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Hexarelin vs Ipamorelin: Best Guide in 2023
Hexarelin (a.k.a. examorelin) is a synthetic analogue of ghrelin as is ipamorelin. The two peptides are therefore both growth hormone secretagogue receptor agonists. Ipamorelin is just five amino acids long while hexarelin is six. Despite their similar derivation and near identical size, hexarelin and ipamorelin have some important differences. Hexarelin, for instance appears to have important heart health properties while ipamorelin has significant impact on bone health. Both peptides stimulate the GH axis and therefore share a number of actions in common, but considering them to be identical would be a mistake. Research reveals that these peptides have very different secondary effects, a fact that highlight just how important the amino acid sequence is to the function of a peptide or protein.
Both ipamorelin and hexarelin stimulate the natural release of more growth hormone (GH) than does growth hormone releasing hormone (GHRH). They are, in fact, synergistic with GHRH and cause significant increases in plasma GH levels even at low doses. Interestingly, these peptides are also synergistic with sex hormones, like testosterone, with sex hormones boosting the GH-elevating effects of growth hormone secretagogue receptor (GHS-R) agonists. Both peptides also show a partial and reversible tachyphylaxis, meaning that tolerance to their GH-releasing effects occurs with long-term administration (usually several months) and is thought to result from a change GHS-R density. A hiatus from use will re-establish GH release parameters.
Hexarelin Structure vs. Ipamorelin Structure
Peptide Sequence: Aib-His-D-2Nal-D-Phe-Lys
Molecular Formula: C38H49N9O5
Molecular Weight: 711.868 g/mol
PubChem CID: 9831659
CAS Number: 170851-70-4
Source: PubChem
URL: Ipamorelin
Data deposited in or computed by PubChem
Sequence: His-D-Trp(2-Me)-Ala-Trp-D-Phe-Lys
Molecular Formula: C47H58N12O6
Molecular Weight: 887.059 g/mol
PubChem CID: 6918297
CAS Number: 140703-51-1
Source: PubChem
URL: Examorelin
Data deposited in or computed by PubChem
Sequence: Aib-His-D-2-Nal-D-Phe-Lys-NH2
Hexarelin and Ipamorelin Impact Body Composition and Growth Hormone Secretion
It should come as no surprise, given their origins as ghrelin derivatives, that hexarelin and ipamorelin promote lean body mass and help to reduce adipose tissue. Research in rat models of cachexia shows that hexarelin regulates muscle cell health by controlling calcium flow and mitochondrial function. In other words, it seems that hexarelin plays an important role in regulating the energy dynamics of muscle cells, helping them make the most efficient use of the energy available to them[1]. Ipamorelin has been shown to regulate nitrogen balance in the body by decreasing nitrogen wasting in the liver[2]. Combined with their effects on the GH axis, these unique effects of hexarelin and ipamorelin help to boost their impact on muscle growth and supplement the effects of growth hormone and insulin-like growth factor 1.
Of course, both peptides impact appetite and dietary food choices. As ghrelin receptor agonists, both hexarelin and ipamorelin help to fine-tune the response of GH to food intake. This fine-tuning is a supplemental effect to growth hormone-releasing hormone, an important point to note because ghrelin and all of its analogues actually preserve normal pulsatile secretion of GH. Research in animal models has shown that preserving the pattern of GH release, even while boosting levels of the hormone, is important to avoiding side effects[3].
Ghrelin and its analogues function peripherally and in the central nervous system (CNS). In the CNS, research shows that ghrelin increases feeding behavior but that it does not simply boost hunger levels. Rather, ghrelin influences visual processing, attention, and memory centers of the brain as they relate to food. Thus, ghrelin is active in behaviors related to food choice such as smell, taste sensitivity, and even food reward[4], [5].
