Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

Ipamorelin - Highly Selective

Growth Hormone Stimulant
Ipamorelin
GHS + Ghrelin
GHSR
GH
Ipa functions

Ipamorelin is a synthetic pentapeptide that has growth hormone releasing

properties, acting as a selective agonist of the ghrelin/growth hormone
secretagogue receptor (GHS) (Raun et al. 1998). It has been extensively studied
due to its highly selective action on growth hormone (GH) release (Raun et al.
1998). The Growth hormone secretagogue receptor (GHSR), also known as
ghrelin receptor, was first identified as the target of the growth hormone
secretagogue (GHS)(Howard et al. 1996). Growth hormone secretagogues
stimulate growth hormone release through activation of this specific GPCR
expressed in the somatotrophs of the anterior pituitary gland (Cheng et al. 1991;
McKee et al. 1997). Its endogenous ligand was identified a few years later from
stomach extracts and named ghrelin when Kojima et al. used the Chinese
hamster ovary cell line expressing the rat GHSR to screen various tissue
preparations for the characteristic increase in intracellular calcium
concentrations ([Ca2+]i) induced by the GHSs (Kojima et al. 1999).
GHSRs have many physiological functions including: (1) the release of various
hormones such as growth hormone, adrenocorticotropic hormone, cortisol, and
prolactin (Hosoda et al. 2006); (2) modulation of food intake and energy
metabolism (Sun et al. 2004); (3) influences on glucose and lipid metabolism
(Murray et al. 2005); (4) regulation of gastrointestinal motility and secretion
(Murray et al. 2005), and pancreatic function (Date et al. 2002); (5) regulation of
cell proliferation and survival (Kim et al. 2004); (6) attenuation of
proinflammatory cascades and regulation of immune function that play
important roles in aging and gastrointestinal homeostasis (Smith et al. 2005);
and (7) cell protection in the nervous and the cardiovascular systems (Smith et
al. 2007). Such diversified functions of GHSR suggest the complexity of GHSR-
mediated intracellular signalling pathways (Yin et al. 2014).

The Growth hormone-releasing peptide (GHRP) receptor or growth hormone secretagogue

receptor1a is activated by small synthetic peptide resulting in the release of growth hormone from
the pituitary (Davenport et al., 2005). Almost 20 years ago, ipamorelin was characterized as the
first selective GHRP receptor agonist, showing no significant effect on plasma ACTH and cortisol
levels (Raun et al., 1998). Later, a 28-amino acid peptide isolated from rat stomach was
discovered as the endogenous ligand of the GHS receptor and called ghrelin (Kojima et al.,

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

1999). Endogenous ghrelin is a multifunctional hormone involved in the regulation of appetite,

feeding behavior, and GI motility. Regulation of food intake (Ueno et al., 2005) and stimulation of
gastric motility and secretion (Masuda et al., 2000; Fujino et al., 2003) are among the most
important biological effects of ghrelin. Hence, treatment with ghrelin mimetics or ghrelin could be
of benefit to the patient after abdominal surgery. Preclinical studies in rodent models of
postoperative ileus have shown that both ghrelin and small molecule synthetic agonists of the
GHS receptor accelerate gastric emptying (Trudel et al., 2002; Poitras et al., 2005; Venkova et al.,
2007). Repetitive ipamorelin dosage, a synthetic peptidomimetic that selectively stimulates the
ghrelin receptor and causes growth hormone release (Raun et al., 1998), accelerates
gastrointestinal transit in a rat model of postoperative ileus. The results support the concept that
repetitive intravenous infusions of the GHS receptor agonist ipamorelin could improve
Gastrointestinal motility and support the overall recovery after abdominal surgery. Clinical
development of ipamorelin for the treatment of postoperative ileus is underway.

