of GHRP-1 was used. The Alanine (Ala) common to the GHRPs was replaced with Aib to form a pentapeptide whose structure is represented as:

Aib-His-D-2-Nal-DPhe-Lys-NH2​

Note: Aib = Aminoisobutyryc acid and D-2-Nal = "D" form of 2’-naphthylalanine

Ipamorelin was found to release GH with high potency and efficacy without significant effects on plasma ACTH or cortisol levels or on prolactin. Keep in mind that the main endogenous GH releasing compound, GHRH itself has a slight effect on ACTH and cortisol and that the other GHRPs can have varying effects on ACTH, cortisol and prolactin. Therefore ipamorelin is the most selective GHRP receptor-active GH secretagogue. It is highly specific for GH release and nothing more.

The GH release profile is weaker then GHRP-2 and Hexarelin but compares favorably to GHRP-6.

GHRPs

All of these GHRPs are effective in stimulating growth.

The stimulatory effect on GH release for all the GHRPs is persistent. The GHRPs hexarelin and GHRP-2 have been reported to increase growth velocity in children with short stature/GHD.[SUP]1,2[/SUP]

The GHRPs enhance the amplitude of the physiological GH pulses [SUP]3[/SUP], whereas an s.c. injection of GH induces a bell-shaped curve of serum GH concentrations that are continuously high for more than 12 hours. [SUP]4[/SUP]

It has also been found that 12 weeks of treatment with either ipamorelin or GHRP-6 increased bone mass in young adult female rats.

1 - Laron Z, Frenkel J, Deghenghi R, Anin S, Klinger B & Sibergeld A 1995 Intranasal administration of the GHRP hexarelin accelerates growth in short children. Clinical Endocrinology 43 631–635

2 - Mericq V, Cassorla F, Salazar T, Avila A, Iniguez G, Bowers C & Merriam G 1998 E?ects of eight months treatment with graded doses of a growth hormone (GH)-releasing peptide in GH-de?cient children. Journal of Clinical Endocrinology and Metabolism 83 2355–2360.

3 - Smith R, Van Der Ploeg L, Howard A, Feighner S, Cheng K, Hickey G, Wyvratt MJ, Fischer M, NargundR&Patchett A 1998 Peptidomimetic regulation of growth hormone secretion. Endocrine Reviews 18 621–645

4 Oscarsson J, Johannsson G, Johansson J-O, Lundberg P-A, Lindstedt G & Bengtsson B-Å 1997 Diurnal variation in serum insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations during daily subcutaneous injections of recombinant human growth hormone in GH-de?cient adults. Clinical Endocrinology 46 63–68

5 - Svensson J, The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats, Journal of Endocrinology (2000) 165, 569–577​

 

[gymrat827]

Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2) that displays high GH releasing strength and efficacy in vitro and in vivo. Ipamorelin was established within a group of compounds missing the central dipeptide Ala-Trp of growth hormone-releasing peptide GHRP-1. Ipamorelin is a wonder peptide that is taken 300mcg twice daily or you could lower the dose for 3 times daily, side effects include head pressure and or rushes. It can be taken at any time but taking it about 30-45 minutes before a workout would be great because of the pulse in GH allowing for maximum growth. Taking with your anabolic would be also a great idea because of the obvious effects that they have on GH/IGF release and production.