Now, as it turns out, ghrelin actually stimulates the intake of foods rich in fat and sugar while promoting the deposition of fat, the opposite of what one would think given its additional role as a growth hormone secretagogue. Interestingly, ipamorelin and hexarelin do not share this feature. Research in rats shows that ipamorelin’s effects on blood sugar promote the entry of glucose into muscle cells as opposed to adipose tissue. Thus, even though ipamorelin stimulates intake of sugar-rich foods, it tends to favor muscle growth over fat growth. Hexarelin has similar effects on blood sugar but has the added effect of lower insulin resistance, thus lowering the amount of fat building that is taking place[6].
Ipamorelin and Bone Health
One of ipamorelin’s unique benefits is that it stimulates the growth of bones. Research in rats indicates that ipamorelin causes a four-fold increase in bone deposition and increases bone mineral density[7], [8]. Ipamorelin is under investigation as a potential treatment for osteoporosis and bone loss associated with chronic disease.
Ipamorelin is widely known to be one of the most selective GH stimulating peptides. Research shows that ipamorelin has no effects on prolactin, adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, or follicle-stimulating hormone. Its effects on bone health, body composition, and more are almost entirely mediated through the GH/IGF-1 axis. Hexarelin is not quite a selective as ipamorelin and has been shown to slightly stimulate the release of prolactin, adrenocorticotropic hormone, and cortisol.
Hexarelin and Heart Health
Hexarelin is a CD36 receptor binder. Research in mice suggest that this can help to protect heart cells from injury by preventing apoptosis (programmed cell death). Mice treated with hexarelin and then subjected to simulated cardiac ischemia have improved heart function as a result of better overall survival of heart muscle cells[9], [10].
Beyond promoting the acute survival of heart muscle cells, hexarelin benefits the heart by helping to offset the long-term effects of oxidative stress in heart failure. This can prevent cardiac remodeling from occurring and thus reduce the pathological changes that lead to a decline in hear function following cardiac injury. There is also evidence to indicate that hexarelin alters the function of the sympathetic nervous system following heart injury, shifting it away from sympathetic activation and toward parasympathetic activation. This results in lower blood pressure, reduced heart rate and, over the long term, reductions in cardiac remodeling. Research in mice treated with the peptide hexarelin demonstrates reductions in cardiac scar formation following injury[11], [12].
Ipamorelin vs Hexarelin in Memory Formation
As noted earlier, ghrelin impacts memory. This is an evolutionary adaptation that links calorie rich food to the formation of pleasurable memories and may also link undesirable (potentially poisonous) food to bad memories. The ability to remember where to find good food is clearly critical to survival, but scientists wanted to know if ghrelin and its analogues might promote a more general, widely applicable form of memory and neurogenesis, so they tested the effects of these peptides on mice. This hypothesis is not without a functional foundation in science. Growth hormone secretagogue receptor activation increases long-term dendrite spine density and increases the strength of connections between neurons. In other words, stimulating the growth hormone secretagogue receptor improves memory so ipamorelin and hexarelin should theoretically boost memory as well.
As it turns out, both ipamorelin and hexarelin stimulate the growth of neurons (neurogenesis) as well as synaptic growth. Research in mice shows that hexarelin is particularly effective in promoting neurogenesis in the sub-granular zone and dentate gyrus of the hippocampus. These areas of the brain are important not just for consolidating memory, but for the formation of new memories. The peptide hexarelin appears to cause these effects by promoting the proliferation and survival of neuron progenitor cells[13]. So, if the research interest is memory and neurogenesis, then the option of either one of these two peptides is good. If, however, budget constraints force a choice, then hexarelin benefits in the brain appear to be more robust.
Ghrelin Mimetics and Pain Perception
It has long been known that ghrelin is a potent anti-nociceptive agent. In particularly, ghrelin helps to alleviate non-inflammatory visceral pain as well as somatic mechanical pain. Recent research using rats reveals that ipamorelin has similar properties. This research included another ghrelin mimentic known as HM01, but it did not include hexarelin. Does this mean that hexarelin doesn’t have pain-relieving properties?