There are several synthetic peptides that act on the GHS receptor and stimulate
GH release, like Ipamorelin, GHRP-2 and -6 and sermorelin. Ipamorelin functions
mainly through the brain and liver and has been shown to increase in the
production of muscle tissue while creating weight gain that was not fat
dependent, increase bone density, and promote faster recovery from injury. This
is achieved by promoting growth factor release from liver cells leading to
subsequent elevated IGF-1 levels in blood which stimulates systemic body
growth (Fuh & Bach 1998; Beck et al. 2014; Venkova et al. 2009). Growth
hormone secretagogue action of Ipamorelin leads to changes in primary
operation of pituitary gland which has a role in regulating most endocrine system
related processes, including growth and metabolism, pain relief and temperature
regulation.

The growth hormone secretagogue receptor also binds to ghrelin, another

peptide hormone produced by cells in the gastrointestinal tract. Ghrelin secretion
is promoted when the stomach is empty and gastric distension stops the
secretion of Ghrelin (Dornonville de la Cour et al. 2004). Ghrelin acts by inducing
food seeking behaviour and stimulates the motility of the gut to prepare the
body for food intake (Anon 2008). Ghrelin also has receptors in the dopamine
neurons of the so-called cholinergic-dopaminergic reward system, consists of
reward perception (Howick et al. 2017).

The GHSR/GHDP gene encodes the G-protein coupled GHS receptor, which plays a role in energy
homeostasis and regulation of body weight. These two variant transcripts (1 a and 1b) are evolutionary
conserved in fish and swine. The 1a transcript encodes the functional receptor protein for the Ghrelin
ligand and defines a neuroendocrine pathway for growth hormone release. Mutations in this gene are
associated with autosomal idiopathic short stature (Yin et al. 2014).

When it comes to peptides, you are going to want a slow and steady
release for a strong, clean pulse that mimics natural GH release times. This
is going to be better for gains and keeping unwanted side effects down.

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

Ipamorelin acts like a ghrelin mimetic, but, unlike GHRP-6, it has shown to
be more stable in suppressing somatostatin and stimulating GH release.

Ipamorelin - Mode of Action

Ipamorelin has shown to significantly increase plasma growth
hormone (GH) levels in both animals and humans (Raun et al. 1998;
Gobburu et al. 1999; Pietra et al. 2011) by itself.
This is due to both its suppression of somatostatin (an antagonist to
GHRH) and stimulation of release of GH from the anterior pituitary, similar
to GHRP-2 and GHRP-6 which are compounds from the same class (growth
hormone releasing peptides).

Like GHRP-2 and GHRP-6, ipamorelin does not affect prolactin, follicle-
stimulating hormone (FSH), luteinizing hormone (LH), or thyroid-
stimulating hormone (TSH) levels (Raun et al. 1998).
The specificity of Ipamorelin and absence of effect on FSH, LH and
prolactin leads to less chance of gynecomastia in male users.
However, unlike pralmorelin (GHRP-2) and GHRP-6, but similarly to growth
hormone-releasing hormone (GHRH), ipamorelin does not stimulate the
secretion of adrenocorticotropic hormone (ACTH) or cortisol, and is highly
selective for inducing the secretion only of GH (Raun et al. 1998).

Development
Originally, Ipamorelin was developed by Novo Nordisk for the treatment of
paralytic ileus after surgery. Postoperative ileus is the term given to the
cessation of intestinal function following surgery. Although all surgical
procedures put the patient at risk for POI, gastrointestinal tract surgeries
in particular are associated with a temporary cessation of intestinal
function. The duration of POI varies, lasting from a few hours to several
weeks. Prolonged postoperative ileus, also known as pathologic
postoperative ileus, can be caused by a myriad of pathologic processes
that are treated with limited success by clinical and pharmacologic
management
In paralytic ileus, the peristaltic movements of the intestines are
disrupted, and ipamorelin enhances the gut motility as it acts on the same
receptor as Ghrelin, which is responsible for preparing the stomach for
food intake.
Studies in rats comparing the effects of ipamorelin to similar synthetic
peptides have compared the efficacy and potency of this chemical to that
of ghrp-6.
However, studies in swine have found that ipamorelin also affects LF, FHS,
THS and PRL plasma levels, which ghrp based peptides typically do not.
Also unlike ghrp peptides, ipamorelin has not been found to release ACTH
or significantly affect cortisol plasma levels, even at very large
applications.
This makes the reactions and behavior of ipamorelin in test subjects such
as rats and swine increasingly similar to ghrh (Raun et al. 1998).