A study I came upon had an objective of investigating the effects on longitudinal bone growth rate, body weight, and GH release. Ipamorelin in various doses ranging from 0, 18, 90 and 450 μg’s a day; had been injected three times a day for 15 days to test the group’s reactions. After specific labeling procedures, results of days 0, 6, and 13 came in. LGR was determined by measuring the distance between the respective luminous bands in the proximal tibia metaphysis. Ipamorelin dose-dependently raised LGR from 42 μm a day in to 44, 50, and 52 μm a day in the trial groups. There was also a distinct and dose-dependent effect on body weight gain. The treatment of the group did not effect total IGF-I levels, or serum markers of bone development and restoration. Although; the number of tartrate-resistant acid phosphatase cells in the wide portion of the tibia did not change significantly with treatment, which personally in my opinion is a good thing. The reaction of the pituitary to an aggressive i.v. dose of Ipamorelin or GHRH showed that the plasma GH response was notably reduced after Ipamorelin, but unchanged after GHRH. The endogenous pituitary GH content was not down regulated by Ipamorelin treatment. This study clearly demonstrates Ipamorelin is the most selective GH releaser one can use for their GH needs. Like GHRP-2 and unlike GHRP-6 ipamorelin never induces hunger in mammals/humans. Ipamorelin acts synergistically when applied during a native GHRH (growth-hormone releasing hormone) pulse or when taken together with GHRH or a GHRH analog such as Sermorelin or GRF 1-29 which we will touch upon further in the read. The synergy comes from the suppression of somatostatin and the fact that ipamorelin increases GH release per-somatotrope, while GHRH such as CJC-1295 increases the number of somatotropes releasing GH.T hen comes also a derived effect of neuronal excitation in the hypothalamus caused by ipamorelin, which endures for approximately 3 hours after injection; just like GHRP-2 and GHRP-6.


In actual research from another study, Ipamorelin released GH from primary rat pituitary cells with a force and value similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). Another source demonstrated that using GHRP and growth hormone-releasing hormone antagonists clearly demonstrated that Ipamorelin, just as GHRP-6, spikes GH release through a GHRP base receptor.

Another paper demonstrates, within pentobarbital anaesthetized rats, ipamorelin released GH with a strength and value comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). Another document states that in healthy swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. There is a consistency that is very comparable to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed was stronger in its delivery but had a lower value (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). Also note that none of the GH releasers tested affected FSH, LH, PRL or TSH blood serum plasma levels. Note that injections of both GHRP-6 and GHRP-2 resulted in increased plasma levels of Acetylcholine and Cortisol. However, ipamorelin DID NOT release Acetylchloine or Cortisol in levels notabley different from that of GHRP-2 and GHRP-6 post GHRH spike.

This lack of rise on Acetylcholine and Cortisol blood plasma levels was clearly noted even at injections more than 200-fold higher than the ED50 for GH release. Ipamorelin is the first successful GHRP receptor agonist with specific selectivity for GH release similar to that presented by GHRH. The exact selectivity of Ipamorelin makes this compound a vital peptide candidate for future research and peptide utilization. (1)

Ipamorelin doesn’t cause sudden spikes in prolactin nor cortisol like GHRP-2 and GHRP-6 are able to do so. Ipameolin is slow in its delivery unlike GHRP’s which spike GH levels at a more rapid rate. The way I like to think of it is you have Viagra which is faster and more potent at first which also causes more complications, but then you have Ipamerolin which is like cialis in that it takes time to get into the system but lasts longer and is more efficient in its delivery without as much complications due to its smoother transition. It is a ideal for people on calorie restricted intake because it DOES NOT stimulate appetite like GHRP-6 is known to do to an extremity. GHRP-6 at the saturation dose 100mcg will not increase prolactin and cortisol, but it MAYBE could cause a slight rise at really high doses such as 300mcg or more. Ipamorelin does not desensitize its effects as long as there are breaks of around at minimum of 2-3 hours.


The fact that Ipamorelin does not spike cortisol like other GHRP’s is something crucial to note. Cortisol is a catabolic hormone and that means at higher levels it becomes detrimental to muscle. Don’t get me a wrong a healthy level of cortisol is needed just as a healthy level of fat is needed. As with anything coming from an external source, one never knows how their body will respond to an external substance which means that certain GHRP’s will do more harm than good unlike Ipamorelin which does not spike cortisol leading to a favorable testosterone/GH to cortisol ratio.


Prolactin is a testosterone inhibiting hormone which has its role in homeostasis but is clearly a mother’s favorite hormone, or as I like to call it “the caring hormone”. At elevated levels it causes the mammary gland to excrete lactate aka milk, this is why people on tren complain about a gooey substance coming from the nipples. Unlike other GHS’s Ipamorelin will not cause a significant rise in prolactin which could lead to some serious issues especially if one is taking a progestin based cycle. High prolactin has also been associated with a decline in cognitive function which another reason not to over look ipamorelin.