Introduction to the Hexarelin vs Ipamorelin Debate

Hexarelin (also known as examorelin) and Ipamorelin are synthetic analogues of ghrelin, both acting as growth hormone secretagogue receptor agonists. Despite their similar origins and nearly identical sizes—hexarelin is six amino acids long while ipamorelin is five—they exhibit significant differences. Hexarelin, for example, has notable heart health properties, while ipamorelin significantly impacts bone health. Both peptides stimulate the growth hormone (GH) axis and share many actions, but they are not identical. Research highlights how even slight variations in amino acid sequences can result in substantially different effects.

Hexarelin and Ipamorelin: GH Secretion and Body Composition

Both hexarelin and ipamorelin stimulate the natural release of more GH than growth hormone-releasing hormone (GHRH) alone. They work synergistically with GHRH, causing significant increases in plasma GH levels even at low doses. These peptides are also synergistic with sex hormones, such as testosterone, which amplify the GH-elevating effects of growth hormone secretagogue receptor (GHS-R) agonists. Both peptides exhibit partial and reversible tachyphylaxis, meaning tolerance to their GH-releasing effects can develop with long-term administration. However, a break from their use can restore GH release parameters.

Impact on Body Composition and GH Secretion

Given their origins as ghrelin derivatives, hexarelin and ipamorelin promote lean body mass and help reduce adipose tissue. Research in rat models of cachexia shows that hexarelin regulates muscle cell health by controlling calcium flow and mitochondrial function, playing a crucial role in regulating muscle cell energy dynamics. On the other hand, ipamorelin regulates nitrogen balance in the body by decreasing nitrogen wasting in the liver, enhancing muscle growth and supplementing the effects of GH and insulin-like growth factor 1.

Both peptides also impact appetite and food choices, fine-tuning the GH response to food intake while preserving the natural pulsatile secretion of GH. Research in animal models shows that maintaining the pattern of GH release is crucial to avoiding side effects.

In the central nervous system (CNS), ghrelin and its analogues influence feeding behavior by affecting visual processing, attention, and memory centers related to food. Interestingly, ghrelin stimulates the intake of foods rich in fat and sugar while promoting fat deposition, a trait not shared by ipamorelin and hexarelin. Research indicates that ipamorelin promotes glucose entry into muscle cells rather than adipose tissue, favoring muscle growth over fat growth. Similarly, hexarelin lowers insulin resistance, reducing fat accumulation.

Ipamorelin and Bone Health

Ipamorelin uniquely stimulates bone growth, increasing bone deposition and mineral density significantly in rat studies. It is being investigated as a potential treatment for osteoporosis and bone loss associated with chronic disease. Known for its selectivity in stimulating GH release, ipamorelin does not affect other hormones like prolactin, adrenocorticotropic hormone, or thyroid-stimulating hormone. This selective action makes it particularly useful for research focused on bone health.

Hexarelin and Heart Health

Hexarelin binds to the CD36 receptor, which helps protect heart cells from apoptosis (programmed cell death). Research in mice shows that hexarelin improves heart function following simulated cardiac ischemia by enhancing heart muscle cell survival. Additionally, hexarelin mitigates the long-term effects of oxidative stress in heart failure, preventing cardiac remodeling and reducing pathological changes post-cardiac injury. It also influences the sympathetic nervous system, promoting parasympathetic activation, lowering blood pressure, reducing heart rate, and decreasing cardiac remodeling.

Memory Formation and Neurogenesis

Both ipamorelin and hexarelin stimulate neuron growth (neurogenesis) and synaptic growth. Research in mice shows that hexarelin is particularly effective in promoting neurogenesis in brain regions crucial for memory formation. It enhances the proliferation and survival of neuron progenitor cells, making it more robust in supporting memory and neurogenesis compared to ipamorelin.

Pain Perception

Ghrelin and its mimetics, including ipamorelin, are known for their potent anti-nociceptive properties, alleviating non-inflammatory visceral pain and somatic mechanical pain. While specific research on hexarelin‘s pain-relieving properties is limited, it is reasonable to speculate that, as a GHS-R agonist, hexarelin likely shares these effects.

Anti-Aging Effects

While neither ipamorelin nor hexarelin has been directly investigated for anti-aging properties, they are thought to mitigate the effects of aging by restoring GH and IGF-1 levels. Research suggests that declines in the GH/IGF-1 axis with age contribute to physiological and cognitive decline. By rejuvenating this axis, these peptides may promote better function and reduce age-related disabilities.

Bioavailability

A significant difference between the two peptides is their administration methods. Ipamorelin requires sub-Q injection, while hexarelin is orally active, making hexarelin easier to administer, particularly in animal models.

Summary

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.