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

Ipamorelin was identified as lacking the central dipeptide Ala-Trp of growth

hormone-releasing peptide (GHRP)-1.
Several hormonal therapies have been used regulate growth hormones in the
human body so far. Growth Hormone is released by the anterior pituitary and
must flow through the blood stream until it reaches the liver where it is
metabolized and promotes production of IGF-1. IGF-1 in blood acts on target
tissue cells to aid in repair and regeneration.
HGH Human Growth Hormone is a bio-identical hormone, either of recombinant
or cadaveric origin that is administered via injection to enter the blood stream.
Transported by blood to the liver, it stimulates production of IGF-1.
Ipamorelin Ipamorelin, like Sermorelin, is a secretagogue that stimulates the
production of GH in the pituitary and hypothalamus, The difference with
Ipamorelin is that it also stimulates the liver to produce more IGF-1.
Ipamorelin was created by eliminating the Ala-Trp bond found in the middle of the
the other non-selecive GHRPs, and replaced with Aib(Aminoisobutyric acid) GH
release profile is weaker than GHRP-2.
Synergistic action is seen when applied with a native GHRP or another ghrp
analog, through suppression of somatostatin and neuronal excitation of the
hypothalamus, enduring approx. 2-3 after injection, all without affecting LH, FSH ,
PRL and TSH blood plasma levels.

Current Growth Hormone Uses:

Research data suggests benefits of using GH in the frail elderly as well as in
osteoporosis, in catabolic states and wasting conditions, e.g. following surgery.
Convincing effects following GH treatment in obesity have also been reported
(Howick et al. 2017)
Key benefits of this peptide are its ability to increase muscle and bone growth,
relieve pain, better regulate blood pressure. This has led to its widespread use as
a supplement in the bodybuilding industry to gain muscle mass (Jenkins 2001;
Jenkins 1999).
Hexarein came in at the top spot as the most potent GHRP, but it also touted
high side effects and quick desensitization. The other end of the spectrum is
Ipamorelin the mildest GHRP. But dont let its mild characteristics fool you, this
pentapeptide can be used to spur a very large GH pulse that produces the least
amount of side effects. Ipamorelin can easily be ran at 1200mcgs a day without
breaching desensitization levels. Studies have shown that large saturation doses
of Ipamorelin had almost no effect on the bodys natural GH production. This is
ideal for athletes or bodybuilders concerned with shutting down their bodys
natural GH production.

Looking at Ipamorelins functions, it can be said that it is similar to GHRP-6 in the

way of increasing ghrelin and gastric motility, as well as, targeting a selective GH
pulse. Though, the hunger sides on Ipamorelin are virtually zero. This makes it a
much more versatile peptide for before-bed time dosing. Unlike GHRP-6 and
GHRP-2, Ipamorelin was shown at high doses to have almost no direct impact on
cortisol or prolactin production. This means users can dose higher and with
greater frequency without having to be worried about cortisol and acetylcholine

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

blood plasma levels being elevated. In short, it may be the mildest GHRP, but it
is in no way the weakest. In fact, as a GHRP, it has shown to be one of longest
lasting, and, at higher doses, the most potent. Ipamorelins function is a slow
building one that is much more like the bodys natural growth hormone (GH)
release. This makes it the healthiest choice in the bunch!

How does it Work?

After an athlete administers Ipamorelin, a selective pulse is sent that stimulates

the hypothalamus/pituitary to release GH. This pulse can endure for
approximately three hours after injection. Once the GH pulse is sent, the cells go
directly to the muscle to support development while staying clear of any possible
bone or cartilage growth. This is good for Ipamorelin users, as long term usage
will effect lean body muscle growth without the possibility of experiencing any
bone or cartilage deformities. The same cannot be said for synthetic HGH users,
who experience pronounced side effect in swelling joints and even in some cases
Carpel Tunnel. Ipamorelin will increase cell synthesis, elevate secretion levels of
insulin from pancreatic tissue, and increase ghrelin in the stomach which helps
release GH and control hunger. All of these functions work to promote fat loss,
shuttling of nutrients, and building clean muscle mass.