Probably not. In fact, the research discussed in this section looked at how items that block the ghrelin/growth hormone secretagogue receptor impacted the ability of ipamorelin to alleviate pain. It showed that the growth hormone secretagogue receptor is necessary for ipamorelin’s pain relieving properties to be demonstrated. This same thing is true of ghrelin, suggesting that it is through the receptor itself that these peptides produce their effect[14]. Thus, it would be reasonable to speculate that any growth hormone secretagogue agonist is capable of relieving pain. Though the research remains to be done, it is a good bet that hexarelin is an excellent reliever of pain. Hexarelin benefits in the area of pain perception may be greater than those of ipamorelin given slight structural differences, but that remains to be demonstrated.
Anti-Aging Effects of Ipamorelin and Hexarelin
Neither ipamorelin or hexarelin has been directly investigated for anti-aging properties. However, it is well known that GH/IGF-1 axis decline as a result of aging is one of several mechanisms that likely contributes to the physiologic and cognitive consequences of aging. Because ipamorelin and hexarelin help to restore GH and thus IGF-1 secretion, there is reason to believe that they can help to reduce the effects of aging even if they can’t actually halt the aging process. In other words, hexarelin and ipamorelin can help animals to function better into old age, thus helping to stave off the disability that is often a consequence of advanced age[15].
Recent research suggests that declines in the GH/IGF-1 axis may actually be a result of lack of stimulation. In other words, the GH axis is like any other physiologic system in the body, you either use it or lose it. Because GHRH stimulation decreases with age, the GH/IGF-1 axis itself decreases. Additionally, expression of the GHS-R declines with age, which limits the effects of ghrelin and other naturally occurring GHS-R agonists. Scientists speculate the administration of peptides like hexarelin and ipamorelin may actually rejuvenate the GH/IGF-1 axis, acting as a kind of jump start to a system that has gone dormant[16]. Like everything in nature, the human body functions in a state of balance between build-up and breakdown. When the GH axis faulters, it allows the balance to shift toward breakdown. Stimulation of this axis may help to restore balance and thus promote the maintenance of tissues that would otherwise decline with age.
Bioavailability of Ipamorelin and Hexarelin
One of the biggest differences between ipamorelin and hexarelin is the way in which the two peptides can be administered. While ipamorelin must be administered strictly via sub-Q injection, hexarelin is orally active.This makes hexarelin the easier peptide to administered, particularly in animal models, and thus the peptide of choice when all other considerations are equal.
Summary: Ipamorelin vs. Hexarelin
Both ipamorelin and the similar peptide hexarelin are ghrelin mimetics that stimulate the release of GH by interacting with the growth hormone secretagogue receptor. Both peptides cause substantial increases in GH levels and are synergistic with GHRH, GHRH analogues, and sex hormones in potentiating GH release. While ipamorelin has been investigated in phase II clinical trials for use in bone density improvement and post-operative ileus, hexarelin has been investigated in phase II clinical trials for the treatment of congestive heart failure. Hexarelin is orally bioavailable while ipamorelin must be administered via sub-Q injection. Both peptides potentiate neurogenesis in the central nervous system and have beneficial impacts on body composition.
In short, both peptides are potent GH releasing GHS-R agonists. Their secondary effects, however, help to set them apart. Individuals interested in bone health research may lean toward ipamorelin while those interested in heart research may lean toward the peptide hexarelin. In any case, both peptides have a long track record of safe and successful use in a number of animal models.
Resources
[1] G. Sirago et al., “Growth hormone secretagogues hexarelin and JMV2894 protect skeletal muscle from mitochondrial damages in a rat model of cisplatin-induced cachexia,” Sci. Rep., vol. 7, no. 1, p. 13017, Oct. 2017, doi: 10.1038/s41598-017-13504-y.[2] N. K. Aagaard et al., “Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats,” Growth Horm. IGF Res., vol. 19, no. 5, pp. 426–431, Oct. 2009, doi: 10.1016/j.ghir.2009.01.001.