Sides Effects

Even though Ipamorelin is the mildest and safest on sides out of the entire GHRP
family, it still comes with side effects. Ipamorelin targets GH release like GHRP-6,
but you wont find Ipamorelin effecting FSH, PRL, TSH or LH blood serum plasma
levels like GHRP-6 or GHRP-2. That being said, theoretically, at high doses
Ipamorelin could cause an increase of cortisol or acetylcholine. In practice, when
Ipamorelin is the sole GHRP in a cycle, there is hardly any increase in cortisol and
acetylcholine blood plasma levels. This is even true if the injections are much
higher compared to the effective dose for comparable growth hormone release.
So, what are the side effects that can be expected with Ipamorelin? Most users
will find the common side effect of a head rush-like feeling and slight headaches.
It is suggested that users start supplementation at a lower dose and work their
way up. In addition, it is best to inject Ipamorelin 30-45 minutes before working
out so that the user is getting the double benefit of both growth hormones
working together to maximize results.

Dosage and Usage

Ipamorelin, like other peptides, comes as a freeze dried powder that is very
delicate. You can store it in the refrigerator or at room temperature before
reconstituting. Once reconstituted with bacteriostatic water, the vials must be
stored in a cool dry place like your refrigerator. Insulin syringes are the best way
to administer it, usually via subcutaneous injection.

Of course, using iPamorelin with a GHRH like CJC w/out DAC will give the user the
biggest increase in GH and IGF-1 as GHRPs and GHRHs work together
synergetically. The average dosing for Ipamorelin is 200-300mcg two to three
times daily. Twelve week cycles are quite normal and PCT would be very minimal
mini-pct is fine. If prolactin issues ever arise, there are products that help
reduce prolactin and estrogen-like symptoms. These include aromatase inhibitors
(Aromasin, Arimidex, Letrozole), and anti-prolactin aids like Dostinex
(Cabergoline).

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

Research
In a research setting, GHRPs such as ipamorelin are used to isolate naturally
occurring GHS in animals. Ipamorelin is used in research settings to stimulate
ghrelin, the hunger hormone that is released by ghrelinergic cells of gastro-
intestinal tract (Asakawa et al. 2001; Pietra et al. 2011). Animal studies
frequently create ghrelin infusions in an attempt to increase gastric emptying in
animals that are given diabetic or idiopathic gastroparesis for the sake of study
(Murray et al. 2005; Avau et al. 2013). Ipamorelin is often preferred for research
settings because it has a significantly longer half-life than ghrelin and has a
higher potency than similar peptides when applied in vivo (Micic et al. 1999).
Animals also tend to have a much higher tolerance for high applications of
ipamorelin compared to similar peptides (Beck et al. n.d.).

(1) the release of various hormones such as growth hormone,

adrenocorticotropic hormone, cortisol, and prolactin (Hosoda et al. 2006);
(2) modulation of food intake and energy metabolism (Sun et al. 2004);
(3) influences on glucose and lipid metabolism (Murray et al. 2005);
(4) regulation of gastrointestinal motility and secretion (Murray et al.
2005), and pancreatic function (Date et al. 2002);
(5) regulation of cell proliferation and survival (Kim et al. 2004);
(6) attenuation of proinflammatory cascades and regulation of immune
function that play important roles in aging and gastrointestinal
homeostasis (Smith et al. 2005); and
(7) cell protection in the nervous and the cardiovascular systems (Smith
et al. 2007).
Doesnt increase cortisol or prolactin levels
Doesnt also increase ghrelin production (satiety remains same)
Increases hepatic production of IGF-1
Increased bone density and strength
Increased adipose tissue (body fat) breakdown
Increased muscle strength and size
Increased collagen production
No marked effects on FSH, LH, or TSH plasma levels.
(Raun et al. 1998; Erdmann et al. 2003; Fuh & Bach 1998; Mohammadi et
al. 2011; Smith et al. 2007; Anon n.d.)

The declining activity of the growth hormone-insulin-like grwth factor (IGF-

1) with advancing age contributes to the decreased lean effects

Clinical Trials
A number of clinical trials have been conducted and show favourable tolerance
by volunteers young and old. Two trials were conducted involving Ipamorelin was
in 2007 and 2009 on Postoperative ileus in USA, one using an IV-infusion and
Phase-I/II clinical trials. Ipamorelin was thought to promote normal GI motility
and may have value. Ghrelin demonstrated strong prokinetic effect in a variety
of animal species and humans. The clinical studies were also later conducted
where ipamorelin appeared to assist in GI recovery after abdominal surgery. the
trial was a prospective, randomized, proof-of-concept study evaluating safety and

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Ipamorelin- A Growth Hormone Stimulant [DRAFT] Hannan Mansuri

efficacy of the investigational drug ipamorelin in postoperative patients. Later

clinical studies were conducted at a phase IIb for postoperative ileus,
(ClinicalTrials.gov NCT00672074, NCT01280344) which look promising coming to
the market (Casanueva et al. 1999; Beck et al. n.d.; Veljaa et al. 2002; Klicek et
al. 2008).

References
Beck, D.E. et al., 2014. Prospective, randomized, controlled, proof-of-concept
study of the Ghrelin mimetic ipamorelin for the management of
postoperative ileus in bowel resection patients. International Journal of
Colorectal Disease, 29(12), pp.15271534. Available at:
http://link.springer.com/10.1007/s00384-014-2030-8 [Accessed March 14,
2017].
Fuh, V.L. & Bach, M.A., 1998. Growth hormone secretagogues: mechanism of
action and use in aging. Growth hormone & IGF research: official journal of
the Growth Hormone Research Society and the International IGF Research
Society, 8(1), pp.1320. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10990440 [Accessed March 14, 2017].
Gobburu, J.V.S. et al., 1999. Pharmacokinetic-Pharmacodynamic Modeling of
Ipamorelin, a Growth Hormone Releasing Peptide, in Human Volunteers.
Pharmaceutical Research, 16(9), pp.14121416. Available at:
http://link.springer.com/10.1023/A:1018955126402 [Accessed March 15,
2017].
Howard, A.D. et al., 1996. A Receptor in Pituitary and Hypothalamus That
Functions in Growth Hormone Release. Science, 273(5277), pp.974977.
Available at:
http://www.sciencemag.org/cgi/doi/10.1126/science.273.5277.974 [Accessed
March 14, 2017].
Pietra, C., Friend, J. & Greenwood-Van Meerveld, B., 2011. Preclinical
Pharmacological Profile of Ipamorelin a Novel Gastroprokinetic for Intestinal
Dysmotility - ScienceDirect. Gastroenterology, 140(5), p.S-85. Available at:
http://www.sciencedirect.com.ezproxy.lib.uts.edu.au/science/article/pii/S0016
508511611463 [Accessed March 14, 2017].
Raun, K. et al., 1998. Ipamorelin, the first selective growth hormone
secretagogue. European journal of endocrinology, 139(5), pp.55261.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/9849822 [Accessed March
6, 2017].
Veldhuis, J.D. & Bowers, C.Y., 2010. Integrating GHS into the Ghrelin System.
International Journal of Peptides. Available at:
http://search.proquest.com.ezproxy.lib.uts.edu.au/health/docview/85595719
9/fulltextPDF/40DEEB29EA4A48ABPQ/6?accountid=17095 [Accessed March
14, 2017].
Venkova, K.M. et al., 2009. 716 Efficacy of Ipamorelin, a Novel Ghrelin Mimetic, in
a Rat Model of Postoperative Ileus. Gastroenterology, 136(5), p.A-114.
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[Accessed March 14, 2017].

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